CA2136108A1 - Carbostyril derivatives as matrix metalloproteinases inhibitors - Google Patents
Carbostyril derivatives as matrix metalloproteinases inhibitorsInfo
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- CA2136108A1 CA2136108A1 CA002136108A CA2136108A CA2136108A1 CA 2136108 A1 CA2136108 A1 CA 2136108A1 CA 002136108 A CA002136108 A CA 002136108A CA 2136108 A CA2136108 A CA 2136108A CA 2136108 A1 CA2136108 A1 CA 2136108A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
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Abstract
This invention provides a carbostyril derivative of formula (1), where R1, R2, R3, R4, R5, R6 and n are as defined, or its salt. This carbostyril derivative or its salt possess an excellent matrix metalloproteinases inhibitory action.
Description
2 ~13 610 8 PCTIJP94100434 -- 1 .
DESCRIPTION
CARBOSTYRIL DERIVATIYES AS MATRIX METALI~PROTEINASES INHIBITORS
The present invention relates to carbostyril derivatives, method o~ preparing the same, and extracellular matrix metalloproteinases inhibitor.
BAC~GROUND ART
The extracellular matrix metalloproteinases are - se~reted ~rom mammal animal cells, and decomposes extracellular matrix (~ollagen, type IV collagen, laminin proteoglican, fibrone~tin, elastin, gelatin, etc.~. Abnormal promo~ion of secret~on and aotivity of extracellular matrlx metalloproteinases are considered to induce various diseases, including metastasls, infiltration and proliferation of cancer cells, rheumatoid arthritis, peridontal diseases, corneal ulcer, osteoporosis, other bone absorption diseases, multiple sclerosis, and the like. Substances showing inhibitory actlons of extracellular matrix metalloproteinases include natural products such as TIMP-l, TIMP-2, and a2-macroglobulin.
:- Compounds possessing such inhibitory action are disclosed in the Japanese Patent Laid-open Publication No. 62-230757, WO-905716 and W0-9217460. More speciflcally, the Japanese Patent WO 94/21612 ~13 f~ 10 8 PCT/JP94100434 , Laid-open Publication No. 62-23(:)757 discloses a compound expressed in a formula:
A--C H C O N H C: O--~--C H--R E
RC RF ( 50 ) ~where A denote~ a group HN( OH ) -CO- or HCO-NOH-; RA is an all~yl group wl th Cz to C~; RB is a characteristic group of a natural a-amino a::id of which any existing functional group may be protec:ted, any exist~ ng amino s~roup may be acylated, or any exlsting carboxylic group may be formed into amide (however, excludlng hydrogen atom or methyl group); RC is hydrogen atom, amino, hydroxy, mercapto, Cl to C6 alkyl, Cl to Cs alkoxy, C~. to C6 alkylamins:, Cl to C~ alkylthio Gr aryl-(C1 to C6 alkyl) ~roup, or amino- (Cl to C6 alkyl), hydroxy-(C1 to C6 alkyl), mercapto- (Cl to C6 alkyl) or carboxyl- ~C
to C6 alkyl~ of which amino, hydroxy, mercapto or carboxyl group may be protected, amino group may be acylated, or carboxyl group may be formed into amide; RD is hydrogen atom or methyl group, RE is hydrogen atom, or C1 to C6 alkyl, C1 to C6 alkoxy-Cl to C6 alkyl, di(C1 to C6 alkoxy)-methylene, carboxyl, (C1 to C6 alkyl)-carbonyl, (Cl to C6 alkoxy)-WO94/21612 ~13 610 8 PCT/J~4/0~34 ; - .
carbonyl, arylmethoxycarbonyl, (Cl to C6 alkyl)aminocarbonyl or arylaminocarbonyl; ~F is hydrogen atom or methyl group, R3 and RD may be combined together to form -(CH2)m- group wherein p is 4 to ll; and RD and RF may be combined together to form trimethylene group].
WO-905716 discloses a compound expressed in a formula:
~H O
I H U ~CH2) qB
HONH CO ~ N ~ ~ N / (51) RG o R RJ
twhere RG is hydrogen atom, Cl to C6 alkyl, Cl to C6 alkenyl, phenyl, phenyl (Cl to C6) alkyl, Cl to C6 ~lkylthiomethyl, phenylthiomethyl, substituted phenylthiomethyl, phenyl(Cl to C6)alkylthiomethyl, or hexacyclic thiomethyl group; or RG
2~ denotes -SRX, where RX denotes as follows:
R~ O
H ~ (CH2) qB
HONH CO ~ N ~ N /
- l O Rl RJ
~ S
I (52) WO94/21612 ~13 B 1~ ~ PCTIJ~4100434 _ 4 _ .
twhere RH is hydrogen atom, Cl to C6 alkyl, Cl to C6 alkenyl, phenyl (Cl to C6) alkyl, cycloalkyl (Cl to C6) alkyl, or cycloalkenyl (Cl to C6) alkyl group; RI is amino acid side chain, Cl to C6 alkyl, benzyl, (Cl to C6) alkoxybenzyl, benzyloxy (Cl to C6) alkyl or benzyloxybenzyl group; RJ is hydrogen atom or methyl group; q is an integer of l ~o 6; and B is -NH2 group, substituted noncyclic amine or heterocyclic base].
_ WO-9217460 discloses a compound expressed in a formula:
O R . O
\ NJ~,~ N ~ N H
(~3) 1 : .
where RK is hydro~en atom, Cl to C6 alkyl or -(CH2)r-D-RN.
group; r ls 0 or an integer of l to 6; D ls single bond, or oxygen or sulfur atom; RN is a~yl wh~ch may be substituted or heteroaryl whlch may be substltuted; RL is an alkyl group with C3 to C6; RM is -(CH2)s-E-(C~2)t- group; s is an integer of l ~: to 9, t is an integer o 2 to lO; E is -NR0- group tRO is hydrogen atom, Cl to C6 alkyl, C2 to C6 alkanoyl, Cl to C6 !: alkoxycarbonyl, aryl, aralkyl, or aralkyloxycarbonyl, in which r ~ 25 each aryl group may possess a substltuent): and -~CH2)s- is WO94~16~ 13 610 8 PCT/~4/00434 ;- , bonded to a carbon atom indicated by * in formula (53)].
At the present, however, a compound having a strong inhibitory action while low in toxicity has not been discovered yet.
~ISCLOSURE OF THE INVENTIQN
It is hence a primary object of the invention to present a novel compound excellent in extracellular matrix metalloproteinases inhibltory ~ction and also low in toxicity.
1~ According to the invention, there i~ provided a carbost:yril derivative expressed ~n formula (1):
R6 R~
RS -ONH-CO-CH-CH-CON ~ ~R4) n Rl O l3 (1) R
twhere ~1 denotes hydrogen atom or group -A-Rla (A shows a lower a1kylsne group, Rla is hydrogen atom, amino group, phthal~mido group, thienylthio group, lower alkanoylthio group, mercapto group, phenyl group whlch may possess one to three groups selected from the group consisting of halogen atom, hydroxyl group, lower alkyl group, lower alkoxy group, , WO94/21612 ~ 13 ~ 10 8 PCT/J~4/00~4 carboxy group, lower alkoxycarbonyl group and lower alkylenedioxy group as substituent, carboxy group, lower alkoxy carbonyl group, phenylthio group or lower alkylthio group);
R2 is hydrogen atom or lower alkyl group;
R3 is hydrogen atom, hydroxyl group, lower alkoxy group, lower alkoxy-lower alkoxy group, lower alkoxy-lower alkoxy-lower alkoxy group, lower alkoxy-lower alkoxy-lower alkoxy-lower alkoxy group or group: -B-R3a tB is lower alkylene group, lower alkenylene group or lower alkynylene group, R3a is hydrogen atom, hydroxy group, lower alkoxy group, lower alkoxy-lower alkoxy group, phenyl group which may possess one to three groups selected from the group consisting of halogen atom, cyano group, hydroxy group, lower alkyl group, lower alkoxy group, carboxy group and lower alkoxycarbonyl group as substituent, thlenyl group which may !, I possess halogen atom as substituent, phthalimido group, ¦ carboxy group, lower alkoxycarbonyl group or group:
-Co-N(R3b)R3C (where R3b is hydrogen atom or lower alkyl group, R3c is hydrogen atom, lower alkyl group or lower alkoxy group, and group -N(R3b)-R3C may form a saturated heterocyclic ring with five or six members which may further possess one hetero atom selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom)};
R4 is hydrogen atom, halogen atom, hydroxyl group, WO94121bl2 ~1 3 G ~ Q ~ PCT/J~4/00434 lower al~yl group, lower alkoxy group, or lower alkylenedioxy group;
R5 is hydrogen atom, benzoyl group, lower alkanoyl group, or phenyl-lower alkyl group;
R6 is alkyl group with l to 12 carbon atoms, lower alkoxy-lower alkyl group, or phenyl-lower alkyl group which may possess lower alkylenedioxy group as substituent on the phenyl ring: and - n is 1 or 2], and its salt.
The carbostyril derivative and its salt of the vention possess an excellent extracellular matrix 1 metalloproteinases inhibitory action, in particular, the ¦~ inhibitory actlon on Stromelysin purified from the culture ; supernatant of mouse colon cancer cell (Colon 26 Cell), inhibitory actlon on lnterstitial collagenase purified from ~ the culture supernatant of human fibroblast cell (Detroit 551 :~ Cell), and inhibitory action on type IV collagenase purified from the culture supernatant of human pulmonary fibrosarcoma ; cell (HT-1~80 Cell), and are low in toxiclty and superior in oral absorptlon.
That is, the compound of the invention is characterized by high inhibitory actions, low toxicity, excellent oral absorption, long duration of effect, high ~afety, and stability of pharmaceutical preparations.
The carbostyril derivative expressed in formula (l) of , ~, WO94/21612 213 610 8 PCT/JW41~34 _ the invention and its salts are useful in clinical fields as pr~phylactic and therapeutic agents for diseases and episodes related with extracellular matrix metalloproteinases (interstitial collagenase, type IV collagenase, Stromelysin, etc.), such as metastasis, infiltration or proliferation of various cancer cells, rheumatoid arthritis, periodontal diseases, corneal ulcer, osteoporosis, other bone absorption diseases, multiple 5clerosis, hypomyelination, diseases -accompanied by vascularization, dermal and gastrointestinal ulceratlon, and wound he ling and postoperative symptoms, for example, colon anastomosis characterized by ele~ation of collagenase level, increase of collagen destruction caused in relation with diabetes mellitus, atherosclerosis, prolif-eratlon due to suture of blood vessels, nephritis, and others.
DETAILED DESCRIPTION OF THE INVENTION
The groups disclosed in the specification are specifically as follows, whether they exlst independently or among other groups.
Examples of lower alkylene group include methylene, methylmethylene, ethylene, dimethylmethylene, trimethylene, l- i I
methyltrimethylene, 2-methyltrimethylene, 2,2-dimethyl-trimethylene, tetramethylene, pentamethylene, hexamethylene groups, and other alkylene groups of straight chain or branched chain with l to 6 carbon atoms.
WO94/21612 ~13 ~ L ~ 8 PCT/P~4/00434 g Examples of thienylthio group include 2-thienylthio,
DESCRIPTION
CARBOSTYRIL DERIVATIYES AS MATRIX METALI~PROTEINASES INHIBITORS
The present invention relates to carbostyril derivatives, method o~ preparing the same, and extracellular matrix metalloproteinases inhibitor.
BAC~GROUND ART
The extracellular matrix metalloproteinases are - se~reted ~rom mammal animal cells, and decomposes extracellular matrix (~ollagen, type IV collagen, laminin proteoglican, fibrone~tin, elastin, gelatin, etc.~. Abnormal promo~ion of secret~on and aotivity of extracellular matrlx metalloproteinases are considered to induce various diseases, including metastasls, infiltration and proliferation of cancer cells, rheumatoid arthritis, peridontal diseases, corneal ulcer, osteoporosis, other bone absorption diseases, multiple sclerosis, and the like. Substances showing inhibitory actlons of extracellular matrix metalloproteinases include natural products such as TIMP-l, TIMP-2, and a2-macroglobulin.
:- Compounds possessing such inhibitory action are disclosed in the Japanese Patent Laid-open Publication No. 62-230757, WO-905716 and W0-9217460. More speciflcally, the Japanese Patent WO 94/21612 ~13 f~ 10 8 PCT/JP94100434 , Laid-open Publication No. 62-23(:)757 discloses a compound expressed in a formula:
A--C H C O N H C: O--~--C H--R E
RC RF ( 50 ) ~where A denote~ a group HN( OH ) -CO- or HCO-NOH-; RA is an all~yl group wl th Cz to C~; RB is a characteristic group of a natural a-amino a::id of which any existing functional group may be protec:ted, any exist~ ng amino s~roup may be acylated, or any exlsting carboxylic group may be formed into amide (however, excludlng hydrogen atom or methyl group); RC is hydrogen atom, amino, hydroxy, mercapto, Cl to C6 alkyl, Cl to Cs alkoxy, C~. to C6 alkylamins:, Cl to C~ alkylthio Gr aryl-(C1 to C6 alkyl) ~roup, or amino- (Cl to C6 alkyl), hydroxy-(C1 to C6 alkyl), mercapto- (Cl to C6 alkyl) or carboxyl- ~C
to C6 alkyl~ of which amino, hydroxy, mercapto or carboxyl group may be protected, amino group may be acylated, or carboxyl group may be formed into amide; RD is hydrogen atom or methyl group, RE is hydrogen atom, or C1 to C6 alkyl, C1 to C6 alkoxy-Cl to C6 alkyl, di(C1 to C6 alkoxy)-methylene, carboxyl, (C1 to C6 alkyl)-carbonyl, (Cl to C6 alkoxy)-WO94/21612 ~13 610 8 PCT/J~4/0~34 ; - .
carbonyl, arylmethoxycarbonyl, (Cl to C6 alkyl)aminocarbonyl or arylaminocarbonyl; ~F is hydrogen atom or methyl group, R3 and RD may be combined together to form -(CH2)m- group wherein p is 4 to ll; and RD and RF may be combined together to form trimethylene group].
WO-905716 discloses a compound expressed in a formula:
~H O
I H U ~CH2) qB
HONH CO ~ N ~ ~ N / (51) RG o R RJ
twhere RG is hydrogen atom, Cl to C6 alkyl, Cl to C6 alkenyl, phenyl, phenyl (Cl to C6) alkyl, Cl to C6 ~lkylthiomethyl, phenylthiomethyl, substituted phenylthiomethyl, phenyl(Cl to C6)alkylthiomethyl, or hexacyclic thiomethyl group; or RG
2~ denotes -SRX, where RX denotes as follows:
R~ O
H ~ (CH2) qB
HONH CO ~ N ~ N /
- l O Rl RJ
~ S
I (52) WO94/21612 ~13 B 1~ ~ PCTIJ~4100434 _ 4 _ .
twhere RH is hydrogen atom, Cl to C6 alkyl, Cl to C6 alkenyl, phenyl (Cl to C6) alkyl, cycloalkyl (Cl to C6) alkyl, or cycloalkenyl (Cl to C6) alkyl group; RI is amino acid side chain, Cl to C6 alkyl, benzyl, (Cl to C6) alkoxybenzyl, benzyloxy (Cl to C6) alkyl or benzyloxybenzyl group; RJ is hydrogen atom or methyl group; q is an integer of l ~o 6; and B is -NH2 group, substituted noncyclic amine or heterocyclic base].
_ WO-9217460 discloses a compound expressed in a formula:
O R . O
\ NJ~,~ N ~ N H
(~3) 1 : .
where RK is hydro~en atom, Cl to C6 alkyl or -(CH2)r-D-RN.
group; r ls 0 or an integer of l to 6; D ls single bond, or oxygen or sulfur atom; RN is a~yl wh~ch may be substituted or heteroaryl whlch may be substltuted; RL is an alkyl group with C3 to C6; RM is -(CH2)s-E-(C~2)t- group; s is an integer of l ~: to 9, t is an integer o 2 to lO; E is -NR0- group tRO is hydrogen atom, Cl to C6 alkyl, C2 to C6 alkanoyl, Cl to C6 !: alkoxycarbonyl, aryl, aralkyl, or aralkyloxycarbonyl, in which r ~ 25 each aryl group may possess a substltuent): and -~CH2)s- is WO94~16~ 13 610 8 PCT/~4/00434 ;- , bonded to a carbon atom indicated by * in formula (53)].
At the present, however, a compound having a strong inhibitory action while low in toxicity has not been discovered yet.
~ISCLOSURE OF THE INVENTIQN
It is hence a primary object of the invention to present a novel compound excellent in extracellular matrix metalloproteinases inhibltory ~ction and also low in toxicity.
1~ According to the invention, there i~ provided a carbost:yril derivative expressed ~n formula (1):
R6 R~
RS -ONH-CO-CH-CH-CON ~ ~R4) n Rl O l3 (1) R
twhere ~1 denotes hydrogen atom or group -A-Rla (A shows a lower a1kylsne group, Rla is hydrogen atom, amino group, phthal~mido group, thienylthio group, lower alkanoylthio group, mercapto group, phenyl group whlch may possess one to three groups selected from the group consisting of halogen atom, hydroxyl group, lower alkyl group, lower alkoxy group, , WO94/21612 ~ 13 ~ 10 8 PCT/J~4/00~4 carboxy group, lower alkoxycarbonyl group and lower alkylenedioxy group as substituent, carboxy group, lower alkoxy carbonyl group, phenylthio group or lower alkylthio group);
R2 is hydrogen atom or lower alkyl group;
R3 is hydrogen atom, hydroxyl group, lower alkoxy group, lower alkoxy-lower alkoxy group, lower alkoxy-lower alkoxy-lower alkoxy group, lower alkoxy-lower alkoxy-lower alkoxy-lower alkoxy group or group: -B-R3a tB is lower alkylene group, lower alkenylene group or lower alkynylene group, R3a is hydrogen atom, hydroxy group, lower alkoxy group, lower alkoxy-lower alkoxy group, phenyl group which may possess one to three groups selected from the group consisting of halogen atom, cyano group, hydroxy group, lower alkyl group, lower alkoxy group, carboxy group and lower alkoxycarbonyl group as substituent, thlenyl group which may !, I possess halogen atom as substituent, phthalimido group, ¦ carboxy group, lower alkoxycarbonyl group or group:
-Co-N(R3b)R3C (where R3b is hydrogen atom or lower alkyl group, R3c is hydrogen atom, lower alkyl group or lower alkoxy group, and group -N(R3b)-R3C may form a saturated heterocyclic ring with five or six members which may further possess one hetero atom selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom)};
R4 is hydrogen atom, halogen atom, hydroxyl group, WO94121bl2 ~1 3 G ~ Q ~ PCT/J~4/00434 lower al~yl group, lower alkoxy group, or lower alkylenedioxy group;
R5 is hydrogen atom, benzoyl group, lower alkanoyl group, or phenyl-lower alkyl group;
R6 is alkyl group with l to 12 carbon atoms, lower alkoxy-lower alkyl group, or phenyl-lower alkyl group which may possess lower alkylenedioxy group as substituent on the phenyl ring: and - n is 1 or 2], and its salt.
The carbostyril derivative and its salt of the vention possess an excellent extracellular matrix 1 metalloproteinases inhibitory action, in particular, the ¦~ inhibitory actlon on Stromelysin purified from the culture ; supernatant of mouse colon cancer cell (Colon 26 Cell), inhibitory actlon on lnterstitial collagenase purified from ~ the culture supernatant of human fibroblast cell (Detroit 551 :~ Cell), and inhibitory action on type IV collagenase purified from the culture supernatant of human pulmonary fibrosarcoma ; cell (HT-1~80 Cell), and are low in toxiclty and superior in oral absorptlon.
That is, the compound of the invention is characterized by high inhibitory actions, low toxicity, excellent oral absorption, long duration of effect, high ~afety, and stability of pharmaceutical preparations.
The carbostyril derivative expressed in formula (l) of , ~, WO94/21612 213 610 8 PCT/JW41~34 _ the invention and its salts are useful in clinical fields as pr~phylactic and therapeutic agents for diseases and episodes related with extracellular matrix metalloproteinases (interstitial collagenase, type IV collagenase, Stromelysin, etc.), such as metastasis, infiltration or proliferation of various cancer cells, rheumatoid arthritis, periodontal diseases, corneal ulcer, osteoporosis, other bone absorption diseases, multiple 5clerosis, hypomyelination, diseases -accompanied by vascularization, dermal and gastrointestinal ulceratlon, and wound he ling and postoperative symptoms, for example, colon anastomosis characterized by ele~ation of collagenase level, increase of collagen destruction caused in relation with diabetes mellitus, atherosclerosis, prolif-eratlon due to suture of blood vessels, nephritis, and others.
DETAILED DESCRIPTION OF THE INVENTION
The groups disclosed in the specification are specifically as follows, whether they exlst independently or among other groups.
Examples of lower alkylene group include methylene, methylmethylene, ethylene, dimethylmethylene, trimethylene, l- i I
methyltrimethylene, 2-methyltrimethylene, 2,2-dimethyl-trimethylene, tetramethylene, pentamethylene, hexamethylene groups, and other alkylene groups of straight chain or branched chain with l to 6 carbon atoms.
WO94/21612 ~13 ~ L ~ 8 PCT/P~4/00434 g Examples of thienylthio group include 2-thienylthio,
3-thienylthio and other thienylthio groups.
Examples of lower alkanoylthio group include formyl-thio, acetylthio, propanoylthio, butanoylthio, isobutanoyl-thio, pentanoylthio, hexanoylthio groups, and other alkanoyl-thio grnups of which alkanoyl portion is an alkanoyl group of straight ch~in or branched chain with 1 to 6 carbon atoms.
Examples of lower alkyl group include methyl, ethyl, -propyl, isopropyl, butyl, tertiary butyl, pentyl, hexyl groups, and other alkyl groups o~ straight chain or branched chain with 1 to 6 carbon atoms.
Examples o~ lower alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, ter~iary butoxy, pentyloxy, hexyloxy groups, and other alkoxy groups of stralght chain or branched chain with 1 to 6 carbon atoms.
Examples of lower alkenylene group include vinylene, allylene, isopropenylene, 2-butenylene, 3-pentenylene, 4-hexenylene, 2-methyl-butenylens groups,and other alkenylene groups of straight chain or branahed chain with 2 to 6 carhon Z0 atoms.
Examples of lower alkynylene group lnclude ethynylene, l-propynylene, 2-propynylene, 2-butynylene, 3-pentynylene, 4-hexynylene, 2-methyl-2-butynylene groups, and o~her alkynylene : groups of straight chain or branched chain with 2 to 6 carbon atoms.
W094/21612 ~13 61 ~8 pcTlp~4looa4 , , -- 1 0 --Examples of halogen atom include fluorine atom, bromine atom, chlorine atom, and iodine atom.
Examples of lower alkoxycarbonyl group include ' methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxy-¦ 5 carbonyl, butoxycarbonyl, tertiary butoxycarbonyl, pentyloxy-¦ carbonyl, hexyloxycarbonyl ~roups, and other alkoxycarbonyl group of which alkoxy portion is an alkoxy group of straight chain or branched chain with 1 to 6 carbon atoms.
- Examples of thienyl group which may possess a halogen atom as a substituent include 5-fluoro-2-thienyl, 5-bromo-2-~ thienyl, 3-bromo-2-thienyl, 5-chloro-2-thienyl, 5-chloro-3-¦ thienyl, 4-chloro-2-thienyl, 4-chloro-3-thienyl, 5-iodo-2-thienyl groups, and other thienyl group which may possess a halogen atom as a substituent.
Examples of saturated heterocyclic group of five members or s$x members that may further possess one hetero :~ atom selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom include 1-pyrrolidinyl, l-piperidlnyl, l-imidazolid~nyl, l-piperadinyl, morpholino, and thiomorphollno groups.
Examples of lower alkanoyl group include ~Qrmyl, . ~ , acetyl, propanoyl, butanoyl, isobutanoyl, pentanoyl, hexanoyl groups, and other alkanoyl groups of straight chain or branched chain with 1 to 6 carbon atoms.
Examp1es of phenyl-lower alkyl group include benzyl, WO94/21612 PCT/J~4/00434 3 6 :~ 0 8 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 2-methyl-3-phenylpropyl, 2-phenylpropyl groups, and other phenyl-lower alkyl groups of which alkyl portion is an alkyl group of straight chain or branched chain with 1 to 6 carbon atoms.
Examples of lower alkylenedioxy group include methylenedioxy, ethylenedioxy, trimethylenedioxy groups, and other alkylenedioxy groups with 1 to 3 carbon atoms.
~ Examples of phenyl-lower alkyl group which may possess a lower alkylenedioxy group a~ a substituent on the phenyl ring include, aslde from the phenyl-lower alkyl group presanted above, 2,3-methylenedioxybenzyl, 3,4-methylenedioxy-benzyl, 3,4 ethylenedioxybenzyl, 3,4-tr~methylenedioxybenzyl, 2-(3,4-methylenedioxyphenyl)ethyl, 3-(3,4-methylenedioxy-: 15 phenyl~propyl, 4-(3,4-methylenedioxyphenyl)butyl, 5-(3,4-methylenedioxyphenyl)pentyl, 6-(3,4-methylenedioxyphenyl)hexyl groups, and other alkyl groups of which alkyl portion is a stralght chain or branched chain with 1 to 6 carbon atoms, and further examples may also include phenylalkyl groups which may ~0 possess an alkylenedioxy group with 1 to 3 carbon atoms as a substltuent on the phenyl ring.
Examples of phenyl group which may possess one to ` three groups selected from the group consisting of halogen .
.~ atom, hydroxy group, lower alkyl group, lower alkoxy group, carboxy group, lower alkoxycarbonyl group and lower WO94/21612 ~13 6 1 0 8 PCTIJ~41OOa4 ~
alkylenedioxy gxoup as substituent include 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 2,4-diohlorophenyl, 3,5-dichlorophenyl, 2,4,6-trichlorophenyl, 3-iodephenyl, 3,5-diiodephenyl, 2-bromophenyl, 3,5-dibromopheny, 2,4,6-tribromophenyl, 4-fluorophenyl, 2-fluorophenyl, 2,6-difluorophenyl, 2,4,6-trifluorophenyl, 4-hydroxyphenyl, 2,4-dihydroxyphenyl, 4-methylphenyl, 3-ethylphenyl, 2-methylphenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, ~ 4-propylphenyl, 3-isopropylphenyl, 2-butylphenyl, 4-pentylphenyl, 3-hexylphenyl, 4-t-butyl-2-methylphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 2-methoxyphenyl, 3,5-dimethoxyphenyl, 2,4,6-trimethoxyphenyl, 4-propoxyphenyl, 3-isopropoxyphenyl, 2-butoxyphenyl, 4-pentyloxyphenyl, 3-hexyloxyphenyl, 4-t-butoxy-2-methoxyphenyl, 4-butyl-2-methoxyphenyl, 2-carboxyphenyl, 4-carboxyphenyl, 3,4-I dicarboxyph2nyl, 4-methoxycarbonylphenyl, 2-~ propoxycarbonylphenyl, 4-methoxycarbonyl-3-carboxyphenyl, 3, ¦ 4-methylenedioxyphenyl, 2-methyl-3,4-methylenedioxyphenyl.
Examples of lower alkylthio group include methylthio, ethylthio, isopropylthio, butylthio, tertiary butylthio, pentylthio, hexylthio group and other alkylthio groups of , . I
¦ straight chain or branched chain with 1 to 6 carbon atoms.
I ~ Examples of lower alkoxy-lower alkoxy group include ¦~- methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy, ~ 25 methoxypropoxy, propoxymethoxy, butoxymethoxy, t-L ~
W094nl6~ ~ ~ 3 610 8 PCT/JW4/00434 -butoxypropoxy, butoxyethoxy, isopropoxypropoxy, propoxyethoxy, t-butoxymethoxy, pentyloxymethoxy, methoxypentyloxy, hexyloxymethoxy, methoxyhexyloxy, hexyloxyexyloxy, and other alkoxy-alkoxy group of which each alkoxy portion is alkoxy group of straight chain or branched ch~in with 1 to 6 carbon atoms.
Examples of lower alkoxy-lower alkoxy-lower alkoxy group include methoxymethoxymethoxy, methoxymethoxyethoxy, -methoxyethoxyethoxy, ethoxyethoxymethoxy, ethoxyethoxyethoxy, methoxyethoxypropoxy, propoxymethoxyethoxy, isopropoxypropoxypropoxy, butoxyethoxymethoxy, t-butoxymethoxypropoxy, butoxyethoxymethoxy, . isopropoxymethoxypropoxy, propoxyethoxyethoxy, t-butoxymethoxymethoxy, pentyloxyethoxyethoxy, methoxypentyloxypentyloxy, hexyloxymethoxyethoxy, methoxymethoxyhexyloxy, hexyloxyhexyloxyethoxy, and other :., ;
alkoxy-alkoxy-alkoxy group of which each alkoxy portion is alkoxy group of straight chain or branced chain with 1 to 6 carbon atoms.
20: Examples of lower alkoxy-lower alkoxy-lower alkoxy-lower alkoxy group include methoxymethoxymethoxymethoxy, 1~;, ' i j ! ' methoxyethoxymethoxyethoxy, methoxyethoxypropoxyethoxy, ; ethoxyethoxymethoxymethoxy, methoxyethoxyethoxyethoxy, : - methoxyethoxypropoxyporopoxy, propoxymethoxyethoxyethoxy, ~ 25 isopropoxy(2-methyl)propoxyethoxypropoxy, s, :
,",~
I ~
butoxyethoxyethoxymethoxy, t-butoxyethoxymethoxypropoxy, butoxyethoxymethoxybutoxy, isopropoxymethoxypropoxyethoxy, propoxyethoxyethoxyethoxy, t-butoxymethoxymethoxymethoxy, pentyloxyethoxyethoxyethoxy, methoxypentyloxypentyloxymethoxy, hexyloxymethoxyethoxyhexyloxy, methoxymethoxyhexyloxymethoxy, hexyloxyhexyloxyethoxyethoxy, and other alkoxy-alkoxy-alkoxy-alkoxy group of which each alkoxy portion is alkoxy group of straight chain or branched chain with 1 to 6 carbon atoms.
- Examples of alkyl group wlth 1 to 12 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl, 2~4-dimethylpentyl, hexyl, 3-methylhexyl, 2,3,6-trimethylhexyl, heptyl, 4-isobutylheptyl, octyl, 2-ethyloctyl, nonyl, decyl, undecyl, dodecyl, and other alkyl groups of straight chain or branched chain with 1 to 12 carbon ; 15 atoms.
Examples of lower alkoxy-lower alkyl group include ~:
methoxymethyl, ethoxymethyl, isopropoxyethyl, methoxyethyl, ¦ 3-ethoxypropyl, 2-methoxybutyl, tertiary butoxyethyl, 5-methoxypentyloxy, 3-methoxypentyloxy, 4-methoxyhexyloxy, 2-propoxyexyloxy, and other alkoxy-alkyl groups wherein each of alkoxy grol~p and alkyl group is straight chain or branched ¦ chain with 1 to 6 carbon atoms.
¦: Meanwhile, if n denotes 2, R4 indicates a similar group or a different group. , Compounds expressed in iormula (1) include all of WO94/216~ PCT/~4/0~34 ~13~
stereoisomer, optical isomer, and geometrical isomer.
The compounds and material compounds of the invention may be manufactured in various methods, and for example, the compounds of the invention may be manufactured by the method shown in reaction scheme 1 or reaction scheme 2 below.
j Reaction Scheme 1 ~R~N--CO--CE~--CH--COOH
I + RS ONH~
: (3) : lS R6 R~
~ RS -ONH-CO-CH -CH-CON ~ tR4) n : ( ï ) ~where Rl,R2, R3, R4, R5, R6 and n are same as defined above.]
~ ' The method shown in reaction scheme 1 is a method of - reaction between the amine compound of formula (3) and the carboxylic acld of Sormula (2) by ordlnary amide bond formatlon reactlon.
~::
WO94121612 P~T/J~4100434 ~ 1 3 ~ 1 ~ 8 In the amide bond formation reaction, the condition of the known amide bond formation reaction can be easily applied.
For example, (i) a mixed acid anhydride method, that is, a i~
method of reaction of carboxylic acid (2) with alkyl-5 halocarboxylic acid to form a mixed acid anhydride, which is allowed to react with amine (3), (ii) an active ester method, that i~, a method of changing carboxylic acid (2) into an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide _ester, and l-hydroxybenzotriazole ester which is allowed to 10 react with am~ne (3), (lii) a carbodiimide method, that is, a method of condensation reaction of carboxylic acid (2) with amine (3) in the presence of activator such as dicyclohexylcarbodiimide and carbonyldiimidazole, and (iv) other methods, such as a method of reaction of carboxylic acid 15 (2) with dehydrating agent such as acetic anhydride to form c~rboxylic anhydride, which rsacts wlth amine (3), a method of r reaction of ester by carboxylic acid (2) and lower alcohol with amine (3), and a method of reaction of acid hallde of car~oxylic ac~d (2), that ~s, carboxylic halide with amine 20 (3~. Among these methods, th~ active ester method or mixed acid anhydride method is pre~erred.
The mixed acid anhydride used in the mixed acid anhydrlde method (i) is obtained by an ordinary Schotten-Baumann reaction, and by reacting with amine (3) without 25 isolating, usually, the compound in formula (l) is obtained.
WO94~1612 213 6 ~ 0 8 PCT/3~4/00434 .. ..
- 17 ~
The Schotten-Baumann reaction is conducted in the presence of an basic compound. Usable basic compounds are conventional compounds used in Schotten-Baumann reaction, including triethylamine, trimethylamine, pyridine, dimethyl aniline, N-methyl morpholine, 1,5-diazabicyclo[4,3,0]nonene-5 (DBN), 1.8-dizaibicyclot5,4,0]undecene-7 (DBU), 1,4-diazabicyclo [2,2,2]-octane (DABCO), other organic bases, potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, and other inorganic bases. The reaction is performed generally at about -20 to 100 C, preferably 0 to 50 ~, and the reaction time is about 5 minu~es to 10 hours, ; preferably 5 minutes to 2 hours. The reaction between the . obtained mixed acid anhydride and amine (3) is usually conducted at about -20 to 150~, preferably 10 to 50C, and the reaction time is about 5 minutes to 10 hours, preferably 5 minutes to 5 hours. The mixed acid anhydride method is generally conducted ~n a sol~ent. The usable solvents are all conventional solvents used in ~ixed acid anhydride, and specific examples include chloroform, dichloromethane, dichloroethane and other halogenated hydrocarbons; benzene, toluene, xylene and other aromatic hydrocarbons; diethyl ether, diisopropyl ether, tetrahydrofurane, dimethoxy ethàne and other ethers; methyl acetate, ethyl acetate, other esters;
~ N,N-dimethyl formamide, dimethyl sulfoxide, acetonitrile, ¦ 25 hexamethylphosphoric acid triamide and other non-protonic ;'~
::~
I' WO94/21612 PCT/J~4/00434 d ~
polar solvent; and their mixed solvents. Examples of alkyl- ¦
halocarboxylic acid to be used in mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, and isobutyl chloroformate.
As the blending rate of the carboxylic acid (2) and alkyl~
halocarboxylic acid (3~ used in this method, equal mols should be used generally, but the alkylhalocarboxylic acid and carboxylic acid (2) may be used in a range of O.5 to 1 mol to amine (~).
Among other methods (iv), in the case of the method of reaction of carboxylic acid halide wlth amine (3), this reaction is carried out in the presence of a basic compound, ~n a proper solvent. As the basic compound, known compounds may be widely used, and for example~ aslde from the basic compound used in the Schotten-8aumann reaction, sodium ~ hydroxide, potassium hydroxide, sodium hydridet and potassium I hydrlde may be used. As the solvent, aside from the solvent ~- used in the mixed acid anhydrlde method, for example, ~ methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, 1 20 ethyl cellosolve, methyl cellosolve and other alcohols;
! pyridine; acetone; and water may be used. The blending rate I of amine (3) and carboxylic acid halide is not particularly ~: limited, and may be selected in a wide range, and the latter should be used at least by equal mol to the former, preferably O.5 to equal mol. Ihe rezctlon ls usually conducted at about ,, . . .. . , ., . ~ . .. ,.~ , , . , . . ... . . ~ , . .
W094/21612 ~ t 3 6 1 0 8 PCTIJ~4/00434 -20 to 180 C, preferab1y 0 to 150 C, and the reaction ls generally terminated in about S minutes to 30 hours. I
In the case of the method of reaction o~ the ester s obtained from carboxylic acid (2) and lower alcohol with amine 5 (3), the reaction is conducted in a proper solvent, in the presence of a basic compound. Examples of the basic compound include sodium hydroxide, potassium hydroxide, sodium alcoholate, and potassium alcoholate. Examples of solvent include methanol, ethanol and other alcohols;
10 tetrahydrofurane, dioxane and other ethers; and dimethyl formamide and other polar solvents. The blending rate of amine (3) and carbox~lic acid ether $s not particularly limited, and may be selected in a wide range, but usually the former should be used at least an equal mol of the latter, 15 ~preferably 2 to 5 times mol. The quantity of use of the basic compound may be about l to 3 times mol of the carboxylic acid ester. The reaction is conducted usually at about -20 to 180 ~ ~, preferably about 0 to 40 C, and the reaction is usually ;~ termlnated in about 5 minutes to 30 hours.
- 20 The am~de bond format~on reaction shown in reaction scheme l may be also executed by a method of reaction between carboxylic acid (2) and amine (3) in the presence of condensation agent, such a~ triphenylphosphine, diphenyl phosphinyl chloride, phenyl-N-phenyl phosphoramide chIoridate, diethyl chlorophosphenite, diethyl cyanophosphate, azide W094n16l2 PCTIJ~410~34 ~`136108 diphenyl phosphate, bis (2-oxo-3-axazolidinyl) phosphinic chloride, and other phosphorus compounds.
This reaction is conducted in the presence of the solvent and ba~ic compound used in the method of reaction of carboxylic acid halide with amine (3), usually at about -20 to 150 C, preferably about 0 to lO0 C, and the reaction is usually terminated in about S minutes to 30 hours. The content of the condensation agent and carboxylic acid (2) may be at least about an equal mol of ami~ (3), pr~ferably about equal mol to double mol.
I
Reaction Scheme 2 R6 R~ (R4) n 15R5-ONHCo-CH-CH-CON
(l-A) R3 ¦¦reductionreaction -~ 20 R - llsaponification R6 R2 .
., . 1I I /(R4)n - H-O~CO-CH-CH-CON
R O l3 (l-B) W094~1612 ~1 3 61 0 8 PCTIJ~4/0004 twhere Rl, R2, R3, R4, R6, and n are same as defined above;
R5 denotes benzoyl group, lower alkanoyl group or phenyl-lower alkyl group; and X is a halogen atom.}
The reaction of transforming the compound of formula (l-A) into the compound of formula (l-B) is effected by presenting the compound of formula (l-A) for ordinary reduction reaction or saponification reaction.
In the reduction reaction, the conditions of the known - reduction reaction may be easily applied. For example, a catalytic reduction can be conducted in a proper solvent t in the presence of a catalyst. Ordinary solvents can be widely used, for example, methanol, ethanol, isopropanol and other alcohols; hexane, cyclohexane, other hydrocarbons; diethylene glycol dimethyl ether, dioxane, tetrahydrofurane, diethyl ., ether and other ethers; methyl acetate, ethyl acetate and other esters; N,N-dimethyl formamide and other polar solvents;
water; acetlc acid; and thelr mixed solvents. Examples of - reduclng catalyst include palladium, pallad$um-black, 1 ~ ~
~ palladium-carbon, platinum, platlnum oxide, copper chromite, I, ~20 and Raney nickel. The quantlty of use of such catalyst may be about 0.001 to 2 times of the welght of the compound of formula (1-A). The reaction may be conducted under pressure, but when performing at ordinary pressure, the reaction temperature may be about 10 to 60 C, preferably 20 to 40 C, ~-~ 25 and the reaction is terminated generally in about 1 hour to 5 "
:~
wo 94/21612 ~ ~ 3 6 1 0 ~ PCT/~4/00434 days. 8esides, when a hydrogen supply source such as cyclohexene, cyclohexadiene, formic acid, ammonium formate, and isopropyl alcohol is used, it may be conducted in a proper solvent, in the presence of a catalyst. As the solvent, the sama solvent as in the catalytic reduction may be used.
Examples of catalyst include palladium, palladium-black, and , palladium-carbon. The quantity of use of the ~atalyst may be i about 0.01 to 2 times of the weight of the compound of formula A), the reaction temparature is about 10 to lOO C and the ~ 10 reaction is generally terminated in about 1 minu~e to 3 days.
! In saponification reaction, the conditions of ordinary ¦ saponification may be widely applied. For example, using an ord~nary basic compound, the react~on may be conducted.
Examples of basic compound include sodium hydroxide, potassium hydroxlde, sodium carbonate, potassium carbonate, and other inorganic bases. The quantity of use of such basic compound may be about 1 to 6 mols ln 1 mol of the compound ln formula (1-A). The reacti4n ~s usually conducted at about -lO to 50 and th~ reaction is generally terminated in about 30 minutes to 24 hours.
The reactlon for transforming the compound in formula , (1-~ into the compound in formula (1-A) is conducted in a pro~er solvent, in the presence of a basic compound, by reaction between the compound expressed in a formula R5 -X or (RS )2 ~where R5 and X are same as defined above] and the f~;
.~
WO94/21612 ~l 3 61 Q 8 PCTIJ~4/00434 compound in formu1a (1-8). Examples of solvent include polar solvents such as N,N-dimethyl formamide, and halogenated hydrocarbOnS such as dichloromethane. Examples of basic compound include pyridine, triethylamine, N-methylmorpholine, and other organic bases. The quantity of use of such basic compound may be about l to 3 times mol in l mol of the compound in formula (l-~). The reaction temperature may be -lO to 50 C and the reaction is generally terminated in about lO minutes to 24 hours.
The ~ompound in formula (2) whlch is a starting mater~al in reaction sch@me l may be manufactured in various methods. For example, it may be manufactured in the me~hods shown in the re~ction schemes 4, 6, 7, 8, and 9.
~eactlon scheme 3 (R9) 2 CH-CH-Rl~-> (R9) 2 C~C~-COOH
Examples of lower alkanoylthio group include formyl-thio, acetylthio, propanoylthio, butanoylthio, isobutanoyl-thio, pentanoylthio, hexanoylthio groups, and other alkanoyl-thio grnups of which alkanoyl portion is an alkanoyl group of straight ch~in or branched chain with 1 to 6 carbon atoms.
Examples of lower alkyl group include methyl, ethyl, -propyl, isopropyl, butyl, tertiary butyl, pentyl, hexyl groups, and other alkyl groups o~ straight chain or branched chain with 1 to 6 carbon atoms.
Examples o~ lower alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, ter~iary butoxy, pentyloxy, hexyloxy groups, and other alkoxy groups of stralght chain or branched chain with 1 to 6 carbon atoms.
Examples of lower alkenylene group include vinylene, allylene, isopropenylene, 2-butenylene, 3-pentenylene, 4-hexenylene, 2-methyl-butenylens groups,and other alkenylene groups of straight chain or branahed chain with 2 to 6 carhon Z0 atoms.
Examples of lower alkynylene group lnclude ethynylene, l-propynylene, 2-propynylene, 2-butynylene, 3-pentynylene, 4-hexynylene, 2-methyl-2-butynylene groups, and o~her alkynylene : groups of straight chain or branched chain with 2 to 6 carbon atoms.
W094/21612 ~13 61 ~8 pcTlp~4looa4 , , -- 1 0 --Examples of halogen atom include fluorine atom, bromine atom, chlorine atom, and iodine atom.
Examples of lower alkoxycarbonyl group include ' methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxy-¦ 5 carbonyl, butoxycarbonyl, tertiary butoxycarbonyl, pentyloxy-¦ carbonyl, hexyloxycarbonyl ~roups, and other alkoxycarbonyl group of which alkoxy portion is an alkoxy group of straight chain or branched chain with 1 to 6 carbon atoms.
- Examples of thienyl group which may possess a halogen atom as a substituent include 5-fluoro-2-thienyl, 5-bromo-2-~ thienyl, 3-bromo-2-thienyl, 5-chloro-2-thienyl, 5-chloro-3-¦ thienyl, 4-chloro-2-thienyl, 4-chloro-3-thienyl, 5-iodo-2-thienyl groups, and other thienyl group which may possess a halogen atom as a substituent.
Examples of saturated heterocyclic group of five members or s$x members that may further possess one hetero :~ atom selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom include 1-pyrrolidinyl, l-piperidlnyl, l-imidazolid~nyl, l-piperadinyl, morpholino, and thiomorphollno groups.
Examples of lower alkanoyl group include ~Qrmyl, . ~ , acetyl, propanoyl, butanoyl, isobutanoyl, pentanoyl, hexanoyl groups, and other alkanoyl groups of straight chain or branched chain with 1 to 6 carbon atoms.
Examp1es of phenyl-lower alkyl group include benzyl, WO94/21612 PCT/J~4/00434 3 6 :~ 0 8 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 2-methyl-3-phenylpropyl, 2-phenylpropyl groups, and other phenyl-lower alkyl groups of which alkyl portion is an alkyl group of straight chain or branched chain with 1 to 6 carbon atoms.
Examples of lower alkylenedioxy group include methylenedioxy, ethylenedioxy, trimethylenedioxy groups, and other alkylenedioxy groups with 1 to 3 carbon atoms.
~ Examples of phenyl-lower alkyl group which may possess a lower alkylenedioxy group a~ a substituent on the phenyl ring include, aslde from the phenyl-lower alkyl group presanted above, 2,3-methylenedioxybenzyl, 3,4-methylenedioxy-benzyl, 3,4 ethylenedioxybenzyl, 3,4-tr~methylenedioxybenzyl, 2-(3,4-methylenedioxyphenyl)ethyl, 3-(3,4-methylenedioxy-: 15 phenyl~propyl, 4-(3,4-methylenedioxyphenyl)butyl, 5-(3,4-methylenedioxyphenyl)pentyl, 6-(3,4-methylenedioxyphenyl)hexyl groups, and other alkyl groups of which alkyl portion is a stralght chain or branched chain with 1 to 6 carbon atoms, and further examples may also include phenylalkyl groups which may ~0 possess an alkylenedioxy group with 1 to 3 carbon atoms as a substltuent on the phenyl ring.
Examples of phenyl group which may possess one to ` three groups selected from the group consisting of halogen .
.~ atom, hydroxy group, lower alkyl group, lower alkoxy group, carboxy group, lower alkoxycarbonyl group and lower WO94/21612 ~13 6 1 0 8 PCTIJ~41OOa4 ~
alkylenedioxy gxoup as substituent include 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 2,4-diohlorophenyl, 3,5-dichlorophenyl, 2,4,6-trichlorophenyl, 3-iodephenyl, 3,5-diiodephenyl, 2-bromophenyl, 3,5-dibromopheny, 2,4,6-tribromophenyl, 4-fluorophenyl, 2-fluorophenyl, 2,6-difluorophenyl, 2,4,6-trifluorophenyl, 4-hydroxyphenyl, 2,4-dihydroxyphenyl, 4-methylphenyl, 3-ethylphenyl, 2-methylphenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, ~ 4-propylphenyl, 3-isopropylphenyl, 2-butylphenyl, 4-pentylphenyl, 3-hexylphenyl, 4-t-butyl-2-methylphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 2-methoxyphenyl, 3,5-dimethoxyphenyl, 2,4,6-trimethoxyphenyl, 4-propoxyphenyl, 3-isopropoxyphenyl, 2-butoxyphenyl, 4-pentyloxyphenyl, 3-hexyloxyphenyl, 4-t-butoxy-2-methoxyphenyl, 4-butyl-2-methoxyphenyl, 2-carboxyphenyl, 4-carboxyphenyl, 3,4-I dicarboxyph2nyl, 4-methoxycarbonylphenyl, 2-~ propoxycarbonylphenyl, 4-methoxycarbonyl-3-carboxyphenyl, 3, ¦ 4-methylenedioxyphenyl, 2-methyl-3,4-methylenedioxyphenyl.
Examples of lower alkylthio group include methylthio, ethylthio, isopropylthio, butylthio, tertiary butylthio, pentylthio, hexylthio group and other alkylthio groups of , . I
¦ straight chain or branched chain with 1 to 6 carbon atoms.
I ~ Examples of lower alkoxy-lower alkoxy group include ¦~- methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy, ~ 25 methoxypropoxy, propoxymethoxy, butoxymethoxy, t-L ~
W094nl6~ ~ ~ 3 610 8 PCT/JW4/00434 -butoxypropoxy, butoxyethoxy, isopropoxypropoxy, propoxyethoxy, t-butoxymethoxy, pentyloxymethoxy, methoxypentyloxy, hexyloxymethoxy, methoxyhexyloxy, hexyloxyexyloxy, and other alkoxy-alkoxy group of which each alkoxy portion is alkoxy group of straight chain or branched ch~in with 1 to 6 carbon atoms.
Examples of lower alkoxy-lower alkoxy-lower alkoxy group include methoxymethoxymethoxy, methoxymethoxyethoxy, -methoxyethoxyethoxy, ethoxyethoxymethoxy, ethoxyethoxyethoxy, methoxyethoxypropoxy, propoxymethoxyethoxy, isopropoxypropoxypropoxy, butoxyethoxymethoxy, t-butoxymethoxypropoxy, butoxyethoxymethoxy, . isopropoxymethoxypropoxy, propoxyethoxyethoxy, t-butoxymethoxymethoxy, pentyloxyethoxyethoxy, methoxypentyloxypentyloxy, hexyloxymethoxyethoxy, methoxymethoxyhexyloxy, hexyloxyhexyloxyethoxy, and other :., ;
alkoxy-alkoxy-alkoxy group of which each alkoxy portion is alkoxy group of straight chain or branced chain with 1 to 6 carbon atoms.
20: Examples of lower alkoxy-lower alkoxy-lower alkoxy-lower alkoxy group include methoxymethoxymethoxymethoxy, 1~;, ' i j ! ' methoxyethoxymethoxyethoxy, methoxyethoxypropoxyethoxy, ; ethoxyethoxymethoxymethoxy, methoxyethoxyethoxyethoxy, : - methoxyethoxypropoxyporopoxy, propoxymethoxyethoxyethoxy, ~ 25 isopropoxy(2-methyl)propoxyethoxypropoxy, s, :
,",~
I ~
butoxyethoxyethoxymethoxy, t-butoxyethoxymethoxypropoxy, butoxyethoxymethoxybutoxy, isopropoxymethoxypropoxyethoxy, propoxyethoxyethoxyethoxy, t-butoxymethoxymethoxymethoxy, pentyloxyethoxyethoxyethoxy, methoxypentyloxypentyloxymethoxy, hexyloxymethoxyethoxyhexyloxy, methoxymethoxyhexyloxymethoxy, hexyloxyhexyloxyethoxyethoxy, and other alkoxy-alkoxy-alkoxy-alkoxy group of which each alkoxy portion is alkoxy group of straight chain or branched chain with 1 to 6 carbon atoms.
- Examples of alkyl group wlth 1 to 12 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl, 2~4-dimethylpentyl, hexyl, 3-methylhexyl, 2,3,6-trimethylhexyl, heptyl, 4-isobutylheptyl, octyl, 2-ethyloctyl, nonyl, decyl, undecyl, dodecyl, and other alkyl groups of straight chain or branched chain with 1 to 12 carbon ; 15 atoms.
Examples of lower alkoxy-lower alkyl group include ~:
methoxymethyl, ethoxymethyl, isopropoxyethyl, methoxyethyl, ¦ 3-ethoxypropyl, 2-methoxybutyl, tertiary butoxyethyl, 5-methoxypentyloxy, 3-methoxypentyloxy, 4-methoxyhexyloxy, 2-propoxyexyloxy, and other alkoxy-alkyl groups wherein each of alkoxy grol~p and alkyl group is straight chain or branched ¦ chain with 1 to 6 carbon atoms.
¦: Meanwhile, if n denotes 2, R4 indicates a similar group or a different group. , Compounds expressed in iormula (1) include all of WO94/216~ PCT/~4/0~34 ~13~
stereoisomer, optical isomer, and geometrical isomer.
The compounds and material compounds of the invention may be manufactured in various methods, and for example, the compounds of the invention may be manufactured by the method shown in reaction scheme 1 or reaction scheme 2 below.
j Reaction Scheme 1 ~R~N--CO--CE~--CH--COOH
I + RS ONH~
: (3) : lS R6 R~
~ RS -ONH-CO-CH -CH-CON ~ tR4) n : ( ï ) ~where Rl,R2, R3, R4, R5, R6 and n are same as defined above.]
~ ' The method shown in reaction scheme 1 is a method of - reaction between the amine compound of formula (3) and the carboxylic acld of Sormula (2) by ordlnary amide bond formatlon reactlon.
~::
WO94121612 P~T/J~4100434 ~ 1 3 ~ 1 ~ 8 In the amide bond formation reaction, the condition of the known amide bond formation reaction can be easily applied.
For example, (i) a mixed acid anhydride method, that is, a i~
method of reaction of carboxylic acid (2) with alkyl-5 halocarboxylic acid to form a mixed acid anhydride, which is allowed to react with amine (3), (ii) an active ester method, that i~, a method of changing carboxylic acid (2) into an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide _ester, and l-hydroxybenzotriazole ester which is allowed to 10 react with am~ne (3), (lii) a carbodiimide method, that is, a method of condensation reaction of carboxylic acid (2) with amine (3) in the presence of activator such as dicyclohexylcarbodiimide and carbonyldiimidazole, and (iv) other methods, such as a method of reaction of carboxylic acid 15 (2) with dehydrating agent such as acetic anhydride to form c~rboxylic anhydride, which rsacts wlth amine (3), a method of r reaction of ester by carboxylic acid (2) and lower alcohol with amine (3), and a method of reaction of acid hallde of car~oxylic ac~d (2), that ~s, carboxylic halide with amine 20 (3~. Among these methods, th~ active ester method or mixed acid anhydride method is pre~erred.
The mixed acid anhydride used in the mixed acid anhydrlde method (i) is obtained by an ordinary Schotten-Baumann reaction, and by reacting with amine (3) without 25 isolating, usually, the compound in formula (l) is obtained.
WO94~1612 213 6 ~ 0 8 PCT/3~4/00434 .. ..
- 17 ~
The Schotten-Baumann reaction is conducted in the presence of an basic compound. Usable basic compounds are conventional compounds used in Schotten-Baumann reaction, including triethylamine, trimethylamine, pyridine, dimethyl aniline, N-methyl morpholine, 1,5-diazabicyclo[4,3,0]nonene-5 (DBN), 1.8-dizaibicyclot5,4,0]undecene-7 (DBU), 1,4-diazabicyclo [2,2,2]-octane (DABCO), other organic bases, potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, and other inorganic bases. The reaction is performed generally at about -20 to 100 C, preferably 0 to 50 ~, and the reaction time is about 5 minu~es to 10 hours, ; preferably 5 minutes to 2 hours. The reaction between the . obtained mixed acid anhydride and amine (3) is usually conducted at about -20 to 150~, preferably 10 to 50C, and the reaction time is about 5 minutes to 10 hours, preferably 5 minutes to 5 hours. The mixed acid anhydride method is generally conducted ~n a sol~ent. The usable solvents are all conventional solvents used in ~ixed acid anhydride, and specific examples include chloroform, dichloromethane, dichloroethane and other halogenated hydrocarbons; benzene, toluene, xylene and other aromatic hydrocarbons; diethyl ether, diisopropyl ether, tetrahydrofurane, dimethoxy ethàne and other ethers; methyl acetate, ethyl acetate, other esters;
~ N,N-dimethyl formamide, dimethyl sulfoxide, acetonitrile, ¦ 25 hexamethylphosphoric acid triamide and other non-protonic ;'~
::~
I' WO94/21612 PCT/J~4/00434 d ~
polar solvent; and their mixed solvents. Examples of alkyl- ¦
halocarboxylic acid to be used in mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, and isobutyl chloroformate.
As the blending rate of the carboxylic acid (2) and alkyl~
halocarboxylic acid (3~ used in this method, equal mols should be used generally, but the alkylhalocarboxylic acid and carboxylic acid (2) may be used in a range of O.5 to 1 mol to amine (~).
Among other methods (iv), in the case of the method of reaction of carboxylic acid halide wlth amine (3), this reaction is carried out in the presence of a basic compound, ~n a proper solvent. As the basic compound, known compounds may be widely used, and for example~ aslde from the basic compound used in the Schotten-8aumann reaction, sodium ~ hydroxide, potassium hydroxide, sodium hydridet and potassium I hydrlde may be used. As the solvent, aside from the solvent ~- used in the mixed acid anhydrlde method, for example, ~ methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, 1 20 ethyl cellosolve, methyl cellosolve and other alcohols;
! pyridine; acetone; and water may be used. The blending rate I of amine (3) and carboxylic acid halide is not particularly ~: limited, and may be selected in a wide range, and the latter should be used at least by equal mol to the former, preferably O.5 to equal mol. Ihe rezctlon ls usually conducted at about ,, . . .. . , ., . ~ . .. ,.~ , , . , . . ... . . ~ , . .
W094/21612 ~ t 3 6 1 0 8 PCTIJ~4/00434 -20 to 180 C, preferab1y 0 to 150 C, and the reaction ls generally terminated in about S minutes to 30 hours. I
In the case of the method of reaction o~ the ester s obtained from carboxylic acid (2) and lower alcohol with amine 5 (3), the reaction is conducted in a proper solvent, in the presence of a basic compound. Examples of the basic compound include sodium hydroxide, potassium hydroxide, sodium alcoholate, and potassium alcoholate. Examples of solvent include methanol, ethanol and other alcohols;
10 tetrahydrofurane, dioxane and other ethers; and dimethyl formamide and other polar solvents. The blending rate of amine (3) and carbox~lic acid ether $s not particularly limited, and may be selected in a wide range, but usually the former should be used at least an equal mol of the latter, 15 ~preferably 2 to 5 times mol. The quantity of use of the basic compound may be about l to 3 times mol of the carboxylic acid ester. The reaction is conducted usually at about -20 to 180 ~ ~, preferably about 0 to 40 C, and the reaction is usually ;~ termlnated in about 5 minutes to 30 hours.
- 20 The am~de bond format~on reaction shown in reaction scheme l may be also executed by a method of reaction between carboxylic acid (2) and amine (3) in the presence of condensation agent, such a~ triphenylphosphine, diphenyl phosphinyl chloride, phenyl-N-phenyl phosphoramide chIoridate, diethyl chlorophosphenite, diethyl cyanophosphate, azide W094n16l2 PCTIJ~410~34 ~`136108 diphenyl phosphate, bis (2-oxo-3-axazolidinyl) phosphinic chloride, and other phosphorus compounds.
This reaction is conducted in the presence of the solvent and ba~ic compound used in the method of reaction of carboxylic acid halide with amine (3), usually at about -20 to 150 C, preferably about 0 to lO0 C, and the reaction is usually terminated in about S minutes to 30 hours. The content of the condensation agent and carboxylic acid (2) may be at least about an equal mol of ami~ (3), pr~ferably about equal mol to double mol.
I
Reaction Scheme 2 R6 R~ (R4) n 15R5-ONHCo-CH-CH-CON
(l-A) R3 ¦¦reductionreaction -~ 20 R - llsaponification R6 R2 .
., . 1I I /(R4)n - H-O~CO-CH-CH-CON
R O l3 (l-B) W094~1612 ~1 3 61 0 8 PCTIJ~4/0004 twhere Rl, R2, R3, R4, R6, and n are same as defined above;
R5 denotes benzoyl group, lower alkanoyl group or phenyl-lower alkyl group; and X is a halogen atom.}
The reaction of transforming the compound of formula (l-A) into the compound of formula (l-B) is effected by presenting the compound of formula (l-A) for ordinary reduction reaction or saponification reaction.
In the reduction reaction, the conditions of the known - reduction reaction may be easily applied. For example, a catalytic reduction can be conducted in a proper solvent t in the presence of a catalyst. Ordinary solvents can be widely used, for example, methanol, ethanol, isopropanol and other alcohols; hexane, cyclohexane, other hydrocarbons; diethylene glycol dimethyl ether, dioxane, tetrahydrofurane, diethyl ., ether and other ethers; methyl acetate, ethyl acetate and other esters; N,N-dimethyl formamide and other polar solvents;
water; acetlc acid; and thelr mixed solvents. Examples of - reduclng catalyst include palladium, pallad$um-black, 1 ~ ~
~ palladium-carbon, platinum, platlnum oxide, copper chromite, I, ~20 and Raney nickel. The quantlty of use of such catalyst may be about 0.001 to 2 times of the welght of the compound of formula (1-A). The reaction may be conducted under pressure, but when performing at ordinary pressure, the reaction temperature may be about 10 to 60 C, preferably 20 to 40 C, ~-~ 25 and the reaction is terminated generally in about 1 hour to 5 "
:~
wo 94/21612 ~ ~ 3 6 1 0 ~ PCT/~4/00434 days. 8esides, when a hydrogen supply source such as cyclohexene, cyclohexadiene, formic acid, ammonium formate, and isopropyl alcohol is used, it may be conducted in a proper solvent, in the presence of a catalyst. As the solvent, the sama solvent as in the catalytic reduction may be used.
Examples of catalyst include palladium, palladium-black, and , palladium-carbon. The quantity of use of the ~atalyst may be i about 0.01 to 2 times of the weight of the compound of formula A), the reaction temparature is about 10 to lOO C and the ~ 10 reaction is generally terminated in about 1 minu~e to 3 days.
! In saponification reaction, the conditions of ordinary ¦ saponification may be widely applied. For example, using an ord~nary basic compound, the react~on may be conducted.
Examples of basic compound include sodium hydroxide, potassium hydroxlde, sodium carbonate, potassium carbonate, and other inorganic bases. The quantity of use of such basic compound may be about 1 to 6 mols ln 1 mol of the compound ln formula (1-A). The reacti4n ~s usually conducted at about -lO to 50 and th~ reaction is generally terminated in about 30 minutes to 24 hours.
The reactlon for transforming the compound in formula , (1-~ into the compound in formula (1-A) is conducted in a pro~er solvent, in the presence of a basic compound, by reaction between the compound expressed in a formula R5 -X or (RS )2 ~where R5 and X are same as defined above] and the f~;
.~
WO94/21612 ~l 3 61 Q 8 PCTIJ~4/00434 compound in formu1a (1-8). Examples of solvent include polar solvents such as N,N-dimethyl formamide, and halogenated hydrocarbOnS such as dichloromethane. Examples of basic compound include pyridine, triethylamine, N-methylmorpholine, and other organic bases. The quantity of use of such basic compound may be about l to 3 times mol in l mol of the compound in formula (l-~). The reaction temperature may be -lO to 50 C and the reaction is generally terminated in about lO minutes to 24 hours.
The ~ompound in formula (2) whlch is a starting mater~al in reaction sch@me l may be manufactured in various methods. For example, it may be manufactured in the me~hods shown in the re~ction schemes 4, 6, 7, 8, and 9.
~eactlon scheme 3 (R9) 2 CH-CH-Rl~-> (R9) 2 C~C~-COOH
(4) (5) ~ ~
R3 (6) ~ Rt R~ 4 ! (R ~ 2 CH- CH-CON ~ tR ) n O
(7) R3 WO 94/21612 2 1 3 6 1 0 ~ PCT/JP94/OO
r .
~ 24 ~
[where R2, R3, R4, R6, and n are same as defined above; and R9 and R10 denote selectively eliminatable ester groups such as phenyl-lower alkoxycarbonyl group and lower alkoxycarbonyl group.]
The compound in formula (5) is manufactured by eliminating the protective group of carboxyl group of the compound in formula (4). For elimination of protective group, the method of eliminating the protective group of ordinary ~arboxyl group may be widely applied, for example, the method of treating with acid, the method of us$ng catalytic reduction, and the method by saponification.
In the case of the method of treating with acid, the compound in formula (5) may be manufactured by treating the compound in formula ( 4 ) in the presence of the acid, in a proper solvent or without using solvent. Examples of acid may include organic acid such as trifluoroacetic acid, and inorganic acld such as hydrogen fluoride and hydrogen : chloride. The acid may be u~ed excessively to l mol of the compound in formula ~4). Ordinary solvents may be widely used, including halogenated hydrocarbons such as dichloromethane, ethers such as dioxane, esters such as ethyl acetate, acetic acid, and others. The reaction proceeds usually around -40 to 60 ~C, preferably -20 to 40 C, and the reaction is generally terminated in about l minute to 5 hours. r t~
In the case of the method of using catalytic WO94/~1612 21~ fi l ~ ~ PCT/~4/0~34 reduction, the conditions of known reduction reaction may be widely applied. For example, the reaction may be conducted in the same condition as in the reduction reaction shown in reaction sGheme 2.
In the case of the method of using saponification, the conditions of the ordinary saponification may be widely applied. For example, an ordinary basic compound may be used.
Examples of basic compound include sodium hydroxide, potassium ~hydroxide, sodium carbonate, potassium carbonate, and other inorganic bases. The quantity of use of suoh basic compound may be abo~t 1 to 3 mols in 1 mol of the compound in formula (4). The reaction is generally conducted at abou~ -10 to 50 ~ and the reaction is generally terminated in about 30 minutes to 24 hours.
The compound in ~ormula (7) may be prepared by reaction between the compound in formula (5) and the compound ~n formula (6) by ordinary amide bsnd formation reaction. The amide bond formation reaction can be conducted in the same manner as in the method of reaction scheme l.
WO 94nl612 2 1 3 ~ l o 8 PCT/JP94/00434 React~on scheme 4 (R9 ) t --CH--CH--CON~(R ) n O I
(7) R3 R6 R~
/(R ) n HOOC--C~ --CH--t:ON~
O I
! ( 2 - A) ~ ~where R2, R3, R4, R6, R9, and n are same as defined above.]
i lS The compound ln formula (2-A) is manufactured by presenting the reaction in fo~mula (7) for eliminatlon j reaction of carboxyl protective group ln a proper solvent, and 3 heating the reactlon product after elimination reaction in a proper solvent.
In the elimlnation react~on of the carboxyl protectlve group, the conditions of known elimination reaction of carboxyl protective group may be widely applied.
For example, the eliminatlon re2ction of the carboxyl protect~ve group is conducted in the same manner as the ¦ 25 elimination reaction of the carboxyl protective group shown WO94/21612 ~13 61 Q 8 PCT/J~4/0~34 I
in reaction scheme 3.
As the solvent when heating the reaction product after j elimination reaction of carboxyl protective group, aromatic I hydrocarbons such as toluene and benzene may be used. The ¦ 5 reaction tempera'ure is about 50 to 120 C and it is preferred to react while refluxing. Generally, the reaction is terminated in about 1 minute to 3 days.
Reaction scheme 5 R~ Rt ~R~)2 Ci~-CH-CON ~ (R4) n (7) R3 HOOC-C-CH-CON ~ (R4) n (9) R
,',, twhere R2, R3, R4, R6, R9, and n are same as defined above.]
The compound in formula (9) is manufactured by presentlng the compound in formula (7) to elimination reaction of carboxyl protective group in a proper solvent, W094a161Z ~13 ~10 8 ~ PCTaR4l00434 ~
subjecting the reaction product after the elimination reaction to Mannich reaction with aliphatic secondary amine in a proper solvent, in the presence of formaldehyde, and heating the reaction product after the Mannich reaction.
In the elimination reaction of the carboxyl protective group, the conditions of known elimination reaction of carboxyl protective group may be widely applied.
For example, the elimination reaction is conducted in the same manner as the elimination reaction of carboxyl protective group shown in reaction scheme 3. When presenting the reaction product after the elimination reaction of carboxyl protective group to Mannich reaction, as the solvent, for xample, water, methanol, ethanol, isopropanol and other alcohols may be used, and as the aliphatic secondary amine, ~ 15 for example, dimethylamine, diethylamine, and piperidine may : be used. The quantity of use of the aliphatic secondary amine may be about 1 to 2 t~mes mol of the compound in formula (7).
:~ The quantity of use of formaldehyde is about l to 2 times mol of the compound in ~ormula (7). The reaction temperature is 20 lO to 60 C, preferably about 20 to 40 ~, and the reaction is ; generally terminated in about l hour to 3 days~
When heating the reaction product after the Mannich reaction, the reaction solution finishing the Mannich reaction -~; may be heated or refluxed at reaction temperature of about 50 Z5 to 120C. Generally, the reaction is terminated in about l :' WO g4121612 2 1 3 6 1 ~ 8 PCT/JP94/00434 minute to 1 day.
Reaction scheme 6 R~R2 (R4 ) n HOOC--C--CH--CON~
(9) R~
- ¦ Rll--SH ~1 0) R6 R~
HOOC-Ch-CH-CON ~ (R4) n S-RIl R3 (2-B~
¦ twhære ~2, R3, R4, R6, and n are same as defin d above; and R11 denotes thlenyl gruup, lower alkanoyl group, phenyl group, 1 20 or lower alkyl group.]
¦ The compound ln formula (2-B) is manufactured by ! reaction between the compound in formula t9) and the compound ! in formula (lO) in a proper solvent or without using solvent.
!- Examples of solvent include methanol, ethanol, and other alcohoLs. The quantity of use of the compound ln formula (1O) I
W094nl612 ~ ~ 3 610 ~ PCT/J~4lOOD4 is excessive to 1 mol of the compound in formula (9) or equivalent to the solvent amount. The reaction is usually conducted at lO to 120 C, preferably 20 to 100 C, and the reaction is yenerally terminated in about 1 hour to 10 days in a dark place.
The compound of which R~ denotes a lower alkyl group : in the compound in formula (2) is obtained by presenting the compound in formula (9) to ordinary reduction reaction. In this reductlon reaction, the reactlon conditions of ordinary reductlon reaction may be widely employed, for example, same as ln th~ reduction conditlon shown in reaction scheme 2.
Reactlon scheme 7 1~ R6 Rt I HOOC-CH-CH-CON ~ (R4) n CE~ I
(2-C) R12_ . , (R )2 HOOC-CH-CH-CON ~ (R4) n l~2 R3 SH (2-D) ':
~.~94121612 PCT/J~4/00434 h 1 3 S 1 ~ 8 ~where R2, R3, R4, R6, X, and n are same as defined above; and Rl2 denotes lower alkanoyl group or lower alkyl group.]
The react~on to obtain the compound in formula (2-D) from the compound in formula (2-C) is effected by
R3 (6) ~ Rt R~ 4 ! (R ~ 2 CH- CH-CON ~ tR ) n O
(7) R3 WO 94/21612 2 1 3 6 1 0 ~ PCT/JP94/OO
r .
~ 24 ~
[where R2, R3, R4, R6, and n are same as defined above; and R9 and R10 denote selectively eliminatable ester groups such as phenyl-lower alkoxycarbonyl group and lower alkoxycarbonyl group.]
The compound in formula (5) is manufactured by eliminating the protective group of carboxyl group of the compound in formula (4). For elimination of protective group, the method of eliminating the protective group of ordinary ~arboxyl group may be widely applied, for example, the method of treating with acid, the method of us$ng catalytic reduction, and the method by saponification.
In the case of the method of treating with acid, the compound in formula (5) may be manufactured by treating the compound in formula ( 4 ) in the presence of the acid, in a proper solvent or without using solvent. Examples of acid may include organic acid such as trifluoroacetic acid, and inorganic acld such as hydrogen fluoride and hydrogen : chloride. The acid may be u~ed excessively to l mol of the compound in formula ~4). Ordinary solvents may be widely used, including halogenated hydrocarbons such as dichloromethane, ethers such as dioxane, esters such as ethyl acetate, acetic acid, and others. The reaction proceeds usually around -40 to 60 ~C, preferably -20 to 40 C, and the reaction is generally terminated in about l minute to 5 hours. r t~
In the case of the method of using catalytic WO94/~1612 21~ fi l ~ ~ PCT/~4/0~34 reduction, the conditions of known reduction reaction may be widely applied. For example, the reaction may be conducted in the same condition as in the reduction reaction shown in reaction sGheme 2.
In the case of the method of using saponification, the conditions of the ordinary saponification may be widely applied. For example, an ordinary basic compound may be used.
Examples of basic compound include sodium hydroxide, potassium ~hydroxide, sodium carbonate, potassium carbonate, and other inorganic bases. The quantity of use of suoh basic compound may be abo~t 1 to 3 mols in 1 mol of the compound in formula (4). The reaction is generally conducted at abou~ -10 to 50 ~ and the reaction is generally terminated in about 30 minutes to 24 hours.
The compound in ~ormula (7) may be prepared by reaction between the compound in formula (5) and the compound ~n formula (6) by ordinary amide bsnd formation reaction. The amide bond formation reaction can be conducted in the same manner as in the method of reaction scheme l.
WO 94nl612 2 1 3 ~ l o 8 PCT/JP94/00434 React~on scheme 4 (R9 ) t --CH--CH--CON~(R ) n O I
(7) R3 R6 R~
/(R ) n HOOC--C~ --CH--t:ON~
O I
! ( 2 - A) ~ ~where R2, R3, R4, R6, R9, and n are same as defined above.]
i lS The compound ln formula (2-A) is manufactured by presenting the reaction in fo~mula (7) for eliminatlon j reaction of carboxyl protective group ln a proper solvent, and 3 heating the reactlon product after elimination reaction in a proper solvent.
In the elimlnation react~on of the carboxyl protectlve group, the conditions of known elimination reaction of carboxyl protective group may be widely applied.
For example, the eliminatlon re2ction of the carboxyl protect~ve group is conducted in the same manner as the ¦ 25 elimination reaction of the carboxyl protective group shown WO94/21612 ~13 61 Q 8 PCT/J~4/0~34 I
in reaction scheme 3.
As the solvent when heating the reaction product after j elimination reaction of carboxyl protective group, aromatic I hydrocarbons such as toluene and benzene may be used. The ¦ 5 reaction tempera'ure is about 50 to 120 C and it is preferred to react while refluxing. Generally, the reaction is terminated in about 1 minute to 3 days.
Reaction scheme 5 R~ Rt ~R~)2 Ci~-CH-CON ~ (R4) n (7) R3 HOOC-C-CH-CON ~ (R4) n (9) R
,',, twhere R2, R3, R4, R6, R9, and n are same as defined above.]
The compound in formula (9) is manufactured by presentlng the compound in formula (7) to elimination reaction of carboxyl protective group in a proper solvent, W094a161Z ~13 ~10 8 ~ PCTaR4l00434 ~
subjecting the reaction product after the elimination reaction to Mannich reaction with aliphatic secondary amine in a proper solvent, in the presence of formaldehyde, and heating the reaction product after the Mannich reaction.
In the elimination reaction of the carboxyl protective group, the conditions of known elimination reaction of carboxyl protective group may be widely applied.
For example, the elimination reaction is conducted in the same manner as the elimination reaction of carboxyl protective group shown in reaction scheme 3. When presenting the reaction product after the elimination reaction of carboxyl protective group to Mannich reaction, as the solvent, for xample, water, methanol, ethanol, isopropanol and other alcohols may be used, and as the aliphatic secondary amine, ~ 15 for example, dimethylamine, diethylamine, and piperidine may : be used. The quantity of use of the aliphatic secondary amine may be about 1 to 2 t~mes mol of the compound in formula (7).
:~ The quantity of use of formaldehyde is about l to 2 times mol of the compound in ~ormula (7). The reaction temperature is 20 lO to 60 C, preferably about 20 to 40 ~, and the reaction is ; generally terminated in about l hour to 3 days~
When heating the reaction product after the Mannich reaction, the reaction solution finishing the Mannich reaction -~; may be heated or refluxed at reaction temperature of about 50 Z5 to 120C. Generally, the reaction is terminated in about l :' WO g4121612 2 1 3 6 1 ~ 8 PCT/JP94/00434 minute to 1 day.
Reaction scheme 6 R~R2 (R4 ) n HOOC--C--CH--CON~
(9) R~
- ¦ Rll--SH ~1 0) R6 R~
HOOC-Ch-CH-CON ~ (R4) n S-RIl R3 (2-B~
¦ twhære ~2, R3, R4, R6, and n are same as defin d above; and R11 denotes thlenyl gruup, lower alkanoyl group, phenyl group, 1 20 or lower alkyl group.]
¦ The compound ln formula (2-B) is manufactured by ! reaction between the compound in formula t9) and the compound ! in formula (lO) in a proper solvent or without using solvent.
!- Examples of solvent include methanol, ethanol, and other alcohoLs. The quantity of use of the compound ln formula (1O) I
W094nl612 ~ ~ 3 610 ~ PCT/J~4lOOD4 is excessive to 1 mol of the compound in formula (9) or equivalent to the solvent amount. The reaction is usually conducted at lO to 120 C, preferably 20 to 100 C, and the reaction is yenerally terminated in about 1 hour to 10 days in a dark place.
The compound of which R~ denotes a lower alkyl group : in the compound in formula (2) is obtained by presenting the compound in formula (9) to ordinary reduction reaction. In this reductlon reaction, the reactlon conditions of ordinary reductlon reaction may be widely employed, for example, same as ln th~ reduction conditlon shown in reaction scheme 2.
Reactlon scheme 7 1~ R6 Rt I HOOC-CH-CH-CON ~ (R4) n CE~ I
(2-C) R12_ . , (R )2 HOOC-CH-CH-CON ~ (R4) n l~2 R3 SH (2-D) ':
~.~94121612 PCT/J~4/00434 h 1 3 S 1 ~ 8 ~where R2, R3, R4, R6, X, and n are same as defined above; and Rl2 denotes lower alkanoyl group or lower alkyl group.]
The react~on to obtain the compound in formula (2-D) from the compound in formula (2-C) is effected by
5 saponification or in the presence of amine in a proper solvent. In the case of saponification, the reaction conditions of ordinary saponification reaction may be widely applied, and it may be performed same as in the saponification reaction in, for example, reaction scheme 3. When performing 10 in the presence of amine, usable solvents include methanol, ethanol, and other alcohols. Examples of amine include methylamine, ethylamine, and other aliphatic amines. The quantity of use of amine may be excessive to l mol of the compound shown in formula (2-Ç). The reaction is usually 15 conductsd at about -20 to lO0 ~C and the reaction is generally l: ?
¦ terminated in about 1 minute to 24 hours.
The reaction to obtain the compound in formula (2-C) from the compound in formula (2-D) ls effected by the reaction 'I between the compound expressed in a formula Rl2-X or (Rl2)20 f~ 20 twhere Rl2 and X are same as defined above~ and the compound in formula (2 D~ in a proper solvent, in the presence of a basic compound. Examples of the solvent include halogenated I hydrocarbons such as chloroform, aromatic hydrocarbons such as ¦: benzene and toluene, ethers such as tetrahydrofurane, esters such as ethyl acetate, and polar solvents such as N,N-dimethyl WO94121612 ~ 13 6 1 0 8 PCT/J~4100434,..
formamide. Examples of the basic compound include organic bases such as triethyl amine, and inorganlc bases sucn as potassium carbonate and sodium carbonate. The quantity of use of the basic compound is about 2 to 5 mols in 1 mol of the compound in formula (2-D)- The reaction is conducted usually at about 0 to lO0 C and the re~ction is generally terminated in about 1 minute to 24 hours.
Reactlon scheme 8 R10 RS Rll--X R.l~ R6' \ 1 19 (13) \ 1 19 R9 (12) R9 /R13 (14) !-~ /
:~ `Jl 6 R
R10--C~I--CH--COOH
Rl (1 S) HN~tR4 ) n 3 ( 6 ) Rll-CH-CH-CON ~ (R4) ~
~: R O l I
(16) R3 -HOOC-CH-CH-CON ~ (R4) n : (2--E) R3 :
~'~94n16~ . PCT/J~4/00434 ~13~108 ~where R1, R~, R3, R4, R6, R9, R1~, X, and n are same as defined above; R13 denotes a group -A-R1a (A and Rla same as defined above); and R19 shows lower alkyl group or phenyl-lower alkyl group.]
The compound in formula (14) is manufactured by reaction between the compound in formula ~1~) and the compound in formula (13) in a proper solvent, in the presence of a basic compound. Examples of the basic compound include sodium hydride, potassium hydride, lithium hydride, sodium methylate, and potassium ethylate. Examples of the solvent include ethers such as tetrahydrofurane, and polar solvents such as dimethyl formamide. The quantity of usP of the hasic compound is 1 to 3 times mol ln 1 mol of the compound in formula (12), preferably an equivalent mol. The ~uantity of use of the compound in formula (13) is 1 to 3 times mol in 1 mol of the compound in formula (12), preferably an equivalent mol. The reaction temperatUrQ is usually about 0 to 120C, preferably about 20 to 60~. Generally, the reaction is terminated in about 1 hour to 5 days.
The compound in formula (15) is manufactured by presenting the compound in formula (12) or the compound in formula (14) for elimination reactlon of carboxyl protective group in a proper solvent, and heating the reaction product after the elimination reaction in a proper solvent. In the elimination reaction of carboxyl protective group, the ., .. .. , . ... . . , , , ~,, ~ . . ......... ... .... ... . . .
2 1 36~8 W094nl612 ~CT/J~4/00434 ~_ conditions of known elimination reaction of carboxyl protective group may be widely applied, and the elimination reaction may be conducted same a$ in the reaction shown in, for example, reaction scheme 3. The heating reaction of the r~action product after elimination reaction of carboxyl protective group may be conducted ssme as in the reaction shown in reaction scheme 4.
The compound in formula (16) is manufactured by reaction between the compound in formula (15) and the compound in formula (6) by an ordinary amide bond 4Ormation reaction.
The amide bond format$on reaction may be performed same as in the method of reaction scheme l.
, The compound ln formula (2-E) is manufactured by I presenting the reaction in formula (16) for elimination reaction of carboxyl protective group in a proper so}ven~.
Thls reaction is conducted same as the eliminatlon reaction of carboxyl protective group shown in reaction scheme 3.
The compound in formula ( 15 ) used in reaction scheme 8 may be manuf actured in various methods. For example, by the 20 method shown below, it is manufactured in the same reaction conditions as in the reactions corresponding to those disclosed in W0-9309097.
That is, R6CH2COOH is f~rst treated by halogenating ~: reagent to obtain an acid halide , which is caused to raact with an optlcally active oxazolldlne-2-on ln the presence of ~'~94~16l2 ~ ~ 3 6 10 8 PCT/J~4tO0434 n-butyl lithium to obtain R6CH2COZ, which is then caused to xeact with a-haloacetate XCH2RlO to obtain RlOCH2CH(R6)COZ, and this compound is hydrolyzed to remove an optically active .
oxazolidine-2-on, thereby obtaining RlOCH2CH(R6)COOH [where R6, Rl~, and X are same as defined above; and Z denotes an optically active 2-oxo-oxazolidyl group].
Reaction sche~e 9 Rt5~o ~.15 (19) 11 14C ~2 CH --R14 ~ HOOC--CH~--C--COOH
(1 8) (2 O) R16O~ (2l) Rl4-C~ -C-COOH ~ R14-CH~ - CHCOOEI
(22) (23)
¦ terminated in about 1 minute to 24 hours.
The reaction to obtain the compound in formula (2-C) from the compound in formula (2-D) ls effected by the reaction 'I between the compound expressed in a formula Rl2-X or (Rl2)20 f~ 20 twhere Rl2 and X are same as defined above~ and the compound in formula (2 D~ in a proper solvent, in the presence of a basic compound. Examples of the solvent include halogenated I hydrocarbons such as chloroform, aromatic hydrocarbons such as ¦: benzene and toluene, ethers such as tetrahydrofurane, esters such as ethyl acetate, and polar solvents such as N,N-dimethyl WO94121612 ~ 13 6 1 0 8 PCT/J~4100434,..
formamide. Examples of the basic compound include organic bases such as triethyl amine, and inorganlc bases sucn as potassium carbonate and sodium carbonate. The quantity of use of the basic compound is about 2 to 5 mols in 1 mol of the compound in formula (2-D)- The reaction is conducted usually at about 0 to lO0 C and the re~ction is generally terminated in about 1 minute to 24 hours.
Reactlon scheme 8 R10 RS Rll--X R.l~ R6' \ 1 19 (13) \ 1 19 R9 (12) R9 /R13 (14) !-~ /
:~ `Jl 6 R
R10--C~I--CH--COOH
Rl (1 S) HN~tR4 ) n 3 ( 6 ) Rll-CH-CH-CON ~ (R4) ~
~: R O l I
(16) R3 -HOOC-CH-CH-CON ~ (R4) n : (2--E) R3 :
~'~94n16~ . PCT/J~4/00434 ~13~108 ~where R1, R~, R3, R4, R6, R9, R1~, X, and n are same as defined above; R13 denotes a group -A-R1a (A and Rla same as defined above); and R19 shows lower alkyl group or phenyl-lower alkyl group.]
The compound in formula (14) is manufactured by reaction between the compound in formula ~1~) and the compound in formula (13) in a proper solvent, in the presence of a basic compound. Examples of the basic compound include sodium hydride, potassium hydride, lithium hydride, sodium methylate, and potassium ethylate. Examples of the solvent include ethers such as tetrahydrofurane, and polar solvents such as dimethyl formamide. The quantity of usP of the hasic compound is 1 to 3 times mol ln 1 mol of the compound in formula (12), preferably an equivalent mol. The ~uantity of use of the compound in formula (13) is 1 to 3 times mol in 1 mol of the compound in formula (12), preferably an equivalent mol. The reaction temperatUrQ is usually about 0 to 120C, preferably about 20 to 60~. Generally, the reaction is terminated in about 1 hour to 5 days.
The compound in formula (15) is manufactured by presenting the compound in formula (12) or the compound in formula (14) for elimination reactlon of carboxyl protective group in a proper solvent, and heating the reaction product after the elimination reaction in a proper solvent. In the elimination reaction of carboxyl protective group, the ., .. .. , . ... . . , , , ~,, ~ . . ......... ... .... ... . . .
2 1 36~8 W094nl612 ~CT/J~4/00434 ~_ conditions of known elimination reaction of carboxyl protective group may be widely applied, and the elimination reaction may be conducted same a$ in the reaction shown in, for example, reaction scheme 3. The heating reaction of the r~action product after elimination reaction of carboxyl protective group may be conducted ssme as in the reaction shown in reaction scheme 4.
The compound in formula (16) is manufactured by reaction between the compound in formula (15) and the compound in formula (6) by an ordinary amide bond 4Ormation reaction.
The amide bond format$on reaction may be performed same as in the method of reaction scheme l.
, The compound ln formula (2-E) is manufactured by I presenting the reaction in formula (16) for elimination reaction of carboxyl protective group in a proper so}ven~.
Thls reaction is conducted same as the eliminatlon reaction of carboxyl protective group shown in reaction scheme 3.
The compound in formula ( 15 ) used in reaction scheme 8 may be manuf actured in various methods. For example, by the 20 method shown below, it is manufactured in the same reaction conditions as in the reactions corresponding to those disclosed in W0-9309097.
That is, R6CH2COOH is f~rst treated by halogenating ~: reagent to obtain an acid halide , which is caused to raact with an optlcally active oxazolldlne-2-on ln the presence of ~'~94~16l2 ~ ~ 3 6 10 8 PCT/J~4tO0434 n-butyl lithium to obtain R6CH2COZ, which is then caused to xeact with a-haloacetate XCH2RlO to obtain RlOCH2CH(R6)COZ, and this compound is hydrolyzed to remove an optically active .
oxazolidine-2-on, thereby obtaining RlOCH2CH(R6)COOH [where R6, Rl~, and X are same as defined above; and Z denotes an optically active 2-oxo-oxazolidyl group].
Reaction sche~e 9 Rt5~o ~.15 (19) 11 14C ~2 CH --R14 ~ HOOC--CH~--C--COOH
(1 8) (2 O) R16O~ (2l) Rl4-C~ -C-COOH ~ R14-CH~ - CHCOOEI
(22) (23)
6~ R -CH2 -CHCON ~ (R4) n 20 t24) R3 !
~' ~6 R~
25~ HOOC-CH2 -CH -CON ~ (R4) n (2-A) ~3 W094121612 ~ PCT/J~4/00434~
~ 1 3~
twhere R2, R3, R4, R6, and n are same as defined above, R14 denotes a lower alkoxycarbonyl group; R15 is al~ylidene group with 1 to 12 carbon atoms, lower alkoxy-lower alkylidene group, or phenyl-lower alkylidene group which ma~ possess lower alkylenedioxy group on a phenyl ring as a substituent;
and R16 is a lower alkyl group.]
The compound in formula (20) is obtained by reaction between the compound in formula (18) and the compound in formula (19) in a proper solvent in the presence of a basic compound, and subsequent saponiication (alkaline hydrolysis).
Proper solvents may include methanol, ethanol, isopropyl .~
alcohol, tert-butyl alcohol, and other alcohols. Examples of -~ the ba~ic compound lnclude sodium hydr~de, potassium hydride, ;~ 11thlum hydride, sodium methylate, and potassium ethylate.
15 The quantlty of use of the compound in formula (19) is about 1 ~ to 1.5 mol in 1 mol of the compound in formula (18). The -~ guantity of use of the basic compound is about 1 to 1.5 mol in 1 mol of the compound in formula (18). The reaction ls conducted usually at about 10 to 1~0 ~ and the reaction is 20 generally terminated in about 1 minute to 24 hours.
¦ ~ I The subsequent saponification is performed by using, for example, an ordinary basic compound. Examples of the basic compound include sodium hydroxlde, potassium hydroxide, ;: ~ sodium carbonate, potassium carbonate, and other inorganic t -- 25 bases. The quantity of use of the basic compound may be 2 to ~'~94n1612 .~ 6 l O ~ PCTl~4/00434 i 6 mols in 1 mol of the compound in formula (18). The reaction is usually conducted at about 0 to 100 C and the reaction is generally terminated in about 1 to 24 hours.
The compound in formula (22) is manufactured by causing the compound in formula ~20~ to react with dehydration condensation agent such as acetic anhydride and N,N'-dicyclohexyl carbodiimide (DCC), and presenting the reaction product for react~on with the compound in formula (21). In the reaction between the compound in formula (20~ and acetic , 10 anhydride or DCC, the quantity of u~e of acetic anhydride or ', DCC may be 1 mol or excessive to 1 mol of the compound in i formula (20). The reaction proceeds at about 20 to 120C, and the reaction is generally terminated in about 1 minute to 10 ~ hours~ In the reaction between the reaction product and ~he j 15 compound in formula (21~, the quantity of use of the compound in formula (21) may be excessive to 1 mol of the compound in ~-formula (20). ~he reaction is usually conducted at 10 to 100 ~ and the reaction is generally terminated in about 1 to 24 hours.
The compound ln formula ~23) is obtained by presenting ! the compound in formula (22) to an ordinary reduction ¦ reaction. In this reduction reaction, the conditions of the known reduction reaction may be widely applied. For example, the reaction may be conducted in the same manner as in reaction scheme 2.
~13~1û8 WOg4nl612 PCT/J~4/00434.-~
.
- 38 - ;
The compound in formula (24) is obtained by the reaction between the compound in formula (23) and the compound in formula (6) by ordinary amide bond formation reaction. The amide bond formatio~ reaction is done ln the same manner as in reaction scheme 1.
The compound in formula (2-A) is manufactured by treating the compound in formula (24) in a proper solvent, in the presence of a basic compound. Examples of the proper solvent include methanol, ethanol, and other alcohols.
Examples of the basic compound include inorganic bases sùch as sodium hydroxide and potassium hydroxide, and organic bases such as triethyl amine. The quantlty of use of the basic ,~
:~ compound may be about 1 to 3 mols of 1 mol of the compound in formula (24~. The reaction is usually performed at about O to 40 ~ and the reactlon is generally termlnated in about 1 to 24 hours.
The compound in formula (4) used as a starting material in reaction scheme 3 is manufactured in various methods. For example, lt may be manufactured in the method shown in reactlon scheme 10.
~ .
~ ~94nl612 ~ 1~ 6 1 ~ 8 PCT/JW4/OQ434 , Reaction schemQ lO
g R6 R17-Y R~
I (Z7~ 1 H N -CH-COOH -~ Y-CH-COO~
~ (26) (28) E~terlfication - ~ Y-CH-R
(29) (R~) ~ CHZ
(R ) ~--C~ 1 CH--R
(4) 1~
twhers R6, R9 and Rl are same as defined abo~e; R17 is an : alkalin~ metal such as sodlum, potassium or the like; and Y
denotes a halogen atom.~
: Th~ compound in formula (28) is manufactured by presentlng the compsund in formula (26) and ~he compound in formula (27) for an ordinary diazo coupling reaction in a proper solvent in the presence of a nitrite.
Examples of the nitride include sodium nitrite and potasQiu~ nitrite. The quantity of use of the nitride is about 1 to 1.5 mol ln 1 mol of the compound in formula (26), ~l3~lo~ -W094~1612 , PCT/~410~434 --,, and the quantity of use of the compound in formula (27) is about 1 to l.5 mol in 1 mol of the compound in formula`(26).
- ExampleS of the solvent may include water, hydrochloric acid, sulfuric acid, other acidic solvents, and their mixed solvents. The reaction is usually conducted at about -10 to ~ 100 ~ and the reaction is generally terminated in about l ! minute to 1 day.
, The ~ompound in formula (29) i5 manufactured by ¦ presenting the compound in formula (18) for an ordinary esterificatlon reaction in a proper solvent.
The compound in formula (4) is manufactured by reaction between the compound in formula (29) and the compound in formula(30) ln a proper solvent, in the presence of a basic compoundO Examples of the solvent include polar solvents such lS as dimethylformamide, and halogenated hydrocarbons such as ~- dichloromethane. Examples of the bastc compound include sodium hydride and potasslum t-butoxide. The quantity of use of the baslc compound is about 1 to 3 mols in 1 mol of the compound in formula (29). The reaction is conducted usually at about -20 to 70 C and the reaction is generally terminated ! in about 1 hour to 10 days.
-~; The compound in formula (12) used as a starting material ~n reaction scheme 8 is manufactured in various methods. For example, lt is manufactured in the method shown ln reactlon scheme 11 below.
;- 94~161~ PCT/J~4tO~434 ` ~1 36108 Reaction scheme ll R6 ~6 H~ N--C:H--COOH ----~ HO--CH--COO~
~:2 6) C3 Z) E~.l9_y R6 (33) 1 l9 HO-CH-COO R
(34 R~
R tL2 ~15 ~where R6, R9, ~lO, ~19, and Y are same as defined above.]
,~The compound in formula (~2) 1~ manufactured by ¦presenting the compound in fo~mula (26) for an ordinary diazo coupllng reactlon in a proper sol~ent in the presence of a nitr~te. The diazo coupling reaction is conducted in the same reaction condltlons as in manuf acture of the compound in formula (28) ln reaction scheme lO.
The compound in formula (34) is manufactured by reactlon between the compound in formula (32) and the compound in formula (33) ln a proper solvent, in the presence of a WO94/21612 PCT/J~4/00434~
h ~3 I basic compound. Examples of the solvent include ethers such I as tetrahydrofurane, and aromatic hydrocarbons such as benzene 3 and toluene. Examples of the basic compound include organic bases such as triethyl amine and N-methylmorpholine. The ~ 5 quantity of use of the basic compound is about 1 to 2 mols of 3 1 mol of the compound in formula (32), and the quantity of use of the compound in formula (33) is about 1 to 2 mols of l mol of the compound in formula (32). The reaction temperature is about 0 to 100 C and the reaction is generally terminated in about 1 to 24 hours. The compound in formula (34) may be also I manufactured by presenting for an ordinary ester$fication reaction in a proper solvent.
The compound in formula (12) is manufactured by transforming the compound in formula (34) into sulfonate lS ester, and reactin~ with the compound in formula (3S) in the presence of a basic compound. 'rhe reaction of transforming the compound ln formula (34) into sulfonate ester is realized by reaction w~th acid anhydride such as sulfonic anhydride and acid halide such as sulfonyl hallde, in a proper sol~ent, in the presence of a basic compound. Examples of the solvent include halogenated hydrocarbons such as dichloromethane, and ethers such as tetrahydrofurane. Examples of the basic compound ~nclude organic bases such as pyridine, triethylamine, and N-methylmorpholine. The quantity of use of the basic compound is about l to l.S mol of 1 mol oi the .~.. ~94nl612 .~13 61 ~ 8 PCT/J~4100434 !
!
compound in formula (34). The quantity of use of acid anhydride or acid halide is about 1 to 1.5 mol of 1 mol of the ~ompound in formula (34). The reaction temperature is about 50 to 50 C and the reaction is generally terminated in about 1 minute to 1 day~
I, The reaction between the sulfonate ester of the ¦ compound in formula (34~ and the compound in formula (35) is conducted in a proper solvent, in the presence of a basic compound. Examples of the solvent include polar solvent such as dimethyl formamide and halogenated hydrocarbons such as dlchloromethane. Examples of the basic compound include sodium hydr~de, potassium hydrlde, lithium hydride, sodium methylate, and potassium ethylate. The ~uantity of use of the basic compolnd ls about 1 to 2 mols in 1 mol of the compound : 15 in formula (34), and the quantity of use of the compound (3S) is about 1 to 2 mols in 1 mol of the compound in formula (34).
The reactlon temperature is about -10 to 50 C and the reaction is generally terminated ln about 1 hour to 10 days.
The compound in formula ~6) used in reaction schemes 3, 8 and 9 is a nove~ or known compound, which may be easlly ~, manuactured in a method disclosed, for example, in J. Med.
Chem., 1972, 15, 325, or J. Org. Chem., 1989, 54, 3394. The compound in formula (6) is manufactured in methods shown in the following reactlon schemes 12 and 13.
' :
WO94/21612 ~ 13 610 8 PCTIJ~410043~I -- 44 _ Reaction scheme 12 ~2 R~
E~2i_N~(R4) n R --B--X ~.2~-~;(R4) n o H B--R3a (3 6) (3 8--A) where R2, ~4, R3a, B, X, and n are same as defined above; and R20 d~notes acyl group or ~mlno group protective group.~
The reaction between the compound in formula (36) and the compound ln formula (37) i5 conducted in a proper solvent, in the presence of a basic compound. Examples of the solvent ~ are dioxane, tetrahydrofurane, dlethyl ether, ethylene glycol ¦ dimethyl ether and other ethers; dlmethyl formamide, dimethyl . ~ulfoxide, hexa~ethylene pho~phoric acid triamide and other polar Golvents. Examples of the basic compound include sodi~m hydr~de, potassium hydrlde, llthium hydrlde, sodium methylate, potassium ethylate, and other inorganic bases. The quantity of use of such basic compound is usually about 0.5 to 2 times mol of the compound in ~ormula (36), preferably an equivalent mol. The blending rate of the compound in formula (36) and the compound ln formula (37) is 1 to 3 times the mol of the WQ94/21612 ~13 6 ~ 0 8 PCT/J~4/00434 " 45 I latter to the former, prefera~ly about an equivalent mol. The reaction temperature is usually about -20 to 120 C, preferably about 0 to 60 C, and the r~action is generally te~minated in about 10 minutes to 5 days.
Reaction scheme 13 t - Rt R
j10 R C-N ~ (R ) n R16a_x R20_N ~ R4) (39) (38-B) ~' ~
~ 15 ';:
~.
~where ~2, R4, R20, X and n are same as defined above; and R16a denstes lower alkyl group, lower alkoxy-lower alkyl :~ group, lower alkoxy-lower a}koxy-lower alkyl group, or lower alkoxy-lower alkoxy-lower alkoxy-lower alkyl group.]
- ~ IThe reaction bètween the compound in formula (3g) and l ~ the compound in formula (40) can be conducted in the same : reaction conditions as ln the reaction between the compound in ,, .
~ormula (36) and the compound in formula (37) in reaction -scheme 12.
~ :
W094/21612 ~ pcTlJn4loo434;
The compound in formula (38-A) and the compound in formula (38-B) are transformed into the compound in formula (6) by an ordinary de-protection reaction.
The compound in formula (15) used in reaction scheme 8 is manufactured in various methods. For example, it is manufactured in the method shown in the following reaction scheme 14.
Reactlon scheme 14 \ I 1) de~protectlon C:HCH--COOR~ RIQ--C--CH~COOH
2) Mannlch 11 lS- (12) reaction CH2 (41) ~ ~ r . R6 hydrogenatlon _ ~ Rl0- CH-CH-COOH
CH3 (15-A) ~0 t ~
~where R6, R9, R10, and Rl9 are same as defined above.]
The de-protection of the compound in formula (12) can be effected in the same conditions as in the reaction for obtaining the compound in formula (5) from the compound in V~94~1612 ~ 0 8 PCT/J~4/00434 ...... , ~ ~
formula (4) in reaction scheme 3. The subsequent Mannich reac~ion can ~e effected in the reaction conditions same as the reaction for obtaining the compound in formula (9) from the compound in formula (7) in reaction scheme 5. The hydrogenation of the compound in formula ~41) can be effected ' in the same conditions as in the reaction for reducing the I compound in formula (l-A) to transform into the compound in formula (l-B) in reaction scheme 2.
- The amin~ group, hydroxyl group or other substituent in the intermediate compound shown in the foregoing reaction schemes can be properly protected by an ordinary method not ~ affecting the reaction, and the protective group may be ¦ properly eliminated in an ordinary method after reaction.
¦ The compound in formula (1) of the invention, and ~he 15 intermediate compounds shown in the reaction sohemes for its manufacture may be variously changed in the types of R1, R3, j~ R5, and others contained therein, but they are not limited to ¦ them alone, and varlous changes as effected ordinarily may be applicable.
For example, as the elimination reaction of the protective group of the hydroxyl group, there is an example of de-silylation reaction for obtaining the compound in formula (1-B) from the compound in formula (42) in reaction scheme 15.
', WO94/21612 ~13 61~ PCT/J~4/00434~
-Reactionschemel5 R~ R6 (R ~ N-CO-Ct~-CH-COOH
R3 (23 - ¦ t?. 2 t R 22 R 2 3 S t O N t-t 2 !
~ R~ R6 i (R4) N-Co-CH-CH-CoNH-oSiR2lR2~R23 Rl l~ (42) 1 d~3-9llyl~tlon R2 ~6 (R ~ N-CO-CH-Ct-t-CONH-OH
R3 (l-B) W3 94/21612 ft~ 3 S I O ~ PCT/JPg4/00434 ~-- !
~where R1, R2, R3, R4, R6 and n are same as defined above; and , R21, R22, and R23 are lower alkyl groups.~
1 The reaction between the compound in formula (2) and ¦ the compound in formula (3') can be effected in the same ¦ 5 reaction conditions as in the reaction between the compound in formula (2) and the compound in formula (3) in reaction scheme 1.
In the reaction for leading the compound in formula -(42) into the compound in the formula (l-B), the reaction conditions in ordinary de-silylation may be applied. For example, this de-silylation reaction is effec~ed by using a proper catalyst customarily used in this kind of de-silylation reactlon, for example, a proper amount of hydrochloric acid, sulfuric acid, peschloric acid and other inorganic acids;
~ 15 ~ formic acld, acetic, acid, propion~c acid and other lower ¦ - ~ alkane aclds; benzo~c acid, methane sulfsnic acid, ethane sulfonic acid, benzene sulfonic acid, 4-methylbenzene sulfonic acid and other organic sulfonic acid; and other organic acids, , .
- ~ usually in a solvent. Ex3~ples of ths solvent include ord~ary inert solvents, such as water, methanol, ethanol, ~, isopropanol and other lower alcohols; acetone, methyl ethyl ketone and other ketones; dioxane, tetrahydrofurane, diethyl ~- ether, ethylene glycol dimethyl ether and other ethers;
: benzene, toluene, xylene, chlorobenzene and aromatic hydrocarbo~s; acetic acid, propionic acid, and lower alkane --`~ WO94121612 PCT/JW4100434`
~ 1 3 li 1 0 8 .. ; . . s o ,;
acid; and their mixed solvents. The catalyst may be used in the range from an ordinary catalyst amount to excessive amount, preferably an excessive amount. The reaction temperature is usually about 0 to lO0 C, preferably from room temperature to about 80 C and the reaction is terminated in about 3 minutes to 20 hours.
As the elimination reaction of protective group of amlno group, for example, the following hydrazine decomposition reaction may be presented. For example, when ~0 is a phthalimido-lower alkyl group, by presenting to th~
hydra~ine decomposition for reacting with hydrazine or hydrazine derivative without solvent or in an inert solvent, Rl may be transformed into an amino-lower alkyl group. As the inert solvent used in this reaction, for example, dichloromethane, dichloroethane, chloroform, carbon tetrachloride and halogenated hydrocarbons; methanol, ethanol, and other alcohols may be known. Examples of the hydrazine deri~ative include methyl hydrazlne, ethyl hydrazine, other lower alkyl-substltuted hydrazines, phenyl hydrazine and other aryl-substituted hydrazines. The quantity of use of hydrazine or hydrazine derivative to the startin~ material compound of whlch R1 corresponds to a phthalimldo-lower alkyl group is j usually at least equivalent mol, or preferably eguivalent mol to 10 times mol. The reaction is conducted usually at 0 to lOO ~, preferably O to 80 ~, and the reaction is generally W~94/21612 ;~ 3 6 1 ~ 8 PCTIJ~4100434 i 3 terminated in about 1 to 40 hours.
The compound of the formula (13) used as starting material in reaction scheme 8 is a known compound disclosed, for example, in J. Gen. Chem., 22, 267-269 (1952), and Khim.
5 Geterotsikl. Soedin., ~, 344-345 (1975), among others, and can be easily manufactured according to the method mentioned in j these literatures.
! The compound of the invention may contain an additional salt of a pharmaceutica~ly permitted acid or base ~ 10 compound. ~he salt may be easily formed by acting the~acid ¦ or the b~se. Examples of the acid used in salt formation -~ include inorganlc acids such as hydrochloric acld, sulfuric ~ acld, phosphorlc acid, and hydrobromic acid, and, if -~ necessary, organic aclds such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acld, citric acid, and ¦~ benzoic acid. The base compound used in the salt formatlon I may include, among others, sodium hydroxide, potassium ~ hydroxide, calcium hydroxide, sodium car~onate, and potassium ; hydrogencarbonate.
The compound of formula (1) manufactured in the j foregoing methods and its salt are easily isolated and refined - from the reaction system by ordinary separatian means, such as ~ distillation method, recrystallization method, column -~ chromatography, preparative thin layer chromatography, and ~ 25 solvent extraction method.
wo 94~21612 ~ 1 3 u lO ~ PCT/J~4/00434i ; -; The extracellular matrix metalloproteinases inhibitor of . the invention is used generally in a form of an ordinary pharmaceutical preparation. The pharmaceutical preparation is adjusted by ordinary filler, thickener, binder, humidifier, disintegrating agent, surface active agent, lubricant, and ~i other diluents and vehicles. As the pharmaceutical I preparations, various forms can be selected depending on the ~ purpose of treatment, and representative examples include tablets, pills, powders, liquid, suspension, emulsion, 10 granules, capsules, suppositorles, injections (liquid, suspension, etc.), and ointment. To form into tablets, carriers are used, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, cryst~l cellulose, silicic acid and other vehicles; water, 15 ethanol, propanol, slngle syrup, glucose liquid, starch liguid, gelatin æolution, carboxy methyl cellulose, shellac, methyl cellulose, potasslum phosphate, polyvinyl pyrrolidone and other binders, dry staxch, sodium alginate, agar powder, laminaran powder, sodium hydrogencarbonate, calcium carbonate, 20 polyoxy ethylene sorbitan fatty acid esters, sodium lauryl ~ ~ ~ulfate, monoglyceride stearate, starch, lactose and other ¦ disintegrating agent; sucrose, stearin, cacao butter, , hydrogenated oil and other disintegration suppressors;
I, quaternary ammonium base, sodium lauryl sulfate and other absorption promoters; glycerin, starch and other moisture '' - ,.
~ W~94/21612 ~13 6 ~ ~ ~ PCTlJ~4/oo434 ~ - 53 -¦ retainers; starch, lactose, kaolin, bentonite, colloidal silicic acid and other absorbents; refined talc, stearate, boric acid powder, polyethylene glycol and other lubricants.
Tablets may be manufactured in ordinary coated tables as required, for example, sugar coated tablet, gelatin coated tablet, enteric coated tablet, film coated tablet, double tablet, or multilayer tablet. When forming into pills, carriers are used, such as glucose, lactose, starch, cacao butter, hardened vegetable oil, kaolin, talc and other vehicles; arabic gum powder, tragacanth powder, gelatin, ethanol and other binder; 1 aminaran agar and other disintegrating agents. When forming into suppositories, carriers are used, such as polyethylene glycol, cacao butter, Xlgher alcohol, esters of higher alcoho1, gelatin, and semisynthetic glyceride. Capsules are manufactured according to the conventional manner, and various carriers listed above and the compound of the invention are blended, and put into hard gelatin capsule, hard capsule, etc. When prepared as - ln~ections, liquids, emulsions, and suspensions should be ~: 20 sterilized, and lsotonic wlth the blood. When manufacturing in such forms, diluents are used, such as water, aqueous ,~ , . , , ~
~ solution of lactic acid, ethyl alcohol, propylene glycol, -~ ethoxy isostearyl alcohol, and polyoxyethylene sorbitan fatty . acid ester. In this case, salt, glucose or glycerin enough for preparing an isotonic solution may be contained in the , WO94/21612 PCT/J~4/0~34l'l ~ 1 3 6 1 0 8 ; ~ ~
pharmaceutical preparations, or ordinary dissolution aid, desiccant, soothing agent or the like may be added. As required, further, coloring matter, preservative, perfume, flavor, sweetener, and other medicines may be contained in the pharmaceutical preparations. When manufacturing into paste, cream or gel, diluents are used, for example, white vaseline, paraffin, glycerin, cellulose derivative, polyethylene glycol, silicon, and bentonite.
~ The quantity of the compound of the invention to be contained in the pharmaceutical preparation of the invention ls not particularly defined, but may be selected from a wide range, and it may be usually in a range of 1 to 70 % by welght of the pharmaceutical preparation.
The method of administration of the pharmaceutical lS preparation of the inventlon is not partlcularly limited, and determined properly depending on the age, sex and other j~
condltlons of the patients, sev~rlty of disease, and dosage forms, and usually it is administered systematically or locally, orally or parenterally. For example, tablets, pills, liquid, suspensions, emulsions, granules, and capsules are administered orally, in~ections are admlnistered intravenously, intramuscularly, in~radermally, subcutaneously, or intraperitoneally by mixing with ordinary fluid replacement if necessary. Suppositories are administered intrarectally, ' and o~ntments are applied externally.
WO94~1612 ~ 1~ 6 ~ ~ 8 PCT/J~4/00434 s The dose of the pharmaceutical preparation of the ~ invention may be properly selected depending on the age, body ¦ weight, symptom, therapeutic effect, route of administration, treating time and others, and it is usually administered in a range of ahout O.1 to 100 mg per l kg of body weight, and the daily dose may be administered once da~ly or in several divided portions. Since the dose varies with various condit~ons, it may be enough at a smaller dose or a larger dose beyond tha specified range may be needed, depending on lO the 1ndlvldual cases.
,, :
WO94/2161~ ~13 6 10 8 PCT/J~410~34¦ .
EXAMPLES
Manufacturing examples of compounds used in the invention are shown below, being followed the pharmacological study results of these compounds and pharmaceutical examples.
Reference Example 1 (a) Preparation of 2R-bromo-4-methyl-pentanoic acid 50.0 g of D-leucine was dissolved in a mixed solvent of 112 ml of sulfuric acid and 380 ml of water, and 158 g of potasslum bromide is added, and the reaction solution was~
cooled to -2C. A solution dissol~ing 343.8 g of sodium nitrlte in 100 ml of water was dripped in 1 hour so as to keep the reaction solution at -1 to -2C, and after dripping, the ` solution was stirred for 2 hours in an ice bath. Adding 300 ml of chloroform to the reactlon solution, insoluble matter was filtered off, an organic layer was separated, and the ~ water lay~r was extracted five times in 100 ml of chloroform.
; Combining with the chloroform layer, after drying with magnesium sulfate, the solvent was evaporated in vacuum, and the oaptioned compound was obtalned in a yellow oil form.
Yield: 58.5 g.
!: .
(b) Preparation of tert-butyl 2R-bromo-4-methyl-pentanoate 58.5 g of 2R-bromo-4-methyl pentanoic acid was ; 25 dissolved in 150 ml of dichloromethane, this solution was ,~
.. WO94/21612 PCT/~4/00434 - ~ 1 0 8 c -57-,~
cooled to -40C, and about 50 ml of isobutene was collected.
Keeping at - 40C, 1.5 ml of concentrated sulfuric acid was dripped while stirring, and the tube was sealed and stirred overnight at room temperature~ The reaction vessel was cooled again to -40C or less, the tube was opened, and let stand at room temperature, and when the reaction solution exceeded 10C, it was evaporated in vacuum until the reaction solution was consumed to about half. Adding 200 ml of chloroform to the residue, the chloroform layer was washed with aqueous solution of saturated sod~um hydrogen carbonate (100 ml x 2 times) nd 100 ml of br~ne, and dried over magnesium sulfate and evaporated in vacuum, then the captioned compound was obtained in a yellow oil form. Yield: 67.2 g.
(c) Preparation of benzyl 2-benzyloxycarbonyl-3R-tert-butoxy-carbonyl-5-methyl hexanoate 76.2 g of d~benzyl malonate was dissolved in lO0 ml of ¦dry dimethyl formamide, and 30.0 g of potassium t-butoxide was added while chilling in ice, and the solution was stirred at room ~emperature until potassium t-butoxide is dissolved completely. Cooling again in an ice bath, 120 ml of dimethyl formamide of 67.2 g of tert-butyl 2R-bromo-4-methyl-penanoate was dripped in 1 hour, and the solution was stirred for 4 da~s at 4C. Pouring the reaction solution into 500 ml of saturated ammonium chloride, and after extracting with ethyl , W094~1612 . ~ PCT/J~4/00434~ .
' . -58-.~ acetate (300 ml x 3 times), the organic layer was evaporated ?
in vacuum. Adding 600 ml of diethyl ether to the residue, and after washing in brine (500 ml x 2 times), the solution was P
dried with magnesium sulfate, and the solvent was evaporated ~ 5 in vacuum. The oily residue was purified by column ¦ chromatography (silica gel 900 g, hexane/ethyl acetate = 20/1 ¦ v/v), and the captioned compound was obtained in a colorless oil form. Yield: 71.6 g.
lO Reference Exampl~ 2 ¦ Preparation of 3S-(4-benzyloxy-3-benzyloxycarbonyl-2R-isobutylsuccinyl)amino-3,4-dihydrocarbostyril To 4.06 g of benzyl 2-benzyloxycarbonyl-5-methyl-3R-tert-butoxycarbonylhexanoate, 10 ~l of trifluoroacetic acid 15 was added, and after letting stand for l hour at room temp~rature, the trifluoroacetic acid was evaporated in v8cuum. To the residue, 35 ml of chloroform was added, and it was washed with brlne (10 ml x 2 times), and dried wlth ~ magnesium sulfate anhydride, and evaporated in ~acuum. The ! 29 obtained residue was dissolved in 15 ml of dimethyl formamide, 1.45 g of 3S-amino-3,4-dihydrocarbostyril was added, and while ¦~- cooling in a water bath, 1.21 g of 1-hydroxybenzotriazole and 1.84 g of N,N'-dicyclohexyl carbodiimide were added, and the :~ pH was ad~usted to 8 by N-methylmorpholine, and the solution ~ !
~ was stirred for 20 hours at room temperature. After filtering I
W094/21612 PCT/J~4/00434 ``: 2~36108 off the sediment, the solution was evaporated in vacuum. To the residue, 100 ml of ethyl acetate was addedt and the mixture was washed with lN hydrochloric acid (20 ml x 2 times), saturated aqueous solution of sodium hydrogencarbonate 5 ( 15 ml x 3 times ), and brine ( 10 ml), dried with magnesium sulfate anbydride, and evaporated in vacuum. The oily residue was purified by column chromatography (silica gel 90 g, eluted tn 33% ethyl acetate/hexane, and then in 40% ethyl acetate/h xane), the captioned compound was ob~ained i.n a colorlesQ oily matter. Yield: 3.54 ~. ~
N M R (2 7 O M H z. C D C 13 ) ~ P P m : 8. 0 8 (1 H. s) ~ 7. 3 l (1 O H. s) ~ 6. 9 6 - 7. 3 0 (3 H, m) ~ 6. 7 4 - 6. 7 9 (2 H. m) ~ 5. 0 3 - 5. 2 6 (4 H, m) ~ 4. 5 2 (1 H~ d t, J - l 4 ~ 6 H z) ~ 3. 8 5 (l H. d d. J ~ 1 6~ l O H z) ~ 3. 3 6 (} H, d d. J = 1 6, 6 H z) ~ 2. 9 2 - 3. 1 5 (1 H, m) ~ ~. 6 3 (l H
, t, J = l 5 H z) ~ 1. 5 O - 1. 8 0 (2 H. m) ~ O. 9 5 - l. l 5 (1 H. ~) ~ O. 7 5 - 1. 0 0 (6 H, m) Reference Example 3 ~ Preparation of 3S-(3-hydroxycarbonyl-2R-isobutyl-propanoyl)amino-3,4-dihydrocarbostyril 3.50 g of 3S-(4-benzyloxy-3-benzyloxycarbonyl-2~-isobutylsuccinyl)amlno-3,4 dihydrocarbostyril was dissolved in 35 ml of methanol, and 35 mg of 10% palladium-carbon was ~, WO94/21612 .......................................... PCT/J~4/00434l ~13G10~ -,. !
added, and the solution was saturated with hydrogen. After stirring for a day at ordinary pressure, the catalyst was I filtered off, and the filtrate was concentrated in vacuo. To .~ this residue, 20 ml of toluene was added, and the mixture was heated for 20 minutes in reflux. The reaction solution was concentrated in vacuo, and 10 ml of ethyl acetate was added to the residue, and the mixtur was heated and dissolved, and 2 ml of hexane was added, and after letting stand at room temperature for a day, the precipitating crystals were flltered, and the captioned compound was obtained in a wht'te solid form. Yield: 500 mg.
NMR (2 7 OMHz. DMSO--d6 ) ~ P pm: 8. 1 9 (1 H. d, J=
8Hz) ~ 7. 1 5--7. 30 (lH, m) ~ 7. 1 6 (2H, t, J--7Hz ~ ~ 6. 9 0 (2H. d t. J=8, 7Hz) ~ 4. 4 6 (1 H, d ~, J= 1 - 2, 8Hz) ~ 2. 6 0--3. 0 O (3H. m) ~ 2. 4 3 (1 H. d d. J--1 6. 8Hz) ~ 2. 2 4 (1 H. d d. J--1 6, 6 H z) ~ 1. 0 5--1 .
80 t3H, m) ~ ~. 88 (6H. dd, J=1 6, 6Hz~
, Reference Example 4 ' 1 ' I
Preparat~on of 3S-(4-hydroxy-2R-lsobutyl-3-methylene-succinyl)amino-3,4-dihydrocarbostyril 10.8 g of 35-(4-benzyloxy-3-benzyloxycarbonyl-2R-isobutylsucc~nyl)amlno-3,4-dlhydrocarbostyrll was dlssolved ln , W~g4al6l2 ~;13 6 t ~ ~ PCT/J~4l00434 100 ml of methanol, 1.0 g of 10% palladium-carbon was added, and the solution was saturated wlth hydrogen. After stirring for a day at ordinary pressure, the catalyst was filtered off.
' To ~he reaction solution, ~.2 ml of piperidine was added, and i 5 after stirring for 15 minutes, 4.9 ml of 37% formaldehyde ¦ liquid was added, ~d the soluti3n was stirred for 7 hours at room temperature, and heated for an hour in reflux. The , reaction solution was concentrated in vacuo, dissolved in 200 ml of sat~rated aqueous solution of potassium carbonate, and wa~hed with chloroform (20 ml x 3 times). The water layer was cooled in an ~ce bath, and the pH was adjusted to 1 by concentrated hydrochloric acid, and after extracting with chloroform ( 0 ml x 2 times), it was washed with brine (20 ml~, dried over magnesium sulfate, and evaporated ln vacuum, and the captioned compound wa-~ obtalned in a white solid form.
¦ Yi~ld: 1.98 g.
N M R ( 2 7 O M H z . C D C 1 3 ) ~ ~ ~ m : 8 . 6 9 ( 1 H , s ) ~ 7 .
9 (2H. dd. J=l 4, 7H~) ~ 7. 03 tlH. d. J--7Hz) ~ 6 . 8 2 ( l H. d . J = 7 H z ) ~ 6 . 4 6 ( 1 H. s ) ~ 5 . 8 9 ( 1 H, s ) ~ 4. 5 8 (lH. d t, J=l 3, 6Hz) ~ 3. 6 1(lH. t, J=7 H z) ~ 3. 5 1 (1 H. d t, J=l 5, 6H z) ~ 2.7 6 (1 H. t, J `
--1 5Hz) ~ 1. 5 0--2. 0 0 (3H, m) ~ O. 9 1(6H. d d, J=
1 O, 6 H z~
Re~erence ~xample 5 i ~ W094~1612 PCT/~4tO~34~
~13~10-8 - `
Preparation of 3S-(4-hydroxy-2R-isobutyl-3S-acetyl-thiomethylsuccinyl)amino-3,4-dihydroxycarbostyril ¦ 840 mg of 3S-(4-hydroxy-2R-isobutyl-3S-methylene-succinyl)amino-3,4-dihydrocarbostyril was dissolved in 8 ml of thioacetic acid, and stirred for 4 days in a dark place at 30~. Diethyl ether was added to the reaction solution, and ¦ the precipitating crystals were filtered, and the captioned compound was obtained in a white solid form. Yield: 330 mg.
N M R (2 7 O M H z, C D C 13 ) ~ P P m : 8. 7 0 tl H, b r s)~ 6 . 8 0 - 7. 3 0 (4 H. m) ~ 4. 4 5 - 4. 6 0 (1 H, m) ~ 3. 5 9 ( 1 H, d d. J = 1 5, 6 H z) ~ 2. 8 0 - 3. 4 0 (4 H, m) ~ 2. 6 8 (l H, t, J = 1 5 H z) ~ 2- 3 6 (3 H, s) ~ 1. 1 0 - 1. 8 0 t3 ~, m) ~ O. 9 5 (6 H. d t. J = 1 3, 7 H z) :~
-~; R-ference Example 6 ~--~ (a) Preparatlon of D-leucic acld Wh~le heatlng and stirring 100 ml of agueous solution of 14 g of sodium nit~ite at 90~, 400 ml aqueous solution of ~; 2~ 0.5N sulfuric acld of 25 g of D-leucine was added over 45 mlnutes. After dripping, the solution was stirred for 15 !
¦ minutes until foams were no longer generated. The reaction solutlon was concentrated to 200 ml in vacuo, and the obtained - re~idue was e~tracted with diethyl ether. The diethyl ether ~ 25 layer was washed one w1th lN hydrochlorlc acld, and twlce with .' W~94~1612 PCT1~4/00434 ` 213~1Q8 saturated brine sequentially, and dried ov~r sodium su'fate anhydride, and concentrated in vacuo. The obtained oily residue was left over, crystallized, and the captioned compound was obtained. Yield: 14.50 g.
(b) Preparation of D-leucic acid benzyl ester To 150 ml of tetrahydrofurane of 14.50 of D-lellcic acid, 15.2 g of triethylamine and than 14.4 ml of benzyl bromide are added, and the solution was stirred for 3 hours while refluxing. The insoluble matter produced from ~he reaction solution was filtered of~, and the filtrate was concentrated in ~acuo. The obtained r~sidue was dissolved and extracted in 150 ml of ethyl acetate. The ethyl acetate layer was washed twice with saturated bicarbonate water, ~wice with lS lN hydrochloric acid, and twice with saturated brine sequentially, and dried ovex sodium sulfate anhydride, and concentrated in ~acuo. The obtained oily residue was dried, and the captioned compound was obtained. Yield: 18.34 g.
(c) Preparation of 1,2-dibenzyl-1-t-butyl-4-methyl-1,1,2(R)-pentane-tr~carboxylate To 140 ml of N,N-dimethyl formamide solution of 20.65 g of benzyl t-butylmalonate, 3.30 g of sodium hydride (content ~, 60~) was added, and the solution was stirred for 1 hour at room temperature. On the other hand, to 100 ml solution of -W094nl6~2 ~13 61~ ~ PCT/J~4/00434~
- dichloromethane of 18.34 g of D-leucic acid benzvl ester, 6.66 ml of pyridine was added, and stirred in ice, and 100 ml of dichloromethane of 13.53 ml of anhydrous trifluoromethane sulfonic acid was dripped thereon in 30 minutes. After dripping, the solution was further stirred for 1 hour in ice.
The reaction solution was washed once with water, and one with saturated brine sequentially, and dried with sodium sulfate _ anhydrlde. Filtering off the sodium sulfate anhydride, the filtrate was dripped in 30 minutes on the N,N-dimethyl ormamide soiution abo~e prepared while stirring in ice.
After drlpplng, the solution was stirred overnight at room - temperature. The reaction solution was concen~rated in vacuo, ~ - , and dripped ln 30 minute~. After dripping, the solution was stlrred overnight at room temperature. The reaction solution was concentrated in vacuo, and the obtained residue was extracted ln 300 ml of ethyl acetate. The ethyl acetate layer - was washed twice wlth saturated aqueous solution of sodium hydrogencarbonate, twice with lN hydrochloric acid, and twice with saturated brine sequentially, and dried with sodium sulfate anhydride, and concentrated in ~acuo. The obtained oily résidue was purified by the silica gel column chromatography, and eluted in ethyl acetate/petroleum ether 20~, and the captioned compound was obtained in an oily matter. Yield: l9.O g.
~. '.
', ~
WO94/21612 PCT/J~4/00434 -- ~13fi~0g Reference Example 7 Preparation of l,2-dibenzyl-l-tert-butyl-l-phthalimidomethyl-4-methYl-l,l,2(R)-pentane-tricarboxylate In a 50 ml solution of dimethyl formamide of 6.00 g of l,2-dibenzyl-l-tert-butyl-4-methyl-l,l,2(R)-pentane-tricarboxylate, 653 g (60% content) of sodium hydride was added while stirring in ice, and stirred for 30 minutes. The _ reaction solution was returned to room temperature, and 4.04 g of N-bromomethylphthalimide was added, and stirred for 3 days at room temperature. After neutralizing the reaction solution by adding a small amount of acetic acid, it was concentrated in vacuo. The obtained oily residue was extracted in lO0 ml of ethyl acetate, and the ethyl acetate layer was washed once with water and twlce with saturated brine, and dried with sodium sulfate anhydride, and concentrated in vacuo. The obtained olly residue was purified by silica gel column chromatography, and eluted in chloroform, and the captioned compound was obtained ln an olly ~orm. Yield: 4.00 g.
Reference Example 8 IPreparation of 4-tert-butoxy-2R-isobutyl-3-(R or S)-phthalimidomethylsuccinic acid To a 30 ml solution of methanol of 4.00 g of l,2- ~
dibenzyl-l-tert-butyl-l-phthalimidomethyl-4-methyl-l,l,2(R)- $
pentane-tricarboxylate, 200 mg of lO ~ palladium-carbon was WO 9412l6~ ~13 G 1 0 8 PCT/J~4/00434 added, and hydrogen gas was introduced in vacuo, an~ the solution was stirred for 2 days. From the reaction solution, the catalyst was filtered off by using celite, and the filtrate was concentrated in vacuo. The obtained residue was dissolved in 30 ml of toluene, and 0.70 ml of N-methylmorpholine was added, and the solution was stirred for 7 hours while refluxing. To the reaction solution, 70 ml of toluene was added, and the organic layer was washed twice with lN hydrochlor1c acid, and three times with saturated brine, and drled with sodium sulfate anhydride, and concentrated in ~acuo. The obta~ned oily residue was purified by the sili~a gel column chromatography, and eluted in 2%
methanol/chloroform, and the captioned compound was obtained in a olly form. Yield: 1.00 g.
Reference Example 9 Pre~aration of 3S-(4-tert-butoxy-2R-isobu~yl-3(R or S)-phthalimidomethylsuccinyl)amino-3,4-dihydrocarbostyril To a 10 ml suspension of dimethyl formamide of S00 mg of 4-tert-butoxy-2R-isobutyl-3(R or S)-phthalimidomethyl-succinic acid, 190 mg of l-hydroxybenzotriazole, and 228 mg of 3S-amino-3,4-dihydroxycarbostyril, 290 g o~ N,N'-dicyclohexyl carbodiimide was added while stirring in ice, and was stirred for 2 hours in ice and 18 hours at room temperature. The 2~ :
reaction solution was concentrated in vacuo, and 60 ml of WO94/216~ ~ 0 8 PCT/J~4/00434 ethyl acetate was added to the residuer and the insoluble matter was filtered off. The ethyl acetate layer of the filtrate was sequentially washed with saturated a~ueous solution of sodium hydrogencarbonate (2 times), lN
hydrochloric acid (2 times), and saturated brine (2 times), and dried with sodium sulfate anhydride, and concentrated in vacuo. The obtained oily residue w~s purified by silica gel column chromatography, and eluted in 0.5% methanol/chloroform, ~ and the captioned compound was obtained in a powder form.
Y~eld: 390 mg.
N M R (2 7 0 M H z, C D C 1~ ) ~ P P m : 8. S 2 (1 H. s) ~ 7. 8
~' ~6 R~
25~ HOOC-CH2 -CH -CON ~ (R4) n (2-A) ~3 W094121612 ~ PCT/J~4/00434~
~ 1 3~
twhere R2, R3, R4, R6, and n are same as defined above, R14 denotes a lower alkoxycarbonyl group; R15 is al~ylidene group with 1 to 12 carbon atoms, lower alkoxy-lower alkylidene group, or phenyl-lower alkylidene group which ma~ possess lower alkylenedioxy group on a phenyl ring as a substituent;
and R16 is a lower alkyl group.]
The compound in formula (20) is obtained by reaction between the compound in formula (18) and the compound in formula (19) in a proper solvent in the presence of a basic compound, and subsequent saponiication (alkaline hydrolysis).
Proper solvents may include methanol, ethanol, isopropyl .~
alcohol, tert-butyl alcohol, and other alcohols. Examples of -~ the ba~ic compound lnclude sodium hydr~de, potassium hydride, ;~ 11thlum hydride, sodium methylate, and potassium ethylate.
15 The quantlty of use of the compound in formula (19) is about 1 ~ to 1.5 mol in 1 mol of the compound in formula (18). The -~ guantity of use of the basic compound is about 1 to 1.5 mol in 1 mol of the compound in formula (18). The reaction ls conducted usually at about 10 to 1~0 ~ and the reaction is 20 generally terminated in about 1 minute to 24 hours.
¦ ~ I The subsequent saponification is performed by using, for example, an ordinary basic compound. Examples of the basic compound include sodium hydroxlde, potassium hydroxide, ;: ~ sodium carbonate, potassium carbonate, and other inorganic t -- 25 bases. The quantity of use of the basic compound may be 2 to ~'~94n1612 .~ 6 l O ~ PCTl~4/00434 i 6 mols in 1 mol of the compound in formula (18). The reaction is usually conducted at about 0 to 100 C and the reaction is generally terminated in about 1 to 24 hours.
The compound in formula (22) is manufactured by causing the compound in formula ~20~ to react with dehydration condensation agent such as acetic anhydride and N,N'-dicyclohexyl carbodiimide (DCC), and presenting the reaction product for react~on with the compound in formula (21). In the reaction between the compound in formula (20~ and acetic , 10 anhydride or DCC, the quantity of u~e of acetic anhydride or ', DCC may be 1 mol or excessive to 1 mol of the compound in i formula (20). The reaction proceeds at about 20 to 120C, and the reaction is generally terminated in about 1 minute to 10 ~ hours~ In the reaction between the reaction product and ~he j 15 compound in formula (21~, the quantity of use of the compound in formula (21) may be excessive to 1 mol of the compound in ~-formula (20). ~he reaction is usually conducted at 10 to 100 ~ and the reaction is generally terminated in about 1 to 24 hours.
The compound ln formula ~23) is obtained by presenting ! the compound in formula (22) to an ordinary reduction ¦ reaction. In this reduction reaction, the conditions of the known reduction reaction may be widely applied. For example, the reaction may be conducted in the same manner as in reaction scheme 2.
~13~1û8 WOg4nl612 PCT/J~4/00434.-~
.
- 38 - ;
The compound in formula (24) is obtained by the reaction between the compound in formula (23) and the compound in formula (6) by ordinary amide bond formation reaction. The amide bond formatio~ reaction is done ln the same manner as in reaction scheme 1.
The compound in formula (2-A) is manufactured by treating the compound in formula (24) in a proper solvent, in the presence of a basic compound. Examples of the proper solvent include methanol, ethanol, and other alcohols.
Examples of the basic compound include inorganic bases sùch as sodium hydroxide and potassium hydroxide, and organic bases such as triethyl amine. The quantlty of use of the basic ,~
:~ compound may be about 1 to 3 mols of 1 mol of the compound in formula (24~. The reaction is usually performed at about O to 40 ~ and the reactlon is generally termlnated in about 1 to 24 hours.
The compound in formula (4) used as a starting material in reaction scheme 3 is manufactured in various methods. For example, lt may be manufactured in the method shown in reactlon scheme 10.
~ .
~ ~94nl612 ~ 1~ 6 1 ~ 8 PCT/JW4/OQ434 , Reaction schemQ lO
g R6 R17-Y R~
I (Z7~ 1 H N -CH-COOH -~ Y-CH-COO~
~ (26) (28) E~terlfication - ~ Y-CH-R
(29) (R~) ~ CHZ
(R ) ~--C~ 1 CH--R
(4) 1~
twhers R6, R9 and Rl are same as defined abo~e; R17 is an : alkalin~ metal such as sodlum, potassium or the like; and Y
denotes a halogen atom.~
: Th~ compound in formula (28) is manufactured by presentlng the compsund in formula (26) and ~he compound in formula (27) for an ordinary diazo coupling reaction in a proper solvent in the presence of a nitrite.
Examples of the nitride include sodium nitrite and potasQiu~ nitrite. The quantity of use of the nitride is about 1 to 1.5 mol ln 1 mol of the compound in formula (26), ~l3~lo~ -W094~1612 , PCT/~410~434 --,, and the quantity of use of the compound in formula (27) is about 1 to l.5 mol in 1 mol of the compound in formula`(26).
- ExampleS of the solvent may include water, hydrochloric acid, sulfuric acid, other acidic solvents, and their mixed solvents. The reaction is usually conducted at about -10 to ~ 100 ~ and the reaction is generally terminated in about l ! minute to 1 day.
, The ~ompound in formula (29) i5 manufactured by ¦ presenting the compound in formula (18) for an ordinary esterificatlon reaction in a proper solvent.
The compound in formula (4) is manufactured by reaction between the compound in formula (29) and the compound in formula(30) ln a proper solvent, in the presence of a basic compoundO Examples of the solvent include polar solvents such lS as dimethylformamide, and halogenated hydrocarbons such as ~- dichloromethane. Examples of the bastc compound include sodium hydride and potasslum t-butoxide. The quantity of use of the baslc compound is about 1 to 3 mols in 1 mol of the compound in formula (29). The reaction is conducted usually at about -20 to 70 C and the reaction is generally terminated ! in about 1 hour to 10 days.
-~; The compound in formula (12) used as a starting material ~n reaction scheme 8 is manufactured in various methods. For example, lt is manufactured in the method shown ln reactlon scheme 11 below.
;- 94~161~ PCT/J~4tO~434 ` ~1 36108 Reaction scheme ll R6 ~6 H~ N--C:H--COOH ----~ HO--CH--COO~
~:2 6) C3 Z) E~.l9_y R6 (33) 1 l9 HO-CH-COO R
(34 R~
R tL2 ~15 ~where R6, R9, ~lO, ~19, and Y are same as defined above.]
,~The compound in formula (~2) 1~ manufactured by ¦presenting the compound in fo~mula (26) for an ordinary diazo coupllng reactlon in a proper sol~ent in the presence of a nitr~te. The diazo coupling reaction is conducted in the same reaction condltlons as in manuf acture of the compound in formula (28) ln reaction scheme lO.
The compound in formula (34) is manufactured by reactlon between the compound in formula (32) and the compound in formula (33) ln a proper solvent, in the presence of a WO94/21612 PCT/J~4/00434~
h ~3 I basic compound. Examples of the solvent include ethers such I as tetrahydrofurane, and aromatic hydrocarbons such as benzene 3 and toluene. Examples of the basic compound include organic bases such as triethyl amine and N-methylmorpholine. The ~ 5 quantity of use of the basic compound is about 1 to 2 mols of 3 1 mol of the compound in formula (32), and the quantity of use of the compound in formula (33) is about 1 to 2 mols of l mol of the compound in formula (32). The reaction temperature is about 0 to 100 C and the reaction is generally terminated in about 1 to 24 hours. The compound in formula (34) may be also I manufactured by presenting for an ordinary ester$fication reaction in a proper solvent.
The compound in formula (12) is manufactured by transforming the compound in formula (34) into sulfonate lS ester, and reactin~ with the compound in formula (3S) in the presence of a basic compound. 'rhe reaction of transforming the compound ln formula (34) into sulfonate ester is realized by reaction w~th acid anhydride such as sulfonic anhydride and acid halide such as sulfonyl hallde, in a proper sol~ent, in the presence of a basic compound. Examples of the solvent include halogenated hydrocarbons such as dichloromethane, and ethers such as tetrahydrofurane. Examples of the basic compound ~nclude organic bases such as pyridine, triethylamine, and N-methylmorpholine. The quantity of use of the basic compound is about l to l.S mol of 1 mol oi the .~.. ~94nl612 .~13 61 ~ 8 PCT/J~4100434 !
!
compound in formula (34). The quantity of use of acid anhydride or acid halide is about 1 to 1.5 mol of 1 mol of the ~ompound in formula (34). The reaction temperature is about 50 to 50 C and the reaction is generally terminated in about 1 minute to 1 day~
I, The reaction between the sulfonate ester of the ¦ compound in formula (34~ and the compound in formula (35) is conducted in a proper solvent, in the presence of a basic compound. Examples of the solvent include polar solvent such as dimethyl formamide and halogenated hydrocarbons such as dlchloromethane. Examples of the basic compound include sodium hydr~de, potassium hydrlde, lithium hydride, sodium methylate, and potassium ethylate. The ~uantity of use of the basic compolnd ls about 1 to 2 mols in 1 mol of the compound : 15 in formula (34), and the quantity of use of the compound (3S) is about 1 to 2 mols in 1 mol of the compound in formula (34).
The reactlon temperature is about -10 to 50 C and the reaction is generally terminated ln about 1 hour to 10 days.
The compound in formula ~6) used in reaction schemes 3, 8 and 9 is a nove~ or known compound, which may be easlly ~, manuactured in a method disclosed, for example, in J. Med.
Chem., 1972, 15, 325, or J. Org. Chem., 1989, 54, 3394. The compound in formula (6) is manufactured in methods shown in the following reactlon schemes 12 and 13.
' :
WO94/21612 ~ 13 610 8 PCTIJ~410043~I -- 44 _ Reaction scheme 12 ~2 R~
E~2i_N~(R4) n R --B--X ~.2~-~;(R4) n o H B--R3a (3 6) (3 8--A) where R2, ~4, R3a, B, X, and n are same as defined above; and R20 d~notes acyl group or ~mlno group protective group.~
The reaction between the compound in formula (36) and the compound ln formula (37) i5 conducted in a proper solvent, in the presence of a basic compound. Examples of the solvent ~ are dioxane, tetrahydrofurane, dlethyl ether, ethylene glycol ¦ dimethyl ether and other ethers; dlmethyl formamide, dimethyl . ~ulfoxide, hexa~ethylene pho~phoric acid triamide and other polar Golvents. Examples of the basic compound include sodi~m hydr~de, potassium hydrlde, llthium hydrlde, sodium methylate, potassium ethylate, and other inorganic bases. The quantity of use of such basic compound is usually about 0.5 to 2 times mol of the compound in ~ormula (36), preferably an equivalent mol. The blending rate of the compound in formula (36) and the compound ln formula (37) is 1 to 3 times the mol of the WQ94/21612 ~13 6 ~ 0 8 PCT/J~4/00434 " 45 I latter to the former, prefera~ly about an equivalent mol. The reaction temperature is usually about -20 to 120 C, preferably about 0 to 60 C, and the r~action is generally te~minated in about 10 minutes to 5 days.
Reaction scheme 13 t - Rt R
j10 R C-N ~ (R ) n R16a_x R20_N ~ R4) (39) (38-B) ~' ~
~ 15 ';:
~.
~where ~2, R4, R20, X and n are same as defined above; and R16a denstes lower alkyl group, lower alkoxy-lower alkyl :~ group, lower alkoxy-lower a}koxy-lower alkyl group, or lower alkoxy-lower alkoxy-lower alkoxy-lower alkyl group.]
- ~ IThe reaction bètween the compound in formula (3g) and l ~ the compound in formula (40) can be conducted in the same : reaction conditions as ln the reaction between the compound in ,, .
~ormula (36) and the compound in formula (37) in reaction -scheme 12.
~ :
W094/21612 ~ pcTlJn4loo434;
The compound in formula (38-A) and the compound in formula (38-B) are transformed into the compound in formula (6) by an ordinary de-protection reaction.
The compound in formula (15) used in reaction scheme 8 is manufactured in various methods. For example, it is manufactured in the method shown in the following reaction scheme 14.
Reactlon scheme 14 \ I 1) de~protectlon C:HCH--COOR~ RIQ--C--CH~COOH
2) Mannlch 11 lS- (12) reaction CH2 (41) ~ ~ r . R6 hydrogenatlon _ ~ Rl0- CH-CH-COOH
CH3 (15-A) ~0 t ~
~where R6, R9, R10, and Rl9 are same as defined above.]
The de-protection of the compound in formula (12) can be effected in the same conditions as in the reaction for obtaining the compound in formula (5) from the compound in V~94~1612 ~ 0 8 PCT/J~4/00434 ...... , ~ ~
formula (4) in reaction scheme 3. The subsequent Mannich reac~ion can ~e effected in the reaction conditions same as the reaction for obtaining the compound in formula (9) from the compound in formula (7) in reaction scheme 5. The hydrogenation of the compound in formula ~41) can be effected ' in the same conditions as in the reaction for reducing the I compound in formula (l-A) to transform into the compound in formula (l-B) in reaction scheme 2.
- The amin~ group, hydroxyl group or other substituent in the intermediate compound shown in the foregoing reaction schemes can be properly protected by an ordinary method not ~ affecting the reaction, and the protective group may be ¦ properly eliminated in an ordinary method after reaction.
¦ The compound in formula (1) of the invention, and ~he 15 intermediate compounds shown in the reaction sohemes for its manufacture may be variously changed in the types of R1, R3, j~ R5, and others contained therein, but they are not limited to ¦ them alone, and varlous changes as effected ordinarily may be applicable.
For example, as the elimination reaction of the protective group of the hydroxyl group, there is an example of de-silylation reaction for obtaining the compound in formula (1-B) from the compound in formula (42) in reaction scheme 15.
', WO94/21612 ~13 61~ PCT/J~4/00434~
-Reactionschemel5 R~ R6 (R ~ N-CO-Ct~-CH-COOH
R3 (23 - ¦ t?. 2 t R 22 R 2 3 S t O N t-t 2 !
~ R~ R6 i (R4) N-Co-CH-CH-CoNH-oSiR2lR2~R23 Rl l~ (42) 1 d~3-9llyl~tlon R2 ~6 (R ~ N-CO-CH-Ct-t-CONH-OH
R3 (l-B) W3 94/21612 ft~ 3 S I O ~ PCT/JPg4/00434 ~-- !
~where R1, R2, R3, R4, R6 and n are same as defined above; and , R21, R22, and R23 are lower alkyl groups.~
1 The reaction between the compound in formula (2) and ¦ the compound in formula (3') can be effected in the same ¦ 5 reaction conditions as in the reaction between the compound in formula (2) and the compound in formula (3) in reaction scheme 1.
In the reaction for leading the compound in formula -(42) into the compound in the formula (l-B), the reaction conditions in ordinary de-silylation may be applied. For example, this de-silylation reaction is effec~ed by using a proper catalyst customarily used in this kind of de-silylation reactlon, for example, a proper amount of hydrochloric acid, sulfuric acid, peschloric acid and other inorganic acids;
~ 15 ~ formic acld, acetic, acid, propion~c acid and other lower ¦ - ~ alkane aclds; benzo~c acid, methane sulfsnic acid, ethane sulfonic acid, benzene sulfonic acid, 4-methylbenzene sulfonic acid and other organic sulfonic acid; and other organic acids, , .
- ~ usually in a solvent. Ex3~ples of ths solvent include ord~ary inert solvents, such as water, methanol, ethanol, ~, isopropanol and other lower alcohols; acetone, methyl ethyl ketone and other ketones; dioxane, tetrahydrofurane, diethyl ~- ether, ethylene glycol dimethyl ether and other ethers;
: benzene, toluene, xylene, chlorobenzene and aromatic hydrocarbo~s; acetic acid, propionic acid, and lower alkane --`~ WO94121612 PCT/JW4100434`
~ 1 3 li 1 0 8 .. ; . . s o ,;
acid; and their mixed solvents. The catalyst may be used in the range from an ordinary catalyst amount to excessive amount, preferably an excessive amount. The reaction temperature is usually about 0 to lO0 C, preferably from room temperature to about 80 C and the reaction is terminated in about 3 minutes to 20 hours.
As the elimination reaction of protective group of amlno group, for example, the following hydrazine decomposition reaction may be presented. For example, when ~0 is a phthalimido-lower alkyl group, by presenting to th~
hydra~ine decomposition for reacting with hydrazine or hydrazine derivative without solvent or in an inert solvent, Rl may be transformed into an amino-lower alkyl group. As the inert solvent used in this reaction, for example, dichloromethane, dichloroethane, chloroform, carbon tetrachloride and halogenated hydrocarbons; methanol, ethanol, and other alcohols may be known. Examples of the hydrazine deri~ative include methyl hydrazlne, ethyl hydrazine, other lower alkyl-substltuted hydrazines, phenyl hydrazine and other aryl-substituted hydrazines. The quantity of use of hydrazine or hydrazine derivative to the startin~ material compound of whlch R1 corresponds to a phthalimldo-lower alkyl group is j usually at least equivalent mol, or preferably eguivalent mol to 10 times mol. The reaction is conducted usually at 0 to lOO ~, preferably O to 80 ~, and the reaction is generally W~94/21612 ;~ 3 6 1 ~ 8 PCTIJ~4100434 i 3 terminated in about 1 to 40 hours.
The compound of the formula (13) used as starting material in reaction scheme 8 is a known compound disclosed, for example, in J. Gen. Chem., 22, 267-269 (1952), and Khim.
5 Geterotsikl. Soedin., ~, 344-345 (1975), among others, and can be easily manufactured according to the method mentioned in j these literatures.
! The compound of the invention may contain an additional salt of a pharmaceutica~ly permitted acid or base ~ 10 compound. ~he salt may be easily formed by acting the~acid ¦ or the b~se. Examples of the acid used in salt formation -~ include inorganlc acids such as hydrochloric acld, sulfuric ~ acld, phosphorlc acid, and hydrobromic acid, and, if -~ necessary, organic aclds such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acld, citric acid, and ¦~ benzoic acid. The base compound used in the salt formatlon I may include, among others, sodium hydroxide, potassium ~ hydroxide, calcium hydroxide, sodium car~onate, and potassium ; hydrogencarbonate.
The compound of formula (1) manufactured in the j foregoing methods and its salt are easily isolated and refined - from the reaction system by ordinary separatian means, such as ~ distillation method, recrystallization method, column -~ chromatography, preparative thin layer chromatography, and ~ 25 solvent extraction method.
wo 94~21612 ~ 1 3 u lO ~ PCT/J~4/00434i ; -; The extracellular matrix metalloproteinases inhibitor of . the invention is used generally in a form of an ordinary pharmaceutical preparation. The pharmaceutical preparation is adjusted by ordinary filler, thickener, binder, humidifier, disintegrating agent, surface active agent, lubricant, and ~i other diluents and vehicles. As the pharmaceutical I preparations, various forms can be selected depending on the ~ purpose of treatment, and representative examples include tablets, pills, powders, liquid, suspension, emulsion, 10 granules, capsules, suppositorles, injections (liquid, suspension, etc.), and ointment. To form into tablets, carriers are used, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, cryst~l cellulose, silicic acid and other vehicles; water, 15 ethanol, propanol, slngle syrup, glucose liquid, starch liguid, gelatin æolution, carboxy methyl cellulose, shellac, methyl cellulose, potasslum phosphate, polyvinyl pyrrolidone and other binders, dry staxch, sodium alginate, agar powder, laminaran powder, sodium hydrogencarbonate, calcium carbonate, 20 polyoxy ethylene sorbitan fatty acid esters, sodium lauryl ~ ~ ~ulfate, monoglyceride stearate, starch, lactose and other ¦ disintegrating agent; sucrose, stearin, cacao butter, , hydrogenated oil and other disintegration suppressors;
I, quaternary ammonium base, sodium lauryl sulfate and other absorption promoters; glycerin, starch and other moisture '' - ,.
~ W~94/21612 ~13 6 ~ ~ ~ PCTlJ~4/oo434 ~ - 53 -¦ retainers; starch, lactose, kaolin, bentonite, colloidal silicic acid and other absorbents; refined talc, stearate, boric acid powder, polyethylene glycol and other lubricants.
Tablets may be manufactured in ordinary coated tables as required, for example, sugar coated tablet, gelatin coated tablet, enteric coated tablet, film coated tablet, double tablet, or multilayer tablet. When forming into pills, carriers are used, such as glucose, lactose, starch, cacao butter, hardened vegetable oil, kaolin, talc and other vehicles; arabic gum powder, tragacanth powder, gelatin, ethanol and other binder; 1 aminaran agar and other disintegrating agents. When forming into suppositories, carriers are used, such as polyethylene glycol, cacao butter, Xlgher alcohol, esters of higher alcoho1, gelatin, and semisynthetic glyceride. Capsules are manufactured according to the conventional manner, and various carriers listed above and the compound of the invention are blended, and put into hard gelatin capsule, hard capsule, etc. When prepared as - ln~ections, liquids, emulsions, and suspensions should be ~: 20 sterilized, and lsotonic wlth the blood. When manufacturing in such forms, diluents are used, such as water, aqueous ,~ , . , , ~
~ solution of lactic acid, ethyl alcohol, propylene glycol, -~ ethoxy isostearyl alcohol, and polyoxyethylene sorbitan fatty . acid ester. In this case, salt, glucose or glycerin enough for preparing an isotonic solution may be contained in the , WO94/21612 PCT/J~4/0~34l'l ~ 1 3 6 1 0 8 ; ~ ~
pharmaceutical preparations, or ordinary dissolution aid, desiccant, soothing agent or the like may be added. As required, further, coloring matter, preservative, perfume, flavor, sweetener, and other medicines may be contained in the pharmaceutical preparations. When manufacturing into paste, cream or gel, diluents are used, for example, white vaseline, paraffin, glycerin, cellulose derivative, polyethylene glycol, silicon, and bentonite.
~ The quantity of the compound of the invention to be contained in the pharmaceutical preparation of the invention ls not particularly defined, but may be selected from a wide range, and it may be usually in a range of 1 to 70 % by welght of the pharmaceutical preparation.
The method of administration of the pharmaceutical lS preparation of the inventlon is not partlcularly limited, and determined properly depending on the age, sex and other j~
condltlons of the patients, sev~rlty of disease, and dosage forms, and usually it is administered systematically or locally, orally or parenterally. For example, tablets, pills, liquid, suspensions, emulsions, granules, and capsules are administered orally, in~ections are admlnistered intravenously, intramuscularly, in~radermally, subcutaneously, or intraperitoneally by mixing with ordinary fluid replacement if necessary. Suppositories are administered intrarectally, ' and o~ntments are applied externally.
WO94~1612 ~ 1~ 6 ~ ~ 8 PCT/J~4/00434 s The dose of the pharmaceutical preparation of the ~ invention may be properly selected depending on the age, body ¦ weight, symptom, therapeutic effect, route of administration, treating time and others, and it is usually administered in a range of ahout O.1 to 100 mg per l kg of body weight, and the daily dose may be administered once da~ly or in several divided portions. Since the dose varies with various condit~ons, it may be enough at a smaller dose or a larger dose beyond tha specified range may be needed, depending on lO the 1ndlvldual cases.
,, :
WO94/2161~ ~13 6 10 8 PCT/J~410~34¦ .
EXAMPLES
Manufacturing examples of compounds used in the invention are shown below, being followed the pharmacological study results of these compounds and pharmaceutical examples.
Reference Example 1 (a) Preparation of 2R-bromo-4-methyl-pentanoic acid 50.0 g of D-leucine was dissolved in a mixed solvent of 112 ml of sulfuric acid and 380 ml of water, and 158 g of potasslum bromide is added, and the reaction solution was~
cooled to -2C. A solution dissol~ing 343.8 g of sodium nitrlte in 100 ml of water was dripped in 1 hour so as to keep the reaction solution at -1 to -2C, and after dripping, the ` solution was stirred for 2 hours in an ice bath. Adding 300 ml of chloroform to the reactlon solution, insoluble matter was filtered off, an organic layer was separated, and the ~ water lay~r was extracted five times in 100 ml of chloroform.
; Combining with the chloroform layer, after drying with magnesium sulfate, the solvent was evaporated in vacuum, and the oaptioned compound was obtalned in a yellow oil form.
Yield: 58.5 g.
!: .
(b) Preparation of tert-butyl 2R-bromo-4-methyl-pentanoate 58.5 g of 2R-bromo-4-methyl pentanoic acid was ; 25 dissolved in 150 ml of dichloromethane, this solution was ,~
.. WO94/21612 PCT/~4/00434 - ~ 1 0 8 c -57-,~
cooled to -40C, and about 50 ml of isobutene was collected.
Keeping at - 40C, 1.5 ml of concentrated sulfuric acid was dripped while stirring, and the tube was sealed and stirred overnight at room temperature~ The reaction vessel was cooled again to -40C or less, the tube was opened, and let stand at room temperature, and when the reaction solution exceeded 10C, it was evaporated in vacuum until the reaction solution was consumed to about half. Adding 200 ml of chloroform to the residue, the chloroform layer was washed with aqueous solution of saturated sod~um hydrogen carbonate (100 ml x 2 times) nd 100 ml of br~ne, and dried over magnesium sulfate and evaporated in vacuum, then the captioned compound was obtained in a yellow oil form. Yield: 67.2 g.
(c) Preparation of benzyl 2-benzyloxycarbonyl-3R-tert-butoxy-carbonyl-5-methyl hexanoate 76.2 g of d~benzyl malonate was dissolved in lO0 ml of ¦dry dimethyl formamide, and 30.0 g of potassium t-butoxide was added while chilling in ice, and the solution was stirred at room ~emperature until potassium t-butoxide is dissolved completely. Cooling again in an ice bath, 120 ml of dimethyl formamide of 67.2 g of tert-butyl 2R-bromo-4-methyl-penanoate was dripped in 1 hour, and the solution was stirred for 4 da~s at 4C. Pouring the reaction solution into 500 ml of saturated ammonium chloride, and after extracting with ethyl , W094~1612 . ~ PCT/J~4/00434~ .
' . -58-.~ acetate (300 ml x 3 times), the organic layer was evaporated ?
in vacuum. Adding 600 ml of diethyl ether to the residue, and after washing in brine (500 ml x 2 times), the solution was P
dried with magnesium sulfate, and the solvent was evaporated ~ 5 in vacuum. The oily residue was purified by column ¦ chromatography (silica gel 900 g, hexane/ethyl acetate = 20/1 ¦ v/v), and the captioned compound was obtained in a colorless oil form. Yield: 71.6 g.
lO Reference Exampl~ 2 ¦ Preparation of 3S-(4-benzyloxy-3-benzyloxycarbonyl-2R-isobutylsuccinyl)amino-3,4-dihydrocarbostyril To 4.06 g of benzyl 2-benzyloxycarbonyl-5-methyl-3R-tert-butoxycarbonylhexanoate, 10 ~l of trifluoroacetic acid 15 was added, and after letting stand for l hour at room temp~rature, the trifluoroacetic acid was evaporated in v8cuum. To the residue, 35 ml of chloroform was added, and it was washed with brlne (10 ml x 2 times), and dried wlth ~ magnesium sulfate anhydride, and evaporated in ~acuum. The ! 29 obtained residue was dissolved in 15 ml of dimethyl formamide, 1.45 g of 3S-amino-3,4-dihydrocarbostyril was added, and while ¦~- cooling in a water bath, 1.21 g of 1-hydroxybenzotriazole and 1.84 g of N,N'-dicyclohexyl carbodiimide were added, and the :~ pH was ad~usted to 8 by N-methylmorpholine, and the solution ~ !
~ was stirred for 20 hours at room temperature. After filtering I
W094/21612 PCT/J~4/00434 ``: 2~36108 off the sediment, the solution was evaporated in vacuum. To the residue, 100 ml of ethyl acetate was addedt and the mixture was washed with lN hydrochloric acid (20 ml x 2 times), saturated aqueous solution of sodium hydrogencarbonate 5 ( 15 ml x 3 times ), and brine ( 10 ml), dried with magnesium sulfate anbydride, and evaporated in vacuum. The oily residue was purified by column chromatography (silica gel 90 g, eluted tn 33% ethyl acetate/hexane, and then in 40% ethyl acetate/h xane), the captioned compound was ob~ained i.n a colorlesQ oily matter. Yield: 3.54 ~. ~
N M R (2 7 O M H z. C D C 13 ) ~ P P m : 8. 0 8 (1 H. s) ~ 7. 3 l (1 O H. s) ~ 6. 9 6 - 7. 3 0 (3 H, m) ~ 6. 7 4 - 6. 7 9 (2 H. m) ~ 5. 0 3 - 5. 2 6 (4 H, m) ~ 4. 5 2 (1 H~ d t, J - l 4 ~ 6 H z) ~ 3. 8 5 (l H. d d. J ~ 1 6~ l O H z) ~ 3. 3 6 (} H, d d. J = 1 6, 6 H z) ~ 2. 9 2 - 3. 1 5 (1 H, m) ~ ~. 6 3 (l H
, t, J = l 5 H z) ~ 1. 5 O - 1. 8 0 (2 H. m) ~ O. 9 5 - l. l 5 (1 H. ~) ~ O. 7 5 - 1. 0 0 (6 H, m) Reference Example 3 ~ Preparation of 3S-(3-hydroxycarbonyl-2R-isobutyl-propanoyl)amino-3,4-dihydrocarbostyril 3.50 g of 3S-(4-benzyloxy-3-benzyloxycarbonyl-2~-isobutylsuccinyl)amlno-3,4 dihydrocarbostyril was dissolved in 35 ml of methanol, and 35 mg of 10% palladium-carbon was ~, WO94/21612 .......................................... PCT/J~4/00434l ~13G10~ -,. !
added, and the solution was saturated with hydrogen. After stirring for a day at ordinary pressure, the catalyst was I filtered off, and the filtrate was concentrated in vacuo. To .~ this residue, 20 ml of toluene was added, and the mixture was heated for 20 minutes in reflux. The reaction solution was concentrated in vacuo, and 10 ml of ethyl acetate was added to the residue, and the mixtur was heated and dissolved, and 2 ml of hexane was added, and after letting stand at room temperature for a day, the precipitating crystals were flltered, and the captioned compound was obtained in a wht'te solid form. Yield: 500 mg.
NMR (2 7 OMHz. DMSO--d6 ) ~ P pm: 8. 1 9 (1 H. d, J=
8Hz) ~ 7. 1 5--7. 30 (lH, m) ~ 7. 1 6 (2H, t, J--7Hz ~ ~ 6. 9 0 (2H. d t. J=8, 7Hz) ~ 4. 4 6 (1 H, d ~, J= 1 - 2, 8Hz) ~ 2. 6 0--3. 0 O (3H. m) ~ 2. 4 3 (1 H. d d. J--1 6. 8Hz) ~ 2. 2 4 (1 H. d d. J--1 6, 6 H z) ~ 1. 0 5--1 .
80 t3H, m) ~ ~. 88 (6H. dd, J=1 6, 6Hz~
, Reference Example 4 ' 1 ' I
Preparat~on of 3S-(4-hydroxy-2R-lsobutyl-3-methylene-succinyl)amino-3,4-dihydrocarbostyril 10.8 g of 35-(4-benzyloxy-3-benzyloxycarbonyl-2R-isobutylsucc~nyl)amlno-3,4-dlhydrocarbostyrll was dlssolved ln , W~g4al6l2 ~;13 6 t ~ ~ PCT/J~4l00434 100 ml of methanol, 1.0 g of 10% palladium-carbon was added, and the solution was saturated wlth hydrogen. After stirring for a day at ordinary pressure, the catalyst was filtered off.
' To ~he reaction solution, ~.2 ml of piperidine was added, and i 5 after stirring for 15 minutes, 4.9 ml of 37% formaldehyde ¦ liquid was added, ~d the soluti3n was stirred for 7 hours at room temperature, and heated for an hour in reflux. The , reaction solution was concentrated in vacuo, dissolved in 200 ml of sat~rated aqueous solution of potassium carbonate, and wa~hed with chloroform (20 ml x 3 times). The water layer was cooled in an ~ce bath, and the pH was adjusted to 1 by concentrated hydrochloric acid, and after extracting with chloroform ( 0 ml x 2 times), it was washed with brine (20 ml~, dried over magnesium sulfate, and evaporated ln vacuum, and the captioned compound wa-~ obtalned in a white solid form.
¦ Yi~ld: 1.98 g.
N M R ( 2 7 O M H z . C D C 1 3 ) ~ ~ ~ m : 8 . 6 9 ( 1 H , s ) ~ 7 .
9 (2H. dd. J=l 4, 7H~) ~ 7. 03 tlH. d. J--7Hz) ~ 6 . 8 2 ( l H. d . J = 7 H z ) ~ 6 . 4 6 ( 1 H. s ) ~ 5 . 8 9 ( 1 H, s ) ~ 4. 5 8 (lH. d t, J=l 3, 6Hz) ~ 3. 6 1(lH. t, J=7 H z) ~ 3. 5 1 (1 H. d t, J=l 5, 6H z) ~ 2.7 6 (1 H. t, J `
--1 5Hz) ~ 1. 5 0--2. 0 0 (3H, m) ~ O. 9 1(6H. d d, J=
1 O, 6 H z~
Re~erence ~xample 5 i ~ W094~1612 PCT/~4tO~34~
~13~10-8 - `
Preparation of 3S-(4-hydroxy-2R-isobutyl-3S-acetyl-thiomethylsuccinyl)amino-3,4-dihydroxycarbostyril ¦ 840 mg of 3S-(4-hydroxy-2R-isobutyl-3S-methylene-succinyl)amino-3,4-dihydrocarbostyril was dissolved in 8 ml of thioacetic acid, and stirred for 4 days in a dark place at 30~. Diethyl ether was added to the reaction solution, and ¦ the precipitating crystals were filtered, and the captioned compound was obtained in a white solid form. Yield: 330 mg.
N M R (2 7 O M H z, C D C 13 ) ~ P P m : 8. 7 0 tl H, b r s)~ 6 . 8 0 - 7. 3 0 (4 H. m) ~ 4. 4 5 - 4. 6 0 (1 H, m) ~ 3. 5 9 ( 1 H, d d. J = 1 5, 6 H z) ~ 2. 8 0 - 3. 4 0 (4 H, m) ~ 2. 6 8 (l H, t, J = 1 5 H z) ~ 2- 3 6 (3 H, s) ~ 1. 1 0 - 1. 8 0 t3 ~, m) ~ O. 9 5 (6 H. d t. J = 1 3, 7 H z) :~
-~; R-ference Example 6 ~--~ (a) Preparatlon of D-leucic acld Wh~le heatlng and stirring 100 ml of agueous solution of 14 g of sodium nit~ite at 90~, 400 ml aqueous solution of ~; 2~ 0.5N sulfuric acld of 25 g of D-leucine was added over 45 mlnutes. After dripping, the solution was stirred for 15 !
¦ minutes until foams were no longer generated. The reaction solutlon was concentrated to 200 ml in vacuo, and the obtained - re~idue was e~tracted with diethyl ether. The diethyl ether ~ 25 layer was washed one w1th lN hydrochlorlc acld, and twlce with .' W~94~1612 PCT1~4/00434 ` 213~1Q8 saturated brine sequentially, and dried ov~r sodium su'fate anhydride, and concentrated in vacuo. The obtained oily residue was left over, crystallized, and the captioned compound was obtained. Yield: 14.50 g.
(b) Preparation of D-leucic acid benzyl ester To 150 ml of tetrahydrofurane of 14.50 of D-lellcic acid, 15.2 g of triethylamine and than 14.4 ml of benzyl bromide are added, and the solution was stirred for 3 hours while refluxing. The insoluble matter produced from ~he reaction solution was filtered of~, and the filtrate was concentrated in ~acuo. The obtained r~sidue was dissolved and extracted in 150 ml of ethyl acetate. The ethyl acetate layer was washed twice with saturated bicarbonate water, ~wice with lS lN hydrochloric acid, and twice with saturated brine sequentially, and dried ovex sodium sulfate anhydride, and concentrated in ~acuo. The obtained oily residue was dried, and the captioned compound was obtained. Yield: 18.34 g.
(c) Preparation of 1,2-dibenzyl-1-t-butyl-4-methyl-1,1,2(R)-pentane-tr~carboxylate To 140 ml of N,N-dimethyl formamide solution of 20.65 g of benzyl t-butylmalonate, 3.30 g of sodium hydride (content ~, 60~) was added, and the solution was stirred for 1 hour at room temperature. On the other hand, to 100 ml solution of -W094nl6~2 ~13 61~ ~ PCT/J~4/00434~
- dichloromethane of 18.34 g of D-leucic acid benzvl ester, 6.66 ml of pyridine was added, and stirred in ice, and 100 ml of dichloromethane of 13.53 ml of anhydrous trifluoromethane sulfonic acid was dripped thereon in 30 minutes. After dripping, the solution was further stirred for 1 hour in ice.
The reaction solution was washed once with water, and one with saturated brine sequentially, and dried with sodium sulfate _ anhydrlde. Filtering off the sodium sulfate anhydride, the filtrate was dripped in 30 minutes on the N,N-dimethyl ormamide soiution abo~e prepared while stirring in ice.
After drlpplng, the solution was stirred overnight at room - temperature. The reaction solution was concen~rated in vacuo, ~ - , and dripped ln 30 minute~. After dripping, the solution was stlrred overnight at room temperature. The reaction solution was concentrated in vacuo, and the obtained residue was extracted ln 300 ml of ethyl acetate. The ethyl acetate layer - was washed twice wlth saturated aqueous solution of sodium hydrogencarbonate, twice with lN hydrochloric acid, and twice with saturated brine sequentially, and dried with sodium sulfate anhydride, and concentrated in ~acuo. The obtained oily résidue was purified by the silica gel column chromatography, and eluted in ethyl acetate/petroleum ether 20~, and the captioned compound was obtained in an oily matter. Yield: l9.O g.
~. '.
', ~
WO94/21612 PCT/J~4/00434 -- ~13fi~0g Reference Example 7 Preparation of l,2-dibenzyl-l-tert-butyl-l-phthalimidomethyl-4-methYl-l,l,2(R)-pentane-tricarboxylate In a 50 ml solution of dimethyl formamide of 6.00 g of l,2-dibenzyl-l-tert-butyl-4-methyl-l,l,2(R)-pentane-tricarboxylate, 653 g (60% content) of sodium hydride was added while stirring in ice, and stirred for 30 minutes. The _ reaction solution was returned to room temperature, and 4.04 g of N-bromomethylphthalimide was added, and stirred for 3 days at room temperature. After neutralizing the reaction solution by adding a small amount of acetic acid, it was concentrated in vacuo. The obtained oily residue was extracted in lO0 ml of ethyl acetate, and the ethyl acetate layer was washed once with water and twlce with saturated brine, and dried with sodium sulfate anhydride, and concentrated in vacuo. The obtained olly residue was purified by silica gel column chromatography, and eluted in chloroform, and the captioned compound was obtained ln an olly ~orm. Yield: 4.00 g.
Reference Example 8 IPreparation of 4-tert-butoxy-2R-isobutyl-3-(R or S)-phthalimidomethylsuccinic acid To a 30 ml solution of methanol of 4.00 g of l,2- ~
dibenzyl-l-tert-butyl-l-phthalimidomethyl-4-methyl-l,l,2(R)- $
pentane-tricarboxylate, 200 mg of lO ~ palladium-carbon was WO 9412l6~ ~13 G 1 0 8 PCT/J~4/00434 added, and hydrogen gas was introduced in vacuo, an~ the solution was stirred for 2 days. From the reaction solution, the catalyst was filtered off by using celite, and the filtrate was concentrated in vacuo. The obtained residue was dissolved in 30 ml of toluene, and 0.70 ml of N-methylmorpholine was added, and the solution was stirred for 7 hours while refluxing. To the reaction solution, 70 ml of toluene was added, and the organic layer was washed twice with lN hydrochlor1c acid, and three times with saturated brine, and drled with sodium sulfate anhydride, and concentrated in ~acuo. The obta~ned oily residue was purified by the sili~a gel column chromatography, and eluted in 2%
methanol/chloroform, and the captioned compound was obtained in a olly form. Yield: 1.00 g.
Reference Example 9 Pre~aration of 3S-(4-tert-butoxy-2R-isobu~yl-3(R or S)-phthalimidomethylsuccinyl)amino-3,4-dihydrocarbostyril To a 10 ml suspension of dimethyl formamide of S00 mg of 4-tert-butoxy-2R-isobutyl-3(R or S)-phthalimidomethyl-succinic acid, 190 mg of l-hydroxybenzotriazole, and 228 mg of 3S-amino-3,4-dihydroxycarbostyril, 290 g o~ N,N'-dicyclohexyl carbodiimide was added while stirring in ice, and was stirred for 2 hours in ice and 18 hours at room temperature. The 2~ :
reaction solution was concentrated in vacuo, and 60 ml of WO94/216~ ~ 0 8 PCT/J~4/00434 ethyl acetate was added to the residuer and the insoluble matter was filtered off. The ethyl acetate layer of the filtrate was sequentially washed with saturated a~ueous solution of sodium hydrogencarbonate (2 times), lN
hydrochloric acid (2 times), and saturated brine (2 times), and dried with sodium sulfate anhydride, and concentrated in vacuo. The obtained oily residue w~s purified by silica gel column chromatography, and eluted in 0.5% methanol/chloroform, ~ and the captioned compound was obtained in a powder form.
Y~eld: 390 mg.
N M R (2 7 0 M H z, C D C 1~ ) ~ P P m : 8. S 2 (1 H. s) ~ 7. 8
7 - 7. 7 9 (2 H. m) ~ 7. 7 5 - 7. 6 9 (2 H. m) ~ 7. 5 3 (l H
, d. J = 5 H z) ~ 7. 2 4 - 7. 1 9 (2 H. m) ~ 7. 0 2 (1 H. t, ~:; J = 7 H z) ~ 6. 8 9 (l H. d. J = 8 H z) ~ 4. 6 6 - 4. 5 8 tl H
, m) ~ 4. 1 9 (l H. d d. Jl = 9 H Z~ J2 = 1 4 H z) ~ 3. 8 0 ( 1 H. d d. J1 = 5 H Z~ J2 = 1 4 H z) ~ 3. 6 3 (1 H. d d. J1 =
~ 6 H Z~ J2 = l 5 H z) ~ 3. 5 0 - 3. 4 7 (l H, m) ~ 2. 9 8 - 2.
-~ 8 0 (2 H. m) ~ 1. 7 3 - l. 5 8 (3 H. m) ~ 0. 9 2 (6 H. d d, Jl 7 ~ Z~ J2 = 1 4 H z) :20 Reference Example lO
Preparation o 3,4-methylenedioxybenzylidenesuccinic ac~d Dissolving l9.14 g of metal sodium in 400 ml of W094nl6l2 ~13 61 Q 8 PCT/~W4/0~4 ~
~ -68- 1 ~.
ethanol, 110.8 ml of diethyl succinate and lO0 g of piperonal were added, and the solution was heated and refluxed for 3 hours. The reaction solution was concentrated in vacuo, and the residue was dissolved in 700 ml of water, and washed with 300 ml of diethyl ether. The water layer was stirred in ice, adjusted to pH 1 by concentrated hydrochloric acid, and extracted with 300 ml of diethyl ether. The diethyl ether layer was washed once with saturated brine, and dried over magneslum sulfate anhydride, and concentrated in vacuo. The obta~ned o~ly residue was dissolved by 181.4 g in 350 ml of ethanol, a~d 400 ml of 5N sodium hydroxide was added to stir overnight at room temperature. The reaction solution was concentrated in vacuo, and th~ residue was washed with 200 ml of diethyl ether. The water layer was stirred in ice, ad~usted to pH 1 by concentrated hydrochloric acid, and extracted with 400 ml of ethyl acetate. The ethyl acetate ~ layer was washed with saturated br ne, dried over magnesium : sulfate anhydride, and concentrated in vacuo. To the obtained residue, 300 ml of diethyl ether was addad to solidify, and the captionsd compound was obtained. Yield: 67.34 g.
, ,,, . i ,: ' :. Reference Example ll .:~ .
Preparation of 4-ethoxy-2-(3,4-methylene-dioxybenzylidene)succinlc acid : 25 To 23.5 g of 3,4-methylenedioxybenzylidenesuccinic W094/21612 ~ PCT/J~4/00434 ~J 1361 (18 acid, 200 ml of acetic anhydride was added, and heated in reflux for 2 hours- The reaction solution was concentrated in vacuo, and 200 ml of ethanol was added to the residue, and the mixture was heated in reflux overnight. The reaction solution was concentrated in vacuo, and the residue was extracted with 300 ml of ethyl acetate. The ethyl acetate layer was was~ed ~wice with saturated brine, and dried over magnesium sulfate anhydride, and concentrated in vacuo. To the obtained crystalline residue, diethyl ether was added to wash, and the captioned compound was obtained. Yleld: 17.76 g.
Raference Example 12 Preparat~on of 4-ethoxy-2-pip~ronylsuccinic acid I5 To a lO0 ml solutl4n of ethanol of 9.70 g of 4-ethoxy-2-(3,4-methylenedioxybenzylldene) uccinic acid, 970 mg of 10%
palladium-carbon wa~ added, and catalytic hydrogenation was carrled out overnight at room temperature. The catalyst was filtered off from the reactlon solution by using celite, and the flltrate was conce~trated ln vacuo. The obtained oily residue was dried, and the captioned compound was o~tained.
Yield:~10.36 g.
.
Reference Example 13 Preparation of 3-(4-ethoxy-2-piperonylsuccinyl)-amlno-3,4-dihydrocarbostyril ' WO94~1612 PCT/~4100434 ~13610~
. .
To a 3 ml solution of dimethyl formamide of 260 mg of 3-amino-3,4-dihydrocarbostyril, a 5 ml solution of dichloromethane of 500 mg of 4-ethoxy-piperonylsuccinic acid and 240 mg of l-hydroxybenzotriazole were added, and while stirrlng in ice, 360 mg Q~ N~Nl-diryclohexylcarbodiimide was added, and the mixture was stirred for 2 hours in ice and for , 3 days at room temperature. Insoluble matter was filtered off ¦ from the reactlon solution, and the flltrate was concentrated ln vacuo. To the obtained filtrate, 30 ml of chloroform was '' added to extract, and the chloroform layer was washed :;~ sequentially wlth saturated aqueous solution of sodium hydrogencarbonate, lN hydrochloric acld, and saturated brine, ~-~ and dried over magnesium sulfate anhydride and concentrated in --- vacuo. The obtalned resldue was purifled ~y sllica gel column ''~ 1~
chromatography, and eluted in ethyl acetate/hexane (l:l), and ~- the captio~ed compound was obtained. Yield: lO0 mg.
R~ference Example 14 - Preparat$on of 4-t-butoxy-3-methylene-2R-isobutyl-succinate j '- To a 200iml solutlon of isopropanol of 40.0 g of l,2-dlbenzyl-l-t-butyl-4-methyl-l,l,2~R)-pentane-tricarboxylate, ~: 3.50 g of 10% palladium-carbon was added, and hydrogen gas was -.
lntroduced in vacuo to stir overnight at room temperature.
The catalyst was filtered off from the reaction solution by -, , W094~16~ ~13 ~10 8 PCT/~4/00434 ~
using celite. To the obtained filtrate, 23.72 ml of piperidine and 108.2 ml of 37% aqueous solution of formaldehyde were added, and the mixture was stirred for 2 days at room temperature. The reaction solution was concentrated in vacuo, and the obtained residue was dissolved in 3SO ml of ethyl acetate and extracted. The ethyl acetate layer was washed sequentially with lN hydrochloric acid (300 ml x 1 time and 200 ml x 1 time) and twice wlth saturated ~brine, and dried over sodlum sulfate anhydride, and concentrate~ ~n vacuo. The obtained oily residue was purified by silica gel column chromatography (eluted in 2%
methanol/chloroform), and the captioned compound was obtained in an oily ~orm. Yield: 13.81 g.
N M R (2 7 O M H z; C D C 13 ) ~ ~ P m : 1 1. 0 0 (l H, b s) ~ 6 . 2 9 (l H. s) ~ 5. 6 7 (1 H, s) ~ 3. 5 5 (l H, t, J ~ 8 H z ~;
) ~ 1. 7 6 (l H. d d. Jl = 6 H Z~ ~2 = l 4 H z) ~ 1. 6 3 - l.
4 9 (2H. m) ~ 1. 4 9 (9H. s) ~ O. 9 2 (6 H. d d. Jl = 6 H
Z~ J2 =9Hz) 2~ ;
Re4erence Example 15 Preparation of 4-t-butoxy-2R-isobutyl-3S-methyl- 3 succlnate To a 100 ml solution of ethyl acetate of 13.81 g of WO94/21612 ~ 13 61 ~ 8 PCT/~4/00434 4-t-butoxy-3-methylene-2R-isobutylsuccinate, g70 mg of lQ%
palladium-carbon was added, and hydrogen gas was introduced in vacuo to stir overnight at room temperature. The catalyst was filtered off from th~ ~eaction solution by using celite, and 11.35 ml of dicyclohexylamine was added while stirring in ice.
Immediately~ a white sediment was formed, and was filtered, and washed with a 5mall amount of diethyl ether. The obtained white sediment wa~ recrystallized from 150 ml of ethyl acetate, and 13.50 g of white solid matter was obtained.
The obtained compound (8.20 g) was suspended iIl 2qo ml of ethyl acetate, and the ethyl acetate layer was washed ,~ sequentially with 0.5M sulfuric acid (100 ml x 2 times ~ and ¦ saturated brine (lO0 ml x 3 times ), and dried over magnesium sulf ate anhydride, and concentrated in vacuo . The obtained 15 residue was dried, and the captioned compound was obtained in an oily form. Y~ eld: 4. 60 g.
~MR (2 7 0MH z , C DC 1 3 ) ~ P P m : 1 0. O O ( 1 H, b s ) ~ 2 7 3--2. 6 8 ( 1 H, m) ~ 2. 6 1--2 . 5 5 ~1 H, m) ~ 1. 7 2--1. 6 3 (2H. m) ~ 1. 4 5 (9H, s) ~ 1. 2 9-1. 1 9 (1 H. m ) ~ 1 . 1 7 ~3 H, d. J= 7 H z) ~ 0. 9 1 (6 H, d d. Jl = Z H z ~ J2 = 7 H z) i Referance Example 16 Preparation of 3S-t-butoxycarbonylamino-3,4-~ W094~16~ PCT/~4/00434 =~
" ' ' 1~6l~8 dihydrocarbos~yril 10 g of 3S-amino-3,4-dihydrocarbostyril was dissolved in 100 ml of N,N-dimethylformamide, and, after ice-cooling, 14.8 g of t-butoxycarboxylic anhydride was added, and the pH
was adjusted to 8 by triethylamine. After stirring for 1 hour at OC, returning to room temperature, the pH was adjusted again to 8 by triethylamine, and the solution was stirred for 1 hour. The reaction solution was concentrated in vac~o, and ~ 300 ml of ethyl acetate wa~ added to ~he residue, and the mixture wa~ washed sequentially with lN hydrochloric acld (100 ml x 2 times), aqueous solution of ~aturated ~odium hydrogencarbonate (100 ml x 2 tlme~), and saturated brine (100 ml), and driad over magnesium sulfate anhydride, and e~aporated in vacuum. The olly residue was purified by column 1~ chromatography (slllca gel 200 g, eluted in 33~ ethyl acetate/hexane ), ~nd the obtained oily matter was dried in vacuum, and crystalllz~d, and the captioned c~mpound was obtain~d. Yield: 14.38 g.
2~ NMR (2 7 OMHz. CDC 13 ) ~ p pm: 8. 2 O (1 H, b r s) ~ 7 . 1 8--7. 2 6 (2H. m) ~ 7. O 2 (1 H, d t. J= 1. 7Hz) ~ 6 . 8 O (1 H. d, J=8Hz) ~ 5. 6 2 (1 H, b r s) ~ 4. 3 6 (1 H
, d t. J=l 5, 6Hz) ~ 3. 4 9 tl H, d d, J=l 5, 6Hz) ~ 2 . 8 5 (lH. t. J=l 5Hz) ~ 1. 5 3 (9H, s) W094~16~ PCT/~4/G~434 ~ 1 3 t~ 1 0 8 ~-Reference Example 17 ¦ Preparation of 3S-benzyloxycarbonylamino-3,4-dihy~rocarbostyril 10 g of 3S-amino 3,4-dihydrocarbostyril was suspended in 100 ml of N,N-dimethylformamide, and 1706 ml of benzyl-oxycarbonyl chloride was dripped while stirring in ice, and the pH was adjusted to 8 by triethylamine. After stirrin~ for 1 hour ~t OC, returning to room temperature, the pH was ad~usted again to 8 by triethylam~ne, and the solutiorl was stirred for 1 hour. The reaction solution was concentrated in vacuo, and 300 ml of ethyl acetate was added to the residue, and the insoluble matter was filtered off, and the filtrate was sequentially washed wlth lN hydrochloric acid (100 ml x 2 times), a~ueous solution of saturated sodium hydrogencarbonate (100 ml x 2 times), and saturated brine (100 ml), and dried over magnesium sulfate anhydride. The organic layer was evaporat2d in vacuum, and 5 ml of ~thyl acetate was added to ths obtained oily resldue, and further 50 ml of hexane was added, and the preclpltatlng crystal w~re filtered, and the ~0 captioned compound was o~tained r Yield: 7.2 g.
N M R (2 7 O M H z. C D C 13 ) ~ P P m : 8. 1 6 tl H. b r s) ~ 7 , 3 O - 7. 4 O (S H. m) ~ 7. 1 8 - 7. 2 4 (2 H. m) ~ 7. O 3 ( 1 H. d t, J = 1, 7 H z) ~ 6. 8 O (1 H. d d. J ~ 1, 8 K z) ~ 5 . 8 8 (1 H. b r s) ~ ~. 1 6 (2 H. s) ~ 4. 4 2 (1 H, d t, J =
wo 94nl6l2 ~ 1 3 G ¦ 0 8 PCT/~4/00434 ' -75-!
1 5, 6 H z) ~ 3. 5 2 (1 H, d d, J = 1 5, 6 H z) ~ 2. 8 7 tl H
, t, J = 1 5 H z) Reference Example 18 Prepara~on of 3S-t-butoxycarbonylamino-7-chloro-3,4-¦ dihydrocarboætyril Using a corresponding starting material, the captionedcompound was obtained in the same manner as in ~eference ¦ Example 16.
¦~ N M R (2 7 0 ~ H z. C D C 13 ) ~ ~ P m : 8. 0 4 (1 H. b s) ~ 7.
1 3 (1 H. d. J = 8 H z~ ~ 7. 0 0 tl ~, d d~ Jl - 2 H Z~ J2 =
, d. J = 5 H z) ~ 7. 2 4 - 7. 1 9 (2 H. m) ~ 7. 0 2 (1 H. t, ~:; J = 7 H z) ~ 6. 8 9 (l H. d. J = 8 H z) ~ 4. 6 6 - 4. 5 8 tl H
, m) ~ 4. 1 9 (l H. d d. Jl = 9 H Z~ J2 = 1 4 H z) ~ 3. 8 0 ( 1 H. d d. J1 = 5 H Z~ J2 = 1 4 H z) ~ 3. 6 3 (1 H. d d. J1 =
~ 6 H Z~ J2 = l 5 H z) ~ 3. 5 0 - 3. 4 7 (l H, m) ~ 2. 9 8 - 2.
-~ 8 0 (2 H. m) ~ 1. 7 3 - l. 5 8 (3 H. m) ~ 0. 9 2 (6 H. d d, Jl 7 ~ Z~ J2 = 1 4 H z) :20 Reference Example lO
Preparation o 3,4-methylenedioxybenzylidenesuccinic ac~d Dissolving l9.14 g of metal sodium in 400 ml of W094nl6l2 ~13 61 Q 8 PCT/~W4/0~4 ~
~ -68- 1 ~.
ethanol, 110.8 ml of diethyl succinate and lO0 g of piperonal were added, and the solution was heated and refluxed for 3 hours. The reaction solution was concentrated in vacuo, and the residue was dissolved in 700 ml of water, and washed with 300 ml of diethyl ether. The water layer was stirred in ice, adjusted to pH 1 by concentrated hydrochloric acid, and extracted with 300 ml of diethyl ether. The diethyl ether layer was washed once with saturated brine, and dried over magneslum sulfate anhydride, and concentrated in vacuo. The obta~ned o~ly residue was dissolved by 181.4 g in 350 ml of ethanol, a~d 400 ml of 5N sodium hydroxide was added to stir overnight at room temperature. The reaction solution was concentrated in vacuo, and th~ residue was washed with 200 ml of diethyl ether. The water layer was stirred in ice, ad~usted to pH 1 by concentrated hydrochloric acid, and extracted with 400 ml of ethyl acetate. The ethyl acetate ~ layer was washed with saturated br ne, dried over magnesium : sulfate anhydride, and concentrated in vacuo. To the obtained residue, 300 ml of diethyl ether was addad to solidify, and the captionsd compound was obtained. Yield: 67.34 g.
, ,,, . i ,: ' :. Reference Example ll .:~ .
Preparation of 4-ethoxy-2-(3,4-methylene-dioxybenzylidene)succinlc acid : 25 To 23.5 g of 3,4-methylenedioxybenzylidenesuccinic W094/21612 ~ PCT/J~4/00434 ~J 1361 (18 acid, 200 ml of acetic anhydride was added, and heated in reflux for 2 hours- The reaction solution was concentrated in vacuo, and 200 ml of ethanol was added to the residue, and the mixture was heated in reflux overnight. The reaction solution was concentrated in vacuo, and the residue was extracted with 300 ml of ethyl acetate. The ethyl acetate layer was was~ed ~wice with saturated brine, and dried over magnesium sulfate anhydride, and concentrated in vacuo. To the obtained crystalline residue, diethyl ether was added to wash, and the captioned compound was obtained. Yleld: 17.76 g.
Raference Example 12 Preparat~on of 4-ethoxy-2-pip~ronylsuccinic acid I5 To a lO0 ml solutl4n of ethanol of 9.70 g of 4-ethoxy-2-(3,4-methylenedioxybenzylldene) uccinic acid, 970 mg of 10%
palladium-carbon wa~ added, and catalytic hydrogenation was carrled out overnight at room temperature. The catalyst was filtered off from the reactlon solution by using celite, and the flltrate was conce~trated ln vacuo. The obtained oily residue was dried, and the captioned compound was o~tained.
Yield:~10.36 g.
.
Reference Example 13 Preparation of 3-(4-ethoxy-2-piperonylsuccinyl)-amlno-3,4-dihydrocarbostyril ' WO94~1612 PCT/~4100434 ~13610~
. .
To a 3 ml solution of dimethyl formamide of 260 mg of 3-amino-3,4-dihydrocarbostyril, a 5 ml solution of dichloromethane of 500 mg of 4-ethoxy-piperonylsuccinic acid and 240 mg of l-hydroxybenzotriazole were added, and while stirrlng in ice, 360 mg Q~ N~Nl-diryclohexylcarbodiimide was added, and the mixture was stirred for 2 hours in ice and for , 3 days at room temperature. Insoluble matter was filtered off ¦ from the reactlon solution, and the flltrate was concentrated ln vacuo. To the obtained filtrate, 30 ml of chloroform was '' added to extract, and the chloroform layer was washed :;~ sequentially wlth saturated aqueous solution of sodium hydrogencarbonate, lN hydrochloric acld, and saturated brine, ~-~ and dried over magnesium sulfate anhydride and concentrated in --- vacuo. The obtalned resldue was purifled ~y sllica gel column ''~ 1~
chromatography, and eluted in ethyl acetate/hexane (l:l), and ~- the captio~ed compound was obtained. Yield: lO0 mg.
R~ference Example 14 - Preparat$on of 4-t-butoxy-3-methylene-2R-isobutyl-succinate j '- To a 200iml solutlon of isopropanol of 40.0 g of l,2-dlbenzyl-l-t-butyl-4-methyl-l,l,2~R)-pentane-tricarboxylate, ~: 3.50 g of 10% palladium-carbon was added, and hydrogen gas was -.
lntroduced in vacuo to stir overnight at room temperature.
The catalyst was filtered off from the reaction solution by -, , W094~16~ ~13 ~10 8 PCT/~4/00434 ~
using celite. To the obtained filtrate, 23.72 ml of piperidine and 108.2 ml of 37% aqueous solution of formaldehyde were added, and the mixture was stirred for 2 days at room temperature. The reaction solution was concentrated in vacuo, and the obtained residue was dissolved in 3SO ml of ethyl acetate and extracted. The ethyl acetate layer was washed sequentially with lN hydrochloric acid (300 ml x 1 time and 200 ml x 1 time) and twice wlth saturated ~brine, and dried over sodlum sulfate anhydride, and concentrate~ ~n vacuo. The obtained oily residue was purified by silica gel column chromatography (eluted in 2%
methanol/chloroform), and the captioned compound was obtained in an oily ~orm. Yield: 13.81 g.
N M R (2 7 O M H z; C D C 13 ) ~ ~ P m : 1 1. 0 0 (l H, b s) ~ 6 . 2 9 (l H. s) ~ 5. 6 7 (1 H, s) ~ 3. 5 5 (l H, t, J ~ 8 H z ~;
) ~ 1. 7 6 (l H. d d. Jl = 6 H Z~ ~2 = l 4 H z) ~ 1. 6 3 - l.
4 9 (2H. m) ~ 1. 4 9 (9H. s) ~ O. 9 2 (6 H. d d. Jl = 6 H
Z~ J2 =9Hz) 2~ ;
Re4erence Example 15 Preparation of 4-t-butoxy-2R-isobutyl-3S-methyl- 3 succlnate To a 100 ml solution of ethyl acetate of 13.81 g of WO94/21612 ~ 13 61 ~ 8 PCT/~4/00434 4-t-butoxy-3-methylene-2R-isobutylsuccinate, g70 mg of lQ%
palladium-carbon was added, and hydrogen gas was introduced in vacuo to stir overnight at room temperature. The catalyst was filtered off from th~ ~eaction solution by using celite, and 11.35 ml of dicyclohexylamine was added while stirring in ice.
Immediately~ a white sediment was formed, and was filtered, and washed with a 5mall amount of diethyl ether. The obtained white sediment wa~ recrystallized from 150 ml of ethyl acetate, and 13.50 g of white solid matter was obtained.
The obtained compound (8.20 g) was suspended iIl 2qo ml of ethyl acetate, and the ethyl acetate layer was washed ,~ sequentially with 0.5M sulfuric acid (100 ml x 2 times ~ and ¦ saturated brine (lO0 ml x 3 times ), and dried over magnesium sulf ate anhydride, and concentrated in vacuo . The obtained 15 residue was dried, and the captioned compound was obtained in an oily form. Y~ eld: 4. 60 g.
~MR (2 7 0MH z , C DC 1 3 ) ~ P P m : 1 0. O O ( 1 H, b s ) ~ 2 7 3--2. 6 8 ( 1 H, m) ~ 2. 6 1--2 . 5 5 ~1 H, m) ~ 1. 7 2--1. 6 3 (2H. m) ~ 1. 4 5 (9H, s) ~ 1. 2 9-1. 1 9 (1 H. m ) ~ 1 . 1 7 ~3 H, d. J= 7 H z) ~ 0. 9 1 (6 H, d d. Jl = Z H z ~ J2 = 7 H z) i Referance Example 16 Preparation of 3S-t-butoxycarbonylamino-3,4-~ W094~16~ PCT/~4/00434 =~
" ' ' 1~6l~8 dihydrocarbos~yril 10 g of 3S-amino-3,4-dihydrocarbostyril was dissolved in 100 ml of N,N-dimethylformamide, and, after ice-cooling, 14.8 g of t-butoxycarboxylic anhydride was added, and the pH
was adjusted to 8 by triethylamine. After stirring for 1 hour at OC, returning to room temperature, the pH was adjusted again to 8 by triethylamine, and the solution was stirred for 1 hour. The reaction solution was concentrated in vac~o, and ~ 300 ml of ethyl acetate wa~ added to ~he residue, and the mixture wa~ washed sequentially with lN hydrochloric acld (100 ml x 2 times), aqueous solution of ~aturated ~odium hydrogencarbonate (100 ml x 2 tlme~), and saturated brine (100 ml), and driad over magnesium sulfate anhydride, and e~aporated in vacuum. The olly residue was purified by column 1~ chromatography (slllca gel 200 g, eluted in 33~ ethyl acetate/hexane ), ~nd the obtained oily matter was dried in vacuum, and crystalllz~d, and the captioned c~mpound was obtain~d. Yield: 14.38 g.
2~ NMR (2 7 OMHz. CDC 13 ) ~ p pm: 8. 2 O (1 H, b r s) ~ 7 . 1 8--7. 2 6 (2H. m) ~ 7. O 2 (1 H, d t. J= 1. 7Hz) ~ 6 . 8 O (1 H. d, J=8Hz) ~ 5. 6 2 (1 H, b r s) ~ 4. 3 6 (1 H
, d t. J=l 5, 6Hz) ~ 3. 4 9 tl H, d d, J=l 5, 6Hz) ~ 2 . 8 5 (lH. t. J=l 5Hz) ~ 1. 5 3 (9H, s) W094~16~ PCT/~4/G~434 ~ 1 3 t~ 1 0 8 ~-Reference Example 17 ¦ Preparation of 3S-benzyloxycarbonylamino-3,4-dihy~rocarbostyril 10 g of 3S-amino 3,4-dihydrocarbostyril was suspended in 100 ml of N,N-dimethylformamide, and 1706 ml of benzyl-oxycarbonyl chloride was dripped while stirring in ice, and the pH was adjusted to 8 by triethylamine. After stirrin~ for 1 hour ~t OC, returning to room temperature, the pH was ad~usted again to 8 by triethylam~ne, and the solutiorl was stirred for 1 hour. The reaction solution was concentrated in vacuo, and 300 ml of ethyl acetate was added to the residue, and the insoluble matter was filtered off, and the filtrate was sequentially washed wlth lN hydrochloric acid (100 ml x 2 times), a~ueous solution of saturated sodium hydrogencarbonate (100 ml x 2 times), and saturated brine (100 ml), and dried over magnesium sulfate anhydride. The organic layer was evaporat2d in vacuum, and 5 ml of ~thyl acetate was added to ths obtained oily resldue, and further 50 ml of hexane was added, and the preclpltatlng crystal w~re filtered, and the ~0 captioned compound was o~tained r Yield: 7.2 g.
N M R (2 7 O M H z. C D C 13 ) ~ P P m : 8. 1 6 tl H. b r s) ~ 7 , 3 O - 7. 4 O (S H. m) ~ 7. 1 8 - 7. 2 4 (2 H. m) ~ 7. O 3 ( 1 H. d t, J = 1, 7 H z) ~ 6. 8 O (1 H. d d. J ~ 1, 8 K z) ~ 5 . 8 8 (1 H. b r s) ~ ~. 1 6 (2 H. s) ~ 4. 4 2 (1 H, d t, J =
wo 94nl6l2 ~ 1 3 G ¦ 0 8 PCT/~4/00434 ' -75-!
1 5, 6 H z) ~ 3. 5 2 (1 H, d d, J = 1 5, 6 H z) ~ 2. 8 7 tl H
, t, J = 1 5 H z) Reference Example 18 Prepara~on of 3S-t-butoxycarbonylamino-7-chloro-3,4-¦ dihydrocarboætyril Using a corresponding starting material, the captionedcompound was obtained in the same manner as in ~eference ¦ Example 16.
¦~ N M R (2 7 0 ~ H z. C D C 13 ) ~ ~ P m : 8. 0 4 (1 H. b s) ~ 7.
1 3 (1 H. d. J = 8 H z~ ~ 7. 0 0 tl ~, d d~ Jl - 2 H Z~ J2 =
8 H z) ~ 6. 8 1 (1 H. d. J = 2 H z) ~ 5. 5 6 (1 ~, b s) ~ 4.
3 8 - 4. 2 9 (l H. m) ~ 3. 4 8 ~l H. d d. Jl = 6 H z~ J~ = 1 ; 15 5 H z) ~ 2. 8 0 (1 H. t, J = 1 5 H z) ~ 1~ 4 8 (9 H. s) ~,.. .
~:~ '' :
`,'~" ~
~ Reference Example 19 ¦ 20 P~eparation of 3S-t-butoxycarbonylamlno-7-chloro-1-. hydroxy~3,4-dlhydrocarbostyrll ¦ To a 30 ml solutlon of dlmethyl formamide of 4.00 g of ~S-amino-7-chloro-1-hydroxy-3,4-dihydrocarbostyril .
, hydrochloride, while stirring in ice, 1.64 ml of N-methyl-morpholine was added, and a 10 ml solution of dimethyl , WOg4~l612 PCT/JP94/OM34 213l~L08 formamide of 3.90 g of di-t-butyldicarbonate was added and :~ stirred for 2 hours at room temperature. The reaction solution was concentrated in vacuo, and 50 ml of water was ~, added to the residue to solidify and filter. The crude product was washed with diethyl ether, and the captioned co~pound was obta~ ned. Yield: 1.84 g.
N M R ( 2 7 O M H z . D M S O--d 3 ) 3 p p m: 1 O . 6 3 ( 1 H ~ s ) 7 . 2 7 ~ l H. d, J = 8 H z ) ~ 7 . 2 5 ( 1 H. d . J = 9 H z ) ~ 7 .
1 6 ( 1 H , d .- J = 2 H z ) ~ 7 . O 6 ( 1 H , d d ~ J 1 = 2 H Z ~ J 2 8Hz) ~ 4. 28--4. 24 (lH. m) ~ 3. OO (lH. s~ ~ 20 9 7 ( l H. d . J--4 H z ) ~ 1 . 4 1 t 9 H . s ) Reference Example 20 Preparation of 3S-t-butoxycarbonylamlno~l-hydroxy-3,4-dihydrocarbo~ty~il Uslng a corresponding star~ing material, the captioned compound was obtained in the same manner as in Reference Exam~le 19.
M R (2 7 O M H z. C D C 13 ) ~ p p m : 8. 8 5 (1 H. b s) ~ 7.
2 0 (2 H. t. J = 8 H z) ~ 7. 0 1 (1 H, d t. Jl = 1 H Z~ J2 -8 H z) ~ 6. 8 5 tl H. d. J = 8 H z) ~ 5. 6 6 (1 H. d. J = 5 H
z) ~ 4. 3 9 - 4. 3 1 (l H. m) ~ 3. 4 8 (l H. d d. Jl = 6 H z J2 = 1 5 H z) ~ 2. 8 5 (l H, t, J = 1 5 H z) ~ 1. 4 9 (9 H, s) J
WO94t216~ ~13 ~ L Q ~ PCT/J~4/00434 ~, Reference Example 21 ~ Preparation of 3S-t-butoxycaronylamino-l-hexyloxy-3,4-I dihydrocar~ostyril To a 5 ml solution of dimethyl formamide of 700 mg of ~, 3S-t-butoxycarbonylamino-l-hydroxy-3,4~dihydrocarbostyril, 110 ~ ~g of sodium hydr~de (60% content) was addad while stirring in ! ice-cooling, and 15 mlnutes later, 641 mg of iodo hexane was ¦ ~ added, and the solution was stirred for 2 hours at room temperature. The raaction solutlon was concentrated in ~acuo, and the obtained residue was extracted with 30 ml of ethyl acetate. The ethyl acetate layer was washed sequentially twice with lN hydrochlor~c acid and twice with saturated brlne, and dried with magnesium sulfate anhydride, and concentrated in vacuo. The obtained oily residue was purified by silica gel column chromatography, and eluted in chloroform, and the captioned compou~d was obtained. Yield: 630 mg.
NMR (270h~Hz. CDC13 ) ~m: 7. 30 (lH, t, J=8H
z) ~ 7. 2 1 (2H. d. J = 9 H z~ ~ 7. 0 7 (1 H. t d. Jl = 1 H
, . Z~ J2 =7Hz) ~ 5. 6 0 (1 H, b s) ~ 4. 3 7--4. 3 2 (1H, m 4. 1 2 (1 H, q, J--7H z) ~ 4. 0 2 (1 H. q, J=7 H z) ~
3. 4 3 (lH. d d. Jl =SHz, J2 =1 SHz) ~ 2,. 8 0 (1 H. t , J--1 5Hz) ~ 1. 82--1. 7 0 (2H, m) ~ 1. 4 8 (9H. s) 1, 5 4--1. 3 0 (6H. m) ~ 0. 9 0 (3H. t, J=7 Hz) 1~ .
~:
wog4nl612 PCT/n~4/00434 ' ~`f~ 78-~~ , e ~ Reference Example 22 ¦ 5 Preparation of 3S-(4-t-butoxy-2R-i ob~tyl-3S-me~hyl-succinyl) amino-l-hexyloxy-3,4-dihydrocarbostysil To 630 mg of 3S-t-butoxycarbonylamino-l-hexyloxy-3~4-dihydrocarbostyril, 5 ml of trifluoroacetic acid was added to dlssolve, and the solution was let stand at room temperature lO for ~O minutes. The reaction solution was concentrated in :`
vacuo, and the obtained residue was dissolved in 10 ml of I tetrahydrofurane. To thi~ solution, wh~le stirrlng in ice-j cooling, triethylamin~ was added to neutralize, and a lO ml solution of tetrahydrsfurane of 247 mg of l-hydroxybenzotriazole and 446 mg of4-t~butoxy-2R-isobutyl-3S-methylsuccinate was added, and 130 ~l of triethylamine and ¦ 377 mg of dicyclohexylcarbodiimide were added, and the mixture ¦ was stirred fos 2 hourR in ice-cooling and overnight at room ! temperature. The form~d ~nsolubla matter was filterated off from the ,reaction solution, and tha filtrate was concentrated in vacuo. The obtained oily resldue was dissolved and extracted with 50 ml o~ ethyl acetate. The ethyl acetate layer was washed sequentially twice with saturated aqueous solution of sodium hydrogencarbonate, twice with lN
hydrochloric acid, and twica with sa~urated brine, and dried WOg4n1612 ~13 ~1~ 8 PCT1~4/QO~4 over magnesium sulfate anhydride, and concentrated in ~acuo.
The obtained oily residue was purified by the silica gel column chromatography, and eluted in chloroform, and the captioned compound was obtained. Yield: 740 mg.
M R (2 7 O M ~ z. C D C 13 ) ~ P P m : 7. 3 O ~1 H, t, J = 8 H
z) ~ 7. 2 1 (2 H. d. 3 = 9 H z) ~ 7. O 7 (l H. d t. Jl = l H
Z' J2 = 8 H z) ~ 6. 7 O (l H. d. J = ~ H z) ~ 4. 6 3 - 4. 5 O
(lI~. m) ~ 4. l 3 tl H, ~, J = 8 H z) ~ 4. O 2 (l H, q. J =
8 H z) ~ 3. 5 l (l H. d d. Jl = 6 H Z~ J2 = l 5 H z) ~ 2- 7 3 (l H. t, J = l 5 H z) ~ 2. 5 6 - 2. 5 3 (2 H, m) ~ l. 8 l - l . 6 9 (4 H. m) ~ l. 5 2 - l. 3 O t6 H. m) ~ l. 4 6 (9 H, s) l. l 8 - l. O 9 (4 H, m) ~ O. 9 5 - O. 8 6 (9 H, m) ~: 15 ~ Reference Example 23 : Preparatlon of 3S-(4-benzyloxyam~no-2R-isobutyl-3S-: methylsucclnyl)amlno-l-hexyloxy-3,4-dihydrocarbostyril To 740 mg of 3S-(4-t-butoxy-2R-isobutyl-3S-methyl-~ucc~nyl~amino-l-hexyloxy-3,4-dlhydrocarbostyril, 5 ml of trifluoroacetic acld was added to dissolve, and the solution was let stand at room temperature for 9O minutes. The : reactlon solutlon was concentrated in ~acuo, and the obtained aily resldue was dissolved in 50 ml of ethyl acetate to extract. The ethyl acetate layer was washed three times with hl3fil:08 ~
saturated brine, and dried over magnesium sulfate anhydride, and concentrated in vacuo. The obtained oily residue was dried, and dissolved in lO ml of dimethyl formamide, and while stirring in ice-cooling, a 5 ml dimethyl formamide solution of 306 mg of 1-hydroxybenzotriazole and 362 mg of benzyloxyamine hydrochlo~ide with 231 ~1 of Nmethyl morpholine was added, and further 120 ~1 of N-methyl morpholine and 434 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, and the mixture was stirred for 2 hours in ice-cooling ' 10 and ov~rnight at room temperature. The reaction solution was ¦ concentrated in vacuo, and 50 ml of ethyl acetate was added to ¦ the obtain d oily residue to extract. The e~hyl acetate layer ¦ was washed sequentially twice with saturated aqueous solution ¦ of sodium hydrogencarbonate, twice with lN hydrochloric acid, and twice with saturated brlne, and dried over magnesium sulfa~e anhydride, and concentrated in vacuo. Adding dlethyl ether to the obtalned crystalline residue, it was filtered and dried, and the captioned compound was obtained. Yield: 430 mg.
i. N M ~I(2 7 O M H z. D M S O - t~ Pm: 1 1. 1 O (1 H, s ) ~
8. 5 7 (1 H, d, J = 8 H z) ~ 7. 4 O - 7. 3 5 (6 H, m) ~ 7. 3 ; O (1 H, t, J = 8 H z) ~ 7- 1 4 tl H. d. J ~ 7 H z) ~ 7. O 6 ( 1 H. t, J = 7 H z) ~ 4. 7 9 (2 H. s) ~ 4. 6 3 - 4. 5 4 (1 H, m) ~ 4. O 1 - 3. 9 5 t2 H. m) ~ 3. O 5 (1 H, t, J = 1 3 H z) ~ 2. 9 3 (1 H. d t. Jl = 7 H Z~ J2 = 1 5 H z) ~ 2. 5 2 - 2. 4 WO94/2161~ PCT/J~4/00~34
3 8 - 4. 2 9 (l H. m) ~ 3. 4 8 ~l H. d d. Jl = 6 H z~ J~ = 1 ; 15 5 H z) ~ 2. 8 0 (1 H. t, J = 1 5 H z) ~ 1~ 4 8 (9 H. s) ~,.. .
~:~ '' :
`,'~" ~
~ Reference Example 19 ¦ 20 P~eparation of 3S-t-butoxycarbonylamlno-7-chloro-1-. hydroxy~3,4-dlhydrocarbostyrll ¦ To a 30 ml solutlon of dlmethyl formamide of 4.00 g of ~S-amino-7-chloro-1-hydroxy-3,4-dihydrocarbostyril .
, hydrochloride, while stirring in ice, 1.64 ml of N-methyl-morpholine was added, and a 10 ml solution of dimethyl , WOg4~l612 PCT/JP94/OM34 213l~L08 formamide of 3.90 g of di-t-butyldicarbonate was added and :~ stirred for 2 hours at room temperature. The reaction solution was concentrated in vacuo, and 50 ml of water was ~, added to the residue to solidify and filter. The crude product was washed with diethyl ether, and the captioned co~pound was obta~ ned. Yield: 1.84 g.
N M R ( 2 7 O M H z . D M S O--d 3 ) 3 p p m: 1 O . 6 3 ( 1 H ~ s ) 7 . 2 7 ~ l H. d, J = 8 H z ) ~ 7 . 2 5 ( 1 H. d . J = 9 H z ) ~ 7 .
1 6 ( 1 H , d .- J = 2 H z ) ~ 7 . O 6 ( 1 H , d d ~ J 1 = 2 H Z ~ J 2 8Hz) ~ 4. 28--4. 24 (lH. m) ~ 3. OO (lH. s~ ~ 20 9 7 ( l H. d . J--4 H z ) ~ 1 . 4 1 t 9 H . s ) Reference Example 20 Preparation of 3S-t-butoxycarbonylamlno~l-hydroxy-3,4-dihydrocarbo~ty~il Uslng a corresponding star~ing material, the captioned compound was obtained in the same manner as in Reference Exam~le 19.
M R (2 7 O M H z. C D C 13 ) ~ p p m : 8. 8 5 (1 H. b s) ~ 7.
2 0 (2 H. t. J = 8 H z) ~ 7. 0 1 (1 H, d t. Jl = 1 H Z~ J2 -8 H z) ~ 6. 8 5 tl H. d. J = 8 H z) ~ 5. 6 6 (1 H. d. J = 5 H
z) ~ 4. 3 9 - 4. 3 1 (l H. m) ~ 3. 4 8 (l H. d d. Jl = 6 H z J2 = 1 5 H z) ~ 2. 8 5 (l H, t, J = 1 5 H z) ~ 1. 4 9 (9 H, s) J
WO94t216~ ~13 ~ L Q ~ PCT/J~4/00434 ~, Reference Example 21 ~ Preparation of 3S-t-butoxycaronylamino-l-hexyloxy-3,4-I dihydrocar~ostyril To a 5 ml solution of dimethyl formamide of 700 mg of ~, 3S-t-butoxycarbonylamino-l-hydroxy-3,4~dihydrocarbostyril, 110 ~ ~g of sodium hydr~de (60% content) was addad while stirring in ! ice-cooling, and 15 mlnutes later, 641 mg of iodo hexane was ¦ ~ added, and the solution was stirred for 2 hours at room temperature. The raaction solutlon was concentrated in ~acuo, and the obtained residue was extracted with 30 ml of ethyl acetate. The ethyl acetate layer was washed sequentially twice with lN hydrochlor~c acid and twice with saturated brlne, and dried with magnesium sulfate anhydride, and concentrated in vacuo. The obtained oily residue was purified by silica gel column chromatography, and eluted in chloroform, and the captioned compou~d was obtained. Yield: 630 mg.
NMR (270h~Hz. CDC13 ) ~m: 7. 30 (lH, t, J=8H
z) ~ 7. 2 1 (2H. d. J = 9 H z~ ~ 7. 0 7 (1 H. t d. Jl = 1 H
, . Z~ J2 =7Hz) ~ 5. 6 0 (1 H, b s) ~ 4. 3 7--4. 3 2 (1H, m 4. 1 2 (1 H, q, J--7H z) ~ 4. 0 2 (1 H. q, J=7 H z) ~
3. 4 3 (lH. d d. Jl =SHz, J2 =1 SHz) ~ 2,. 8 0 (1 H. t , J--1 5Hz) ~ 1. 82--1. 7 0 (2H, m) ~ 1. 4 8 (9H. s) 1, 5 4--1. 3 0 (6H. m) ~ 0. 9 0 (3H. t, J=7 Hz) 1~ .
~:
wog4nl612 PCT/n~4/00434 ' ~`f~ 78-~~ , e ~ Reference Example 22 ¦ 5 Preparation of 3S-(4-t-butoxy-2R-i ob~tyl-3S-me~hyl-succinyl) amino-l-hexyloxy-3,4-dihydrocarbostysil To 630 mg of 3S-t-butoxycarbonylamino-l-hexyloxy-3~4-dihydrocarbostyril, 5 ml of trifluoroacetic acid was added to dlssolve, and the solution was let stand at room temperature lO for ~O minutes. The reaction solution was concentrated in :`
vacuo, and the obtained residue was dissolved in 10 ml of I tetrahydrofurane. To thi~ solution, wh~le stirrlng in ice-j cooling, triethylamin~ was added to neutralize, and a lO ml solution of tetrahydrsfurane of 247 mg of l-hydroxybenzotriazole and 446 mg of4-t~butoxy-2R-isobutyl-3S-methylsuccinate was added, and 130 ~l of triethylamine and ¦ 377 mg of dicyclohexylcarbodiimide were added, and the mixture ¦ was stirred fos 2 hourR in ice-cooling and overnight at room ! temperature. The form~d ~nsolubla matter was filterated off from the ,reaction solution, and tha filtrate was concentrated in vacuo. The obtained oily resldue was dissolved and extracted with 50 ml o~ ethyl acetate. The ethyl acetate layer was washed sequentially twice with saturated aqueous solution of sodium hydrogencarbonate, twice with lN
hydrochloric acid, and twica with sa~urated brine, and dried WOg4n1612 ~13 ~1~ 8 PCT1~4/QO~4 over magnesium sulfate anhydride, and concentrated in ~acuo.
The obtained oily residue was purified by the silica gel column chromatography, and eluted in chloroform, and the captioned compound was obtained. Yield: 740 mg.
M R (2 7 O M ~ z. C D C 13 ) ~ P P m : 7. 3 O ~1 H, t, J = 8 H
z) ~ 7. 2 1 (2 H. d. 3 = 9 H z) ~ 7. O 7 (l H. d t. Jl = l H
Z' J2 = 8 H z) ~ 6. 7 O (l H. d. J = ~ H z) ~ 4. 6 3 - 4. 5 O
(lI~. m) ~ 4. l 3 tl H, ~, J = 8 H z) ~ 4. O 2 (l H, q. J =
8 H z) ~ 3. 5 l (l H. d d. Jl = 6 H Z~ J2 = l 5 H z) ~ 2- 7 3 (l H. t, J = l 5 H z) ~ 2. 5 6 - 2. 5 3 (2 H, m) ~ l. 8 l - l . 6 9 (4 H. m) ~ l. 5 2 - l. 3 O t6 H. m) ~ l. 4 6 (9 H, s) l. l 8 - l. O 9 (4 H, m) ~ O. 9 5 - O. 8 6 (9 H, m) ~: 15 ~ Reference Example 23 : Preparatlon of 3S-(4-benzyloxyam~no-2R-isobutyl-3S-: methylsucclnyl)amlno-l-hexyloxy-3,4-dihydrocarbostyril To 740 mg of 3S-(4-t-butoxy-2R-isobutyl-3S-methyl-~ucc~nyl~amino-l-hexyloxy-3,4-dlhydrocarbostyril, 5 ml of trifluoroacetic acld was added to dissolve, and the solution was let stand at room temperature for 9O minutes. The : reactlon solutlon was concentrated in ~acuo, and the obtained aily resldue was dissolved in 50 ml of ethyl acetate to extract. The ethyl acetate layer was washed three times with hl3fil:08 ~
saturated brine, and dried over magnesium sulfate anhydride, and concentrated in vacuo. The obtained oily residue was dried, and dissolved in lO ml of dimethyl formamide, and while stirring in ice-cooling, a 5 ml dimethyl formamide solution of 306 mg of 1-hydroxybenzotriazole and 362 mg of benzyloxyamine hydrochlo~ide with 231 ~1 of Nmethyl morpholine was added, and further 120 ~1 of N-methyl morpholine and 434 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, and the mixture was stirred for 2 hours in ice-cooling ' 10 and ov~rnight at room temperature. The reaction solution was ¦ concentrated in vacuo, and 50 ml of ethyl acetate was added to ¦ the obtain d oily residue to extract. The e~hyl acetate layer ¦ was washed sequentially twice with saturated aqueous solution ¦ of sodium hydrogencarbonate, twice with lN hydrochloric acid, and twice with saturated brlne, and dried over magnesium sulfa~e anhydride, and concentrated in vacuo. Adding dlethyl ether to the obtalned crystalline residue, it was filtered and dried, and the captioned compound was obtained. Yield: 430 mg.
i. N M ~I(2 7 O M H z. D M S O - t~ Pm: 1 1. 1 O (1 H, s ) ~
8. 5 7 (1 H, d, J = 8 H z) ~ 7. 4 O - 7. 3 5 (6 H, m) ~ 7. 3 ; O (1 H, t, J = 8 H z) ~ 7- 1 4 tl H. d. J ~ 7 H z) ~ 7. O 6 ( 1 H. t, J = 7 H z) ~ 4. 7 9 (2 H. s) ~ 4. 6 3 - 4. 5 4 (1 H, m) ~ 4. O 1 - 3. 9 5 t2 H. m) ~ 3. O 5 (1 H, t, J = 1 3 H z) ~ 2. 9 3 (1 H. d t. Jl = 7 H Z~ J2 = 1 5 H z) ~ 2. 5 2 - 2. 4 WO94/2161~ PCT/J~4/00~34
9 (1 H, m) ~ 2. l 7 2. 1 3 (l H. m) ~ l. 7 l-- l. 2 9 (1 0 H, m) ~ O. 9 7 (3 H. d, J = 7 H z) ~ O~ 9 O - O. 7 9 (l O H, m) ~eference Example 24 Preparation of 3S-t-butoxycarbonylamino-1-(4-cyanobenzyl)-3,4-dihydrocarbostyril To a 5 ml solution o~ dime~hyl formamide of 600 mg of 3S-t-butoxycarbonylamino-3,4-dihydrocarbostyril, while st~rrlng in ice-coollng, 96 mg of sodium hydride (60~ contant) wa added, and 150 minutes later, 494 mg of a-bromo-p-tolunitrile was added, and the mixture was stirred for 2 hours at room tem~erature. To the reaction solu~ion, 30 ml of ethyl acetate waQ added to extract. The ethyl acetate layer was washed once with lN hydrochloric acid, and three times with saturated brine, and dried over ma~neqlum sulfate anhydrlde, - and concentrated in vacuo. Th~ obtalned oily res$due was pur~fled by sillca gel column chromatography (eluted ~n chloroform), and the captionad compound was obtained. Yield:
20 760 mg.
! ~: N ~ R (2 7 O M H z. C D C 13 ) ~ p p m : 7. 6 2 (2 H. d. J =`8 H
z) ~ 7. 3 2 (2 H. d, J = 9 H z) ~ 7. 2 5 (1 H. d. J - 8 H z) 7. l 7 tl H. t, J = 8 H z) ~ 7. 0 5 (l H, ~ d. Jl = l H z, 25 J2 = 7 H z) ~ 6. 7 7 tl H. d d. Jl = 1 H Z~ J2 = 8 H z) ~ 5-7 1 tl H. b s) ~ 5. 4 6 tl H, d. J - l 7 H z) ~ 4. 9 7 (l H.
WO94/21612 PCT/JW4/00434 ', d. J = 1 6 H z) ~ 4. 5 O - 4. 4 O (l H, m) ~ 3. 4 8 (l H, d d Jl = 6 H Z~ J2 = l 5 H z) ~ 2. 8 8 (l H. t, J = 1 5 H z) ~ 1 , 4 8 (9 H. s) s Reference Example 25 Preparation of 3S~t-butoxycarbonylamino-1-(5-chloro-2-thienylmethyl~-3,4-dihydrocarbostyril Using 5-chloro-2-chloromethylthiophene and a correspondlng starting material, the captioned compound was obt~ined in the same manner as in Reference ~xample 24.
N M R (2 7 O M H z, C D C 13 ) ~ P ~ m : 7. 2 8 - 7. 2 O (2 H. m ) ~ 7. l 1 - 7. 0 2 (2 H, m) ~ 6. 7 9 (l H. d, J = 4 H z) ~ 6 : . 7 2 (1 H. d. J = 4 H z) ~ 5. 7 5 tl H, b s) ~ 5. 3 2 (1 H.
d, J - 1 6 H z) ~ 5. O 3 tl H, d, J ~ 1 6 H z) ~ 4. 3 4 - 4. 2 9 tl H ~) ~ 3. ~ 3 (l H. t d. Jl = S H Z~ J2 l 5 . 8 O (1 H. t, J = 1 5 H z) ~ 1. 4 8 (g H. s) ~eference ~xampl~ 26 P.reparaff on o l-benzyloxy-3S~t-butoxycarbonylamino-3,4-dihydrocarbostyril Using benzyl bromlde and a co~responding starting materlal, the captloned compound was obta~ned in the same manner as in Reference Example 24.
.
W094~1612 PCTIJ~4100434 ~:L3611)8 -~3-M R (2 7 O M H z. C D C 13 ) ~ p p m : 7. 5 2 - 7. 4 7 (2 H, m ) ~ 7. 4 0 - 7. 3 5 (3 H. m) ~ 7. 3 1- 7. l 8 (3 H. m) ~ 7.
0 6 (l H, t d. J1 = Z H Z~ J2 = 7 H z) ~ 5. 5 9 (l H. b s) ~
5. l 3 (l H. d, J = l O H z) ~ 5. 0 3 (1 H, d. J - 9 H z) ~ 4 . 4 0 - 4. 3 5 (l H. m) ~ 3. 4 2 (l H. d d. Jl = 6 H Z~ J2 =
l 5 H z~ ~ 2. 7 8 (l H~ t, J = l 5 H z) ~ l. 4 8 (9 H, s) Reference Example 27 Preparation of 3S-t-butoxycarbonylamino-7-chloro-l-ethoxy-3,4-dihydrocarbostyril Using iodoethane and a corresponding star~ing material, the captloned compound was ob~ained in the same manner as in Reference Example 21.
¦ N M R t2 7 0 M H z. C D C 13 ~ ~ p ~ m : 7. 2 l (l H, d. J = 2H
z~ ~ 7. l 3 (l H. d. J = 8 H z) ~ 7. 0 4 (l H. d d. Jl = 2 H
Z' J2 = 8 H z~ ~ 5. 5 6 (l H, b s) ~ 4. 3 5 4. 2 9 tl H. m 4. l 8 (2 H. q d, Jl = 7 H Z~ J2 = l 6 H z) ~ 3. 4 2 (l H
, d d. ~1 ~ 5 H Z~ J2 = l ~ H z) ~ 2. 7 6 (l H. t. J = l 5 H z ) ~ l. 4 7 (9 X. ~) ~ l. 4 0 (3 H. t, J = 7 H z) Reference Example 28 Preparation of 3S-amino-l-isobutoxy-3,4-dihydrocarbostyril Using ~sobutoxy amine, the captioned compound was obtained according to the method described in J. Org. Chem.
19~9, 54, 3394.
WO94121612 PCTIJ~4/00434 i~l36108 !~.
-8~-N M R t2 7 O M H z. C D C 13 ) ~ p p m : 7. l 5 - 7. 3 5 (3 H, m ) ~ 7. 0 5 (l H. t, J ~ 7 H z) ~ 3. 9 3 (l H. t. J = 7 H zj ~
3. 7 8 (l H, t, J - 7 H z) ~ 3. 6 2 (l H, d d. J = 1 3. 6 H z ) ~ 3. 1 0 (1 H. d d, J = 1 5. 6 H z) ~ 2. 8 3 (1 H. t. J - 1 5 H z) ~ 2. 0 5 - 2. 2 5 (l H r m) ~ 1. 0 8 (3 H. d. J = 5 H z ) ~ 1. 0 5 (~ H. d. J = 5 H z) Reference Example 29 Preparation of 3S-t-butoxycarbonylamino-l-ethoxy-3,4-dihydrocarbos~yrll Using iodoe~hane and a corresponding starting materlal, the captioned compound was obtained in the same ~ mannQr as $n Reference Exampl~ 21.
j N M R ~2 7 O M H z. C D C 13 ) ~ ~ p m : 7. 2 0 - 7. 2 3 (3 H.. m i ) ~ 7. 0 7 (l H. d t, J = 1, 7 H z) ~ 5. 5 9 (1 H. b r s) ~ 4 ,~ . 3 4 (1 H. t t, J = l 4. 6 H z) ~ 4. l 6 (1 H. q, J = 7 H z) ¦ ~ 4. l 3 tl ~, q. J = 7 H z) ~ ~. 4 2 (l H, d d, J = 6, 1 4 H
¦ z) ~ 2. 8 l (1 H. t, J = 1 4 H z) ~ 1. 4 8 (9 H. s) ~ l. 3 9 ¦ (3 H. t, J = 7 H z) Refsr~nce Example 30 P~eparation of 3S-benzyloxycar~onylamino-l-ethoxy-methyl-3,4-dihydrocarbos~yr~l Uslng ethoxymethyl chloride and a corresponding starting material, the captioned compound was ob~ained in the same manner as in Refer~nce Ex mple 24.
N M R (2 7 0 M H z, C D C 13 ) ~ ~ p m : 7. 3 9 - 7. 2 8 (7 H, m ) ~ 7~ 2 1 (l H. d. J = 7 H z) ~ 7. 0 9 (1 H. t d. Jl = l H z wo 94el612 .', ~ 3 6 1 0 8 PCTIJP94/004~4 . J2 = 7 H z) ~ 5. 9 5 ~1 H, ~ s) ~ 5. 7 8 (1 H. d, J = 1 1 H
z) ~ 5. 1 5 (2 H, s) ~ 4. 9 5 (1 H. d, J = I 1 H z) ~ 4. 4 2 _ 4. 3 7 (1 H. m) ~ 3. 6 1 ~2 H. ~ d. J1 = 7 H Z J2 = 3 H z ) ~ 3. 4 6 (1 H, d d. Jl = 5 H ~ J2 = 1 4 H z) ~ 2. 8 2 (l H
, t, J = 1 5 H z) ~ 1. 2 1 (3 H, t, J = 7 H z) Reference Example 31 Preparation of 3S-benzyloxycarbonylamino-l-hexyloxy-methyl-3,4-dihydrocarbostyril Using a starting material corresponding to hexyloxy-methyl chloride, the captioned ~o~pound was obtained in the same manner as ~n Reference Example 24.
N M R (2 7 O M H z. C D C 1~ ) ~ P P m : 7. 3 9 - 7. 2 8 (7 H. m ) ~ 7. 2 1 (1 H. d. J = 7 H z) ~ 7. O 9 (1 H. t d. Jl ~ 1 H ~
~ J2 = 7 H z) ~ 5. 9 6 (i H. b s) ~ 5. 7 7 (1 H, d. J = 1 1 H
z) ~ 5. 1 5 (2 H, s) ~ 4. 9 5 ~1 ~, d. J - 1 l H z) ~ 4. 4 2 - 4. 3 7 (1 H. m) ~ 3. 5 7 - ~. 4 2 (3 H. m) ~ 2. 8 2 (1 H, t, J = 1 5 H z~ ~ 1. 5 8 - 1. 5 1 (2 H, ~) ~ 1. 3 3 - 1. 2 1 ( ¦~ 6 H. m) ~ O. 8 5 ~3 H. t, J = 7 H z) ¦ Reference Example 32 ¦ 20 P~eparation of 3S-benzyloxycarbonylamino-l-methoxy-I methyl-3~4~dihydrocarbostyril ¦ Using methoxymethyl chloride and a corresponding starting matert al, the captioned compound was obtained in the ~-same manner as in Reference Example 24.
,~ 25 1 WOg4nl612 213 610 8 PCT/J~4/00434 I
N M R (2 7 O M H z. C D C 13 ) ~ ~ p m : 7. 1 5 - 7. 5 0 (8 H. m 1, ) ~ 7. 0 9 (1 H. t, J ~ 7 H z) ~ 5. 9 5 (I H. b r s) ~ 5. 7 0 (1 H, d. J = 1 0 H z) ~ 5. 1 5 (2 H. s) ~ 4. 9 5 ~I H. d. J
= 1 O H z) ~ 4. 4 1 tl H. d t, J = 1 4, 5 H z) ~ 3. 4 6 (1 H, t d d. J = 1 4, 5 H z~ ~ 3. 3 9 (3 H. s) ~ 2. 8 3 (1 H. t. J =
1 4 H z) Reference Example 33 Prepara~ion of l-benzyl-3S-t-butoxycarbonylami.no-3,4-dlhydrocarbostyril - Using benzyl bromlde and a corresponding starting material, the captionad compound was obtained in the same manner as in Reference Example 24.
N M R (2 7 O M H z, C D C 13 ) ~ ~ ~ m : 7~ 3 6 - 7. 1 2 (7 H, m ) ~ 7- 9 1 ~1 H- t d- Jl - 7 ~ Z~ J2 = 1 H z) ~ 6. 9 0 (1 H.
d~ J = 8 H z) ~ 5. 8 1 (l H, b s) ~ 5. 4 4 (l H. d, J = 1 5 H
z) ~ 4. 9 1 (1 H. d. J = 1 6 H æ) ~ 4. 4 4 - 4. 3 9 (1 H. m) ~ 3. 4 8 (1 H. d d. Jl = 6 H Z~ J2 ~ 1 5 H z~ ~ 2. 8 6 (1 H, : t. J = 1 5 H z) ~ lo 4 8 (9 H. s) Reference Example 34 Pæeparation of 3S-t-butoxycarbonylamino-1-(4-met~oxy-carbonylb~nzyl)-3,4-dihydrocarbostyril Us~ng 4-methoxycarbonylbenzyl bromide and a corresponding starting material, the captioned compound was t .
obtained in the Qame manner aq in Reference Example 24.
N M R (2 7 0 ~ H z. C D C 13 ) ~ P P m : 7. 9 9 (2 H, , d. J = 8 H z) ~ 1. 2 7 (2 H, d. J = 7 H z) ~ 7. 2 3 (l H, d, J - 7 H z WO94/21612 ~ ~ 3 610 8 PCT/~4100434 ) ~ 7. 1 4 (1 H. t. J = 7 H z) ~ 7. 0 2 (1 H. t d, Jl = 1 H z ~ J2 - 8 H z~ ~ 6. 8 2 (1 H, d, J = 8 H z) ~ 5. 7 7 (1 H. b s ) ~ 5. 4 8 (1 H, d, J = 1 7 H z) ~ 4. 9 7 (1 H. d, J - 1 7 H z ) ~ 4. 4 8 - 4. 3 9 (1 H. m~ ~ 3. 9 0 (3 H, s) ~ 3. 4 9 (1 H
, d d. il = 5 H Z~ J2 = 1 4 H z) ~ 2. 8 8 (1 H. t, J - I 5 H z ) ~ 1. 4 9 (9 H, s) Reference Example 35 Preparation of 3S-t-butoxycarbonylamino~ -methoxy-benzyl)-3,4-dihydrocarbostyril Using 4-methoxybenzyl chloride and a corresponding startlng materlal, the captioned compound was obtained i~ the same manner as in ~e~erence Example 24.
NMR t270MHz. C:DC13 ) ~PPm: ?. 28--7. 1 3 (4H. m - ) ~ 7. 0 3--6. 9 1 (2H. m) ~ fi. 8 4 t2H, d. J= 9 Hz) ~ 5 . 8 1 (1 H. b s) ~ 5- 3 4 (1 H, d, J= 1 6 H z) ~ 4. 8 8 (1 H
, d. J=l 6Hz) ~ 4. 4 1--4. 3 6 ~1 H. m) ~ 3. 7 7 (3H. s ) ~ 3. 4 6 (1 H. d d. il =7Hz~ J2 = 1 6Hz) ~ 2. 8 4 (1 H
, t, J=1 5Hz) ~ 1. 4 8 (9~, s) Reference~Example 36 Preparat1on of ~S-t-butoxycarbonylamino-l-phthallmido-methyl-3,4-dihydrocarbostyril Using N-bromomethyl phthallmlde and a corresponding starting material, the captioned ~ompound was obtained in the same manner as in Reference Example 24.
wo94nl6l2 ~ 13 6 1 0 8 PCT/~4/00434 -8~- ~
N M R (2 7 O M H z, C D C 13 ) ~ p ~ m : 7. 8 1 (2 H. d d, J = 6 . 3 H z) ~ 7~ 0 1 ~2 H. d d, J = 6. 3 H z) ~ 7. 1 0 - 7. 3 5 ( ! 3 H, m) ~ 7. 0 2 (1 H, t. J - 7 H z) ~ 6. 2 4 (1 H. d, J = l 4 H z) ~ 5. 7 5 5. 9 O (l H. m) ~ 5. 7 4 (1 H. d. J - 1 4 H
z) ~ 4. 3 1 (l H, d t. J = 1 4. 5 H z) ~ 3. 3 7 (l H. d d, J
= l 4. 5 H z) ~ 2- 8 l (l H. t, J = 1 4 H z) ~ 1. 4 7 (9 H. s ) Reference Example 37 Preparation of 3S-t-butoxycarbonylamino-1-ethoxy-carbonylmethyl-3,4-d~hydrocarbostyril - Using ethyl lodoacetate or ethyl bromoacetate and a i lO corresponding starting materlal, the captioned compound was obtained ln the same manner as ~n Reference Example 24.
N M R ( 2 7 O M H z . C D C: 1 3 ) ~ m: 7 . 2 3 ( 2 H . d . J = 8 H
z~ ~ 7. O 6 (1 H. t, J~8 H z) ~ 6. 7 9 (1 H. d. J= 8H z) ~ ~. 6 8 (1 H. b r s) ~ 4. 8 8 (1 H. d, J = 1 7 H z) ~ 4. 4 7 (lH. d. J=l 7Hz) ~ 4. 3 6 (lH. d t, J=l 4, 5Hz) ~ 4 . 2 1 ( 2 H. ~, J = 7 H ~ ) ~ 3 . 4 4 ( l H, d d . J = 1 4, 5 H z ) 2 . 8 1 ( 1 H, t . J = 1 4 H z ) ~ 1 . 4 7 ( 9 H, s ) ~ I . 2 6 ( 3 ~- H , t . J = 7 H z ) 2~ -Reference Example 38 Preparat~on of 3S-t-butoxycarbonylamino-7-chloro-1-ethoxycarbonylmethyl-3,4-dihydrocarbostyril Uslng ethyl bromoacetate and a corresponding starting mater~al, the captioned compound was obtained in the same manner a~ ln ReferenCe Example 24.
WO g4/21612 PCT/JP94/00434 ~ ~ 3 ~ 1 0 ~
N M R t2 7 O M H z, C D C 13 ) ~ p p m : 7. 1 6 (1 H, d. J = ~ H
z) ~ 7. O 4 (1 ~, d d, J - 8, 2 H z) ~ 6. 7 8 (1 H. d, J = 2 H z) ~ 5. 6 4 tl H, b r s) ~ 4. 8 2 (1 H, d. J = 1 8 ~ z) ~ 4 ~-. 4 5 (1 H, d, J = 1 8 H z) ~ 4. 2 5 - 4. 4 5 (1 H, m) ~ 4. 2 4 (2 H. q. J = 7 H z) ~ 3. 4 3 (1 H. d d. J = 1 5, 5 H ~) ~ 2 . 8 2 (1 H. t, J = 1 5 H z) ~ 1. 4 7 (9 H. s) ~ 1. 2 8 (3 H.
t, J = 7 ~ z) Reference Example 39 Preparation of l-benzyloxycarbonylmethyl-3S-t-butoxy-earbonylamino-3,4-dihydrocarbostyril Uslng benzyl bromoacetate and a corresponding starting materlal, the eaptioned compound was obtalned in the same manner ai~ ln Refer~nee Example 24.
N M R ~2 7 O M H z. C D C 13) ~ p p m : 7. 1 O - 7. 4 O t7 H. m 7. O 5 (1 H. t, J = 8 H z) ~ 6. 7 5 tl H, d. J - 8 H z) ~
5. 6 7 (l H. b r s) ~ 5. 1 8 (2 H. s) ~ 4. 9 O tl H. d. J=
1 8 H z) ~ 4. 5 6 (l H. d. J = 1 8 H z) ~ 4. 3 6 (l H. d t, J
= 1 4, 5 H z) ~ 3. 4 2 (1 H. d d. J = 1 4, S H z) ~ 2. 8 3 (1 H. t, J = 1 4 H z) ~ 1. 4 7 (9 H, s) : 20 Reference Example 40 Preparation of 3S-t-butoxyearbonylamino-l-carboxy-methyl-3~ 4-dihy~roearbostyril ~:
2.98 g of 1-benzyloxyearbonylmethyl-3s-t-butoxy-carbonylamino 3,4-dihydroearbostyril obtained in Reference wos4nl6l2 PCT/J~4/00434 ~13~i08 --so Example 39 was dissolved in 10 ml of methanol, and 200 mg of
20 760 mg.
! ~: N ~ R (2 7 O M H z. C D C 13 ) ~ p p m : 7. 6 2 (2 H. d. J =`8 H
z) ~ 7. 3 2 (2 H. d, J = 9 H z) ~ 7. 2 5 (1 H. d. J - 8 H z) 7. l 7 tl H. t, J = 8 H z) ~ 7. 0 5 (l H, ~ d. Jl = l H z, 25 J2 = 7 H z) ~ 6. 7 7 tl H. d d. Jl = 1 H Z~ J2 = 8 H z) ~ 5-7 1 tl H. b s) ~ 5. 4 6 tl H, d. J - l 7 H z) ~ 4. 9 7 (l H.
WO94/21612 PCT/JW4/00434 ', d. J = 1 6 H z) ~ 4. 5 O - 4. 4 O (l H, m) ~ 3. 4 8 (l H, d d Jl = 6 H Z~ J2 = l 5 H z) ~ 2. 8 8 (l H. t, J = 1 5 H z) ~ 1 , 4 8 (9 H. s) s Reference Example 25 Preparation of 3S~t-butoxycarbonylamino-1-(5-chloro-2-thienylmethyl~-3,4-dihydrocarbostyril Using 5-chloro-2-chloromethylthiophene and a correspondlng starting material, the captioned compound was obt~ined in the same manner as in Reference ~xample 24.
N M R (2 7 O M H z, C D C 13 ) ~ P ~ m : 7. 2 8 - 7. 2 O (2 H. m ) ~ 7. l 1 - 7. 0 2 (2 H, m) ~ 6. 7 9 (l H. d, J = 4 H z) ~ 6 : . 7 2 (1 H. d. J = 4 H z) ~ 5. 7 5 tl H, b s) ~ 5. 3 2 (1 H.
d, J - 1 6 H z) ~ 5. O 3 tl H, d, J ~ 1 6 H z) ~ 4. 3 4 - 4. 2 9 tl H ~) ~ 3. ~ 3 (l H. t d. Jl = S H Z~ J2 l 5 . 8 O (1 H. t, J = 1 5 H z) ~ 1. 4 8 (g H. s) ~eference ~xampl~ 26 P.reparaff on o l-benzyloxy-3S~t-butoxycarbonylamino-3,4-dihydrocarbostyril Using benzyl bromlde and a co~responding starting materlal, the captloned compound was obta~ned in the same manner as in Reference Example 24.
.
W094~1612 PCTIJ~4100434 ~:L3611)8 -~3-M R (2 7 O M H z. C D C 13 ) ~ p p m : 7. 5 2 - 7. 4 7 (2 H, m ) ~ 7. 4 0 - 7. 3 5 (3 H. m) ~ 7. 3 1- 7. l 8 (3 H. m) ~ 7.
0 6 (l H, t d. J1 = Z H Z~ J2 = 7 H z) ~ 5. 5 9 (l H. b s) ~
5. l 3 (l H. d, J = l O H z) ~ 5. 0 3 (1 H, d. J - 9 H z) ~ 4 . 4 0 - 4. 3 5 (l H. m) ~ 3. 4 2 (l H. d d. Jl = 6 H Z~ J2 =
l 5 H z~ ~ 2. 7 8 (l H~ t, J = l 5 H z) ~ l. 4 8 (9 H, s) Reference Example 27 Preparation of 3S-t-butoxycarbonylamino-7-chloro-l-ethoxy-3,4-dihydrocarbostyril Using iodoethane and a corresponding star~ing material, the captloned compound was ob~ained in the same manner as in Reference Example 21.
¦ N M R t2 7 0 M H z. C D C 13 ~ ~ p ~ m : 7. 2 l (l H, d. J = 2H
z~ ~ 7. l 3 (l H. d. J = 8 H z) ~ 7. 0 4 (l H. d d. Jl = 2 H
Z' J2 = 8 H z~ ~ 5. 5 6 (l H, b s) ~ 4. 3 5 4. 2 9 tl H. m 4. l 8 (2 H. q d, Jl = 7 H Z~ J2 = l 6 H z) ~ 3. 4 2 (l H
, d d. ~1 ~ 5 H Z~ J2 = l ~ H z) ~ 2. 7 6 (l H. t. J = l 5 H z ) ~ l. 4 7 (9 X. ~) ~ l. 4 0 (3 H. t, J = 7 H z) Reference Example 28 Preparation of 3S-amino-l-isobutoxy-3,4-dihydrocarbostyril Using ~sobutoxy amine, the captioned compound was obtained according to the method described in J. Org. Chem.
19~9, 54, 3394.
WO94121612 PCTIJ~4/00434 i~l36108 !~.
-8~-N M R t2 7 O M H z. C D C 13 ) ~ p p m : 7. l 5 - 7. 3 5 (3 H, m ) ~ 7. 0 5 (l H. t, J ~ 7 H z) ~ 3. 9 3 (l H. t. J = 7 H zj ~
3. 7 8 (l H, t, J - 7 H z) ~ 3. 6 2 (l H, d d. J = 1 3. 6 H z ) ~ 3. 1 0 (1 H. d d, J = 1 5. 6 H z) ~ 2. 8 3 (1 H. t. J - 1 5 H z) ~ 2. 0 5 - 2. 2 5 (l H r m) ~ 1. 0 8 (3 H. d. J = 5 H z ) ~ 1. 0 5 (~ H. d. J = 5 H z) Reference Example 29 Preparation of 3S-t-butoxycarbonylamino-l-ethoxy-3,4-dihydrocarbos~yrll Using iodoe~hane and a corresponding starting materlal, the captioned compound was obtained in the same ~ mannQr as $n Reference Exampl~ 21.
j N M R ~2 7 O M H z. C D C 13 ) ~ ~ p m : 7. 2 0 - 7. 2 3 (3 H.. m i ) ~ 7. 0 7 (l H. d t, J = 1, 7 H z) ~ 5. 5 9 (1 H. b r s) ~ 4 ,~ . 3 4 (1 H. t t, J = l 4. 6 H z) ~ 4. l 6 (1 H. q, J = 7 H z) ¦ ~ 4. l 3 tl ~, q. J = 7 H z) ~ ~. 4 2 (l H, d d, J = 6, 1 4 H
¦ z) ~ 2. 8 l (1 H. t, J = 1 4 H z) ~ 1. 4 8 (9 H. s) ~ l. 3 9 ¦ (3 H. t, J = 7 H z) Refsr~nce Example 30 P~eparation of 3S-benzyloxycar~onylamino-l-ethoxy-methyl-3,4-dihydrocarbos~yr~l Uslng ethoxymethyl chloride and a corresponding starting material, the captioned compound was ob~ained in the same manner as in Refer~nce Ex mple 24.
N M R (2 7 0 M H z, C D C 13 ) ~ ~ p m : 7. 3 9 - 7. 2 8 (7 H, m ) ~ 7~ 2 1 (l H. d. J = 7 H z) ~ 7. 0 9 (1 H. t d. Jl = l H z wo 94el612 .', ~ 3 6 1 0 8 PCTIJP94/004~4 . J2 = 7 H z) ~ 5. 9 5 ~1 H, ~ s) ~ 5. 7 8 (1 H. d, J = 1 1 H
z) ~ 5. 1 5 (2 H, s) ~ 4. 9 5 (1 H. d, J = I 1 H z) ~ 4. 4 2 _ 4. 3 7 (1 H. m) ~ 3. 6 1 ~2 H. ~ d. J1 = 7 H Z J2 = 3 H z ) ~ 3. 4 6 (1 H, d d. Jl = 5 H ~ J2 = 1 4 H z) ~ 2. 8 2 (l H
, t, J = 1 5 H z) ~ 1. 2 1 (3 H, t, J = 7 H z) Reference Example 31 Preparation of 3S-benzyloxycarbonylamino-l-hexyloxy-methyl-3,4-dihydrocarbostyril Using a starting material corresponding to hexyloxy-methyl chloride, the captioned ~o~pound was obtained in the same manner as ~n Reference Example 24.
N M R (2 7 O M H z. C D C 1~ ) ~ P P m : 7. 3 9 - 7. 2 8 (7 H. m ) ~ 7. 2 1 (1 H. d. J = 7 H z) ~ 7. O 9 (1 H. t d. Jl ~ 1 H ~
~ J2 = 7 H z) ~ 5. 9 6 (i H. b s) ~ 5. 7 7 (1 H, d. J = 1 1 H
z) ~ 5. 1 5 (2 H, s) ~ 4. 9 5 ~1 ~, d. J - 1 l H z) ~ 4. 4 2 - 4. 3 7 (1 H. m) ~ 3. 5 7 - ~. 4 2 (3 H. m) ~ 2. 8 2 (1 H, t, J = 1 5 H z~ ~ 1. 5 8 - 1. 5 1 (2 H, ~) ~ 1. 3 3 - 1. 2 1 ( ¦~ 6 H. m) ~ O. 8 5 ~3 H. t, J = 7 H z) ¦ Reference Example 32 ¦ 20 P~eparation of 3S-benzyloxycarbonylamino-l-methoxy-I methyl-3~4~dihydrocarbostyril ¦ Using methoxymethyl chloride and a corresponding starting matert al, the captioned compound was obtained in the ~-same manner as in Reference Example 24.
,~ 25 1 WOg4nl612 213 610 8 PCT/J~4/00434 I
N M R (2 7 O M H z. C D C 13 ) ~ ~ p m : 7. 1 5 - 7. 5 0 (8 H. m 1, ) ~ 7. 0 9 (1 H. t, J ~ 7 H z) ~ 5. 9 5 (I H. b r s) ~ 5. 7 0 (1 H, d. J = 1 0 H z) ~ 5. 1 5 (2 H. s) ~ 4. 9 5 ~I H. d. J
= 1 O H z) ~ 4. 4 1 tl H. d t, J = 1 4, 5 H z) ~ 3. 4 6 (1 H, t d d. J = 1 4, 5 H z~ ~ 3. 3 9 (3 H. s) ~ 2. 8 3 (1 H. t. J =
1 4 H z) Reference Example 33 Prepara~ion of l-benzyl-3S-t-butoxycarbonylami.no-3,4-dlhydrocarbostyril - Using benzyl bromlde and a corresponding starting material, the captionad compound was obtained in the same manner as in Reference Example 24.
N M R (2 7 O M H z, C D C 13 ) ~ ~ ~ m : 7~ 3 6 - 7. 1 2 (7 H, m ) ~ 7- 9 1 ~1 H- t d- Jl - 7 ~ Z~ J2 = 1 H z) ~ 6. 9 0 (1 H.
d~ J = 8 H z) ~ 5. 8 1 (l H, b s) ~ 5. 4 4 (l H. d, J = 1 5 H
z) ~ 4. 9 1 (1 H. d. J = 1 6 H æ) ~ 4. 4 4 - 4. 3 9 (1 H. m) ~ 3. 4 8 (1 H. d d. Jl = 6 H Z~ J2 ~ 1 5 H z~ ~ 2. 8 6 (1 H, : t. J = 1 5 H z) ~ lo 4 8 (9 H. s) Reference Example 34 Pæeparation of 3S-t-butoxycarbonylamino-1-(4-met~oxy-carbonylb~nzyl)-3,4-dihydrocarbostyril Us~ng 4-methoxycarbonylbenzyl bromide and a corresponding starting material, the captioned compound was t .
obtained in the Qame manner aq in Reference Example 24.
N M R (2 7 0 ~ H z. C D C 13 ) ~ P P m : 7. 9 9 (2 H, , d. J = 8 H z) ~ 1. 2 7 (2 H, d. J = 7 H z) ~ 7. 2 3 (l H, d, J - 7 H z WO94/21612 ~ ~ 3 610 8 PCT/~4100434 ) ~ 7. 1 4 (1 H. t. J = 7 H z) ~ 7. 0 2 (1 H. t d, Jl = 1 H z ~ J2 - 8 H z~ ~ 6. 8 2 (1 H, d, J = 8 H z) ~ 5. 7 7 (1 H. b s ) ~ 5. 4 8 (1 H, d, J = 1 7 H z) ~ 4. 9 7 (1 H. d, J - 1 7 H z ) ~ 4. 4 8 - 4. 3 9 (1 H. m~ ~ 3. 9 0 (3 H, s) ~ 3. 4 9 (1 H
, d d. il = 5 H Z~ J2 = 1 4 H z) ~ 2. 8 8 (1 H. t, J - I 5 H z ) ~ 1. 4 9 (9 H, s) Reference Example 35 Preparation of 3S-t-butoxycarbonylamino~ -methoxy-benzyl)-3,4-dihydrocarbostyril Using 4-methoxybenzyl chloride and a corresponding startlng materlal, the captioned compound was obtained i~ the same manner as in ~e~erence Example 24.
NMR t270MHz. C:DC13 ) ~PPm: ?. 28--7. 1 3 (4H. m - ) ~ 7. 0 3--6. 9 1 (2H. m) ~ fi. 8 4 t2H, d. J= 9 Hz) ~ 5 . 8 1 (1 H. b s) ~ 5- 3 4 (1 H, d, J= 1 6 H z) ~ 4. 8 8 (1 H
, d. J=l 6Hz) ~ 4. 4 1--4. 3 6 ~1 H. m) ~ 3. 7 7 (3H. s ) ~ 3. 4 6 (1 H. d d. il =7Hz~ J2 = 1 6Hz) ~ 2. 8 4 (1 H
, t, J=1 5Hz) ~ 1. 4 8 (9~, s) Reference~Example 36 Preparat1on of ~S-t-butoxycarbonylamino-l-phthallmido-methyl-3,4-dihydrocarbostyril Using N-bromomethyl phthallmlde and a corresponding starting material, the captioned ~ompound was obtained in the same manner as in Reference Example 24.
wo94nl6l2 ~ 13 6 1 0 8 PCT/~4/00434 -8~- ~
N M R (2 7 O M H z, C D C 13 ) ~ p ~ m : 7. 8 1 (2 H. d d, J = 6 . 3 H z) ~ 7~ 0 1 ~2 H. d d, J = 6. 3 H z) ~ 7. 1 0 - 7. 3 5 ( ! 3 H, m) ~ 7. 0 2 (1 H, t. J - 7 H z) ~ 6. 2 4 (1 H. d, J = l 4 H z) ~ 5. 7 5 5. 9 O (l H. m) ~ 5. 7 4 (1 H. d. J - 1 4 H
z) ~ 4. 3 1 (l H, d t. J = 1 4. 5 H z) ~ 3. 3 7 (l H. d d, J
= l 4. 5 H z) ~ 2- 8 l (l H. t, J = 1 4 H z) ~ 1. 4 7 (9 H. s ) Reference Example 37 Preparation of 3S-t-butoxycarbonylamino-1-ethoxy-carbonylmethyl-3,4-d~hydrocarbostyril - Using ethyl lodoacetate or ethyl bromoacetate and a i lO corresponding starting materlal, the captioned compound was obtained ln the same manner as ~n Reference Example 24.
N M R ( 2 7 O M H z . C D C: 1 3 ) ~ m: 7 . 2 3 ( 2 H . d . J = 8 H
z~ ~ 7. O 6 (1 H. t, J~8 H z) ~ 6. 7 9 (1 H. d. J= 8H z) ~ ~. 6 8 (1 H. b r s) ~ 4. 8 8 (1 H. d, J = 1 7 H z) ~ 4. 4 7 (lH. d. J=l 7Hz) ~ 4. 3 6 (lH. d t, J=l 4, 5Hz) ~ 4 . 2 1 ( 2 H. ~, J = 7 H ~ ) ~ 3 . 4 4 ( l H, d d . J = 1 4, 5 H z ) 2 . 8 1 ( 1 H, t . J = 1 4 H z ) ~ 1 . 4 7 ( 9 H, s ) ~ I . 2 6 ( 3 ~- H , t . J = 7 H z ) 2~ -Reference Example 38 Preparat~on of 3S-t-butoxycarbonylamino-7-chloro-1-ethoxycarbonylmethyl-3,4-dihydrocarbostyril Uslng ethyl bromoacetate and a corresponding starting mater~al, the captioned compound was obtained in the same manner a~ ln ReferenCe Example 24.
WO g4/21612 PCT/JP94/00434 ~ ~ 3 ~ 1 0 ~
N M R t2 7 O M H z, C D C 13 ) ~ p p m : 7. 1 6 (1 H, d. J = ~ H
z) ~ 7. O 4 (1 ~, d d, J - 8, 2 H z) ~ 6. 7 8 (1 H. d, J = 2 H z) ~ 5. 6 4 tl H, b r s) ~ 4. 8 2 (1 H, d. J = 1 8 ~ z) ~ 4 ~-. 4 5 (1 H, d, J = 1 8 H z) ~ 4. 2 5 - 4. 4 5 (1 H, m) ~ 4. 2 4 (2 H. q. J = 7 H z) ~ 3. 4 3 (1 H. d d. J = 1 5, 5 H ~) ~ 2 . 8 2 (1 H. t, J = 1 5 H z) ~ 1. 4 7 (9 H. s) ~ 1. 2 8 (3 H.
t, J = 7 ~ z) Reference Example 39 Preparation of l-benzyloxycarbonylmethyl-3S-t-butoxy-earbonylamino-3,4-dihydrocarbostyril Uslng benzyl bromoacetate and a corresponding starting materlal, the eaptioned compound was obtalned in the same manner ai~ ln Refer~nee Example 24.
N M R ~2 7 O M H z. C D C 13) ~ p p m : 7. 1 O - 7. 4 O t7 H. m 7. O 5 (1 H. t, J = 8 H z) ~ 6. 7 5 tl H, d. J - 8 H z) ~
5. 6 7 (l H. b r s) ~ 5. 1 8 (2 H. s) ~ 4. 9 O tl H. d. J=
1 8 H z) ~ 4. 5 6 (l H. d. J = 1 8 H z) ~ 4. 3 6 (l H. d t, J
= 1 4, 5 H z) ~ 3. 4 2 (1 H. d d. J = 1 4, S H z) ~ 2. 8 3 (1 H. t, J = 1 4 H z) ~ 1. 4 7 (9 H, s) : 20 Reference Example 40 Preparation of 3S-t-butoxyearbonylamino-l-carboxy-methyl-3~ 4-dihy~roearbostyril ~:
2.98 g of 1-benzyloxyearbonylmethyl-3s-t-butoxy-carbonylamino 3,4-dihydroearbostyril obtained in Reference wos4nl6l2 PCT/J~4/00434 ~13~i08 --so Example 39 was dissolved in 10 ml of methanol, and 200 mg of
10% palladium-carbon suspended in 10 ml of methanol was added, and the mixture was saturated with hydrogen. After stirring for 1 day at ordinary pressure, the catalyst was filtered off, 5 and the filtrate was e~aporated in vacuum, and the captioned compound was obtained in a white solid form. Yield: 2.0 g.
~MR (2 7 OMHz. CDC 13 ) ~ ~ pm: 7. 2 0--7. 2 6 t2H, m 7 . O 5 ( 1 H . t . J = 7 H z ) ~ 6 . 8 1 ( 1 H . d , J = B H z ) 5 . 6 9 ( 1 H . b r s ) ~ 4 ~ 8 9 ( 1 H . d . J ~ 1 8 H z ) ~ 4 . 4 5 1 H. d. J=l 8Hz~ ~ 4. 3 1--4. 3 8 (lH, m) ~ 3. 3 7--3.
43 (lH? m) ~ 2. 86 tlH, t, J=l 5Hz~ ~ 1. 46 (9H, s 1- ) I
¦~ Reference Example 41 ¦ Preparation of 3S-t-butoxycarbonylamino-l-propoxy-carbonylmethyl-3,4-dihydrocarbostyril ~:~ 600 mg of 3S-t-butoxycarbonylamino-1-carboxymethyl-: 20 3,4-dihy~rocarbostyrll obtained ln Reference Example 40 was dissolved in 10 ml of dichloromethane, and 420 ~1 of propanol I
; was added and cooled in an lce bath, and 247 ~1 of N-methyl-morpholine, 430 mg of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimlde hydrochloride, and 11 mg of dimethylaminopyridine were add~d, and the mixture was stirred for 20 hours at room WO94/21612 ~ ;0; 8 PCT/~4/00434 temperature. The reaction solution was evaporated in vacuum, and 40 ml of ethyl acetate was added to the residue, which was sequentially washed with 15 ml of lN hydrochloric acid, 15 ml of aqueous solution of saturated sodium hydrogencarbonate, and 10 ml of saturated brine, and dried over magnesium sulfate, and evaporated in vacuum, and the captioned compound was obtained in a colorless oil form. Yield: 600 mg.
N M R (2 7 0 M ~ z. C D C 13 ~ ~ p p m : 7. 2 3 (2 H, d. J - 7 H
z)~7.06tlH.t.J-7Hz)~6.79(1H.d.J=7Hz) ~5.68(1H.brs)~4.87(1H.d.J=17Hz~4.50 (lH.d.J=17Hz)~4.35tl~,d t, J=14,5Hz)~4 .11(2H.t,J=7HZ)~3.45(1~.dd.J=14,5Hz) ~2.86(1H.t.J=14Hz)~1.63(2H.dq.J=7,7H
z)~1.48(9H.s)~0.86(3H.t.J-7Hz) , Reference Example 42 Preparatlon of 3S-t-butoxycarbonylamino-l-isopropoxy-carbonylmethyl-3,4-dihydrocarbostyril Using 2-propanol and a correæponding starting material, the captioned compound was obtained in the same manner as ln Reference Example 41~
NMR(27oMHz~cDcl3)~ppm:7~23t2H~d~J=8H
z)~7.06(1H.t,J=8Hz)~6.78(1H.d,J=8Hz) WO94/21612 ~ ~ 6 i~ ~ PCT/J~4/00434 . .
5. 6 9 (1 H. b r s) ~ 4. 9 5 - S. 1 5 (1 H. m) ~ 4. 8 1 (I
H. d. J = 1 7 H z) ~ 4. 4 7 ~1 H, d, J = 1 7 H z) ~ 4. 3 5 tl H. d t. J - 1 4, 5 H z) ~ 3. 4 5 (1 H. d d, J = 1 4, 5 H z) ! 2. 8 6 (1 H. t. J = 1 4 H z) ~ 1. 4 7 (9 H. s) ~ 1. 2 0 ~ 1.
3 0 ~6 H. m) Reference Example 43 Preparation of 3S-ben~yloxycarbonylamino-l=t-butoxy-- carbonylmethyl-3,4-dihydrocarbostyril ¦ Using t-butyl bromoacetate and a corresponding ¦ -starting material, the captioned compound was obtained in the 1~ same manner as in Reference Example 24.
N M R (2 7 O M ~ z. C D C 1~ ) ~ P ~ m : 7. 2 3 - 7. 3 9 (5 H, m 7. 7 (2 H, t. J = 8 H z) ~ 6. 7 9 (2 H, d. J = 8 H z) ~
¦ 5. 9 7 (1 H. b r s) ~ 5. 1 4 (2 H. s) ~ 4. 7 4 (1 H. d, J =
1 7 H z~ ~ 4. 3 4 - 4- 4 5 (2 H. m~ ~ 3. 4 7 (1 H. d d, J ~ 1 4, 6 H z) ~ 2. 8 8 (l H, t, J = 1 4 H z) ~ 1. 4 2 (9 H. s) :~-:~ Reerence Example 44 ~ Preparation of l-amlnocarbonylmethyl-3S-t-butoxy-¦ 2~ carbonylamino-3,4-dihydrocarbostyril Using iodoacetamide and a corresponding startlng material, the captioned compound was obtained in the same ~ manner as in Reference Example 24.
-: N M R (2 7 0 M H z. C D C l3 ) ~ ~ P m : 7. 1 5 - 7. 3 5 (2 H. m ~: 25 ) ~ 7. 0 5 - 7. 1 5 (2 H. m) ~ 6. 1 3 (1 H. b r s) ~ 5. 6 0 ( ;
~ wo94nl6l2 ~1 3 ~ PCT/~4/00434 .
1 H. b r s) ~ 5- 4 4 (1 H. b r s) ~ 4. 9 S (I H. d. J - l 6 H
z) ~ 4. 3 8 (l H. d t. J ~ 1 4, 6 H z) ~ 4. l 9 (1 H, d. J =
l 6 H z) ~ 3- 3 - 3- 5 0 (1 H, m) ~ 2. 8 8 (l H. t. J = 1 4 H z) ~ 1. 4 7 (9 H, s) Reference Example 45 Preparation of 3S-t-butoxycarbonylamino-l-(N-methyl-aminocarbonylmethyl)~3,4-dihydrocarbostyril 500 mg of 35-t-butoxycarbonylamino-1-carboxymethyl-3,4-dihydrocarbostyril was dissolved in lO ml of dichloromethane, and while stirring in ice-cooling, 240 mg of l-hydroxybenzotriazole, 0.21 ml of N-methylmorpholine, and 358 mg of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, and the mixture was s~irred for lO
minutes, and 0.34 ml of N-methylmorpholine and 210 mg of methylamine hydrochloride were added, and the mixture was ! st~rred ov~rnlght at room temperature. ~he reaction solution ~: was rioncentrated in ~acuo, and 30 ml of dichloromethane was ¦ added to the residue, and it was washed sequentially with 15 ¦ ml of lN hydrochloric acid, 15 ml of aqueous solution of saturated sodlum hydrogencarbonate, and 15 ml of saturated brine, and dried over magnes~um sulfate anhydride. Evaporated in vacuum, the captioned compound was o~tained in a white ~.
solid form. Yield: 540 mg.
I
W094nl612 ~ ~ 3 610 ~ PCT/nW410044 ~ M R (2 7 O M H z. C D C 13 ) ~ P P m : 7. 0 6 - 7. 3 2 (4 H, m ) ~ 6. 1 2 (1 H, b r s) ~ 5. 5 9 (1 H. b r 5) ~ 4. 9 4 (1 H, d. J = 1 6 H z) ~ 4- 3 4 ~ 4 4 4 tl H, m) ~ 4. 1 0 (1 H. d, J = 1 6 H z) ~ 3. 4 1 (1 H. d d, J - 1 5, 8 H z) ~ 2. 8 7 (1 H
, t. J = 1 5 H z) ~ 2. 8 2 (3 H. d. J = 5 H z) ~ 1. 4 8 (9 H,.m) Reference Example 46 Preparation of 3S-t butoxycarbonylamino-l-~N-propyl-aminocarbonylmethyl) 3,4-dihydrocarbostyril Us~ng 1-propylamine and a corresponding starting ~materlal, the captioned compound was obtained in the same manner as ln Reference Example 45.
N M R (2 7 0 M H z, C D C 13 ) ~ ~ P m : 7. 0 6 7. 3 2 t4 H, m ) ~ 6. 0 1 (1 H. b r s) ~ 5. 6 O (1 H, b r s) ~ A. 9 2 (1 H.
d, J = 1 6 H z) ~ 4- 3 4 - 4. 4 2 (1 H, m) ~ 4. 1 4 (1 H. d.
J = 1 6 H z) ~ 3. 4 3 tl H. d d, J - 1 5, 8 H z) ~ 3. 2 2 (2 H
. d~. 3 = 2~ 7 H z) ~ 2. 8 6 (l H, t, J = 1 5 H z) ~ 1. 4 2 -1. 5 3 (1 l~H~ m) ~ O. 8 6 (3 H, t, J ~ 7 H z) Reference Example 47 Preparat1on of 3S-t-butoxycarbonylamino-l-(N-methoxy-aminocarbonylmethyl~-3,4-dihydrocarbostyril Using methoxyamine and a corresponding starting material, the captioned compound was obtained in the same manner as in Reference Exampl~ 45.
N M R (2 7 O M H z. C D C 13 ) ~ p p m : 9. 0 6 (1 H. s) ~ 7. 1 `
5 - 7. 4 0 (3 H. m) ~ 7- 0 9 (1 H. t, J - 8 H z) ~ 5. 5 5 (1 W094~1612 PCT/~4/00434 ~1~61 ~8 H. b r s) ~ 4. 7 5 - 4. 9 5 ~l H, m) ~ 4. 3 6 (l H. d t,. J =
1 4, 6 H z) ~ 4- Q O - 4- 2 0 (1 H. m) ~ 3. 7 8 (3 ~. s) . 3 9 (1 H. d d. J = l 4, 5 H z) ~ ~. 8 6 (1 H, t, J = l 4 H z ) ~ 1. 4 8 (g H. s) Re~erence Example 48 Preparation of 3S-t-~utoxycarbonylamino-l-(N,N-dimethylaminocarbonylmethyl)-3,4-dihydrocarbostyril Using dimethylamine and a corresponding s~arting ~ material, the captioned compound was obtained in the same manner as in Reference Example 45.
~ M R (2 7 O M H Z. C D C 13 ) ~ P P m : 7. 2 0 - 7. 2 6 (Z H. m ) ~ 7. 0 3 (l H. t, J = 8 H z) ~ 6. 7 8 (1 H. d. J = 8 H z) ~
5. 7 8 (l H. b r s) ~ 4. 9 3 ~l H, d. J = l 7 H z) ~ 4. 5 0 ( 1 H. d. J = 1 7 H z) ~ 4. 3 4 - 4. 4 3 (1 Hl m) ~ 3. 3 9 - 3.
¦ 4 6 (1 H, m) ~ ~. 1 3 t3 H, s) ~ 2. 9 9 (3 H. s) ~ 2. 9 O ( l H, t, J - 1 4 H z) ~ 1. 4 7 (9 H, s) ~eference Exampl@ 49 Preparation of 3S-t-butoxycarbonylamino-l-morpholino-carbonylmethyl 3,4-dihydrocar~ostyril Using morpholine and a corresponding starting material, the captioned compound was obtained in the same manner as in Reference Example 45.
~ M R (2 7 O M H z. C D C 13 ) ~ p p m : 7. 2 2 (2 H. d, J = 7 H
z) ~ 7. O 5 (1 H~ t. J = 7 H z) ~ 6. 8 O tl H, d, J = 7 H z) ` wo 94nl6~2 ~ 1 3 6 1 0 8 PCT/~4/004~4 , . .
5. 6 6 (l ~. b r s) ~ 4. 9 2 (l H, d. J = 1 6 H z) ~ 4. 5 2 (1 H. d. J = 1 6 H z-3 ~ 4. 3 9 (1 H. d t. J = 1 4, 5 H z) ~ 3 ! 7 3 (4 H. d d. J = l 5, 4 H z) ~ 3. 6 1 (4 H, d d, J = 1 5, 4 H z) ~ 3. 4 3 (l H. d d. J - l 4, 5 H z) ~ 2. 9 0 (l H. t.
J~ J = 1 4 H z) ~ l. 4 7 (9 H. s) ! 5 Reference Example 50 ¦ Preparation of 1-allyl-3S-t-butoxycarbonylamino-3,4-dihydrocarbostyril Using allyl bromide and a corresponding starting ~material, the captioned compound was obtained in the same manner as ln Reference Example 24.
N M R t2 7 0 M H z. C D C l3 ) ~ ~ ~ m : 7. 2 3 (l H. d. J 3 8 H
z) ~ 7. 2 l (l H. d. J = 7 H z) ~ 7. 0 6 - 6. 9 9 (2 H. m) ~
5. g 4 ~ S. 8 2 (l H. m) ~ 5. 7 5 tl H. b s) ~ 6. 2 3 - 5. l ¦ 2 (2 H. m) ~ 4. 8 8 - 4. 7 8 (l H. m) ~ 4. 3 5 - 4. 2 6 (2 H
, m) ~ 3. 4 4 (l H. d d. Jl = 5 H Z~ J2 = l 5 H z) ~ 2. 8 1 ( l H. t. J = 1 S H z3 ~ l. 4 8 (9 H. s) ~: .
Reference Example 51 Preparation of 3S-t-hutoxycarbonylamino-1-cinnamyl- 1 2~ 3,4-dihyd~ocarbostyril Uslng a starting material corresponding to cinnamyl bromide, the captioned compound was obtained in the same ~1~manner as in Ref~rence Example 24. .
M R (2 7 0 M H z. C D C l3 ) ~ ~ ~ m : 7. 3 6 - 7. 1 9 t7 H. m 7. 1 0 - 7. 0 l (2 H. m~ ~ 6. 5 4 (l H. d. J = 1 6 ~ z) .
Wo94/21612 ~ 1 3 ~10 8 PCT/J~4/00434 . . i 6. 2 4 (1 H. t d. Jl ~ 1 6 H Z J2 = 6 H z) ~ 5. 7 6 (1 H, b ) 4 9 9 (1 H. d d d, J1 = 2 H Z J2 3 ) ~ 4. 4 6 (1 H. d d d. J1 = 1 H Z J2 = 6 H z. J3 = 1 6 H z) ~ 4. 3 7 - 4. 3 1 (1 H. m) ~ 3. 4 5 (1 H. d d. J1 = 5 H z. I
2 = 1 5 H z) ~ 2. 8 3 (1 H. t, J ~ 1 5 H z) ~ 1. 4 8 (9 H. s) Reference Example 52 Preparation of 3S-t-butoxycarbonylamino-1-methyl-3,4-dihydrocarbostyril Using iodomethane and a corresponding starting ~ material, the captioned compound was obtained in the same manner as in Reference Example 24.
~ M R (2 7 O M ~ z. C D C 13 ) ~ P P m : 7. 2 0 - 7. 3 2 (2 H. m ) ~ 6. 9 8 - 1. O 8 t2 H. m) ~ 5. 7 1 (1 H. b r s) ~ 4. 1 9 -4. 2 8 (1 H. m) ~ 3. 4 8 - 3. 5 0 (1 H. m) ~ 2. 7 8 (1 H. t , J = 1 5 H z) ~ 1. 4 8 t9 H. s) Reference Example 53 Preparation of 3S-t-butoxycarbonylamino-1-ethyl-3,4-dlhydrocarbostyrll Uslng iodoethane and a corresponding starting materlal, the captioned compound was obtained in the same manner as in Reference Example 24.
W094/21612 -~ 13 6 1~ 8 pcTl~4looa4 ~g8-~ M R (2 7 O M H z. ~ D C 13 ) ~ P P m : 7. 1 5 - 7. 3 5 (2 H. m ) ~ 7. 0 3 (2 H. t, J = 7 H z) ~ 5. 7 4 (l H, b r s) ~ 4. 2 4 (1 H. d t. J - l 4. 5 H z) ~ 3. 8 5 ~ 4. 2 0 (2 H, m) ~ 3. 4 l (l H. d d. J - l 4- 5 H z) ~ 2. 7 5 (1 H. t, J = 1 4 H z) 1. 4 7 (9 K, s) ~ l. 2 6 (3 H. t, J - 7 H z) Reference Example 54 Preparation of 1-benzyloxyethyl-3S-t-butoxyoarbonyl-amino-3,4-dihydrocarbostyril Uslng 1-benzyloxy-2-iodoethane and a corresponding starting material, the captioned compound was obtained in the same manner as in Reference Example 24.
N M R (2 7 O M H z. C D C l3 ) ~ ~ p ~ : 7. l 5 - 7. 4 0 (8 H, m ¦ ) ~ 6. 9 5 - 7. l O (l H, m) ~ 5. 7 1 (l H, b r s) ~ 4. 5 2 ( 2 H. s~ ~ 4. l 5 - 4. 3 5 (2 H. ~) ~ 3. 9 5 - 4. 1 5 tl H, m ) ~ 3. 7 3 (2 H. t~ J = 6 H z) ~ 3. 3 9 (l H. d d. J - l 4, 6 I H z) ~ 2. 7 6 ~L H, t, J = l 4 H z) ~ 1. 4 7 (9 H. s) ~-- Reference Example 55 Preparation of 3S-t-butoxycarbonylamino-1-(2-hydroxy-ethyl)-3,4-dlhydrocarbo tyril 1.50 g of 1-benzylo~yethyl-3S-t-butoxycarbonylamino-3,4-dihydrocarbostyril was dissolved in 10 ml of ethanol, and 100 mg of 20% palladium hydrox$de-on-carbon ( wet ) was added, and the mixture was saturated with hydrogen. After s~irring I for 1 day at ordinary pressure, the catalyst was filtered away, the filtra~e was concentrated in vacuo, and the captloned compound was obtained. Yield: 1.05 g.
W094121612 ~ 13 6 1 Q 8 PCT/nW4100434 _99_ i N M R (2 7 O M H z. C D C 13 ~ S p P m : 7. 0 0 - 7. ~ O (4 H, m ) ~ 5. 7 0 (1 H. b r s) ~ 4. 1 5 - 4. 4 0 (2 H, m) ~ 3. 8 0 -4. 1 5 (3 H. m) ~ 3~ 4 0 (1 H, d d. J = 1 5. 7 H z) ~ 2. 8 1 (1 H. t. J = 1 5 H z) ~ 2- 2 3 (1 H. b r s) ~ 1. 4 7 (9 H. s ) Reference Example 56 Preparation of 3S-t butoxycarbonylamino-l-(2-propynyl)-3,4 dihydrocarbostyril Using propalgyl bromide and a corresponding starting material, the captioned compound was ob~ained in the same manner 2S in Re~erence Example 24.
N M R (2 7 O M H z. C D C 13 ) ~ P P m : 7. 2 1 7. 3 S (~ H, m ) ~ 7. 0 8 (1 H~ d t, J = 1, 7 H z) ~ 5. 6 8 tl H. b r s) ~ 4 . 9 5 (1 H. d d. J = 1 7, 2 H z) ~ 4. 4 7 (1 H. d d, J ~ 1 7, 2 H z) ~ 4. 2 5 - 4. 4 4 (1 H. m) ~ 3. 4 2 (1 H. d d, J = 1 5 t 5 H z~ ~ 2. 8 0 (l H, t, J = 1 S H z) ~ 2. 2 4 (l H. t, J =
2 H z) ~ 1. 4 7 t9 H. s) Reference Example 57 Preparation of 7-chloro-3S-phthalimido-3,4-dlhydrocarbostyril 2~82 g of 3S-amlno-7-chloro-3, 4-dihydrocarbostyril was suspended in 40 ml of dimethylformamide, and 3.46 g of N-carboethoxyphthallmide and 1. 52 g of sodium carbonate were added, and the mixture was stirred overnight at room tsmperature. The reaction solution was concentrated in ~racuo, and 50 ml of water was added to the residue, and the WO94/21612 PCTIJ~4/00434 ~ 1 3 6 1 0 ~ f r --1~) 0 ~ precipitates were filtered. The crude product was washed with 5' 30 ml of ethyl acetate and 30 ml of methanol, and the ~, captioned compound was obtained in a pale brown powder form.
Yield: 4.02 g.
MMR(270MHz, DMSO-d6)~ppm:10.69(1H, brs), 7.89-7.97~4H, m), 7.25(1H, d, Js8Hz), 7.04(1H, dd, J=8,2Hz), 6.95(1H, d, J=2Hz), 5.06(lH, dd, J=15,7Hz)~ 3.66(lH, t, J=15Hz), 3.15(lH, dd, Jal5,7Hz) .
Reference Example 58 Preparation of 3S-triphenylmethylamino-3,4-dihydrocarbostyril 2.26 g of 3S-amino-3,4-dlhydrocarbostyril was suspended in ~0 ml of dimethyl formamide, and while stirring ln ice-cooling, 5.03 g of triphenylmethyl chloride was added, and the pH was ad~usted to 8 by triethylamine. After stlrring for 1 hour at 0~, returnlng to room temperature, the pH was adJusted again to 8 by triethylamine, and the solution was stirred for 1 hour. The reaction solution was concentrated in vacuo, and 100 ml of ethyl acetate was added, and it was washed seguentlally with lN hydrochloric acid (80 ml), aqueous solution of saturated sodium hydrogencarbonate (50 ml x 2 times), and saturated brine (S0 ml x 2 times), and dried over magneslum sulfate anhydr~de, and evaporated in vacuum. To the ;, ' ~:
W094/21612 ~ 1~ 610 8 PCT/~4/00434 .
-101~
residue, n-hexane was added, precipitates were filtered, and the captioned compound was obtained. Yield: 5.34 g.
NMR(270MHz, CDC13)~ppm:7.52-7.57(6H, m), 7.44(lH, br), 7.19-7.32(9H, m), 7.10(1H, t, J=8Hz), 6.87(1H, t, Ja8Hz), 6.69(lH, d, J-8Hz), 6.64(1H, d, J-8Hz), 3.41(lH, dd, J-6~15Hz), 2.46(1H, t, J=15Hz), 1.65(1H, dd, J=6.15Hz) Reference Example 59 Preparation of 3S-(tert-butoxycarbonyl)amino-7-chloro-1-methoxy-3,4-d~hydrocarbostyri~
Using ~odomethane and a corresponding starting material, the captioned compound was obtained in the same ,,~
~ 15 manner as ln Reference Example 21.
,~
NMR(270MHz, CDC}3)8ppm:7.22tlH, d, J-2Hz), 7.14(1H, d, ~-8Hz), 7.05~1H, dd, J-2~8Hz), 5.55(1H, br), ~ 4.34(1H, dt, J-14,6Hz), 3.94t3H, 5), 3.42(1H, dd, J~14,6Hz), ; ~20 2.77(1H, t, J-14Hz), 1.48~9Hr s) Reference Example 60 't`
: Preparation o~ 3~-(4-hydroxy-ZR-isobutyl-3S-methyl-succlnyl)amino-1-methoxymethyl-3,4-dihydrocarbostyril W094/2l612 ~ U ~ PCT/J~4/OW4 -10~-3S-(4-hydroxy-2R-isobutyl-3-ethenysuccinyl)amino-l-methoxymethyl-3,4-dihydrocarbostyril (800 mg, 2.14 mmol) obtain~d in the same manner aS in Reference Example 4 was dissolved in ethanol (10 ml), and 10% palladium-carbon (100 mg~ was added, and the mixture was saturated with hydrogen.
After stirring for 1 day at ordinary pressure, the catalyst was filtered off, and the solvent was evaporated in ~acuo, and the captioned compound was obtained. Yield: 790 mg.
NMR(270MHz, DMSO-d6)~ppm:8.50( lH, d, J~8Hz ), 7.15-7.35(3H, m), 7.06(1H, t, J-7Hz), 5.48(1H, d, J=lOHz), 5.02(lH, d, J-lOHz), 4.57(lH, dt, J-14~7Hz), 3.26(3H, s), 3.05~1H, t, J-14Hz), 2.94(1H, dd, J-14,7Hz), 2.80-3.20(1H, m), 2.20-2.45(1H, m), 1.4o-l.7ot2H~ m), 0.90-1.20(1H, m), 1.04(3H, d, J-7Hz), 0.90(3H, d, J-7Hz), 0.83(3H, d, J=7Hz) .:
Reference Exampls 61 Preparation of 3S-benzyloxycarbonylamino-1-methoxy- `
~: 20 e~hoxymethyl-3,4-dihydrocarbostyril Using methoxyethoxymethyl chloride and a corresponding starting materiàl, the captioned compound was obtained in the same manner as in Reference Example 24.
MMR(270MHz, CDC13)~ppm:7.20-7.50(7H, m), 7.20(1H, d, WOg4nl612 PCTtJ~4100434 ~ 1 3 6 1 0 8 J=7Hz), 7.09(1H, t, J=7Hz), 5~92~1H, brs), 5.82(1H, d, J=llHz), 5.15(2H, s), 5.01(lH, d, J=llHz), 4.40~lH, dt, J=14,6Hz3, 3.72(2H, dd, J=5.3Hz), 3.53(2H, t, J=5Hz~, 3.41~1H, dd, J-14,6Hz~, 3.37(3H, s), 2.83(1H, t, J=14Hz~
~eference Example 62 Preparation of 4-t-butoxy-2R-isobutyl-3-propyl-succinic acid Using aryl bromide and a corresponding starting material, the capt~oned compound was obtained in the same manner as in Reference Example 8.
NMR(270MHz, CDCl3)~ppm:2.68~1H, dt, Jl-3Hz, J2-9Hz), 2.50(1H, dt, Jl-2Hz, J~lOHz), 1.74-1.12(16H, m), 1.45(9H, s), 0.96-0.87(9H, m) ,- .
Reference Example 63 Preparation of 3-benzyl-4-t-butoxy-2R-isobutyl-~: succlnic acld U.sing benzyl bromide and a corresponding starting material, the captioned compound was obtained in the same ! ~ m?nner as in Reference Example 8.
NMR(270MHz, CDCl3)~ppm:7.26-7.16(5H, m), 2.91-2.74~4H, m), $ 1.77-1.60t2H, m), 1.29-1.18(10H, m), 1.26(9H, s), 0.91(6H, dd, WO94/~1612 PCT/J~4/00434 ~ 1 3 6 1 0 ~ - 104- !
Jl=3HZ, J2=7Hz) Reference Example 64 Preparation of 4-t-butoxy-2R-isobutyl-3-(4-methoxy-benzyl)succini~ acid Using 4-methoxybenzyl chloride and a corresponding - starting matexial, the captioned co~pound was o~tained in the same manner as in Reference Exampla 8.
MMR(270MHz, CDC13)~ppm:7OO9(2H, d, Js9Hz), 6.79(2H, d, J-9Hz), 3.77(3H, s), 2.87-2.72(4H, m), 1.7~-1.59(2H, m), 1.33-1.21(10H, m), 1.28(9H, s), Q.90(6H, dd, Jl~3Hz, J237Hz) I !
Reference Example 65 Preparation of benzyl 2-benzyloxycarbonyl-3S-tert-butoxycar~onyl-5-methylhexanoate U~ing L-leucin, the captioned compound was obtained in the same manner as in Reference Example 1.
25 Re~erence Example 66 ~' WO 94/21612 PCTlJP94/Oû434 l D 8 1os Preparation of 3S-benzyloxycarbonylamino-1-methoxy-methoxyethyl-3,4-dihydrocarbostyril Using l-iodo-2-methoxymethoxyethane and a corresponding starting material, the captioned compound was obtained in the same manner as in Reference Example 24.
NMR(270MHz, CDC13)~ppm:7.15-7.45(8H, m), 7.06(1H, t, J=7Hz), 6.01(1H, brs), 5.15(2H, s), 4.59(2H, q, J=6Hz), 4.25 4.40(1H, ^ m~, 4.25(1H, dt, J-14r5Hz), 4.08(1H, dt, J=14,7Hz), 3.78(2H, 10t, J-5Hz), 3~44(1H, dd, J-15,6Hz), 3.29(3H, s), 2.81(1H, t, J-15~z) Reference Example 67 15Preparation of 4-t-butoxy-2R-lsobutyl-3-(3-ph~nylpropyl)succintc acid Uslng cinnamyl bromide and a corresponding starting material, the eaptloned compound was obtained in the same manner as ln Reference Example 8.
NM~(270MHz, CDC13)~ppm:7.29-7.13(5H, m), 2.71-2.50 (4H, m), 1.74-1.42(15H, m), 1.43(9H, s), 1.20-1.12(1H, m), 0.90(6H, d, J-7Hz) WOg4nl6~ PCT/p~4/00434 Reference Example 68 Preparation of 4-t-butoxy-2R-isobutyl-3-(2-methyl-benzyl)succinic acid Using a-bromo-o-xylene and a corresponding starting ¦ 5 material, the captioned compound was obtained in the same ¦ manner as in Reference Example 8.
NMR(270MEz, CDCl3)6ppm:7.lZ-7.06(4H, m), 2.9l-2.79(4H, m), ~ 2.29(3H, s), 1.77-1.60(2H, m), 1.29-1.17tlOH, m), 1.25(9H, m), 0.92(6H, dd, J1~lHz, J2~6HZ) Reference Example 69 Preparation of 4-t-butoxy-2R-isobutyl-3-(3-methyl--~ 15 benzyl)succinic acld ~: Using -bromo-m-xylene and a corresponding starting mat~r~al, the captloned compound wa~ obtained in the same manner a~ ~n Reference Exa~ple 8.
:
NMR(270MHz, CDCl3)~ppm:7.17-6.95(4H, m), 2.89-2.73(4H, m), 2.29(3H, s), 1.79-1.54(2H, m), 1.31-1.20(10H, m), 1.27(9H, s), 0.9l(6H~ dd, Jl-3Hz, J2-7HZ) ~: ~ .
.
Reference Example 7~
W094/21612 .~ 1 3 ~ 1 0 8 Preparation of 4-t-butoxy-2R-isobutyl-3-(4-methyl-benzyl)succinic acid Using a-bromo-p-xylene and a corresponding starting material, the captioned ~ompound was obtained in the same 5 manner as in Reference Example 8.
NMR(270MHz, CDC13)~ppm:7.05(4H, s), 2.88-2.70(4H, m), - 2.29(3H, s), 1.76-1.59(2H, m), 1.33-1.17(10H, m), 1.28(9H, s), 0.90(6H, dd, J1~4Hz, J2-7Hz) Reference Example 71 Preparation of 4S-isopropyl-3~ oxononyl)-2-oxazolidinone 4S-Isopropyl-2-oxazolidinone (1.02 g, 7.90 mmol) was dlssolved in tetrahydrofurane (25 ml) in nitrogen atmosphere, and cooled to -78~. Dripp$ng n-butyl lithium (1.63M hexane solutlon) (5.09 ml, 8.30 mmol), the solution was stirred for 30 minutes. Adding pelargonyl chloride (5.09 ml, 8.67 mmol), ~he solution was stlrred for 1.5 hours at -78C. The reaction solution was poured into 5~ aqueous solution of ammonium chloride (30 ml), and extracted with ethyl acetate (30 ml x 2 times), and the organic layer was washed with water (10 ml) and saturated brine (20 ml), and dried over magnesium sulfate.
The solvent was evaporated in vacuo, and the captioned .. W094n1612 PCTI~4/00434 s, hl361 08 .~
compound was obtained in a colorless oily form. -Yield: 2.10 g MMR(270MXZ, CDC13)~ppm:4.40(1H, dt, J=8.4Hz), 4~26tlH~ t, J-9Hz), 4.19(1H, dd, J39.3Hz~, 2.7 -3.05(2H, m), 2.25-2.50(1H, m), 1.50-1.75(2H, m), 1.15-1.50(10H, m), 0.91(3H, d, J=7Hz), 0.86(3H, d, J-7Hz), 0.80-l.OO(.~H, m) Reference Example 72 ¦ Preparation of 4S-isopropyl-3-(2~-t-butoxycarbonyl-methyl-l-oxononyl)-2-oxazolidinone Tetrahydrofurane t2.5 ml) was added to diisopropyl-amine (1.~8 ml, 9.85 mmol), being i~e-cooling, n-bu~yl lithium (1.63 M hexane solution) (5.50 ml, 8.97 mmol) was dripped, and the solutlon was stirred for 15 minu~es, and cooled to -78C, and tetrahydrofurane (5 ml) solution of 4S-isopropyl-3-(1-oxononyl)-2-oxazolldinone (2.30 g, 8~54 mmol) was dripped, and the solution was stlrred for 30 minutes at -78~C. Adding t-butylbromoacetate (1.66 ml, 10.28 mmol), the temperature was gradually raised to -5~ while stirring for 7 hours. The I reaction solution was poured into 5~ aqueous solution of ~.`
~mmo~ium chloride, and extracted with ethyl acetate (20 ml x 2 times), and the organic layer was washed sequentially with WO94/21612 PCT/p~4/00434 1361~
los water (~0 ml) and saturated brine (20 ml), and dried over magnesium sulfate. The s~lvent was evaporated in vacuo, and purified by silica gel chromatography (eluted in hexane:ethyl acetate - 14:1), and the captioned compound was obtained.
Yield: 2.19 g.
NMR(270MHz, CDCl3)~ppm:4.43(lH, dt, J-8,4Hz), 4.10-4.35(3H, m), 2.74(1H, dd, J-16,10Hz), 2.42(1H, dd, J-16,4Hz), 2.30-- 2.55tlH, m), 1.41(9H, s), 1.10-1.75(12H, m), 0.93(3H, d~
J~6Hz), 0.88(3H, d, J-6Hz), 0.80-1.10(3H, m) Reference Exa~ple 73 Preparat~on of 3S-t(2R-t-butoxycarbonylmethyl)-(l-oxononyl)]amino-1-methoxy-3,4-dihydrocarbostyril 4S-Isopropyl-3-(2R-t-butoxycarbonylmethyl~l-oxononyl)-2-oxazolldinone (2.19 5, 5.71 mmol) was dissolved in a mixed solvent of tetrahydrofurane-water (3:1, 120 ml~, and ~- cooled to 0~. Adding sequentlally lithium hydroxide hydrate ~79 mg, .11.42 mmol) and 30~ aqueous solution of hydrogen peroxide (2.94 ml), the solutlon was stirred for 1.5 hours at 0~. Adding 1.5N aqueous solution of sodium sulfite (21.5 ml), the solution was stirred for several minutes, and the mixture was poured into methylene chloride (150 ml), and washed sequentially with lN hydrochloric acid (50 ml) and ~. WO94/21612 PCT/~4/00434 ~13610~ " -., -110--saturated brine (20 ml), and dried over magnesium sulfate.
After evaporating the solvent in vacuo, adding dimethyl formamide (10 ml), the solution was ice-cooled, and 3S-amino-1-methOxy-3,4-dihydrOCarbostyril hydrochloride (1.30 g, 5.71 mmol), N-methylmorpholine (628 ~1, 5.71 mmol~, 1-~ hydroxybenzotriazole (873 mg, 5.71 mmol), and dicyclohexyl-¦ carbodiimide (1.18 g, 5.71 mmol) were sequentially added, and ¦ the mixture was stirred for 15 hours at room temperature. The ~ solvent was evaporated in vacuo, ethyl acetate (50 ml) was added, and the mixture was sequentially washed with lN
hydrochloric acid (20 ml), saturated aqueous solution of sodium hydrogen~arbonate (20 ml x 2), and saturated brine (30 ml), and dried over magnesium sulfate. After evaporating the I ~olven~ ln vacuo, ~t was purlfied by silica gel column r 15 chromatography teluted in hexane:ethyl ace~ate o 3:1), and the captioned compound was obtained. Yield: 2.70 g.
NMRt270MHz, CDCl3)~ppm:7~15-7040(3H, m), 7.08(1H, t, J-7Hz) : 6.63(1H, d, J~6Hz), 4.60(1H, dt, J~14,6Hz), 3.94(3H, s), 3-49tlH, .dd, J-15,6Hz), 2.76(1H, t, J~15.Hz), 2.55-2.80(2H, m), 2.30-2.50(1H, m), 1.45t9H, s), 1.20-1.&0(12H, m), 0.87(3H, t, J~7Hz) Reference Example 74 . WO94~1612 PCT/~4/0~34 ;-136~ Q~
Preparation of 7-chloro-1-methoxymethyl-3S-phthalimido-3,4-dihydrocarbostyril Using methoxymethyl chloride and a corresponding ~.
starting material, the captioned compound was obtained in the same manner as in Reference Example 24.
i ~ NMR(270MHz, CDC13)~ppm:7.86-7.93~2H, m), 7.73-7.79(2H, m), ¦ 7.39(1H, d, J-2Hz), 7.06-7.14(2H, m), 5.68(1H, d, J=llHz), - 5.15(1H, dd, J-15,6Hz), 4.99(1H, d, J=llHz), 4.02(1H, t, J-6Hz), -~.41(3H, s), 2.97(lH, dd, J~14,6Hz) Reference Example 75 Preparation of 3(R,S)-benzyloxycarbonylamino-l-tert-butoxyethyl-3,4-dlhydrocarbostyril Uslng l-iodo-2-tert-butoxyethane and a corresponding starting material, the captioned compound was obtained in the same manner as in Reference Example 24.
NMR(270MHz~ CDC13)~ppm:6.99-7.40(9H, m), 6.00(1H, br), 5.12-5.17(2H, m), 4.08-4.35(2H, m), 3.87(1H, dt, J-14,7Hz), 3.55-3.64t3~, m), 2.80(lH, t, J-14Hz), 1.12(9H, s) Re~erence Example 76 WO94/21612 ~ 13 61~ 8 PCT/~4/00434 ; .
Preparation of l-methoxyethyl-3S-triphenylme~hyl-am~no-3,4-dihydrocarbostyril Using l-iodo-2-methoxyethane and a corresponding starting material, the captioned compound was obtained in the same manner as in Reference Example 24.
NMR(270MHz, CDC13)~ppm:7.49-7.54(6H, m~, 7.08-7.~1(11H, m), - 6.88(1H, dt, J~2,8Hz), 6.66(1H, d, J-8Hz), 4.20(1H, dt, J~14,5Hz), 3.98(1H, dt, J-14,7Hz), -~.59(1H, dd, J-7,5Hz)~, 3.37(1H, dd, J~14,5Hz), 3.34(3H, s), 2.36(1H, t, J=14Hz), I.56tlH, dd, J~14,SHz) Reference Example 77 Preparation of 3~R,S)-benzyloxyamlno-l-methoxyethyl-3,4-dihydrocarbostyril Using 1-iodo-2-methoxyethane and a corresponding starting material, the captioned compound was obtained in the 2~ same manner as in Refere~c~ Example 24.
NMR(270MHz, CDC13)~ppm:7.19-7.40(8H, m), 7.05(1H, t, J=7Hz), 5.99(1H, br), 5.15(2H, s), 4.33(1H, dt, ~14,5Hz), 4.25(1H, dt, J~14,5Hz), 4.00(1H, dt, J-14,7Hz), 3.59-3.68(2H, m), 3.44(1H, dd, J-14,5Hz), 3.35(1H, s), 2.81(1H, t, J=14Hz), ~ WO94~1612 .~13 610 g PCT/J~4/00434 -: , i 1~12(9H, s) i Reference Example 78 Preparation of 4-t-butoxy-2R-isobutyl-3-(4-methoxy-carbonylbenzyl)succinic acid ,. Using 4-methoxycarbonylbenzyl bromide and a '~ corresponding starting material, the captioned compound was obtained ln the same manner as in Reference Example 8.
', 10 NMR~270MHz, CDC13)~ppm:7.94(2H, d, J~8Hz), 7.25~2H, d, 3-8Kz)~ 3.90(3H, s), 2.97-2.74(AH, m~, 1.78-1.60(2H, m), 1.29-j 1.18(10H, ~, 1.26(9H, s), 0.91~6H, dd, Jl=3Hz, J2~6HZ) ;
Reference Example 79 Preparation of 4-t-butoxy-3-hexyl-2R-isobutylsuccinic ¦ acid j 20 Usin~ l-iodohexane and a corresponding starting material, the captioned compound was ob~ained in the same ! manner as in Reference Example 8.
¦~ NMR(270MH , CDC13)~ppm:2.71(1H, dt, Jl-4Hz, J2-9Hz), 25 2.52(1H, dt, J1~4Hz, J2-9Hz), 1.76-1.55(2H, m), W0~4121612 PCT1~4/00434 ~136108 1.49(9H, s), 1.30-1.15(11H, m), 0.99-0.88(9H, m) Reference Example 80 Preparation of benzyl 2-benzyloxycarbonyl-3R-t-butoxycarbonyl-pentanoate ¦ Using D-norleucine and a corresponding starting material, the captioned compound was obtained in the same - manner as in Reference Example 1.
Reference Example 81 Preparation of 4-t-butoxy 2R-isobutyl-3-(3,4-methylenedioxybenzyl)succinic acid Us~ng 3,4-methylenedioxybenzyl chloride and a corresponding startlng material, the captioned compound was obtained ln the same manner as in Re~arence Example 8.
.
NMR(270MHz, CDC13)~ppm:6.71-6.60(3H, m), 5.91(2H, s), 2.83-2.69.~4H, m), 1.75~1.56(2~, m), 1.32(9H, s), 1.25-1.16(1H, m), 0.90(6H, dd, Jl-3Hz, J2-7Hz) !
Reference Example 82 Zs Preparation of 4-t-butoxy-3-(3-ethoxycarbonylpropyl)-W094/21612 ~ 0 8 PCT/J~4/0~34 2R-isobutylsuccinic acid Using e~hyl 4-bromocrotonate and a corresponding starting material, the captioned compound was obtained in the same manner as in Referenc~ Example 8.
s NMRt270MHz, CDC13)~ppm:4.12(2H, q, J-?Hz), 2.73-2.63 (lH, m), 2.53-2.46(1H, m), 2.34-2.29(2H, m), 1.73-1.51(6H, m~, 1.46(9H, s), 1.28-1.16(4H, m), 1.25(3H, t, J~7Hz), 0.90(6H, d, J-6Hz) Reference Example 83 Preparation of l-ethoxymethyl-3S-triphPnylmethyl-amino-3,4-dihyd~ocarbostyrll - 15 Using ethoxymethyl chloride and a corresponding , ~, starting material, the captioned compound was obtained in the same manner as in Reference Example 24.
NMR(270MHz, CDCl3)~ppm:7.52(6H, d, J~7Hz), 7.10-7.40(11H, m), 6.93(lH, dt, J-1.7Hz), 6.68(lH, d, J-7Hz), 5.76(lH, d, ~-~ - J~lOHz), 4.94(1H, d, J~lOHz), 3.45-3.60~2H, m), 3.43(1H, dd, J-14.5Hz), 2.44(1H, t, J-14Hz), 1.67(1H, dd, J-14.5Hz), ~- . . , i ~ .
1.19(3H, t, J-17Hz) -~ 25 ': ~
' ,-WO94121612 ~ 1 ~ C1 ~ ~ PCT/J~4100434 / Reference Example 84 j Preparation of 0-butyl-D-serine To a mixed solution of 60~ sodium hydride (28.8 g), imidazole (1.08 g, 15.9 mmol), and dry tetrahydrofurane (270 ml), a mixed solution of N-trityl-D-serine (25.0 g, 72.0 mmol) ~ and dry tetrahydrofurane (150 ml) was dripped in 15 minutes at ¦ -15C, and the mixture was stirred for 45 minutes at -15C.
Further, butyl iodide (65.5 ml, 576 mmol) was added, and the mixture was stirred for 2 hours at -15~. Moreover, at -15C, addin~ 60% sodium hydr~de (12.0 g) and butyl iodide (129 ml, 1.13 mol), the mixture was stirred for 1 day at -20C. Adding water (1 liter) to the reaction solution, it was extracted wlth ether (300 ml x 2), and the organic layer was washed with 5~ aqueous solution of citric acid (200 ml) and sa~urated IS brine (100 ml), and dried over magnesium sulfate. The solvent was evaporated in vacuo, and 50% acetic acid-ethanol solution (100 ml) was added to the obtained oily matter, and the ~lxture was stirred for lS hours at room temperature. The sediment was filtered, and washed with ethanol and ether, and 0-butyl-D.-serine (6.11 g, 53~) was ob~ai~ed.
MMR(270MHz, D20)~ppm:3.75-4.00(3H, m), 3.50-3.70(2H, m), . ~ I .
1.57(2H, dt, J-14.7Hz), 1.33(2H, dtt J-14.7Hz), 0.90(3H, t, J~7Hz ) , 25 WO94/21612 ~13 61~ 8 PCT/J~4/00434 Reference Example 85 Preparation of benzyl 2-benzyloxycarbonyl-3s-tert-butoxycarbonyl-4-butoxy-butylate Using O-butyl-D-serine and a corresponding starting m~terial, the captioned compound was obtained in the same manner as in Ref~rence Example l.
Reference Example 86 Preparat~on of O-nitrophenyl-L-alanine To N-acetyl-O-nitrophenyl-DL-alanine (324 g, l~28 mol), aqueous solution (l.8 li'ers) of lN sodium hydroxide was .~ added to dissolved, and acylase (9.0 g) and cobalt (II) chlor~de hexahydrate (lO0 mg) were se~uentlally added, and the mixture was stirred for 2 days at 37~. After filtering the insoluble matter, the flltrate was evaporated in vacuo, and preclpitatlng crystals were filtered and washed with a small , -:
~ amount of water, and the captioned compound t99.6 g, 37%) was - obtained.
-: 20 ~- Reference Example 87 Preparation of 3S-(4-hydroxy-2-isobutyl-3-methylthiomethylsuccinyl)amino-3,4-dihydrocarbostyril A mixsd liquid of 3S-(4-hydroxy-2-isobutyl-3-;~ 25 acetylthiomethylsuccinyl)amino-3,4-dihydrocarbostyril , W094/21612 PCT/J~4/00434 ~ ~361~
-118- !
(800 mg, 1.97 m mol) and methanol (lO ml) was chilled in ice.
An aqueous solution (8 ml) of lN sodium hydroxide was added, and the mixture was stirred for 40 minutes in ice-cooling.
Methyl iodide (430 ~1, 6.91 m mol) was added, and further the i 5 mixture was stirred for 2 hours in ice-cooling. Then, lN-hydrochlolic acid (10 ml) was added, the precipitating crystals were filtered, and the captioned compound was obtained in a yellow solid (330 mg, 44%).
f 10 NMR(270MHz, DMS0-d6~ppm:10.22(1H, s), 8.47~lH, d, J-8Hz), 7.18(2H, q, J-8Hz), 6.89(2H, dd, J~11,8Hz), 4.43(lH, dt, J~14.7Hz), 2.80-3.20(3H, m), 2.40-2.80(3H, m), 2.04(3H, s), 1.35-1.70(2H, m), 0.90-1.05(1H, m), 0.87(3H, d, J=7Hz);
0.83(3H, do J~7Hz) ~- Reference Example 88 Preparation of 3S-amino-l-ethoxyethoxy-3,4-dlhydrocarbostril ! 20 Sod$um hydrlde, o~lness (186 mg) was washed twice with ¦~ hexane (2 ml), suspended in dimethyl formamide (14 ml), and 3S-amino-1-hydroxy-3,4-dihydrocarbostyril hydrochloride (500 mg, 2.33 m mol) was added. The mixture was stirred for 20 minutes ln lce-cooling and then for l hour in room temperature~
WO94/21612 ,~ U(~ PCT/J~4/00434 The mixture was chilled in ice again, and 2-iodo-ethylethylether (513 mg, 256 m mol) was added. The mixture was stirred for 20 minutes in ice-cooling and for 1 hour in room temperature. The solvent was evaporated in vacuo, and to the obtained residue, water (30 ml) was added. The mixture was extracted twice with dichloromethane (30 ml), and the organic layers were combined, washed with saturated saline water ~30 ml) and dried over magnesium sulfate. The solvent was evaporated in vacuo to obtained the captioned compound (522 mg, go~) NMR(270MHz, CDCl3)~ppm:7.40(1H, t, J-8Hz), 7.1a-7.~5(2H, m), 7.05(1H, t, J-8Hz), 4.20-4.35(2H, m), 3~60-3.80(t2H, m), 3.65(lH, dd, J-13,6~z), 3.53(2H, q, J-7Hz), 3.10(1H, dd, J-15,6Hz), 2.86(lH, t, J~15Hz), 1.23(3H, t, J-7Hz) Re~erence Example 89 Preparatlon of 3S-amino-1-methoxymethoxyethoxy-3,4-2Q dihydrocarbostyrll Using l-iodo-2-methoxymethoxyethane, the captioned compound was obtained in the same manner as in Reference .
Example 88.
MMR(270MHz, CDCl~)~ppm:7.37tlH, d, J-7Hz), 7.33(1H, d, J=7Hz), WO 94/21612 i r ~ O ~ PCT/J~4/00434 -1~0- 1 7.20(1H, d, J=7Hz), 7.05(1H, td, J=7.1Hz), 4.68(2H, s), 4.20-4.40(2H, m), 3.75-3.95(2H, m), 3.64(1H, dd, J=13,6Hz), 3.38(3H, s), 3.11(1H, dd, J=15,6Hz), 2.85(1H, t, J=15Hz) Reference Example 90 Preparation of 3S-t-butoxyc rbonylamino-l-methoxy-7-methoxy-3,4-dihydrocarbostyril Using a corresponding starting material, the captioned 1 10 compound was obtained in the same manner as in Reference Example 21.
NMR(270MHz, CDC13)~ppm:7.11(lH, d, J~8~z), 6.79(lH, d, J=2Hz), 6.60(1~, dd, J~8~2Hz), 5.57~lH, brs), 4.33(lH, dt, ~314,6Hz),.
3.92(3H, s), 3-82(3H, s), 3~36(1H, dd, J~14,4Hz), 2.73(1H, t, ¦ J~14Hz), 1.48(9H, s) , ~
Reference Example 91 Preparatlon of 3S-t-butoxycarbonylamino-l-ethoxy-7-methoxy-3,4-dihydrocarbostyrll Using ethyl lodide and a corresponding startin~
material, the captioned compound was obtained in the same manner as in Reference Example 21.
WO94/21612 ;.~ 61 0~ PCT/J~4/00434 NMR(270MHz, CDCl3)~ppm:7.11(lH, d, J=8Hz), 6.79tlH, d, J=3Hz), 6.59(1H, dd, J=8,3Hz), 5.57(1H, brs), 4.31(1H, dt, J=14,6Hz), 4.05-4.25t2H, m), 3.82(3H, s), 3.37(1H, dd, J=15,6Hz), 2.72(1H, t, J=15Hz), 1.49(9H, S), 1.38(3H, t, J-7Hz) s Reference Example 92 Preparation of 3S-t-butoxycarbonylamino-l-methoxyethyl-6,7-methylenedioxy-3,4-dihydrocarbostyr~l Using l-iodo-2-methoxyethane and a corresponding starting material, the captloned compoun~ was obtained in the same manner as ~n Reference Example 24.
,~ .
: NMR(270MHz, DMS0-d6)~pp~:6.89(1H, s), 6.65(1H, s), 5.94(2H, , -~ ~
~ : dd, J1-lHz, J2~2Hz), 5.70(1H, bs), 4.25-4.14(2H, m), 3.93-.
~ 15 3.82tlH, m), 3.62-3.60(2H, m), 3.34(3H, s), 3.29-3.23(lH, dd, , ~ J1-5Hz, J2-14Hz), 2.67(lH, t, J~15~z), 1.47(9H, s) ''~
, ~ , :~
Reference Exampl- 93 ~;; 20 Preparation of 3-benzyloxycarbonylamino-6,7-~- dimethoxy-1-methoxymethyl-3,4-dihydrocarbostyril~
Using methoxymethyl chloride and a corresponding start~ng materlal, the captioned compound was obtained in the same manner as in Reference Example 24.
~ 25 :
WO94/21612 PCT/J~4/00434 3610~
-122- ~
NMR(270MHz, CDC13)~ppm:7.30-7.34(5H, m), 6.96(1H, s), 6.71(1H, s)j 5.96(1H, brs), 5.71(1H, d, J=llHz), 5.15(2H, s), 4.89(1H, d, J=llHz), 4.38(1H, dt, J=14,5Hz), 3.88(3H, s), 3.86(3H, s), 3.40(3H, s), 3.36(1H, dd, J=14~5Hz), 2.76(1H, t, J=14Hz) s Reference Example 94 Preparation of 3-amino-6,7-dimethoxy-3,4-dihydrocarbostyril hydrochloride Using 2-nitro-4,5-d~methoxybenzyl chloride, the captioned compound was obtained in accordance with a method descrlbed in J. Med. Chem. 1972, 15, 325.
NMR(270MHz, DMS06~)~ppm:10.49(1H, s), 8.52(3H, s), 6.92(1H, s), 6.56~1H, s), 4.06-4.16(1H, m), 3.72(3H, s), 3.70(3H, s), 3.12(1H, dd, J-14,7Hz), 2.98(1H, t, Jsl4.Hz) Reference Example 95 Prep ration of 8-methoxy-1-methoxyethyl-3S-tritylamino-3,4-dihYdrOCar~OStYrll Us~n~ l-iodo-2-methoxyethane and a corresponding start~ ng mater~ al, the captioned compound was obtained in the same manner as in Reference Example 24.
.
~ ~ NMR(270MHz~ CDC13)~ppm:7.49-7.45(6H, m), 7.30-7.18(9H, m), WO94/21612 PCT/J~4/00434 !
6.90(1H, t, J=8Hz), 6.74(1H, d, J=8Hz), 6.25(~H, d, J=8Hz), `~
, 4.45(2H, m), 4.14-4.0~(1H, m), 3.80(3H, s), 3.49-3.41(2H, m), '' 3.28(1H, dd, Jl-5Hz, J2=14Hz), 3.23(3H, s), 2.36(1H, t, J=14Hz), 1.28(1H, dd, Jl-5Hz, J2=15Hz) S
I Reference Example 96 ¦ Preparation of l-methoxyethoxy-3S- -triphenylmethylamino-3,4-dihydrocarbostyril ¦ Uslng l~iodo-2-methoxyethane and a corresponding ¦ 10 starting material, the captioned compound was obtained in the ! same manner as in Reerence Exampla 24.
NMR(270MHz, CDC13)~ppm:7~51-7.56~6~, m), 7.22-7.32(11H, m), 6.91(1H, dt, J~2.7Hz), 6.66(1H, d, J-7Hz), 4.23-4.30(1H, m), 15 4.08-4.20~lH, m), 3.95(lH, d, J-3H~), 3.63-3.76(2H, m), ; 3.44(1H, ddd, J-14,5, 3Hz), 3-39t3H, s), 2.33(1H, t, J-14Hz), 1.56(lH, dd, J-14.5Hz) .
¦~ 20 Reference Example 97 Preparation of 3S-amino~l-methoxyethoxymethoxyethoxy-3,4-dihydrocarbostyril -Using l-iodo-2-methoxyethoxymethoxyethane and a correspondlng startlng material, the captioned compound was obtained in the sama manner as in ~eference Example 88.
, WO94/21612 PCT/J~4/00434 i~l3~108 --NMR(270MHz, CDC13)~ppm:7.10-7.45(3H, m), 7.06(1H, td, J=7.2Hz), 4.77(2H, s), 4.20-4.40t2H~ m), 3.7S-3.95(2H, m), 3.45-3.75(5H, m), 3.38(3H, s), 3.11(1H, dd, J=15.6Hz), , 5 2.86(lH, t, JY15Hz3 j Reference Example 98Preparation of 3S-amino-l-methoxye~hoxyethoxy-3,4-dihydrocarbostyril Us~ng 1-~odo-2-methoxyethoxyetane and a corresponding starting material, the captioned compound was obtained in the same manner as in Reference Example 88.
NMR(270MHz, CDC13)~ppm: 7.39(1H, t, J~7~z), 7.10-7.35(2H, m), i 7.05(1H, t, J-7Hz), 4.20-4.40(2H, m), 3.70-3.90(2H, m), 3.50-3.70(5H, m), 3.40(3H, s), 3.1~(1H, dd, J~15.6Hz), 2.86(1H, t, J-15Hz) !
2Q Example l Preparatlon of 3S-t4-(N-hydroxyamino)-2R-isobutyl-succinyl]amino-3~4-dihydrocarbostyril 240 mg of 3S-~4-(N-benzyloxyamino)-2R-isobutyl-~- succinyl]amino-3,4-dihydrocarbostyril was dissol~ed in 10.8 ml of ethanol, and 1.2 ml of cyclohexene and 60 mg of 10%
WO94/21612 ~ PCT/J~4/00434 -125- , palladium-carbon wexe added, and the mixture was stirred for 20 minutes in reflux. Filtering off the catalyst, the filtrate was concentrat~d in vacuo. The residue was purified by column chromatography (silica gel 20 g, chloroform/methanol = 20~1 v/v), and the captioned compound was obtained in a white solid form. Yield: llO mg.
a ]D - -49 ~c~l, methanol) N M R (2 7 O M H z. D M S O - d~ ) ~ p p m : 1 O. 3 8 (1 H. b r s ) ~ 1 O. 2 O (1 H, s) ~ 8. 7 O (1 H. b r s) ~ 8. 1 5 (1 H. d , J = 8 H z) ~ 7. 1 6 (2 H, t, J = 7 H z) ~ 6. 9 O t2 H, d d.
J = 1 6, 8 H z) ~ 4. 4 4 (1 H. d t, J - 1 2, 8 H z) ~ 2. 7 O -3. O O (3 H, m) ~ 2. 1 7 (1 H, d d. J = 1 4, 6 H z) ~ 2. O 4 (1 H. d d. J = 1 4, 7 H z) ~ 1. 4 O - 1. 7 O (2 H. m) ~ 1. O
O - 1. 3 O (1 H. m) ~ O. 8 6 (6 H. d d. J = 1 2, 6 H z) Exampl~ 2 Uslng a corresponding starting material, 3S~ ( N-hydroxyamino)-2R-isobutylsuccinyl~amino-7-methoxy-3,4-d~hydrocarbostyrll was obtained in the same manner as in Example 1.
M R (2 7 O M H z. D M S O - d3 ) ~ p p m : 1 O. 3 6 (1 H, b r s ) ~ 1 O. 1 4 (1 H. s) ~ 8. 7 O tl H. s) ~ 8. 1 3 (1 H. d. J
- 8 H z) ~ 7. O 8 (1 H, d. J = 8 H z) ~ 6. 5 1 (1 H, d d, J =
, WO94/21612 PCT/J~4/00434 61~8 . 8, 2 H z) ~ 6. 4 6 ~1 H, d. J = 2 H z) ~ 4. 4 2 (l H. d t. J
` = 1 3, 8 H ~) ~ 3. 7 0 (3 H, s) ~ 2. 6 5 - 3. 0 0 (3 H, m) ~
2. 1 7 (1 H. d d, J = 1 4, 6 H z) ~ 2. 0 1 (1 H. d d. J = 1 4 , 7 H z) ~ 1. 2 0 - l. 7 0 (2 H, m) ~ l. 0 0 - l. 2 0 (1 H. m ) ~ 0. 8 6 (6 H t d d. J = 1 3, 6 H z) Example 3 Using a corresponding starting material, 3S- r 4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-l-methoxy-3,4-dlhydrocarbostyr~l was obtained in the same manner as in 10 Exampla 1.
t a ] D - -19 ( c~1, methanol ) ~MR (2 7 OMHz. 3MS O--d~ p pm: 1 O. 4 5 (1 H, b r s 8 . 7 1 ( 1 H. b r s ) ~ 8 . 3 6 ( 1 H. d, J = 8 H z ~ ~ 7 . 3 1 ( 2 H. d d, J--1 6, 8 H z ) ~ 7 . 1 6 ( 1 H. d, J = 8 H z ) ~ 7 .
15 O 7 (1 H. t. J=8Hz) ~ 4. 6 O (lH, d t, J- 1 3, 8 Hz) ~
3. 8 2 (3H. s) ~ 2. 8 5--3. 1 5 (2H, m) ~ 2. 7 Q--2. 8 5 ( 1 H . m ) ~ 2 . 1 8 t 1 H . d d . J--1 4 , 6 H z ) ~ 2 . O 1 ( 1 H .
t t. J= 1 4, 8H z) ~ 1. 4 O~ l. 7 5 (2H. m) ~ 1. O O--1.
1 5 (1 ~ O. 8 7 (6 H, t d~ J ~; 1 3, 6 H z) 20 Example 4 Preparatlon of 3S- t 4- ( N-hydroxyamino ) -ZR-isobutyl-3S-acetyLthiomethylsuccinyl]amlno-3,4-dihydrocarbostyril 330 mg of 3S-(4-hydroxy-2R-isobutyl-3S-acetyl-thiomethylsuccinyl)amino-3,4-dihydrocarbostyril was dissol~ed in a mixed solvent of 1 ml of dimethyl formamide and 3.5 ml of WO 94/21612 w 13 610 ~ PCT/J~4100434 -127- ~ ~
dichloromethane, and cooled in an ice bath, and 110 mg of l-hydroxybenzotriazole, 107 ~l of N~methylmorpholine~ and 186 mg of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, and the mixture was further stirred for 1 hour in an ice bath, and a solution of 57 mg of hydroxylamine hydrochloride and 89 ~1 of N-methylmorpholine dissolved in O.S
ml of dimethyl formamide was added. After stirring for l hour in an ice bath, the reaction solution was concentrated in vacuo. The residue was dissolved in lO ml of butanol, and washed in 5 ml of water, and evaporated in vacuum. The residue was purified by column chromatography (silica gel 20 g, chloroform/methanol ~ 20/1 v/v), and the captioned compound was obtain~d in a white solid form. Yield: 45 mg.
t a JD - -49 (c-1, methanol) N M R (2 7 O M H z, D M S O - tB ) ~ P p m : l 0. 6 l (l H, s) ~
l 0. 2 3 (l H, s) ~ 8. 9 2 (l H. s) ~ 8. 5 1 (l H, d. J = 8 H z) ~ 7. 1 0 - 7. 2 0 (2 H, m) ~ 6. 9 1 (2 H. d d, J = l S, 8 H z) ~ 4. 5 1 (l H. C. J = 9 H z) ~ 2. 8 0 - 3. 2 O (4 H. m ) ~ 1. 4 0 - l. 6 0 (2 H. m) ~ O. 8 0 - 1. 0 0 (1 H, m) ~ O.
8 3 (6 H. t d. J = l 2~ 6 H z) Example 5 Preparation of 3S-r4-(N-hydroxyamlno)-2R-lsobutyl-3S-~ mercaptomethylsuccinyl]amino-3,4-dihydrocarbostyril 14 mg of 3S-C4-(N-hydroxyamino)-2~-isobutyl-3S-acetyl-thiomethylsuccinyl]amino-3~4-dhydrocarbos~yril was dissolved in l ml of methanol, and 200 ~l of methylamine 40~-methanol , WO 94121612 PCT/J~4/00434 `~J ~6~0S
solution was dripped. After stirring for 1 hour at room temperature, precipitating crystals were filtered, and the captioned compound was obtained in a white solid form. Yield:
4 mg.
NM R ( 2 7 O MH z . DM S O--d 6 ) ~ P p m: 1 0 . 5 9 ( 1 H , s ) ~
1 O. 1 1 (1 H. s) ~ 8. 9 5 (1 H. s) ~ 8. 5 4 (1 H. d. J=8 H z) ~ 7. 0 5--7. 2 5 (2H, m) ~ 6. 8 2 (2 H. d d, J = 1 6.
8 H z ) ~ 4 . 4 0--4 . 6 0 ( 1 H . m ) ~ 2 . 6 0--3 . 3 0 ( 4 H . m ) ~ 1. 4 5--1. 7 0 t2H. m) ~ O. 8 O--1. 1 0 (1 H. m) ~ û. 8 4 (6H. dd. J=l 2t 6Hz) Example 6 Using a correspondlng starting material, 3S-~4-(N-: hydroxyamlno)-2R-lsobutyl-3S-(2-thienyl~hiomethyl)succinyl]
~ amino-3,4-dihydrocarbostyril was obtained in the same manner j as in Exampla 4.
a ]D ~ 52- (c-l, methanol) N M R (2 7 O M H z. D M S O - d~ ~ ~ p p m : 1 O. 7 0 tl H, s) ~
1 O. 2 2 (1 H. s) ~ 8. 9 5 (1 H, s) ~ 8. 4 7 (1 H. d, J = 7 . ~ H z) ~ 7. 6 0 (1 H. d, J = 4 H z) ~ 7. 1 0 - 7. 2 0 (3 H. m) 7. 0 5 (l H. d d, J = 3. 5 H z) ~ 6. 9 0 (2 H. d d. J = 1 7 . 8 ~ z) ~ 4. 3 7 (1 H. d t. J = 1 4. 7 H z) ~ 2. 8 0 - 3. 2 0 (4 H. m) ~ 1. 4 0 0 1. 6 0 (2 H, m) ~ O. 8 0 - 1. 0 0 (l H.
m) ~ O. 8 2 (6 H. d d, J = 1 O. 6 H z) ' WO94/21612 PCT/J~4/00434 Example 7 Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-3(R
or s)-phthalimidomethylsuccinyl]amino-3,4-dihydrocarbostyril To a 20 ml suspension of dimethyl formamide of 320 mg of 3S-[4-(N-benzyloxyamino)-2R-isobutyl-3(R or S)~phthalimido-methylsuccinyl]amino-3,4-dihydrocarbostyril, 200 mg of 10%
palladium-carbon was added, ~nd hydrogen gas was i~troduced in vacuo, and the mixture was stirred for 2 days. The catalyst was filtered away from the reaction solu~ion by using celite, lO and the flltrate was concentrated in vacuo. Adding 200 ml of methano~ to the cry5talline residue, it was heated and dissolved, and the remaining catalyst was filtered off by uslng cellte. The f iltrate was concentrated in vacuo, and the .
pr~cipitatlng sediment was f iltered and dried, and the ::aptioned compound was obta~ned in a whlte solid form. Yield:
172 mg.
NMR t2 7 OMHz. DMSO--dB ) ~ ~ Pm: 1 O. 4 7 (lH. s) ~
1 O. 1 2 ( 1 H. s ) ~ 8 . 6 B ( 1 H, s ) ~ 8. 5 0 ( 1 H, d. J = 8 H z) ~ 7. 8 8--7. 8 0 (4H. m) ~ 7. 1 6 (2H. t, J=8H z) 6 9 0 ( 2 H. d d . J 1 = 8 H Z . J 2 3 (LH. m) ~ 3. 9 0--3. 8 5 (1 H. m) ~ 3. 50--3. 4 3 llH
, m) ~ 2. 9 7 (2H. d, J~ 1 1 H z) ~ 2. 6 3--2. 5 9 (2H. m ) ~ 1. 6 2--1. 5 3 (2H, m) ~ O. 9 5--0~ 8 1 (7H. m) ~ WO94/21612 PCT/~4/00434 ~ 1~610~
Example 8 Preparation of 3S-[4-(N-benzoyloxyamino)-2R-isobutyl-succinyl]amino-3,4-dihydrocarbostyril 180 mg of 3S-~4-(N-hydroxyamino)-2R-isobutylsuccinyl]
amino-3,4-dihydrocarbostyril was dissolved in a mixed solvent of 2 ml of dimethyl formamide and 2 ml 9f dichloromethane, cooled in a water bath, 220 ~1 of pyridine and 88 -~1 of benzoyl chloride were added, and the mixture was stirred for 30 minutes in an ice bath. The reaction solution was concentrated in vacuo, 30 ml of chloroform was added, and it was washed by lO ml of lN hydrochloric acid and lO ml of water, and dried over magnes$um sulfate, and evaporated in vacuum. To the resldue, lO ml of diethyl ether was added, precipitating crystals were filtered, and the captioned compound was obtained in a white solld form. Yield: llO mg.
N M R (2 7 O M H z. C D C 13 ) ~ ~ p m : 1 O. 4 8 (1 H. b r s) 8. O 8 (2 H. d, J = 7 H z) ~ 7. 7 4 (l H. s) ~ 7. 6 2 (l H.
t, J = 7 H z) ~ 7. 4 6 t2 H, t, J = 7 H z) ~ 7. 1 O - 7. 2 5 ( 2 H. m) ~~7. O l (2 H. t, J = 7 H z) ~ 6. 7 4 (l H. d. J = 7 H z) ~ 4. 5 5 (l H. d t, J = l 4, 7 H z) ~ 3. 4 O ~l H. d d, J = 1 5, 6 H z) ~ 2. 6 5 - 3. 3 O (3 H, m) ~ 2. 4 9 (l H. d d , 3 = 1 5, 3 H z) ~ l. O O - 1. 8 O (3 H. m) ~ O. 9 6 (6 H. d d. J - 1 2, 6 H z) ~ W094/21612 r~l,Jr~,u~
!l .
Example 9 . Preparation of 3-[4-(N-hydroxyamino)-2-piperonyl-succinyl]amino-3,4-dihydxocarbostyril To 10 ml of methanol solution of 49 mg of ~ hydroxylamine hydrochloride, while stirring in ice-cooling, 10 ¦ ml of methanol solution of 66 m~ of potaSsium hydroxide was ¦ added and stirred for 5 minutes, and 3 ml solution of dimethyl formamlde of 100 mg of 3-(4-ethoxy-2-piperonyls~ccinyl) amino-3,4-dihydrocarbostyril was added, and s~irred overnight at r~om temperature. The reaction solution was neutralized with acetic ac~d, the insoluble matter was filtered off, and the filtrate was concentrated in vacuo. The residue was extracted wlth 2Q ml of n-butanol. After washing ~he organic layer three times by water, it was concentrated in ~acuo. The residue was puri~ied by sillca gel preparation ~chloroform:
methanol ~ 7:1), and the capt~oned compound was obtained.
~-~ Yield: 4.47 mg.
,~
- : 20 N M R ( 2 ? O M ~ z . D M S Q--t B ) ~ P p m : 1 0 . 4 0 t 1 H , b r s 1 0. 2 9: (1H. b r s) ~ 8. 7 0 (1H. b r s) ~ 8. 1 7 (1 H
, d. J=8Hz) ~ 7. 1 7 (2H, t, J--7Hz) ~ 6. 9 6--6. 6 1 ~- (SH. m) ~ S. 9 7 (2H, s) ~ 4. 5 1--4. 4 2 (1 H. m) ~ 3.
1 0--2. 6 2 (4H, m) ~ 2. 4 9--1. 9 3 (3H. m) ~ , WU~ O~ PCT/J~4/00434 I Example 10 Preparation of 3S-r4-(N-benzyloxyamino)-2R-isobutyl-3 i 5 (R or S)-phthalimidomethylsuccinyl] amino-3,4-j dihydrocarbostyril 99O mg of 3S-(4-tert-butoxy-2R-isobutyl-3 (R or S)-¦ phthalimidomethylsuccinyl)amino-3,4-dihydrocarbostyril was dissolved in 5 ml of dichloromethane, and 10 ml of 4N hydrogen chloride/dioxane was added, and let stand at room temperature for 2 hours. The reaction solution was concentrated in vacuo, ¦ and the residue was dissolved in 50 ml of ethyl acetate. The ethyl acetate layer was wasAed by saturated brine (2 ti~es), and dried by sodium sulfate anhydride, and concentrated in IS vacuo. The obtalne~ residue was dried and powdered (660 mg).
To 10 ml solutlon o~ tetrahydrofurane of 660 mg of the obtained powder, N-methylmorpholine was added by 1~0 ~1 while cooling and stirring in ice-salt, and 240 ~1 of isobutyl chloroormate was added and stlrred ~or 5 minutes. In ~; 20~ successiQn, addlng lO ml o~ dimethyl formamide of 573 mg of benzyloxyamine, the solution was stirred for 1 hour at room ` temperature whlle maintaining at p~ 8. The reaction solution was con'centratediln vacuo, and 20 ml of water was added to the residue to solidlfy and filter. The crude product was washed t with ethyl acetate and diethyl ether, and the cap~ioned ,' ' .
, : :, : ,:
,~
.
~.
WO94/21612 136~0~
compound was obtained in a white solid form. Yield: 330 mg.
M R (2 7 O M H z, D M S O - d6 ) ~ P P m : 1 1. 1 8 (l H. s) 1 O. 2 4 (l ~.. s) ~ 8. 5 7 (1 H, d, J = 8 H z) ~ 7. 9 2 - 7.
8 4 (4 ~. m) ~ 7. ~ 2 - 7. l 5 (7 H. m) ~ 6. 9 7 - 6. 9 l (2 H. m) ~ 4. 6 7 - 4. 3 7 (3 H, m) ~ 4. O O - 3. 8 5 (1 H. m) ¦ ~ 3. 6 O - 3. 5 O (l H. m) ~ 3. O 3 ~2 H. d, J ~ l O H z) ~ 2 . 7 2 - 2. 6 9 (2 H. m) ~ 1. 5 9 - l. 5 4 (2 H. m) ~ O. 9 8 -I O. 8 3 t7 H. m) t 10 Example 11 ,~
Preparation of 3S-~4-(N-benzyloxyamino)-2R-isobutyl-succinyl]amino-3,4-dihydrocarbostyril 500 mg of S-(3-carboxy-2R-isobutylpropionyl)amino-3,4-dihydrocarbostyril was dissol~ed in 5 ml o dimethyl 15 formam~de, and 329 mg of O-benzylhydroxylamine was added, and I cooled in an ice bath, and 213 mg of l-hydroxybenzotriazole, j - 259 ~1 of N-methylmorphollne, and 368 mg of 1-ethyl-3-t3-dimethylaminopropyl)carbodiimide hydrochloride were added, and the m~xture was stirred for 3 hours in an ice bath and 15 20 hours at room t~mperature. The reaction solution was concentrated in vacuo, and 50 ml of ethyl acstate was added to the resid~e, and it was washed by lO ml of water, lO ml of lN
hydrochloric acid, saturated aqueous solution of sodium hydrogencarbonate (lO ml x ~ times), ànd lO ml of brine, and 25 dried over magnesium sulate, and evaporated in vacuum. The v~ V~ U~ PCT/J~4/00434 residue was purified by column chromatography (silica gel SO
g, chloroform/methanol - 40/1 v/~), and the captioned compound was obtained in a white solid form. Yield: 300 mg.
~JMR (2 7 OMHz, CDC 13 ) ~ P P m : 8. 5 7 (1 H. b r s) ~ 7 . 7 9 (1 H. b ~ s) ~ 7. 3 8 (5H, s) ~ 7. 1 8 t2H. d d! J=
1 4. 7Hz) ~ 7~ 0 1 (1 H. t. J=7Hz) ~ 6. 7 8 ~1 H. d. J
= 7 H z ) ~ 4 . 9 0 ( 2 H. s ) ~ 4 . 4 S--4 . 6 0 ( 1 H. m) ~ 3 . 3 5--3. 5 0 (1 H. m) ~ 2. 8 0--2. 9 8 (1 H. m) ~ 2. 8 0 (1 H
, t, J--1 4Hz) ~ 2. 20--2. 50 (2H, m) ~ 1. 20--1..40 (3H. m) ~ O. 94 (6H, dt, J=16, 6Hz) ::, Example 12 Us~ng a corresponding starting mat~rial, 3S-t4-(N-bensyloxy~mino)-2R-isobutylsuccinyl]amlno 7-methoxy-3,4--d$hydrocarbostyril was obtained in the same manner as in ExamplQ 11.
~ -s, ~
NMR (270M~Hz.: CDC13 ) ~ppm: 8. 90 (lH. s) ~ 8. 4 Z~ 9 ~ 1 H . s ) ~ 7 . 3 4 ( 5 H . s ) ~ 7 . 0 5--7 . 1 5 ( 1 H . m ) ~ 6 . 9~ 9 t l N. d . J = 8 H.z ) ~ 6 . S 1 t l H . d d . J = 8, 2 H z ) ~
- 6. 4 1 (1}~. s) ~ 4. 8 8 ~2H. s) ~ 4. 4 0--4. 5 5 (1 H. m 3 . ? 3 ( 3 H . s ) ~ 3 . 2 5--3 . 4 s t l H, m ) ~ 2 . 9 0 ~ 3 .
1 0 ( 1 H . m ) ~ 2 . 6 6 t l ~I, t, J
~ 1 4 E~ z ) ~ 2 . 1 5--2 . 5 0 ( 2 H . m ) ~ 1 . 5 0--1 . 8 0 ( 2 H .
25 - m) ~ 1. 2 0--1. 4 0 ( l H. m) ~ O . 9 4 ( 6 H. d d . J--1 9, 6 ~:~ H z) '''~'~',:
., ,; - . .
, i ~ , , - ~ ~
wos4nl612 ~ PCT/J~4/00434 Example 13 Using a corresponding starting material, 3S-[4-(N-benzyloxyamino)-2R-isobutylsuccinyl]amino-1-methoxy-3,4-dihydrocarbostyril was obtained in the same manner as in Example 11~
N M R (2 7 O M ~ z. C D C 1.3 ) ~ p p m : 8. 6 9 (l H. s) ~ 7. 3 7 ~5 H. s) ~ 7. 1 5 - 7. 3 5 (~ H. m) ~ 7. 0 7 (1 H. t. J =
7 H z) ~ 6. 6 7 (1 H. d. J = 6 H z) ~ 4. 9 0 t2 H, s) ~ 4. 4 O - 4. 6 0 (1 H. m) ~ 3. 9 2 ~3 H. s) ~ ~. 2 5 - 3. 4 5 (l H
, m) ~ 2. 7 5 - 2. 9 5 (2 ~. m) ~ 2. 2 0 - 2. 5 0 (2 H. m) ~
l. 5 0 - 1. 8 0 (2 H. m) ~ l. 2 0 - 1. 3 5 (2 H, m) ~ O. ~ 3 (6 H, d d. J ~ l 6, 6 H z) ; 15 EXample 14 Preparation of l-hexyloxy-3S-[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsucclnyl]amino-3,4-dihydrocarbostyrll ~; To a lS ml solutlon of tetrahydrofurane of 400 mg of 3S-t4-(N-benzyloxyamino)-ZR-lsobutyl-3S-methylsuccinyl]amino-1-hexyloxy-3,4-dihydrocarbostyril, 150 mg of 10~ palladium-carbon and 1.0 ml of cyclohexene were added and stirred for 30 minutes while refluxing. The catalyst was filtered off from the reaction solutlon by using celite, and the filtrate was concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (eluted in 3~
W094/21612 ~ PCTI~4/00434 methanol/chloroform), and the captioned compound was obtained.
Yield: 250 mg.
M R t2 7 O M H z. D ~ S O - d~ ) ~ p p m : l 0. 4 8 (l H, s) ~
8. 7 6 (1 H. s) ~ 8- 5 5 (l H, d. J - 8 H z) ~ 7. 3 S - 7. 2 7 (2 H. m) ~ 7. l 4 (l H, d, J - 7 H z~ ~ 7. 0 6 (l H, t, J
7 ~ 2) ~ 4. 6 3 - 4- 5 8 (1 H, m) ~ 4. 0 0 (1 H, d, J = 7 H
z) ~ 3. 9 7 (1 H. d. J = 7 H z) ~ 3. 0 6 (1 H. t, J = 1 3 H z ) ~ 2. 9 4 (1 H. d d. Jl ~ 7 H Z~ J2 = 1 6 H z) ~ 2. 5 l - 2.
4 5 tl H. m) ~ 2~ 2 0 - 2. 1 3 (l H. m) ~ l. 7 1 - l. 2 7 tl O H. m) ~ O. 9 7 (3 H. d. J - 7 H z) ~ O. 9 2 - O. 8 0 (l O H
, m) I Example 15 ¦ Preparat$on of 1-(4-cyanobenzyl)-3S-[4-(N-hydroxy-I:~ amino~-2R-isobutyl-3S-methylsucrinyl]amino-3,4-dihydrocarbostyril ¦ After conducting a reaction between the compound of Reference Example 24 and a corresponding staring material, the capt~oned compound was obtained in the same manner as in Example 16.
20 N M R ~ ~ 7 O M H z, D M S O--d ~ p m : l O . 4 9 ( l H . s ) 8 . 7 7 ( 1 H. s ) ~ 8 . 5 4 ( 1 H, d . J = 9 H z ) ~ 7 . 8 O ( 2 H, : d. J--8 H z) ~ 7. 4 3 (2H, d, J=8 H z) ~ 7. 2 9 tl H. d.
J = 7 H z ) ~ 7 . 1 7 ( 1 H. t . J = 8 H z ) ~ 7. 0 0 (l H. t. J -7H z) ~ 6. 9 O (1 H. d. J=8H z) ~ 5. 3 O (l H. d. J= l 7 Hz) ~ 5. 1 9 (lH, d. J--1 7E~z) ~ 4. 7 5--4. 7O (1H. m 3 . 1 5 ( 1 E~ , ~ , J = 1 5 H z ) ~ 3 . O O ( 1 H . d d ~ J 1 = 6 H
Z~ J2 =1 5Hz) ~ 2. 5 5--2~ 4 9 (l H~ m) ~ 2. 2 l--2. l 5 WO 94/21612 ~'~ 13 ~ PCT/JP94/00434 (1 H. m) ~ 1. 5 8 - 1 ~ 4 3 ( 2 H . m ) ~ 0 . 9 9 ( 3 H , d . J = 7 H ~) ~ 1. 0 1 - 0. 7 9 (1 H. m) ~ 0. 8 3 ( 6 H . d d . J 1 = 7 H
z J - 1 8 ~ z) Example 16 Preparation of 1-(5-chloro-2-thienylmethyl)-3S-t4-~N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]amino-3,4-dihydrocarbostyril To 920 mg of 3S-(4-t-butoxy-2R-isobutyl-3S-methyl-succinyl~amino-l-(5-chloro-2-thienylmethyl)-3,4-dihydrocarbostyril obtained in the same manner as in Reference Example 22 by using a corresponding starting material, 5 ml of tr~fluoroacet~c acid was added to dissolve, and let stand at room temperature for 90 minutes. The reac~ion solution was : concentrated in vacuo, and the obtained oily residue was extracted in ~0 ml of ethyl acetate. The ethyl acetate layer : was washed three times ~n saturated brlne, dried over .~ .
magnesium sulfate anhyd~ide, and concentrated in vacuo. The obtalned resldue was drled (790 mg). To a 10 ml solution of ~ tetrahydrofurane of 390 mg of the obtained compaund, while : 20 cooling and stirring in ice/salt, 126 ~1 of N-methyl-morpholine and 111 ~1 of isobutyl chloroformate were added, and the mixture was stirred for 15 minutes. To the reaction solution, 195 mg of 0-(t-butyld~methyl5ilyl)hydroxyamine was added, and stirred overnight at room temperature. The in oluble matter was filtered off from the reaction solution, WO94/21612 PCT/J~4/00434 ; ~3~;~G~
and 4 ml of acetic acid and 4 ml of water were added to the filtrate, and stirred for 3 hours at room temperature. The reaction solution was concentrated in vacuo, and the obtained residue was dissolved and extracted in 50 ml of ethyl acetate.
The ethyl acetate layer was washed three times in saturated brine and two times in water, and concentrated in ~acuo. The obtained resldue was purified by silica gel column chromatography (eluted in 3~ methanol/chloroform), and ~he captioned compound was obtained in a white solid form. Yield:
170 mg.
NMR (2 7 OMHt. DMSO--d6 ) ~ P Pm: 1 O. 4 8 ~l H. s) ~
8. 7 6 (l H. s) ~ 8. 5 2 (l H. d. J=8 H z) ~ 7. 2 g--7. 2 5 ( 3 H. m) ~ 7 . 0 6--7 . 0 0 ( 2 H, m) ~ 6 . 9 4 ( l H. d . J =
4 H z) ~ 5. 2 3 t2H. d. J ~ 3 ~I z) ~ 4. 6 2--4. 5 7 (l H. m ) ~ 3 . 0 4 ~t 1 H. t . J = 1 4 H z ) ~ 2 . 9 3 ( 1 H. d d J 1 = 6 E~
Z ~ J 2 = l 5 H z ) ~ 2 . 5 4--2 . 4 7 t l H . m ) ~ 2 . 2 0--2 . l 4 - ( 1 H. m) ~ 1. 6 0--l 4 2 ( 2 H, r~) ~ O . 9 8 ( 3 H, d, J _ 7 z) ~ l. O 0--0. 8 0 (1 H. m) ~ O. 8 5 (6 H. d d. Jl = 6 H
Z' J2 = 1 7H z) Example 17 Preparation of 3s-t4-(N-hy`droxyamino)-2R-isobutyl-3 methylsuccinyl]amlno-3,g-dihydrocarbostyril Using a correspondlng starting material, the captioned compound wa9 obtalned in the 9~me manner as in Example 14.
WO 94/Z1612 ~ ~ PCT/JP94/00434 NM R ( 2 7 0 MH z, DM S O--d 6 ) ~ P P m: l 0 . 4 8 ( 1 H. s ) ~
1 0. 1 8 (l H. s) ~ 8- 7 5 (I H. s) ~ 8~ 3 7 ( 1 H, d . J = 8 H z) ~ 7. 2 0--7. 1 3 (2 H~ m) ~ 6. 9 5--6. 8 6 (2 H. m) ~
4 . 5 l --4 . 4 6 ( 1 H. m) ~ 2 . 9 9--2 . 9 3 ( 2 H, m) ~ 2 . S 1 --2. 4 4 (I H, m) ~ ~. 2 0--2. 1 4 (l H. m) ~ 1 . 6 0--! . 4 0 ( 2 H. m) ~ 0. 9 7 ( 3 H. d . J = 7 ~ z ) ~ 0 . 9 8--0 . 8 0 ( 1 H, m) ~ O. 8 4 (6 H. d d. Jl ~ 6 H Z~ J2 = l 5 H z) Example 18 Preparation of 1-hydroxy-3S-~4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]amino-3,4-dihydrocarbostyril After conducting a reaction between the compound of Reference Example 26 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 14.
N M R (2 7 O M H z, D M S O - dB ) 8 P P m : l 0. 4 g (2 H. b s) . 7 6 (1 H. s) ~ 8. 5 4 (1 H. d. J = 8 H zj ~ 7. 3 2 - 7.
2 0 (3 H. m~ ~ 7. 0 l (l ~, e d. J1 = 2 H Z~ J2 - 7 H z) ~ 4 . 6 4 - 4. 5 4 (1 H. m) ~ 3. 0 6 (l H, t, J = l 5 H z) ~ 2. 9 3 (1 H. d d. il ~ 7 H Z~ J2 = l 6 H z) ~ ~. 5 l - 2. 4 5 (L H
, m~ ~ 2. 2 0 - 2. l 4 ~1 H. m) ~ l. 6 5 - 1. 4 2 (2 H. m) ~
9 8 (3 ~- d- J = 7 H z) ~ l. O O 0.... 8 0 tl H. m) ~ O- 8 5 (6 H~ d d, Jl = 7 ~ Z' J2 ~ l 6 H Z) Example 19 Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-3S-m~thylsuccinyl]amino-l-methoxy-3,4-dihydrocarbostyril Using a corresponding starting material, the captioned W094121612 PCT/J~4/00434 ~36 1~8 -140- . I
compound was obtained in the same manner as in Example 14.
M R (2 7 O M H z. D M S O - d6 ) ~ P p m : 1 O. 4 8 (1 ~, s) 8. 1 6 tl H. s) ~ 8. 5 5 (1 H, d, J = 8 H z) ~ 7. 3 6 - 7. 2 B (2 H. m) ~ 7. 1 6 t1 H. d, J = 8 H z) ~ 7. 0 7 tL H, t. J
= 7 H z) ~ 4. 6 6 - 4. 6 1 tl H. m) ~ 3. 8 3 (3 H, s) ~ 3. 0 6 2. 9 3 (2 H. m) ~ 2. 5 2 - 2. 4 4 (1 H. m) ~ 2. 2 0 - 2.
L 3 (1 H. m) ~ 1. 5 7 - 1. 4 2 ~2 ~. m) ~ O. 9 7 (3 K. d, J
= 7 H z) ~ O. 9 8 - O. 8 1 (1 H. m) ~ O. 8 4 (6 H. d d. J1 =
10 6 H z, J2 = 1 4 H z) Example 20 Preparation of 7-chloro-1-ethoxy-3S-~4-(N-hydroxy-amino)-2R-isobutyl-3S-methylsuccinyl]am~no-3,4-dihydrocarbostyril After conducting a reactlon between the compound of Reference Example 27 and a corresponding starting material, the captloned compound was obtalned in the ~ame manner as in Exampl~ 14.
N M R (2 7 O M H z. D M S O - d~ p m : 1 O. 4 8 (l H. s) 8. 7 7 (1 H. s) ~ 8- 5 8 (1 H, d, 3 = ~ H z) ~ 7. 3 2 (1 H.
d. J = 8 H z) ~ 7. 1 3 - 7- 0 9 t2 H, m) ~ 4~ 6 3 - 4. 5 9 tl H, m) ~ 4. 0 6 (2 ~. q. J = 7 H z) ~ 3. 0 4 - 2. 9 5 (2 H. m ) ~ 2. 5 1 - 2. 4 3 (1 H. m) ~ 2. 1 9 - 2. 1 2 (1 H, m) ~ 1.
6 9 - 1. 4 1 (2 H. m) ~ 1. 2 8 (3 H, t, J = 7 H z) ~ O. 9 7 ( 3 H. d. J . 7 ~ z) ~ O. 9 8 - O. 8 0 (1 H, m) ~ O. 8 3 (6 H.
d d. J1 = 7 H Z~ J2 = 1 2 H 2) WOg4/21612 ~.~ <~ PCTIJ~4/00434 Example 21 Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-succinyl]amino-1-isobutoxy-3,4-dihydrocarbostyri.l After conducting a reaction between the compound of Reference Example 28 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
NMR (2 7 OMH z. DMS --d6 ) ~ ~ Pm: l 0. 3 8 ~ l H. s) ~
8. 7 l (l H. s) ~ 8. 3 5 ( l H, d. J--8 H z) ~ 7. 2 5--7. 4 - O (2H, m) ~ 7. 1 5 (1 H. d. -J=7H z) ~ 7. 0 6 (1 H. t. J
=7Hz) ~ 4. 50--4. 70 (1H, m) ~ 3. 7 8 (2H, d t. J=2 2, 7Hz) ~ 2. 70--3. l O (3H. m) ~ 2. l 7 (1 H. d d. J=
l 4, 6 H z ) ~ l . 9 0--2 . l 5 ( 2 H, m) ~ l . 4 O--l . 7 5 ( 2 H
, m) ~ l . O O--l . 2 0 ( l H, m) ~ O. 9 9 ( 6 H. d d, J = 6, 3 1~ }Iz) ~ O. 87 (6H. td. J 81 2, 6Hz) ; ~ Example 22 ~reparation of l-ethoxy-3S-t4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]amino-3,4-dihydrocarbostyril After conducting a reaction between the compound of - Referencs Example 29 and a correspondlng starting material, the captloned compound was obtained ln the same manner as in Example 14.
.
wos4nl6l2 PCT/J~4/00434 0 ~ -142-M R (Z 7 O M H z, D M S O - dB ) ~ P p m : 1 O. 4 9 (! H, s) 8. 7 7 (I H. s) ~ 8- 5 7 (l H. d, J = 8 H z) ~ 7. 3 l (2 H.
t. J = 8 ~ z) ~ 7. 1 6 (1 H, d, J - 8 H z) ~ 7. 0 6 (l H. ~.
J = 8 H z) ~ 4. 5 4 - 4. 6 6 (1 H. m) ~ 4. 0 5 (2 H. q, J = t H z) ~ 2- 9 6 - ~- 0 7 (2 H. m) ~ 2. 4 9 - 2. 5 2 (l H. m) 2. 1 Z - 2. 2 0 (l H. ~) ~ 1. 4 0 - 1. 5 8 (2 H. ~) ~ 1. 2 8 (3 H. t, J = 7 H z) ~ O. 9 8 (3 H. d. J = 7 H z) ~ O. 9 8 - O
. 8 4 (1 H. m) ~ O. 8 4 (6 ~. d d. J = 1 3, 6 H z) Example 23 Prepa~ation of 3R-t4-(N-hydroxyamino)-2R isobutyl- .-succinyl]amino-l-methoxy-3,4-d~hydrocarbostyril Us~ng a corresponding starting material, the captioned compound was obta~ned in the ~ame manner as in Example l.
~ M R (2 7 Q M H z, D M S O - d~ ) ~ P P m : l 0. 4 2 (l H, s) 8. 7 6 (l H. s) ~ 8- 5 1 tl H. d. J = 8 H z) ~ 7. ~ 2 (2 H, d d. J = 1 6, 8 H z) ~ 7. 1 6 (l H. d. J = 8 H z) ~ 7. 0 7 (l H, ~, J = 8 H z) ~ 4- 5 8 (1 H. q. J - 8 H z) ~ 3. 8 3 (3 H, s) ~ 2. 7 0 - 3- 1 0 (3 H, m) ~ 2. 2 2 (1 H, d d. J = l 5, 5 H z) ~ 2. 0 2 (l H. d d. J = 1 5, 9 H z) ~ 1. 4 0 - l. 6 0 (2 ~, m) ~ O. 9 5 - l. 2 0 (l H, m) ~ O. 8 4 (6 H. d, J = 6 H z) Example 24 Preparation of 3R-t4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]amino-l-methoxy-3,4-dihydrocarbostyril Using a corresponding starting material, the captioned WO94/21612 ,~ o PCT/J~4100434 compound was obtained in the same manner as in Example 14.
M R (2 7 O M H z, D M S O - d3 ) ~ P P m : 1 0. 4 8 (1 H, s) 8. 7 6 (l H. s) ~ 8- 6 1 (1 H, d. J = 8 H z) ~ 7. 2 5 - 7. 4 0 (2 H. m) ~ 7. 1 6 (1 H. d, J = 8 H z) ~ 7. 0 7 (1 H. t, J
= 8 H z) ~ 4. 6 6 tl H. d t, J = 1 3, 8 H z) ~ 2. 8 0 - 3. 1 0 (2 H. m) ~ 2. 4 0 - 2- 6 0 (L H, m) ~ 2. O 5 - 2. 3 0 (1 H, m) ~ l. 3 0 - l. 6 0 (2 H. m) ~ l. 0 1 (3 H. d, J = 7 H z) O. 7 5 - 1. 0 5 (1 H, m) ~ 0. 8 1 (6 H, d d, J = 6, 4 H z) Example 25 Preparat~on of l-ethoxymethyl-3(R or S)-~4-(N-~: hydroxyamino)-2R-~sobutylsucclnyl]amino-3,4-dihydrocarbostyrilAfter conducting a reaction between the compound obtained by catalytic reductlon treatmen~ of ~he compound of Ref~rence Example 30 and a corresponding starting material, the captioned compound (dlastereomer l.l mixture) was obtained - ln the qame manner as in Exampl~ 1.
NMR (2 7OMHz. DMSO--d~ ) ~ PPm: 1 O. 4O (1H. b s) :~ 20 ~ 8. 7 6 * 8. 7 2 (1 H. s) ~ 8. 4 4 + 8. 2 8 (l H. d, J = 8 H
.
-- ~ z ) ~ 7 . 2 9--7 . 2 6 (3 H. m~ ~ 7 . O 9--7 . O 3 ( 1 H, m) ~ S
5 6 + 5 . 5 4 ( l H. d . J = I 1 H z ) ~ 5 . O 2 + 5 . O 1 t 1 H, d.
, J = 1 1 H z) ~ 4. 5 3 - 4. 4 8 (1 H . m ) ~ 3 . 5 1 ( 2 H . ~ . J
= 7 H z) ~ 3. 0 0 - 2 . 8 2 ( 3 H, m) ~ 2 . 2 5 - 1 . 9 8 ( 2 H, m ) ~ 1 . 7 O - 1 . 4 5 ( 2 H. m) ~ l. l l (3 H. t, J = 7 H z ) ~ 1 . 1 4 - 1. 0 7 ~l H. m) ~ 0. 9 l - 0. 8 3 (6 H. m) W~94/21bl2 PCT/J~4/00434 ~ ~ 3 6 ~ 144-Example 26 Preparation of l-hexyloxymethyl-3S-~4-(N-hydroxy- c 5 amino)-~R-isobutylsuccinylJamino-3,4-dihydrocarbostyril After conducting a reaction between the compound obtained by ca~alytic reduction treatment of the compound of Reference Example 31 and a corresponding starting material, the captionad compound was obtained in the same manner as in 1~ Example 1.
N M ~ (2 7 O M H z. D M S O - d~ ) ~ p p m : l 0. 3 8 (1 H. s) 8. 7 1 (1 H. s) ~ 8~ 2 8 (l H. d. J = 8 H z) ~ 7. 2 7 (3 H, t. J - 6 H z) ~ 7. 0 6 (l H. t d. Jl = 2 H Z~ J2 = 8 H z) ~ 5 . 5 4 (1 H. d. J = 1 1 ~ z) ~ 5. 0 2 ~1 H, d, J = l 1 ~ z) ~ 4 . 5 6 - 4. 4 S (1 H. m) ~ 3. 4 5 (2 H. t, J = 6 H z) ~ 3. 0 0 - 2. 8 0 (3 H. m) ~ 2. l 8 (1 H. d d. Jl = 6 H Z~ J2 = l 4 z) ~ 2. 0 2 (1 H. d d, Jl = 8 H Z~ J2 ~ 1 5 H 2~ ~ l. 7 5 - l . 5 5 (l H. m) ~ 1. 5 4 - l. 4 5 t3 H. m) ~ l. 2 0 - 1. 0 7 ( 7 H. m3 ~ O. 9 1 - O. 7 8 (9 H, m) 20 EXample 27 Preparatlon of 3S-[4 (N-hydroxyamino)-2R-isobutyl-succinyl]amino-1-methoxymethyl-3,4-dihydrocarbostyril Af~er conducting a reaction between the compound obtained by catalytic reduction treatment of the compound of 25 Reference Example 32 and a corresponding starting materia~, WO 94t21612 PCT/JW4/00434 the captioned compound was obtained in the same manner as in Example 1.
N M R (2 7 O M H z. D M S O - d~ ) ~ P P m : 1 O. 3 9 tl H. b r s ) ~ 8. 7 1 (1 H. b r s) ~ 8. 2 9 (1 H. d. J = 7 H z) ~ 7. i 5 - 7. 3 5 (3 H. m) ~ 7. 0 7 (1 H. ~, J = 7 H z) ~ 5. 4 9 (1 H
, d. J = 1 0 H z) ~ 5. 0 0 (1 H, d, J ~ 1 0 H z) ~ 4. 5 2 (1 H
, d t. J = 1 4, 7 H z) ~ 3- 2 6 (3 H. s) ~ 2. 7 0 - 3. 1 0 (3 H. m) ~ 2. 1 8 (1 H. d d. J = 1 4, 6 H z) ~ 2. 0 2 (l H. d d , J =.1 4, 8 H z) ~ 1. 3 5 - 1. 7 5 (2 H, m) ~ 1. 0 0 - 1. 2 0 (1 H. m) ~ O. 8 8 t6 H. d t. J = 1 4, 6 H z) Example 28 Preparation of l-benzyl-35-t4-(N-hydroxyamino)-2R-~sobutylsuccinyl]amino-3,4-dihydrocarbostyr~l After conductlng a react~on between the compound obtained by trlfluoroacetlc acid treatment of the compound of Reference Example 33 and a corresponding starting material, the captioned compound was obtalned in the same manner as in ~xample 1.
N M R (2 7 0 M H z. D M S O ~ d~ ) ~ p p m : 1 O. 3 9 (1 H. s) ~
~- ~ 8. 7 2 tl H. s) ~ 8. 3 1 (1 H, d. J = 8 H z) ~ 7. 3 4 - 7- 1 4 (8 ~. m) ~ 6. 9 8 (1 H. t, J - 8 H z) ~ 5. 2 2 (1 H. d, J
= 1 6 H z~ ~ 5. 1 0 (1 H. d . J = 1 6 H z) ~ 4. 6 9 - 4. 5 9 (1 - H. m) ~ 3. 0 7 D 2. 9 7 t2 H. m) ~ 2. 8 1 - 2. 7 5 (1 H. m) ~ 2. 2 0 (1 H. d d ~ J 1 = 7 H Z ~ J 2 = 1 5 H z ) ~ 2. 0 3 (1 H.
t d. Jl - 8 H z, J~ = 1 5 H z) ~ 1. 6 5 - 1. 4 5 (2 H. m) ~ 1 , 1 4 - 1. 0 7 (1 H, m) ~ O. 8 7 1 (6 H. d d. il = 7 H Z~ J2 - 1 6 H z) wO94n1612 PCT/J~4/00434 ~.361~
Example 29 Preparation of 3S-[4-(N-hydroxyamino)-2R-isobutyl-succinyl]amino-1-(4-methoxycarbonylbenzyl)-3,4-dihydrocarbostyril Using the compound obtained by trifluoroacetic acid treatment of the compound of Reference Example 34 and a corresponding starting material, the captioned compound was obta~ned in the same manner as in Example 1.
N M R (2 7 0 M H z. D M S 0 - d~ ) ~ p P m : l 0. 3 9 tl H, s) 10 8. 7 2 ~1 H. s) ~ 8. 3 3 (1 H. d. J = 7 H z) ~ 7. 9 1 (2 H.
d. J = 8 H z) ~ 7. 3 7 t2 H, d. J = 8 H z) ~ 7. 2 7 (1 H. d.
J = 7 H z) ~ 7. 1 6 (l H. t, J = 7 H z) ~ 7. 0 0 (l H. t, J =
7 H z) ~ 6. 9 1 (1 H. d. J = 8 ~ z) ~ 5. 3 0 (l H. d. J = l 7 l5 H z) ~ 5. l 7 (1 ~. d. J = 1 7 H z) ~ 4. 7 3 - 4. 6 3 (l H. m ) ~ 3. 8 3 (3 H. s) ~ 3. 0 9 - 2. 9 9 (2 H. m) ~ 2. 8 8 - 2.
7 3 (1 H, ~) ~ 2. 2 0 (1 H. d d. Jl = 7 H Z- J2 = l 5 H ~) ~
2. 0 3 (1 H. d d. Jl = ~ ~ 2, J 2 - 1 5 H z ) ~ 1 . 6 5 - 1 . 4 6 :~ (2 H. m) ~ 1. 1 3 - l- 0 7 (l H. m) ~ 0. 8 7 (6 H. d d, Jl : 20 6 H Z~ J2 = 1 5 H z) Example 30 Preparation of 1-(4-carboxybenzyl)-3(R or S)-[4~(N-hydroxyamino)-2R-isobutylsuccinyl~amino-3,4-dihydrocarbostyril To a mixed solut~on of 5 ml of methanol and 5 ml of 25 tetrahydrofurane of 200 mg of 3S-~4-(N-benzyloxyamino)-2R-W094/21612 "l.5 n 1 ~ ~ PCT/J~4/00434 isobutylsuccinyl]amino-l-(4-methoxycarbonylbenzyl)-3,4-dihydrocarbostyril, 2.0 ml of lN sodium hydroxide was added at room temperature, and stirred overnight. The reaction solution was neutralized by adding lN hydrochloric acid, and concentrated in vacuo. To the obtained residue, 20 ml of e~hyl acetate and 20 ml of water were added, and the solution was shaken to separate the water layer, and the ethyl acetate layer was washed once ~n saturated agueous solution of sodium hydrogencarbonate. The water layer and saturated aqueous s~lution of sodium hydrogencarbonate were put together, stirred in ice-cooling, and the pH was ad~usted to 2 by lN
hydrochloric acid, and the solution was extracted in 30 ml of ethyl acetate. The ethyl acetate layer was washed twice in ¦ saturated brine, dried over sodium sulfat~ anhydride, and concentrated in vacuo. To the obtalned crystalline residue, diethyl ether was added, flltered and dr~ed. Yield: llO mg.
Thu-~ obtalned compound was operated by the same manner ; as in Example l, and the captloned compound (diastereomer l:l ¦ mixture~ was obtaln~d.
N M R (2 7 O M H z. D M S O - d~ ) ~ P P m : I 2. 8 5 (1 H. b s) ~ I 0. 4 I + I 0. 3 9 (I H. s) ~ 8. 7 5 + 8. 7 2 tl H. s) ~ 8 ; . 4 9 + 8. 3 3 (l H. d. J = 8 H z) ~ 7. 8 8 (2 H. d. J = 8 H z ) ~ 7. 3 4 t2 H. d. J = 7 H z) ~ 7. 2 8 (I H. d. J = 8 H z) ~
7. I 1 (l H. t. J = 7 H z) ~ 7. 0 2 - 6. 9 I (2 H, m) ~ S. 3 I (I H, d. J = 1 1 H z) ~ 5- I 6 (l H. d. J = I 7 H z) ~ 4. 7 O - 4. 6 2 (l H. m) . 3- 0 8 - 2- 8 I (3 H. m) ~ 2. 2 2 (I H
WO94/21612 ,~ lU ~ PCT/~4/00434 , d d. Jl = 5 H Z~ J2 = l S H z) ~ 2. 0 3 (1 H, d d. il - 9 H
Z~ J2 = 1 S H z) ~ 1. 5 4 - l. 4 4 (2 H, m) ~ 1. 1 2 - 1. 0 3 (1 H. m) ~ 0. 9 0 - 0, 8 2 (6 H, m) Example 31 Preparation of 3S-t4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl~amino-1-(4-methoxybenzyl)-3,4-dihydrocarbostyril After conducting a reaction between the compound of Reference Example 35 and a corresponding starting material, the captioned ~ompound was obtained in the same manner as in Example 14.
~IMR (2 7 OMHz. DMSO--d3 ) ~ ~ ~m: 1 O. 4 8 (1 H. s) 8. ~ 6 (lH. s) ~ 8. 5 1 (lH, d. J=8Hz) ~ 7. 2 6 (1 H.
d . J = 8 ~I z ) ~ 7 . 1 9--7 . 1 4, ( 3 H, m) ~ 7 . O L--6 . 9 5 ( 2 H. m) ~ 6 . 8 7 ( 2 H, d . J = 9 EI z ) ~ 5 . 1 0 ( 2 H, b s ) ~ 4 .
6 8--4 . 6 3 ( 1 H. m) ~ 3 . 7 0 ( 3 H. s ) ~ 3 . 0 9 ( 1 H, t . J
= 1 5 H z ) ~ 2 . 9 6 ( 1 H. d d . J 1 = 6 ~ Z ~ J 2 1 5 - ~ 5 6--2 . 4 9 ( 1 H . m ) ~ 2 . 2 2--2 . 1 6 ( 1 H . ra ) ~ 1 . 5 8--1 . 44 (2H. m) ~ 1. 0 1--O. 80 (lH, m) ~ O. 9 9 (3H. d, J=7Hz) ~ O. 8 5 (6H. t d. Jl =6 H z. J~ --1 9Hz) Example 32 Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-succinyl]amlno-l-phthalimidomethyl-3,4-dihydrocarbostyril After conducting a reaction between the compound WO94/21612 ~ PCT/J~4/00434 ob~ained by trifluoroacetic acid treatment of the compound of Reference Example 36 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
N M R t2 7 O M H z, D M S O - d6 ) ~ P P m : 1 0. 3 6 (1 H, s) ~-8. 7 l (1 H. s~ ~ 8- 3 6 (1 H. d. J = 8 H z) ~ 7. 8 4 (4 H.
s) ~ 1. 2 5 (3 H. s) ~ 6. 9 0 - 7. l O (1 H. m) ~ 6. 0 5 (1 H. d. J = 1 4 H z) ~ 6. 6 6 (l H, d. J = 1 4 H z) ~ 4. 4 7 (l - H. q, J = 8 H z) ~ 2. 7 0 - 3. 0 O (3 H. m) ~ 2. 1 8 (l H. d 0 d. J = l 4, 7 H z) ~ 2. 0 l (l H, d d. J = l 4, 7 H z) ~ l. 4 O--1 . 8 0 t 2 H . m ) ~ 1 . O O--1 . 2 5 ( 1 H , sn ) ~ O . 8 8 ( 6 H
, d d. J = l 7, 6 H z) -~ Example 33 ~ Preparation of l-ethoxycarbonylmethyl-3S-~4-( N-1~ ~
1~ 15 hydroxyamino)-2R-isobutylsuccinyl~amino-3,4-dihydrocarbostyril 1, After conducting a reactlon between the compound obtalned by trifluoroac-tic acld treatment of the compound of Reference Ex~ample 37 and a corresponding starting materiait the captioned compound was obtained in the same manner as in 20- Exampl~ 1.
NM:R (2 70MHz. DMS O--d~P pm: 1 0. 3 7 (1 H, s) 8. 7 1 tlH. s) ~ 8. 2 9 (1 H.d, J--8H z~ ~ 7. 2 6 (2H, ~ 1 ,-, i .
. ~ t. J=7Hz) ~ 7. 0 6 (1 H. t.J=7 H z) ~ 6. 9 7 (1 H. d.
J=7H z) ~ 4. 8 0 (1 H. d. J= 1 7H z3 ~ 4. 5 6 (1 H. d. J
= 1 7 H z ) ~ 4 . 4 2--4 . 6 5 ( 1 H . m ) ~ 4 . 1 4 ( 2 H . ~ . J = 7 [~ H z ) ~ 2 . 7 0--3 . 1 0 ( 3 H. m) ~ 2 . 1 9 ( 1 H. d d, J = 1 4, ",, ~ ~ , WO94/21612 !'i; PCTtJ~4/00434 ~15Q-7 H z) ~ 2. O 1 (1 H, d d. J = 1 4, 7 H z) ~ 1. 4 O - 1. 7 8 ( 2 H. m) ~ 1. 2 0 (3 H. t. J - 7 H z) ~ 1. 0 0 ~ 1. 2 5 (1 ~.
m) ~ O. 8 7 (6 H, d d. J - I 5, 6 H z) Example 34 Preparation of 3S-[4-(N-hydroxyamino)-2R-isobutyl-succinyl]amino-1-carboxymethyl-3,4-dihydrocarbostyril Using 3S-~4-(N-benzyloxyamino)-2R-isobutylsuccinyl]
amino-l-ethoxycarbonylmethyl-3,4-dihydrocarbostyril obtained in the same manner as in Example 11 by using a corresponding starting material, the captioned compound was obtained in the same manner as in Example 30.
N M R (2 7 O M H z~ D M S O - d~ ) ~ P P m : 1 O. 4 O tl H. s) ~
8. 7 5 (1 H. b r s) ~ 8. 2 1 (1 H. d. J - 7 H z~ ~ 7. 2 1 (2 H. t. J - 7 H z) ~ 6. 9 8 (1 H, t. J = 7 H z) ~ 6. 8 8 (1 H.
d. J = 7 H z) ~ 4. 5 6 ~1 H. d, J = 1 7 H z) ~ 4. 4 7 (1 H, d t. J = 1 4, 7 H z) ~ 4- O 6 (1 H. d. J = 1 7 H z) ~ 2. 6 5 - 3 . O 5 (3 H, m) ~ 2. 1 8 tl H, d d. J = 1 4, 7 H z) ~ 2. O 1 ( 1 H. t d. J = 1 4, 8 H z) ~ L. 4 O - 1. 7 S (2 ~. m) ~ 1. 0 O
', - 1. 2 0 (1 H. m) ~ O. 8 7 (6 H, d d, J = 1 6r 7 H z) 2~
Example 35 Preparation of 7-chloro-1-ethoxycarbonylmethyl-3S-~4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-3,4-dihydrocarbostyr~l After conducting a reaction between the compound W094121612 ' I ~ 6 I Q 8 PCT/J~4/00434 obtained by trifluoroacetic acid treatment of the compound of Reference Example 38 and a corresponding s~arting material, the captioned com~ound was obtained in the same manner as in Example 1.
S N M R (2 7 O M H z. D M S O ~ d6 ) ~ P P m : 1 O. 3 8 (1 H. s) 8. 7 1 (1 H. s) ~ 8- 3 3 (1 H. d, J = 8 H z) ~ 7. 3 1 (1 H, d. J = 7 H z) ~ 7. 1 0 - 7. 2 0 (2 H, m) ~ 4. 7 9 (1 H, d, J
= 1 8 H z) ~ 4. 6 3 (1 H. d, J = 1 8 H z) ~ 4. 4 5 - 4. 6 0 (1 H. m) ~ 4. 1 4 (2 H. q. J = 7 H z) ~ 2. 6 0 - 3. 1 0 (3 H. m ) ~ 2. 1 7 (1 H. d d. J ~-1 4, 6 H z) ~ 2. 0 1 (1 H, d d. J =
1 4, 7 H z) ~ 1. 2 0 - 1. 7 5 (2 H. m) ~ 1. 2 1 (3 H, t, J -7 H z) ~ 1. 0 0 - 1. 2 0 (1 H. m) ~ O. 8 6 (6 H. d d, J = 1 4 I` ~
~ , 6 H ~) : :
Example 36 Preparatlon of 3S-~4-(N-hydroxyamino)-2R-isobutyl-succlnylJa~lno-l-propoxycarbonylmethyl-3,4-dihydrocarbostyril - After conductlng a reactlon between the compound .: ~ o~tained by trifluoroacetlc acld treatment of ~he compound of Reference Example 41 and a correspondlng starting material, the captioned compound was o~tained in the same manner as in Example 1.
.
NMR (2 7 OMH Z. DMS O--d6 ) ~ P Pm: 1 O. 3 8 (1 H. s) ~
8. 7 1 (1 H. S) ~ 8- 3 1 (1 H, d. J=8H z) ~ 7. 2 7 (2H, ~, J = 8 H z) ~ 7. 0 5 (1 H. t, J = 8 H z) ~ 6. 9 8 ( 1 H, d .
J = 8 H z) ~ 4. 8 1 (l H. d. J = 1 7 H z) ~ 4. 5 9 (1 H. d. J
-' :
~13610~
-152- ~
= 1 7 H z) ~ 4. 4 0 4. 5 S (1 H, m) ~ 4. 0 4 (2 H, c. J - 7 H z) ~ 2. 6 5 - 3. 1 0 (3 H, m) ~ 2. l 8 (l H. d d. J = l 4, 6 H z) ~ 2. 0 l (l H. d d. J = l 4, 7 H z) ~ l. 4 0 - 1. 7 5 ( 4 H. m) ~ 1. 0 0 - 1. 2 0 tl H, m) ~ O. 7 5 - I. O O (9 H. m ) Example 37 Prepara~ion of 3S-r4-(N--hydroxyamino)-2R-isobutyl-succinyl~amino-l-isopropoxycarbonylmethyl-3,4-dihydrocarbostyril After conducting a reaction between the compound obtained by trifluoroacetic acid treatment of ~he compound of 1~ Reference Example 42 and a corresponding starting material, the captioned rompound was obtained in the same manner as in Example 1.
N M R t2 7 O M H z, D M S O - dB ) ~ P p m : 1 O. 3 8 (1 H. s) 8. 7 l tl H. s~ ~ 8. 3 1 (l H. d, J = 8 H z) ~ 7. 2 7 (2 H.
t. J - 8 H z) ~ 7. 0 5 (1 H. t, J = 8 H z) ~ 6. 9 4 (l H. d.
J = 8 H z) ~ 4. 9 3 (l H. t t, J = 7, 7 H z) ~ 4. 7 7 tl H. d , J - 1 8 H z) ~ 4. 5 4 (l H. d. 3 = 1 8 ~ z) ~ 4. 4 S - 4. 6 5 ;~ (l H. m) ~ 2. 7 0 - 3. l S (3 H, m) ~ 2. 1 8 (1 H. d d. J =
l 4, 6 H z) ~ 2. 0 1 (1 H, d d. J = 1 4, 7 H z) ~ l. 4 0 - 1.
7 S (2 H, m) ~ l. 2 1 (3 H. d. J = 2 H z) ~ 1. 1 9 (3 H. d.
J = 2 ~ l. O O - 1. 2 0 (l H. m~ ~ O. 8 7 (6 H. d d. J -l 5, 6 H z) Example 38 Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-succinyl]amlno-1-t-butoxycarbonylmethyl-3,4-dihydrocarbostyril WO94/21612 ~ v~ PCT/J~4/00434 -153- ~ , After conducting a reaction betweien the compound obtained by catalytic reduction treatment of the compound of Reference Example 43 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example l.le 43 and a corresponding starting material, the captioned compound wa~ obtained in the same manner as in Example 1.
N M R (2 ~ O M H z. D M S O - d8 ) ~ P P m : 1 O. 3 8 (1 H. b r s ) ~ 8. 7 1 (1 H. b r s) ~ 8. 3 0 (1 H. d. J = 8 H z) ~ 7. 2 S
- 7~ 3 0 t2 H. m) ~ 7. 0 6 (l H, t, Ji-i7 H z) ~ 6. 9 3 (l H
:~ , d, J ~ 7 H z) ~ 4. 7 0 (1 H. d, J = 1 7 H z) ~ 4. 4 4 - 4. 5 4 (2 H. m) ~ 2. 7 S - 3. 0 2 (3 H, m) ~ 1. 9 8 - 2. 2 6 (~ H
~: 15 ~ m) ~ 1. 6 1 - 1. 7 1 (1 H. m) ~ 1. 4 2 - 1. 5 1 (1 H. m) ~
1. 3 9 ~9 H. s) ~ 1. 0 1 - 1. 1 1 (1 H, m) ~ 0. 8 7 (6 H, d d, J-= 1 5, 1 H z~
Example 39 Preparat$on of 1-amlnocarbonylmethyl-3S-~4-(N-hydroxy-~: amino)-2R-isobutylsuccinyl~amino-3,4-dlhydrocarbostyril After conducting a reactlon between the compound obtained by trifluoroacetic acid treatment of the compound of : Reference Example 44 and a correspondlng starting material, the captioned compound was obtained in the same manner as in ','~
f',l i3~
-15~L-Example 1.
N M R (2 7 0 M H z. D M S O - d6 ) ~ P P m : 1 O. 3 9 (1 ~. s) 8. 7 3 (1 H, s) ~ 8- 2 4 (I H. d. J = 8 H z) ~ 7. 5 8 (1.~, s) ~ 7. 1 0 - 7. 3 0 (3 H. m) ~ 7. 0 2 (1 H. t. J = 8 H z) ~
6. 8 4 (1 H. d. J = 8 H z) ~ 4. 6 4 (1 H. d. J = 1 7 H z) ~ 4 . 5 0 4. 7 0 (1 H. m) ~ 4. 1 9 (1 H. d. J = 1 7 H z) ~ 2. 7 O - 3. 1 Q (3 H. m) ~ 2. 1 8 (1 H. d d. J = 1 4, 6 H z) ~ 2.
O 1 (1 H. d d. J = 1 4, 8 H z) ~ 1. 4 0 - i. 7 S (2 H, m) ~ O
. 9 5 - 1. 2 0 (1 H. m) ~ O. 8 7 (6 H, d d. J - 1 S~ 6 H z) Example 40 Preparation of 3S-C4-(N-hydroxyamLno)-2R-isobut succinyl]amlno-l-(N-methylaminocarbQnylmethyl)-3,4-lS dihydrocarbostyril Af~er conducting a reactlon between ~he compound : obtained by trifluoro~c~tic acid treatment of the compound of Reference Example 45 and a corresponding starting material, the captioned ~ompound was obtained in the same manner as in Exampl~ 1.
N M R ~2 7 O M H z. D M S O - d~ p m : 1 O. 3 8 (1 H. b r s ) ~ 8.1 7 1 (1 H. b r s) ~ 8. 2 4 (1 H. d. J = 8 H z~ ~ 8. 0 0 (1 ~. d. J = 5 H z) ~ 7, 2 3 - 7. 2 ? (2 H. m) ~ 7. 0 3 tl H
. ~, J - 7 H z) ~ 6. 8 4 (1 H. d. J = 8 H z) ~ 4. 5 7 - 4. 6 9 (2 H, m) ~ 4. 2 0 (1 H. d. J = 1 7 H z) ~ 2. 9 2 - 3. 0 S (2 H. m) ~ 2. 7 4 - 2. 8 O (l H. m) ~ 2. 6 0 (3 H, d. J = S H z WO94/21612 PCT/J~4100434 -155- ~
) ~ 1. g 8 - 2. 2 S (2 H. m) ~ l. 4 2 - l. 6 8 (2 H. m) ~ l.
0 1 - 1. l 2 (l H. m) ~ 0. 8 7 (6 H. d d, J = 1 5, 7 H z) Example 41 Preparation of 3S-[4-(N-hydroxyamino)-2R-isobutyl-succinyl]amino~ N-propylaminocarbonylmethyl)-3,4-d~hydrocarbostyril After conducting a reaction between ~he compound obtained by trifluoroacetic acid treatment of the compound of Reference Example 46 and a corresponding starting materi.al, the captioned compound was obtained in the same manner as in Example 1.
¦~ ~MR ( 2 7 O MH z . DM S O - d3 ~ ~ P P m : 1 0. 3 8 (l H. b r s ) ~ 8. 7 2 (1 H. b r s3 ~ 8. 2 4 tl H. d. J=8H z) ~ 8. O 8 (1 H. b r s) ~ 7. 2 2 - 7. 2 7 (2 H. m) ~ 7. 0 2 (l H. t. J
= 7 H z) ~ 6. B 4 (l H. d. J - 8 H z~ ~ 4. 5 4 - 4. 6 8 (2 H.
m) ~ 4. 2 5 tl H. d. J ~ 1 7 H z) ~ 2. 9 4 - 3. 0 5 (3 H, m) ~ 2. 7 5 ~ 2. 8 0 (1 H, m) ~ 1. 9 6 - 2. 2 5 (2 H. m~ ~ l. 4 2--1. 6 8 (2 H. m) ~ 1. O 1--1. 1 2 ( 1 E~. m) ~ O. 8 O--O .
9 1 (9 H. m) Exampl~ 42 Preparation of 3S-[4-(N-hydroxyamino)-~R-isobutyl-succinyl]am~no-l-(N-methoxyam~nocarbonylmethyl)-3,4-dihydrocarbostyril WO94/21612 PCT/J~4/00434 ~ 1 3 ~ 156-After conducting a reaction between the compound obtained by trifluoroacetic acid treatment of the compound of Reference Example 47 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
~MR (2 7 OMHz. DMSO--d6 ) ~ P pm: 1 1. 4 O (1 H, s) ~
1 O . 3 9 ( l H. s ) ~ 8 . 7 2 ( l H, s ) ~ 8 . 2 7 ( l H. d . J = 8 H z ) ~ 7 . 2 O--7 . 4 O ( 2 H , m ) ~ 7 . O 4 ( 1 H , t , J = 8 H z ) ~ 6 . 9 1 ( 1 H, d . J = 8 H z ) ~ 4 . 5 9 ( 1 H. d, J = 1 6 H z ) 4 . 4 O--4 . 7 O ( 1 H . m ) ~ 4 . 2 5 ( 1 H . d . J = 1 6 H z ) ~ 3 .
S 9 (~, s) ~ 2. 7 0--3. 1 O (3H. m) ~ 2. 1 9 (1 H. d d, J = 1 4. 7 H z) ~ 2. O 2 ( 1 H. d d, J = 1 4, 7 H z) ~ 1 . 3 O--1 . 8 O ( 2 H . m ) ~ O . 9 O--1 . 2 O ( 1 H . m ) ~ O . 8 7 ( 6 H, d 15 d, Jzl 5, 6H~) j:
~ Example 43 " ~
:~ Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-succinyl}amlno-1-(N,N-dlmethylaminocarbonylmethyl)-3,4-d~hydrocarbostyr~l :
~ After conducting a reaction between ~he compound I
obtalned by trlfluoroacetic acid treatment of the compound of ~^ Reference Example 48 and a corre~pondlng starting material, ~:~ 25 the captioned compound was obtalned in the same manner as in Example 1.
.
wog4nl612 ~ t~ pcTlJ~4loa434 N ~ R (2 7 O M H z, D M S O - d8 ) ~ P P m : 1 O. 3 8 (1 H. b r s ) ~ 8. 7 2 (1 H, b r s) ~ 8. 2 6 (1 H. d. J = 8 H z) ~ 1. 2 O
- 7. 2 6 (2 H. m) ~ 7. O O (1 H. t, J = 8 H z) ~ 6. 8 4 (1 H
. d. J = 8 H z) ~ 4. 9 3 (1 H. d~ J = 1 7 H z) ~ 4. 4 6 - 4. 5 6 (2 H. m) ~ 3- O 9 (3 H, s) ~ 2- 7 3 - 3 O 2 (6 H. m) ~ 1 . 9 ~ - 2. 2 S ~2 H. m) ~ 1- 4 2 - 1. 7 O (2 H, m) ~ 1. O 1 -1 5 L . 1 2 ~1 H. m) ~ O- 8 7 t6 H. d d. J 1 5, 7 H x) ¦ Example 44 I Preparation of 3S-~4-(N-hydroxyamino)-2R-iso~utyl-I succinyl~amino-1 morpholinocarbonylmethyl-3,4-dihydr~carbostyr~l ~ fter conducting a react~on between the compound obtained by trifluoroacetic a id treatment of the compound of Reference Example 4g and a correspondin~ starting material, the capt~oned compound was obtain~d in the same manner as ~n Example 1.
NMR (2 7 OMKz. DMSO--dB ) ~ P P~: 1 O. 3 8 (1 H. s) 8 . 1 1 ~ 1 H . s ) ~ 8 . 2 7 ( 1 H . d . J ~ 8 H z ) ~ 7 . 2 4 ( 2 H .
t, J=8H z) ~ 7. 0 1 (1 H. t. J=8 ~ z) ~ 6. 8 6 ~ 1 H. d, J = 8 H z) ~ 4. 9 7 (1 H. d. J--1 7 H z) ~ 4. 5 7 ( 1 H. d, =1 7Hzl ~ 4. 40--4. 60 (lH, m) ~ 3. 50--3. 7 5 (8H, m ) ~ 2 . 7 0--3 . 2 0 ( 3 H . m ) ~ Z . 1 9 ( 1 E~ . d d . J = 1 4 , 7 Hz) ~ 2. 0 1 (lH. dd. J=l 4. 7Hz) ~ 1. 40--1. 8 0 (2 H. m) ~ O. 95--1. 20 (lH, m) ~ O. 87 (6H, dd. J=l 5 , 6 ~ z) 25 Example 4 5 WO94J21612 'i 13 6 l~ ~ PCT/J~4/00434 Preparation of l-allyl-3S-[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]amino-3,4-dihydrocarbostyril After conducting a reaction between the compound of ~ ReferenCe Example 50 and a corresponding starting material, I . 5 the captioned compound was obtained in the same manner as in Example 16.
NMR (2 7 OMHz. DMSO--d6 ) ~ P pm: 1 O. 4 8 (1 H. s) 8 . 7 7 ( 1 H. s ) ~ 8 . 4 5 ( 1 H. d . J = 8 H z ) ~ 7 . 2 S ~ 2 H, t, J=7Hz) ~ 7. 0 6--6. 9 9 t2H, m) ~ 5. 9 0--5. 8 0 (1 H. m) ~ S . 1 5--5 . 0 6 ( 2 H. m) ~ 4 . 6 9 - 4 . S 3 ( 2 H. m~
4 . 4 1 ( 1 H, d . J--1 7 H z ) ~ 3 . 0 4 ( l H, t, J = 1 5 ~ z ) 2 . 9 3 ( 1 H. d d, J 1 = 6 E~ Z . J 2 = 1 5 H z ) ~ 7 . 5 4--2 . 4 7 (1 H. m) ~ 2. 2 0--2. 1 4 (1 H. n) ~ 1. 6 O--L. 4 2 (2 H
- ~: , m ) ~ O . 9 7 ( 3 H . t . J = 7 H z ) ~ O . 9 8 - O . 8 0 ( 1 H . m ) :~
~ 15 ~ 0. 8 4 t6 H. d t, Jl = 6 H Z~ J a = 1 7 H z) : :
Example 46 . Prepara~on of l-clnnamyl-3S-~4-(N-hydroxyamino)-2~-; lsobutyl-3S-methylsucc~nyl~amino-3,4-dihydrocarbostyril After c~nducting a reactlon between the compound of Reference Example 51 and a correspond~ng material, the c~ptloned compound was obtaln~d ln the same manner as in Example 16.
!~ I , .
~ M R ( 2 7 0 M H z , D M S O--d ~ ) ~ P p m : 1 0 . 4 9 t l H . s ) ; :~ 8. 7 7 (1 H. s) ~ 8. 4 7 (1 H. d, J = 8 H z) ~ 7. 4 0 (2 H.
~.-~:~ d. J=7Hz) ~ 7. 3 2--7. 2 1 (S H. m) ~ 7. 1 6 tl H. t. 3 = 8 H z), 7 . 0 2 ( 1 H. t . J = 8 H z) ~ 6 . 5 2 ( 1 H. d . J = 1 6 H ) 6 3 0 ( l H. t t . J 1 = 5 H Z . J 2 WO94/21612 ~ i. 3 6 1 0 ~ PCTIJ~4100434 -15g-tl H, d d. Jl = 4 H Z~ J2 = 1 7 H z) ~ 4. 6 7 ~ 4. ~ Z (2 ~.
m) ~ 3. O 7 (1 H. ~. J = 1 5 H z) ~ 2. 9 6 (1 H. d d. Jl = 6 H ~ J2 = 1 5 H z) ~ 2- 5 6 - 2- 4 9 (1 H. m) ~ 2. 2 1 - 2. I
5 (1 H. m) . 1. 6 1 - 1- 4 3 (2 H. m) . O. 9 8 (3.~. d. J =
7 H z) ~ - 9 9 - O. 7 9 (1 H, m) ~ O. 8 4 (6 H. d d, Jl = 6 H Z~ J2 = 1 8 H z~
Example 47 Preparation of 3S-[4-(N-hydroxyamino)-2R-isobutyl-succinyl~amino-l-methyl-3,4-dihydrocarbostyril After conducting a reaction between the compound obtained by trifluoroacetic acid treatment of the compound of Reference Example 52 and a corresponding starting material, the capt~oned compound was obtained in the same manner as in ; Example 1.
I5 N M R t2 7 O M H z, D M S O - d~ ) ~ P P m : 1 O. 3 7 (1 H. s) ~
8. 7 1 (1 H. s) ~ 8- 2 O (I H. d. J - 8 H z~ ~ 7. 3 3 - 7. 2 4 t2 H. m~ ~ 7. 1 1 (1 H. d, J - 8 H z) ~ 7. O 4 ~1 H, t, J
-- = 8 H z) ~ 4. 4 9 - 4. 3 9 (1 H, m) ~ 3. 2 8 (3 H. s) ~ 2. 9 ~; 7 - 2. 8 9 (2 H. m) ~ 2. 8 5 - 2. 7 3 (1 H. m) ~ 2. 1 7 (1 H
20 ~ d d. Jl = 6 H Z~ J2 = 1 4 H z) ~ 2. O 1 (1 H. d d, Jl = 7 H
Z' J2 ~ 1 4 H z~ ~ 1. 7 3 - 1. 6 2 (1 H. m) ~ 1. 5 4 - 1. 4 2 (1 H. m) ~ 1. 1 5 - 1. O O (1 H, m) ~ O. 8 7 (6 H. d d. Jl ' ' = 6 H Z~ J2 = 1 5 H z) Example 48 Preparation of l-ethyl-3S-~4-(N-hydroxyamino)-2R-W094121612 PCT/J~4/00434 f. l 3 ~
isobutylsuccinyl]amino-3,4-dihydrocarbostyril After conducting a reaction between the compound obtained by trifluoroacetic acid treatment of the compound of Reference Example 53 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example lo M R (2 7 O M H z. D M S O - d8 ) ~ P P m : I 0. 3 7 (1 H. s) ~
8. 7 1 (1 H. s) ~ 8- 2 0 (1 H, d, J = 8 H z) ~ 7. 2 0 - 7. 3 5 (2 H. m) ~ 7. 1 5 (1 H. d. J = 8 H z) ~ 7. 0 3 tl H. t. J
= 8 H z) ~ 4. 3 5 - 4- 5 0 (1 H. m) ~ 3. 8 0 - 4. 1 0 (2 H, m ) ~ 2. 9 1 (2 H. d. J = 9 H z) ~ 2. 7 0 - 2. 9 0 (1 H. m~ ~ 2 . 1 7 (1 H. d d. J = 1 4, 7 ~ z) ~ 2. 0 1 (1 H. d d. J = 1 4.
8 H z) ~ 1. 4 0 - 1. 8 0 (2 H, m) ~ 1. 1 3 (3 H, ~, J = 7 H z ) ~ 1. 0 0 - 1. 2 5 (1 H. m) ~ O. 8 7 (6 H. d d, J = 1 4, 6 H
Z) Example 49 Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-3S-methylsucclnyl]amino-l-propyl-3,4-dihydrocarbostyril After conducting a reaction between the compound of ~:~ 20 Reference Example 50 and a corresponding starting material, ; the captioned compound was obtained in the same manner as in Example 14.
N M R ( 2 7 O M H z , D M S O--d ~ P P m : 1 O . 4 7 t ~ H . s ) ~
8 . 7 6 ( 1 H. s ) ~ 8 . 4 1 ( 1 H. d . J = 8 H z ) ~ 7 . 2 8--7 . 2 5 t 2 H. m) ~ 7 . 1 4 ( 1 H. d . J = 8 H z ) ~ 7 . O 2 ( 1 H. ~ . J
_ 7 ~ z ) ~ 4 . 5 2--4 . 4 7 ( 1 H. m) ~ 3 . 8 4 ( 2 H. t . J = 8 H
W094t~1612 h1. 3 610 8 PCT/J~4/00434 z) ~ 3. 0 5--2. 8 0 (2 H. m) ~ 2. 5 1--2. 4 6 ( 1 H. m) ~ 2 2 0--2 . 1 6 ( 1 H. m) ~ 1 . 5 9--1 . 4 6 ( 4 H. m) ~ O . 9 6 ( }1, d, J = 7 H z ) ~ O . 9 1 --O . 8 0 ( 1 0 H, m ) Example 50 Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-3S-I methylsuccinyl]amino-l-(3-phenylpropyl~-3,4-dihydrocarbostyril I After conducting a reaction between the compound of Reference Example 5l and a correspond~ng starting ma~erial, ~ the captioned compound was obtained in the same manner as in ¦ Example 14.
¦ ~ M R (2 7 O M H z. D M S O - d6 ) ~ ~ P m : l 0. 4 7 (1 H. s) ~
¦ 8. 7 6 (1 H. s) ~ 8- 4 l (l H, d. J = 8 H z) ~ 7. 3 0 - 7. 1 5 ~ H. m) ~ 7. 0 7 - 6. 9 ~ (2 H. m) ~ 4. 5 1 - 4. 4 6 tl H
, m) ~ 3. 9 2 (2 H. t) ~ 2- 9 8 - 2. 8 8 (2 H. m) ~ 2. 6 4 ( 2 H. t, J = 8 H z) ~ 2. 5 1 - 2. ~ 6 (l H. m) ~ 2. Z 0 - 2. 1 3 (1 H. m) ~ 7 - 1. 7 8 (2 H. m) ~ 1. 6 5 - 1. 3 8 (2 H
. m) ~ O. 9 6 (3 H. d, J = 7 H z) ~ O. 9 8 - O. 8 0 (1 H. m) O ~ O. ~ 4-(6 H. d d. Jl = 6 H Z~ J2 = 1 7 ~ Z) Example 51 ~ Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-¦ succinyl]amino-1-(2-hydroxyethyl)-3,4-dihydrocarbostyril ¦ 25 After conducting a reaction between the compound W094/21612 ~ 3 ~ PCT/J~4/00434 obtained by trifluoroacetic acid treatment of the compGund of ReferenCe Example 55 and a ccrresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
~MR (2 7 O M H z, D M S O - d~ ) ~ P P m : 1 O. 4 9 (1 H, s) 8 . 7 0 (1 H. s) ~ 8- 1 9 (1 H, d, J = 8 H z) ~ 7. 1 5 - ~. 3 5 ~3 K. m) ~ 6. 9 0 - 7- 1 0 (1 H, m) ~ 4. 8 5 (1 H. t. J =
6 H z) ~ 4. 4 6 (l H. d t, J = 1 3~ 8 H zj ~ 3. 9 0 4. 0 5 ( 1 H. m) ~ 3. 8 4 (1 H. d t. J= 1 4, 7 H z) ~ 3. 4 5 - 3. 6 5 (2 H. m) ~ 2. 7 0 - 3- 0 0 (3 H, m) ~ 2. 1 8 (1 H, d d. J =
1 4, 7 H z) ~ 2. 0 4 tl H. d d, J = 1 4, 7 H z) ~ 1. 3 5 - 1.
7 5 t2 H. m) ~ O- 9 5 - 1- 2 0 (1 H. m~ ~ O. 8 7 (6 H. d d, J = 1 5, 7 H z) Example S2 Preparation of 3S-t4-(N-hydroxyamino)-2R-isobutyl-3 methylsuccinyl~ami~o-1-methyl-3,4-d~hydrocarbastyril After conductlng a reaction between th~ compound of Reerence Example 52 and a corresponding starting material, the captlPned compound was obtained in the same manner as in Example 16.
~ M R (2 7 O M H z. D ~ S O - t~ ) ~ P ~ m : 1 O. 4 8 (1 H, b r s ) ~ 8. 7 6 (1 H. b r s) ~ 8. 4 1 (1 H, d. J = 8 H z) ~ 7. 2 5 - 7. 3 3 (2 H. m) ~ 7. 1 1 (1 H. d. J = 8 H ~) ~ 7. 0 3 (1 H
, d. J = 7 H z) ~ 4. 4 4 - 4- S 4 (1 H. m) ~ 3. 2 8 t3 H. s) ~ 2. 8 9 - 3. 0 7 (2 H. m) ~ Z. 4 9 - 2. S 3 (1 H. m) ~ 2. 1 6 ~1 H. d d. J = 1 1, 7 H z) ~ 1. 4 1 - 1. 6 2 (2 H. m) ~ O.
9 6 t3 H. d. J = 7 H z) ~ O- 8 4 - O. 9 6 (1 H. m) ~ O. 8 4 ( 6 H. d d. J = 1 7, 6 H z) WO94/21612 i-~ .3 6 ~ 0 8 PCT/J~4/UO434 Example 53 Preparation of 3S-~4-(N-acPtoxyamino)-2R-isobutyl-succinyl]amino-1-methoxy-3,4-dihydrocarbostyril Using acetic anhydride and a corresponding starting m~terial, the captioned compound was obtained in the same manner as in Example 8.
N M R (2 7 O M H z, D M S O - d~ P m : 1 1. 6 O (1 H. s) ~
8. 3 4 (1 H. d. J - 8 H z) ~ 7. 2 O - 7. 4 O (2 n, m) ~ 7. 1 6 (1 H. d. J a 8 H z~ ~ 7. O 7 (1 H. t, J = 8 H z) ~ 4. 6 1 ( 1 H. d t, J = 1 2, 8 H z) ~ 3~ 8 2 t3 H. s) ~ 2. 6 O - 3. 1 O
(3 H. m) ~ 2. 3 4 (1 H. d d. J = 1 5, 7 H z) ~ 2. 1 1 (1 H.
¦: d d. J = 1 5, 7 H z) ~ 2- 1 5 (3 H. s) ~ 1. 4 O - 1. 8 O (2 H
¦ . , m) ~ 1. O 5 - 1. 4 O (1 H. m) ~ O. 8 7 (6 H. d d, J = 1 5, 6 H z) ¦ Example 54 ¦~ Preparation of 3S-t4-(N-benzoyloxyamino)-2R-isobutyl-:~ 3S-methylsuccinyl~mlno-1-methoxy-3,4-dihydrocarbostyril . Using a correspond~ng startl~g material, the captioned ~: : 20 compound ~as obtained in the same manner as in Example 8.
:' .NM R t 2 7 0 MH z . DM S O--d ~ ) ~ p ~ m: 1 2 . 0 8 ( 1 H. s ) j 8 . 6 4 ( 1 H. d . J = 8 }I z ) ~ 8 . 0 4 ( 2 H, d . J = 7 H z ) ~ 7 .
7 6 (1 H . t, J = 8 H t ) ~ 7 . 6 0 ( 2 H . t, J--8 H 2 ) ~ 7 . 3 7 --7. 29 (2H. m) ~ 7. 1 6 (lH, d. J=7Hz) ~ 7. 0 7 (1 H
, t, J=8Hz) ~ 4. 6 8--4. 6 3 (1 H. m) ~ 3. 8 3 t3 H. s) 3. 0 8 (1 H. t. J=l 3Hz) ~ 2. 9 7 (1 H. d d. Jl =7 H z J2 - 1 6 H z) . 2. 5 5 - 2. 4 1 (2 H. m) ~ 1. 6 O - 1. 5 3 ( WO94/21612 PCT/J~4/00434 ~ 13Glo~
-164- , 2 H. m) ~ 1. 2 1 - 1. 1 5 (1 H, m) ~ 1. 1 0 (3 H, d. J = 6 H
z) ~ 0. 8 7 (6 H. t. J = 7 H z) Example 55 Preparation of 3S-[4-(N-hydroxyamino)-2R-isobutyl-3(R
or S)-phthalimidomethylsuccinyl3amino-l-methoxy-3~4 dihydrocarbos~yril Using a corresponding starting material, the captioned compound was obtained in the same manner as in Example 7.
M R (2 7 O M ~ z, D M S O - d6 ) ~ P P m : 1 O. 4 7 (1 H. s) 8. 6 8 (1 H. s~ ~ 8- 6 5 (1 H. d. J - g ~ z) ~ 7. 8 8 - 7.
O (4 H. m) ~ 7. 3 3 (1 H. t, J = 8 H z) ~ 7. 2 6 tl H. d. J
= 7 H z) ~ 7. 1 6 (1 H. d. J = 7 ~ z) ~ 7. 0 6 tl H. t. J = 7 z) ~ 4. 6 1 - 4. 5 6 (1 H, m) ~ 3. 8 9 (1 H. d d. il = 3 H
~: Z' J2 = 1 5 H z) ~ 3. 8 2 (3 H. s) ~ 3. 4 8 (1 H. d d. Jl ~
Z~ J2 = 1 4 H z) ~ 3- 0 6 - 2- 8 9 (2 ~. m) ~ 2. 7 9 - 2.
6 3 ~2 H. m) ~ 1. 6 7 - 1. 5 4 (3 H, m) ~ O. 8 6 (6 H, d d, Jl = 6 ~ Z~ J2 = 1 5 ~ ~) ' Example 56 P~eparatlon of 3-~4-(N-hydroxyamino)-~R-isobutyl-3(R
or S)-phthalimldemethyl~uccinyl]amino-l-methyl-3,4-i d~hydrocarbostyril - : After conducting a reaction between the compound obtained by trifluoroacetic acld treatment of the compound of Reference Example 52 and a corresponding starting material, . , .
~ ~ .
1 ~ .
W094/21S12 ~ U~lv~ pcr/J~4l~4~4 the captioned compound (diastereomer 1:1 mixture) was obtained in the same manner as in Example 7.
N M R (2 7 O M H z. D M S O - d6 ) ~ P P m : 1 O. S O + 1 O. 4 5 ( 1 H, s) ~ 8~ 7 1 + 8- 6 8 (1 H, s) ~ 8. 6 6 + 8. S 3 (1 H, d , J - 8 H z) ~ 7. 8 8 - 7. 8 O (4 H, m) ~ 7. 3 2 - 7. 2 O (2 H
, m) ~ 7. 1 4 - 6. 9 9 (2 H, m) ~ 4. S 6 - 4. 4 O (1 H, m) ~
4, O 5 + 3. 8 9 (1 H, d d, Jl = 1 O H Z~ J2 = 1 3 H z) ~ 3. 7 O ~ 3. 4 7 (l H. d d. Jl = 4 H Z~ J2 = 1 3 H z) ~ 3. 2 8 (3 H
, 5) ~ 3. O 1 - 2. 8 9 (2 H. ~) ~ 2. 8 2 - 2. 6 S t2 H, m) 1. 7 O - 1. 4 9 (3 H. m) ~ O. 9 1 - O. 8 2 (6 H, m) Example 57 Preparatlon of 3S-~4-( N-hydroxyamino) 2R-isobutyl-3S-methylsuccinyl]amino-1-(2-propynyl)-3,4-dihydrocarbostyril After c~nductlng a reaction between the compound of Re~erence Example 56 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 16.
NMR (2 7 0MH z. DMS C)--d~ P p m : 1 0. 4 9 ( 1 H. b r s .) ~ 8. 7 7 (l H. b r s) ~ 8. 4 8 (1 H, d, J = 8 H ~) ~ 7. 2 O
- 7. 3 6 (3 H. m) ~ 7. O 7 (1 H, t, J = 8 H z) ~ 4. 7 9 (1 H
, d d. J = 1 8. 2 H z) ~ 4. 6 2 (1 H, d d, J = 1 8. 2 H z) ~ 4 . 4 8 - 4. S 8 (1 H. m) ~ 3. O O (1 H, t, J = 1 S H z) ~ 2. 9 1 (1 H. d d. J ~ 1 5. 6 H Z) ~ 2. 4 6 - 2. 5 4 (2 H, m) ~ 2.
: WO94/21612 ) PCT/J~4/00434 ~13~1~3~
1 4 - 2. 2 0 (1 H. m) ~ 1. 5 8 - l. 6 6 (1 H, m) ~ l. 4 6 (!
H. d ~, J = 3. 1 5 H z) ~ 0. 9 7 (3 H. d. J = 7 H z) ~ 0. 9 7 - 0. 8 5 (1 H. m) ~ 0. 8 5 (6 H. d d. J = l 4. 7 H z) Example 58 Preparation of 3S-t4-(N-hydroxyamino)-3S-aminomethyl-2R-isobutylsuccinyl]amino-1-methoxy-3,4-dihydrocarbostyril 50 mg of 3S-~4-(N-hydroxyamino)-2R-isobutyl-3S-- phthalimidomethylsuccinyl]amino-1-methoxy-3,4-dihydrocarbostyril was dissol~ed in 3 ml of dim2thyl ~ormamide, and 19 ~1 of hydrazine monohydrate was added and stirred for 1 hour at room temperature~ The reaction solution ~ was concentrated in vacuo, 1 ml of methanol was added, ~he -~ insoluble matter was filtered away, and the filtrate was ~: 15 evaporated in vacuum, and 3 ml o~ diethyl e~her was added to : the precipitating cryætals to filter, and the captioned compound was obtained t n a white solid form. Yield: 7 mg.
~: : ~ M R ~2 7 O M H 2, D M S O - d ) ~ P P m : 1 0. 5 6 (l H, b r s ) ~ 9- S B (l H, s) ~ 8. 6 0 (1 ~, d, .J = 8 H z) ~ 7. 3 2 (2 ~: H, d d. J ~ 1 5, 7 H z) ~ 7. 1 6 (1 H, d, J = 7 H z) ~ 7. 0 7 tl H, t, J - 7 H z) ~ 4. 6 8 (l H, d t, J = 1 2, 8 H z) ~ 3.
8 2 (3 H, s~ ~ 2. 4 0 - 3. 2 0 t6 H, m) ~ 0. 9 0 - l. 8 0 (3 ~ H, m) ~ 0. 8 7 ~6 H. d d, J = l 8, 6 H z) :~ , -:
-WO9~/21612 PCT/J~4/0~34 Example 59 Preparation of l-aminocarbonylmethyl-3S-[4-(N-hydroxy-amino)-2R-isobutyl-3S-acetylthiomethylsuccinyl]amino-3,4-di~ydrocarbostyril After conducting a reaction between the compound of Reference Example 44 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 4.
NMR(270MHz, DMS0-d~)~ppm:10.62(1H, s), 8.92(1H, s), 8.55~1H, d, J~8Hz), 7.57(1H, s), 7.10-7.35(3H, m), 7.03(1H, t, J-7Hz), 6.86(1H, d, J-7Hz), 4.55-4.75(1H, m), 4.66(1H, d, J=17~z), 4.20(lH, d, J=17Hz), 2.80-3.20(4H, m), 2.40-2.65(lH, m), l5 2.31(3H, s), 2.20-2.40(1H, m), 1.40-1.70(2H, m), 0.80-l.OO(lH, m), 0.87(3H, d, J=7Hz), 0.81(3H, d, J-7Hz) ~:~ Example 60 Preparation.of 7-chloro-3S-~4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-l-methoxy-3,4-dihydrocarbostyril , After conducting a reaction between the compound obtained by trifluoroacetic acid treatment of the compound of Re~erence Example 59 and a corresponding start~ng material, `
the captioned compound was obtained in the same manner as in WO94/21612 PCT/n~4/00434 ~ 1 3 ~ 168-Example 1.
NMR~270MHz, DMSO-d6)~ppm:10.38(lH, brs), 8.72(1~, brs), 8.38(1H, d, J=8Hz), 7.31(1H, d, J-8Hz), 7.11-7.16(2H, m), 4.63(1H, dt, J=11,8Hz), 3.84(3H, s), 2.98(1H, d, J=llHz), 2.97(1H, d, J=8Hz), 2.75-2.76(1H, m), 2.16(1H, dd, J=6,14~z), 2.01(1H, dd, J-8,14Hz), 1.6o-l~65tlH~ m), 1.42-1.49tlH, m), 1.02-1.12(1H, m), 0.87(6H, dd, J36,12Hz) Example 61 Preparation of l-carboxyme~hyl-3S-~4-(N-hydroxy-amino)-2R-isobutyl-3S-methylsuccinyl]amino-3,4-d~hydrocarbostyril After conductlng a reactlon between the compound of :~ :
- ~ ~ : Reference Example 39 and a corresponding starting material, -~ the captioned compound was obtalned in the same manner as in -~ Example 14.
~:~
~ ~ ZO
~: : NMR(270MHz, DMS0-d6)~ppm:10.49(1H, s), 8.75(1H, brs), 8.46(1H, d, J-8Hz), 7.28-7.22(2H, m), 7.02(1H, t, J~8Hz), 6.93(1~,! d, ¦- J~8Hz), 4.69(1H, d, J-l?Hz), 4.57-4.52(1H, m), 4.34tlH, d, ~-~ J~17Hz), 3.05(1H, t, J-lSHz), 2.91tlH, dd, Jl=6Hz, J2-15Hz), 2.51-2.47(1H, m), 2.21-2.15(1H, m), 1.63-1.42t2H, m), 0.99-:
W094/2161? h ~t)~ ~ PCTIJ~4100434 0.80(10H, m), 0.98t3H, d, J=8Hz), 0.85(6H, dd, Jl=6Hz, J2=18HZ ) Example 62 5Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]amino-l-methoxymethyl-3,4-dihydxocarbostyril After conducting a reaction between the compound of Reference Example 60 and a corresponding starting material, I the captloned compound was obtained ln the same manner as in Example 14.
NMR(270MHz, DMSO-d6)~ppm:10.49(1H, s), 8.77(1H, s), 8.49(1H, d, J-8Hz), 7.15-7.35(3H, m), 7.06(1H, t, J-7Hz), 5.47(1H, d, J~lOHz), 5.02(1H, d, 3-lOHz), 4.57'1H, dt, JY14~ 7Hz), 3.27(3H, s), 3.07(lH, t, J~14Hz), 2.91(lH, dd, J-14,6Hz), 2.40-2.60(1H, m), 2.10-2.30(1H, m), 1.50-1.70(1H, m), 1.46(1H, t, J=llHz), 0.80-l.OO(lH, m), Q.98(3H, d, JY7~Z), 0~88~3H, d, J-7Hz), 0.81(3H, d, J-7Hz) ~-~ ~ .
Example 63 Preparation of 3S-t4-(N-hydroxyamino)-2R-isobutyl-3S-acetylthiomethylsuccinyl]amino-1-methoxymethyl-3,4-dihydrocarbostyril ~- : 25After conducting a reaction between the compound of W094/21612 PCTI~4/00434 ~ 1 361~
-170- !
Reference Example 32 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 4.
NMR(270MHz, DMSO-d6)~ppm:10.61(1H, s), 8.91(1H, s), 8.60(1H, d, Js8Hz), 7.15-7.35(3H, m), 7.07(1H, t, J=7Hz), 5.47(1H, d, JSlOHz), 5.03(1H, d, J=lOHz), 4.60(1H, dt, J-13,7Hz), 3.27(3H, s), 2.80-3.20(4H, m), 2.40-2.70(1H, m), 2.20-2.40(1H, m), 2.30t3H, s), 1.4Q-1.70(2H, m), 0.80-l.OO(lH, m), 0.87(3H, d, J-6Hz), 0.81(3H, d, J-6Hz) xample 64 Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl--~S-mercaptomethylsucclnyl~am~no-l-methoxymethyl 3,4-dihydrocarbostyril Using a corresponding start~ng material, the captioned compound was obtained in the same manner as in Example 5.
NMR(270MHZ, DMSO-d6)~ppm:8.55(1H, d, J-~Hz), 7.15-7.30(3H, m), 7.06(1H, t, J-8Hz), 5-47tlH, d, J-lOHz), 5.01tlH, d, J310Hz), 4.53~1~, dt, J~1;4,7Hz), 3.27(3H, s), 3.09(1H, d, J-15Hz), 2.97(1H, dd, J~15,7Hz), 2.40-2.70(3H, m), 2.20-2.40~1H, m), 1.40-1.70(2H, m), 0.80-l.OO(lH, m), 0.~6(3H, d, J-7Hzl, -: 25 o.g2(3H, d, J-7Hz) ::' WO94/21612 ~i ~J ~ PCT/J~4100434 Example 65 Preparation of l-ethoxy-3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-3,4-dihydrocarbostyril After conducting a reaction between the compound obtained by trifluoroacetic acid treatment of the compound of Reference Example 29 and a corresponding starting material, the captioned~ ompound was obtained in the same manner as in Example 1-NMR(270MHz, DMS0-d6)~ppm:10.37(1H, s), 8.71(1~, s), 8.35(1H, d, J~8Hz), 7.35-7.26(2H, m~, 7.16(1H, d, J=8Hz), 7.06(1H, t, 3. J~7Hz), 4.63-4.53(1H, m), 4.04t2H, q, J~7Hz), 3.01-2.92(2H, Z 15 m), 2.80-2.72~1H, m), 2.17(1H, dd, Jl-6Hz, J2=14Hz), 2.01(1H, dd,Jl-8Hz, J2-15Hz), 1.64-1.43(2H, m), 1.28(3H, t, J=7Hz), - 1.12-l.Q4(lH, m), 0.87(6H, dd, J1~6Hz, J2-12Hz) Example 66 Preparation of 3S-t4-(N-hydroxyamino)-2~-isobutyl-~ succlnyl]amino-l-methoxyethoxymethyl-3,4-dihydrocarbostyril j After conducting a reaction between the compo~nd i obtained by catalytic reduction treatment of the compound of Reference Example 61 and a corresponding starting material, W094/21612 PCT/~4100434 _ ~3~
-17~-the captioned compound was obtained in the same manner as in Example 1.
NMR(270MHz, DMS~-d6)~ppm:10.41(1H, s~, 8.73(1H, s), 8.29(1H, d, J=8Hz), 7.25-7.40(3H, m), 7.00-7.15(1H, m), 5.57(1H, d, J-lOHz), 5.02(lH, d, J=lOHz), 4.51(lH, dt, J=14, 7Hz), 3.60(2H, t, J~4Hz), 3.44(2H, t, J=4Hz), 3.22(3H, s), 2.70-3.10(3H, m), 2.18(1H, dd, JS14,7Hz), 2.02(1H, dd, J=14,7Hz), 1.40-1.80(2H, m), 1.00-1.30(1H, m), O.90t3H~ d, J~7Hz), 0.85(3H, d, J=7Hz) Example 67 : Preparation of 3S-t4-(N-hydroxyamino)-2R-isobutyl-3-propylsuccinyl]amino-l-methoxy-3,4-dihydrocarb~styril ~ After conduct~ng a reaction between the compound of ,~
~ Refer~nce Example 62 and a corresponding starting material, ~ :
: the capt~oned compound was obtalned ~n the s~me manner as in :~
Example 14.
20 NMR(270MHz, DMSO-d6)~ppm:10.49(lH, s), 8.78(1H, s), 8.52(1H, d, J-8Hz), 7.36-7.29(2H~ m), 7.16(1H, d, J=8Hz), 7.07(1H, t, J~7Hz)l, 4.67-4.62(1H, m), 3.83(3H, s), 3.04(1H, t, J=16Hz), 2.94(1H, dd, ~1-7Hz, J2~16Hz), 2.52-2.43(1H, m), 2.11-2.09(1H, m), 1.58-1.41(2H, m), 1.24-1.03(4H, m), 0.96-0.80(10H, m) -~ 25 ::
WO94/21612 PCT/J~4100434 Example 68 Preparation of 3S-[3-benzyl-4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-l~methoxy-3,4-dihydrocarbostyril After conducting a reaction between the compound of Reference Example 63 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 14.
NMR(270MHz, DMSO-d6)~ppm:lO.28(~H, s), 8.69-8.65(2H, m), 7.36-7.03(9H, m), 4.68-4.63(lH, m), 3.84(3H, s), 3.12(1H, t, J315Hz), 2.98(1H, dd, Jl-7Hz, J2~l6Hz), 2.75-2.7I~2H, m), 2.58-2.55(1H, m), 2.45-2.39(1~, m), 1.62-1.48(2~, m), 1.03-0.97(lH, m), 0.87(6H, dd, Jl-6Hz, J2-l6Hz) Example 69 ~ Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-¦~ 3-~4-methoxybenzyl)succinyl]amino-l-methoxy-3,4-::20 dihydrocarbostyril After conducting a reaction between the compound of Reference Example 64 and a corresponding starting material, the captioned compound wzs obtained in the same manner as in Example 14.
I WO94/21612 PCT/J~4/00434 ~ ~3~i10 ~
-174- !
NMRt270MHz, DMS0-d6)~ppm:10.25(lH, s), 8.65(1H, d, J=8Hz), ~ 8.64(1H, s), 7.36-7.27(2H, m), 7.16(1H, d, J=7Hz), 7.05(1H, i dt, Jl=lHz, J2-7Hz), 6.99(2H, d, J=9Hz), 6.79(2H, d, J=9Hz), t 4.68-4.63(1H, m), 3.84(3H, s), 3.71(3H, s), 3.11(1H, t, ¦ 5 J=15Hz), 2.98(1H, dd, Jl=7Hz, J2=16Hz), 2.68-2.56(3H, m), 2.39-2.34(1H, m), 1.64-1.54(2H, m~, 1.00-0.96(1H, m), 0.86(6H, dd, Jl=7Hz, J2=16Hz) Example 70 Preparation of l-carboxymethyl-3S- r 4-(N~-hydroxy-am~no)-2R-isobutyl-3(R or S)-phthalimidomethylsuccinyl]amino-~ : 3,4-dihydrocarbostyril :: After conducting a rea~tion between the compound of Reference Example 39 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 14.
: , :
:: NMR(270MHz, DMS0-d6)~ppm:10.50(1H, s), 8.70(lH, bs), 8.57(lH, d, J~8Hz), 7.88-7.80(4H, m), 7.28-7.23(2H, m), 7.02~1H, t, J-7Hz), 6.94(1H, d, J-8Hz), 4.71(1H, d, J-18Hz), 4.50-4.37t2H, m), 3.90(lH, dd, Jl=lOHz, J2=14Hz), 3.48(lH, dd, Jl=5Hz, J2~14Hz), 3.17-2.92(2H, m), 2.84-2.65(2H, m), 1.71-1.54(2H, m), 1.00-0.96~1H~ m), 0.86(6H, dd, J1~7Hz, J2=19Hz) W094/21612 ~ ~ LU ~ PCT/J~4/00434 Example 71 Preparation of 3S-[4-tN-hydroxyamino)-2R-iso~utyl-3S-methylsuccinyl]amino-l-methoxyethoxymethyl-3,4-dihydrocarbostyril After conducting a reaction between a corresponding starting material and the compound obtained by catalytic reduction treatment of the compound of ~eference Example 61, the captioned compound was obtained in the same manner as in Example 62.
NMR(27CMHz, DMSO-d6~ppm:10.49(1H, s), 8.78(1H, s), 8.48(1H, d, J~8Hz), 7.20-7.35(3H, m)! 7.00-7.10(1H, m), 5.56(1H, d, J~lOHz), 5.04(1H, d, J=lOHz), 4.55(1H, dt, J=14,7Hz), 3.60(2H, dd, J-6,3Hz), 3.44(2H, dd, J-6,3Hz), 3.22(3H, s), 3.06(1H, t, J-14Hz), 2.91(1H, dd, J-14,6Hz), 2.45-2.60(1~, m), 2.10-2.30(1H, m), 1.50-1.70(1H, m), 1.47(1H, t, J=13Hz), 0.80-l.lO(lH, m), 0.98~3H, d, J~7Hz), 0.88t3H, d, J~7Hz), 0.81(3H, d, J-7Hz~
Example 72 ~ I Preparation of 3S-~4-(N-hydroxyamino)-2S-isobutyl-succinyl]amino-l-methoxy-3,4-dihydrocarbostyril After conducting a reaction between the compound of Reference Example 65 and a corresponding starting material, WO94/21612 PCT/J~4/00434 .
3~ 10~
the captioned compound was obtained in the same manner as in Example 1.
NMR(270MHz, D~so-d6)~ppm:lo~4ltlHr brs), 8.75(1H, brs), `~
8.50(1H, d, J=8Hz), 7.32(2H, t, J=BHz), 7.16(1H, d, J=8Hz), 7.07(1H, t, J-8Hz), 4.06(1H, dt, J=11,8Hz), 3.83(3H, s), .
2.98(lH, d, J=llHz~, 2.97(1H, d, J-8Hz), 2.79-2.84( lHr m), 2.21(1H, dd, J=5,14Hz), 2.02(1H, dd, J=g,14Hz), 1.42-1.51(2H, .
m), 1.02-1.12(1H, m), 0.84(6H, d, Js6Hz) Example 73 Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-succ~nyl]amlno-l-methoxymethoxyethyl-3,4-dihydrocarbostyril After conducting a reaction between the compound obtained by catalytic reduction treatment of the compound of :~ Reference Example 66 and a correspond~ng starting material, the captioned compound was obtained in the same manner a~ in Example 1.
NMR~270MHz, ~MSO-d6)~ppm:10.37(1H, s), 8.70(1H, s), a.23(1H, . d, J-8Hz), 7.20-7.35(3H, m), 7.03tlH, t, J38Hz), 4.52(2H, q, J~6Hz), 4.40-4.60(1H, m), 4.09(2H, t, J-6Hz), 3.63(2H, t, J-6Hz), 3.17~3H, s), 2.70-3.00(3H, m), 2.18(1H, dd, J=15,6Hz), 2.~1(1H, dd, J~15,7Hz), 1.40-1.80(2H, m), 1.00-1.20(1H, m), WO94/21612 .~ b 10 8 PCTIJ~4/00434 0.90(3H, d, J=7Hz), 0.84(3H, d, J=7~z) Example 74 Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-3-(3-phenylpropyl)succinyl]amino-l-methoxy-3,4-dihydrocarbostyril After conducting a reaction between ~he compound of Reference Example 67 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 14.
NMR(270MHz, DMSO-d6)~ppm:10.52(1H, s), 8.80~lH, s), 8~52(lH, d, J=8Hz), 7.35(1H, t, J~7Hz), 7.30-7.15(7H, m), 7.lO(lH, t, J~7Hz), 4.66-4.61(1H, m), 3.83(3H, s), 2.96(1H, t, J=16Hz), 2.82(1H, dd, Jl~6Hz, J2~l6Hz), 2.56~2.43(3H, m), 2.14-2.09(1H, m), 1.57-1.29(6H, m), 0.95-0.92(lH, m), 0.83(6H, dd, Jl-6Hz, J2~l2Hz) Example 75 ~reparat~on of 35-~4-(N-hydroxyamino)-2R-isobutyl-3-(2-methylbenzyl3succinyl~amino-l-methoxy-3,4-dihydrocarbostyril After conducting a reaction between the compound of WO94/21612 PCT/J~4/00434 ~-~ 1 3 ~ ~ 3 ~ 178~
Reference Example 68 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 14.
NMR(270MHz, DMSO-d6)~ppm:10.21(lH, s), 8.70(lH, d, J=8Hz), 8.60(1H, s~, 7.33(1H, t, J=8Hz), 7.28(1H, d, J=7Hz), 7.16(1H, d, J=8Hz), 7.07-6.56(5H, m), 4.68-4.62(1H, m), 3.84(3H, s), 3.15(1H, t, J=15H ), 2.98~1H, dd, J1=6Hz, J2-16Hz), 2.75-2.71(2H, m), 2.61~2.55(1H, m), 2.42-2.37(1H, m), 2.22(3H, s), 1.63-1.47(2H, m~, 1.00-Q.96(1H, m), 0.87(6H, dd, Jl=6Hz, J2 ' 1 7HZ ) Example 76 Preparation of 3S-r4-(N-hydroxyamino)-2R-isobutyl-3-( 3-methylbenzyl)succinyl]amino-1-methoxy-3,4-dihydrocarbostyrll After conducting a reaction between the compound of ~eferenc~ Example 69 and a corresponding starting material, the capt~oned compound was obtained in the same manner as in Example 14.
, MMR~270MHz, DMS0-d6)~ppm:10.27(1H, s), 8.67-8~64(2H, m), 7.36-7.27(2H, m), 7.~8-6.85(6H, m), 4.68-4.63~1H, m), 3.84(3H, s), 3.12(1H, t, J~15Hz), 2.98(1H, dd, J1=7Hz, J2=16Hz), 2.7S-WO94/21612 PCT/J~4/00434 ~13G~08 2.49(3H, m), 2.44-2.38(1H~ m), 2.26(3H, s), 1.64-1.47(2H, m), 1.01-0.97(1H, m), 0.87(6H, dd, J1=6Hz, J2=16Hz) Example 77 Preparation of 3S-r4-(N-hydroxyamino)-2R-isobutyl-3-(4-methylbenzyl)succinyl]amino-1-methoxy-3,4-dihydrocarbostyril After conducting a reaction between the compound of Reference Example 70 and a corresponding starting material, the captioned compound was obtained ~n ~he same manner as in Example 14.
, .
NMR(270MHz, DMSO-d6)~ppm:10.25(1H, s), 8.66-8.63(2H, m), 7.36-7.27(2H, m), 7.16(1H, d, J-8Hz), 7.08-7.02(3H, m), 6.96(2H, d, J-8Hz), 4.68-4.63(1H, m), 3.84(3H, s), 3.11tlH, t, J-13Hz), 2.98(i~, dd, J1-6Hz, 32~15Hz), 2.75-2.49(3H, m), 2.41-2.35(1H, m), 2~25(3H, s~, 1.61-1.47(2H, m), 1.00-0.82(7H, m), 0.86(6H, dd, J1~6Hz, J2-15Hz) Eyampls 7B
Preparation of ~S-t4-(N-hydroxyamino)-2R-heptyl-succinyl]amino-l-methoxy-3,4-dihydrocarbostyril After conducting a reaction between the compound of Reference Example 73 and a corresponding starting material, the captioned compound was obtained in the same manner as in W094/tl612 PCTtJ~4/Q0434 ~
~.136~
Example 14.
NMR(270MHz, DMSO-d6)~ppm:10.38(lH, s), 8.71(lH, s), 8.32(lH, d, J=8Hz), 7.32(2H, dd, J=16,8Hz), 7.16(1H, d, J=8Hz), 7.07(1H, t, J=8Hz), 4.61(1H, dt, J=12~8Hz), 3.82(3H, s), 2.85-3.10(2H, m), 2.55-2.89(1H, m), 2.20(1H, dd, J=14,7Hz), 2.02(1H, dd, J=14.7Hz), 1.05-1.60(12H, m), 0.87(3H, t, J=6Hz) Example 79 Preparation o~ 3S-~4-(N-acetylhydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxymethyl-3,4-dihydrocarbostyril Using acetic anhydride and a corresponding starting 15 ma~erial, the captioned compound was obtained in ~he same manner as in Example 8.
NMR(270MHz, DMSO-d6)~ppm:11.63(1H, s), 8.33(1H, d, J-8Hz), 7.20-7.35(3H, m), 7.07(1H, t, J~7Hz~, 5.49(1H, d, J=lOHz), 5.00(1H, ~, J~lOHz~, 4.53(1H, dt, 3-13,8Hz), 3.26(3H, s), 2.90-3.10~2H, m~, 2.70-2.90(lH, m), 2.35tlH, dd, J=15,6Hz), 2.18(1H, dd, J-15,8Hz), 2.15(3H, s), 1.40-1.80(2H, m), 1.10-1.35(1H, m), 0.90(3X, d, J-7Hz), 0.85t3H, d, J=7Hz) WO94/21612 ~ l 3 ~ 1 0 8 PCT/J~4/00434 Exampl~ 80 Preparation of 7-chloro-3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-l-methoxymethyl-3,4-dihydrocarbostyril After conducting a reaction between the compound obtained by hydrazine treatment of the compound of Reference ~xample 74 and a oorresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
NMR(270MHz, DMSO-d6)~ppm:10.38(1H, brs), 8.72(lH, brs), 8.32(1H, d, J-8Hz), 7.30(1H, d, J-8Hz), 7.28(1H, d, J-2Hz), 7.13(1H, dd, J=2,8Hz), 5.47(1~, d, J-llHz), 5.06(1H, d, J~llHz), 4.55(lH, dtr J-11,8Hz), 3.26(3H, s), 2.98(1H, d, J~llHz), 2.97(1H, d, Js8Hz~, 2.75-2.84(1H, m), 2.17(1H, dd, J~7, 15Hz ), 2 . Ol(lH, dd, J-8,15Hz), 1.51-1.59(lH, m), 1.43-1.53(1H, m), 1.02-1.12(1H, m), 0.87(6H, dd, J-6,13Hz) Example 81 Preparation of l~tert-butoxyethyl-3S-t4-(N-hydroxy-amino),-2R-isobutylsuccinyl]amino-3,4-dihydrocarbostyril After conducting a reaction be~ween the compound obtained by catalytic reduction treatment of the compound of Reference Example 75 and a corresponding starting material, WO94t21612 PCT/P~4/00434 t 3 ~ - 182- ! .
the captioned compound was obtained in the same manner as in Example 1.
NMR(270MHz, DMSO-d6)~ppm:10.37tlH, brs), 8.70(1H, brs~, 8.20(1H, d, J-8Hz), 7.22-7.31(3H, m), 6.99-7.05(1H, m), 4.43(1H, dt, J~11,8Hz), 4.04(1H, dt, J=14,6Hz), 3.85(1H, dt, J=14,7Hz), 3.45-8.50(1H, m), 2.92(1H, d, J-llHz), 2.91(1H, d, J=8Hz), 2~76-2.82(1H, m), 2.18(1H, dd, J=7,15Hz), 2.01(1H, dd, J~8,15Hz), 1~59-l.67tlH~ m), 1.45-1.54(1H, m), 1.06-1.13(1H, I m), 1.06(9H, s~, 0.87(6H, dd, J=7,14Hz) Example 82 Prepara~ion of 3S-t4-~N-hydroxyamino)-2R-isobutyl-succinyl~amino-1-methoxyethyl-3,4-dihydrocarbostyril After conduct~ng a reactlon between the compound obtained by trifluoroacetic acid treatmant of the compound of Rererence Example 76 and a corresponding starting material, the ca~tioned compound wa obtalned ln the same manner as in Example 1.
NMR(270MHz, DMSO-d6)~ppm:10.37(1H, brs), 8.71(1H, brs), 8.23(1H, d, J-8Hz), 7.23-7.31(3H, m), 7.00-7.06(1H, m), 4.45(1H, dt, J-11,8Hz), 4.01-4.11(2H, m), 3.45-3.54(2H, m), 3.23(3H, s), 2.92(1H, d, J=llHz), 2.91(1H, d, J-8Hz), 2.75-W094121612 ~ ~ 6 ~ ~ ~ PCTIJ~4100434 -1~3-2.79(lH, m), 2.17(lH, dd, J=7,14Hz), 2.01~1H, dd, J=8,14Hz), 1.62-1.66(1H, m), 1.43-1.54(1H, m), 1.08-1,15~1H, m), 0.87(6H, dd, J=7,14Hz) Example 83 Preparation of 3R-~4-(N-hydroxyamino)-2R-isobutyl-succinylJamino-1-methoxymethyl-3,4-dihydrocarbostyril After conductlng a reaction between the compound obtain2d by catalytic reduction treatment of the compound of Reference Example 77 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
NMR(270MHz, DMS0-d6~6ppm:10.40(1H, brs), 8.74(lH, brs), 8.39(1H, d, J-8H2), 7.22-7.31(3H, m), 7.00-7.05(1H, m), 4.43(1H, dt, J-8,11Hz~, 4.02-4.12(2H, m3, 3.49-3.53(2H, m), 3.24(3H, s), 2.91tlH~ d, J-8Hz), 2.90(lH, d, J-llHz), 2.83-2.88tlH, m), 2~11(1H, dd, J-5,14Hæ), 2.01(1H, dd, Js9,14Hz), 2~ 1.44-1.47(2H, ~), 1.05-1.07(1H, m), 0.84t6H, ~d, J=6,2Hz) .
.
Example 84 Preparation of 3S-t4~(N-hydroxyamino)-2R-ethoxye~hyl-succinyl]amlno-1-methoxy-3,4-dihydrocarbostyril W094/21612 PCT/J~4/00434 3 6 1 0~ -184-Transforming 4-ethoxypropionic acid ~Vlado Prelog, Ber. 72B, 1103 6 (1939)] into 4-ethoxypropionyl chloride by using oxalyl chloride, and af~er allowing to react with a corresponding starting material, the captioned compound was obtained in the same manner as in Example 78.
MMR(270MHz, DMSO-d6)~ppm:10.39~1H, brs), 8.71(lH, s), 8.30(lH, d, J=8Hz~, 7.32(2H, dd, J316,8Hz), 7.16(lH, d, J=8Hz), 7.08(1H, t, J-8Hz), 4.61(1H, dt, J~12,8Hz), 3.82(3H, s), 3.41(2H, q, J-8Hz), 3.25-3.50(2H, m), 2.90-3.10(2H, m), 2.70-2.90(1H, m), 2.23(1H, dd, J-15,7Hz), 1.50-1.80(2H, m), 1.11(3H, t, J-7Hz) Example 85 Preparation of 3R-t4-(N-hydroxyamino)-2R-is~butyl-succinyl]am~no-l-methoxymethyl-3,4-dihydrocarbostyril After conducting a reactlon between a corresponding ~tarting material and using a compound obtained by the method of J. Med. Chem. 1972, 15, 325, the capt~oned compound was obtained in the same manner as in Example 27.
NMR(270MHz, DMSO-d6)~ppm:10.41(1H, s), 8.75(1H, s), 8.44(2H, d, J~8Hz), 7.2o-7.35t3H~ m), 7.06(1H, t, J-7Hz), 5.50(1H, d, J-lOHz), 5.01(1H, d, J~lOHz), 4.51(1H, dt, J=lZ,8Hz), 3.26(3H, W094/21S12 PCT/~4l00434 ~1361~8 s), 2.75-3.10(3H, m), 2.22(1H, dd, J=15.5Hz), 2.02(1H, dd, J=15.~Hz), 1.40-1.60(1H, m), 0.95-1.35(2H, m), 0.85(~H, t, J=SHz) Example 86 Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-3S-acetylthiomethylsuccinyl]amino-1-methoxy-3,4-dihydrocarbostyril Using a correspond~ng starting material, the captioned i compound was o~tained in the same manner as in Example 4.
.
; NMR(270MHz, DMS0-d6)~ppm:10.61(lH, s), 8.91(lH, s), 8.67(lH, d, J;-8Hz), 7-34tlH, t, J-8~z), 7.27(lH, d, J-8Hz), 7.17(1~, d, 5~ J-~8Hz), 7.07(lH, t, J~7Hz), 4.67(lH, dt, J=12,8Hz), 3.83~3H, s~, 2,80-3~15(4H, m), 2.25-2.65(1H, m), 2.20-2.40(1H, m), 2.30(3H, s), 1.50-1.70(1H, m), 1.51(1H, t, J~llHz), 0.~3~1H, t, J~llHz), 0.86(3H, d, J-7Hz), 0.82(3H, d, J-7Hz) ~, , 20~-Example 87 Preparation o~ 3S-t4-~N-hydroxyamino)-2R-isobutyl 3S-~ mercaptomethylsuccinyl]amino-l-methoxy-3,4-dihydrocarbostyril -~ Using a corresponding starting material, the captioned ~ -25 compound was obtained in the same manner as in Example 5.
,~' ,~
~ . .
,, ,., W094/21612 PCT/J~4100434 ~2 ~ a s ~ -186-NMR(270MHz, DMSO-d6)~ppm:8.62(1H, d, J=8Hz), 7.32(2H, dd, J=14.7Hz), 7.15(1H, d, J=8Hz), 7.07~1H, t, J-7Hz), 4.58(1H, dt, J=14,7~z), 3.B2(3H, s), 3.10(lH, t, J=15Hz), 2.98(lH, dd, J=15,7Hz), 2.40-1.65(3H, m), 2.20-2.40(1H, m), 1.45-1.70(1H, S m), 1.50(1H, t, J=12Hz), 0.94(1H, t, J=12Hz~, 0.86(3H, d, J-7Hz), 0.82(3H, d, J-7Hz) Example 88 Preparation of 3S-t4-(N-hydroxyamino)-2R-isobutyl-3-(4-methoxycarbonylbenzyl)succinyl~amlno-1-methoxy-3,4-dihydrocarbostyrll After ~onducting a react~on between the compound of Reference Example 78 and a correspondi~g starting material, lS the captioned compound was obtained in the same manner as in - ~ Example 14.
' NMR(270MHz, DMSO-d6)~ppm:10.29(1H, s), 8.70(1H, d, J-8Hz), : 8.66(1H, s), 7.85(2H, d, J-8Hz), 7.36-7.27(2H, m), 7.22(2H, d, J-8Hz), ~.16(1H, d, J~7Hz3, 7.05(1H, t, J37Hz), 4.66-4.61(1H, m), 3.84(6H, s), 3.14(1H, t, J~lSHz), 2.99(1H, dd, J1~7Hz, ~, J2-16Hz), 2. 81-2. 78( 2H, m), 2.60-2.57(lH, m), 2. 46-2.40(1`H, m), 1.62-1.48(2H, m), 1.01-0.97(1H, m), 0.87(6H, dd, Jl-6Hz, J2-16HZ ) -S,-~&
Example 89 Preparation of 3S-[3-hexyl-4-(N-h~droxyamino)-2R-isobutylsuccinyl]amino-l-methoxy-3,4-dihydrocarbostyril After conducting a reaction between the compound of Reference Example 79 and a corre~ponding starting material, the captioned compound was obtained in the same manner as in Example 14.
NMR(270MHz, DMSO-~6)~ppm:10.48~lH, s), 8.77~1H, s), 8.53(lH, d, J-8Hz), 7.34(1~, t, J-8Hz), 7.28~1H, d, J-7Hz), 7.16(1H, d, ~;~ J-8Hz), 7.06(1H, t, J-8Hz), 4.66-4.61(1H, m), 3.83(3H, s), 2.99(1~, t, J313Hz), 2.90(1H, dd, ~1~9Hz, J2-12~z), 2.51-2.4211H, m), 2.09-2.05(1H, m), 1.57-1.41(2H, m), 1.22-1.05(10H, m), 0.95-0.80(10H, m) .
' Example 90 ~: Preparation of 3S-~4-(N-hydroxyamino)-2R-butyl-3S-m~thylsuccinyl]amino-1-methoxy-3,4-dihydrocarbostyril Ater conducting a reaction between the compound of ,~. Reference Example 80 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 62.
WO 94t21612 PCT/~P94/00434 .3~
NMR( 270MHz, DMSO-d6 ) ~ppm: 10 . 49 ( lH, s ), 8 . 76 ( lH, s ), 8 . a2 ( lH, d, J=8Hz), 7.32(2H, dd, JD16,8HZ), 7.16(1H, d, J=8HZ), 7.07(lH, t, J=8Hz), 4.62(lH, dt, J=14,7Hz), 3.83(3H, s), 2.30-2 . 50 ( lH , m ) , 2 . 10- 2 . 30 ( lH , m ) , 1 . 00 - 1 . 50 ( 6H , m ) , 0 . 9 5 ( 3H , d , J=7Hz ), 0 . 85( 3H, t, J=7Hz ) Example 9 1 Preparation of 3S-~4-(N-hydroxyamino)-2R-butyl-succinyl]amino-1-methoxy-3,4-dihydrocarbostyril After conducting a reaction between the compound of Ref rence Example 80 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
NMR(270MHz, DMS0-d6)~ppm:10.38~lH, s), 8.70(lH, s), 8.31(lH, d, J~7Hz), 7.32(2H, dd, J-16,8Hz), 7.16(1H, d, J-8Hz), 7.07(1H, t, J-8Hz), 4.61(1H, dt, J-13,8Hz), 3.82~3H, s), 2.80-3.10(2H, m), 2.55-2.80(lH, m), 2.20~lH, dd, J-14,7Hz), 2.03(1H, dd, J-14,8Hz), 1.10-1.60(6H, m), 0.87(3H, t, J-7Hz) Example 92 Preparat~on of 3S-~4-(N-hydroxyamino)-2R-isobutyl-3-(3,4-methylenedioxybenzyl)succinyl]amino-1-methoxy-3,4-WO94/21612 . PCTIJ~4/00434 dihydrocarbostyril After conducting a reaction between the compound of Reference Example 81 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 14.
NMR(270MHz, DMSO-d6)~ppm:10.28(1H, s), 8.68(1H, s), 8.65(1H, d, JD8Hz), 7.36-7.27t2H, m), 7.16(1H, d, J=7Hz), 7.05(1H, dt, Jl-lHz, J2-7Hz), 6.77(1~, d, J-8Hz), 6.60(lH, d, J-2Hz), 6.52(1H, dd, J1~2Hz, J2~8Hz~, S.95(2H, s), 4.66-4~61(1H, m), 3.84(3H, s), 3.12(lH, t, J-lSHz), 2.98(1H, dd, J~-7Hz, J2-16HZ), 2.66-2.49(3H, m), 2.38-2.32(1H, m), 1.60-1.46(2H, m), 0.99-0.95(1H, m), 0.86(6H, dd, Jl-6Hz, J2=lSHz) ~15 Example 93 ~reparation of 3S-~3-(3-ethoxycarbonylpropyl)-4-(N-hydroxyamlno)-2R-~sobutylsuccinyl3amino-1-methoxy-3,4-dihydrocarbostyr'l After conductln~ a re~ctlon between the compound of Reference Example 82 and a corre~pondlng starting material, ; the capt1oned compound was obtained ln the same manner as in Example 14 NMR(270MHz, DMSO-d6)~ppm:10.53(1H, s), 8.83(1H, s), 8.54(1H, WO94/21612 PCT/3~4/0~34 ~ ~ 1 3 6 1 ~ ~
--190-- ! ~
d, J=8Hz), 7. 4(1H,t, J=8Hz), 7.~8(1H, d, J=8Hz), 7.16(1H, d, J=8Hz), 7.07(1H, t, J=8Hz), 4.69-4.59(1H, m), 4.05~2H, q, J=7Hz), 3.83(3H, s), 3.08-2.93(2H, m), 2.51~2.43tlH, m), 2.32-2.22(2H, m), 2.10-2.06(1H, m~, 1.56-1.31(6H, m), 1.18(3H, t, J 7Hz) 0 95-0 80~7H, m), 0.84(6H, dd, Jl=6~z, J2=12Hz) Example 94 Prepara~ion of 1-ethoxymethyl-35-~4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-3,4-dihydrocarbostyril After conducting a reaction between the compound obtained by catalytic reduct$on treatment of the compound of Reference Example 83 and a corresponding starting material, the captloned compound was obtained in the same manner as in Example 1.
NMR(270MHz, DMSO-d6)~ppm:10~39(1H, s), 8.72(1H, s), 8.28(1H, d, J-8Hz), 7.20-7.35(3H, m), 7006(1H, t, J=7Hz), 5.54(1H, d, J-lOHz), 5~00(lH, d, J~lOHz), 4.50(lH, dt, J-14,7Hz~, 3.51(2H, q, J~7Hz), 2.70-3.10(3H, m), 2.15(1H, dd, J=14,7Hz), 2.01(1H, dd, J-14,7Hz), 1.40-1.80(2H, m), 1.10(3H, t, J~7Hz), 1.00-1.20(1H, m), O.90t3H~ d, J~7Hz), 0.85(3H, d, J-7Hz) W094121612 ~ ~ 3~ 10 8 PCT/JW4/00434 Example 95 ;
Preparation of 3S-[4-(N-hydroxyamino~-2S-butoxymethylsuccinyl]amino-1-methoxy-3,4-dihydrocarbostyril After conducting a reaction between the compound of Reference Example 85 and a corresponding starting material, ~he captioned campound was obtained in the same manner as in Example 1.
NMRt270MHz, DMS0-d6)~ppm:10.37(lH, s), 8.69(1H, s), 8.34(lH, d, J-8Hz), 7.34(1H, t, J~8Hz), 7.28(1H, d, J 8Hz), 7.16(1H, d, J-8Hz), 7.08(1H, t, J-8Hz), 4.58(1H, dt, J~12.8Hz), 3.83(3H, s), 3.30-3.60(4H, m), 2.90-3.10(3H, m), Z,27(1H, dd, J~15.8Hz), 2.11(1H, dd, J-15.~Hz), 1.20-1.60(4H, m), 0.88(3H, t, J~7Hz) Example 96 .
Preparation of 3S-~4-(N-hydroxyamino)-2-isobutyl-3-methyl-thiomethylsuccinyl~amino-3,~-dlhydrocarbostyri~
Using the compound of Reference Example 87 and a corresponding starting materiai, the captioned compound was obtaimed in the same as in Example 4.
NMR(270MHz, DMSO-d6)~ppm:10.61(1H, s), lO.l9(1H, s), 8.87(1H, s), 8.45(1H, d, J~8Hz), 7.18(2H, dd, J-16,8Hz), 6.90(2H, dd, WO94/21612 PCT/J~4/00434 __ 610~
-192- ~
J=16,8Hz), 4.41(1H, dt, J=14.7Hz), 2.80-3.30(3H, m), 2,25-2.70(3H, m), 2.00(3H, s), 1.30-1.70(2H, m), 0.80-l.lO(lH, m), 0.86(3H, d, J=7Hz), 0.82(3H, d, J-7Hz) Example 97 Preparation of ~S-t4-(N-hydroxyamino)-2R-isobutyl-3S-(2-thienylthiomethyl)succinyl]amino-1-methoxy-3,4-dlhydrocarbostyril A~ter conducting a reaction of a corresponding starting material, the captioned compound was obtained in the same manner as in Example 4.
NMR(270MHz, DMS0-d6)~ppm:10.70(1H, s), 8.96(1H, s), 8.64(1H, d, J-8Hz), 7.60(1H, dd, J~5.1Hz), 7.33(1H, t, J38Hz), 7.99-7.30(5H, m), 4.54(1H, dt, J~14,7Hz), 3.81t3H, s); 2.80-3.20(5H, m), 2.30-2.50(1H, m), 1.40-1.6S~2H, m), 0.80-l.OO(lH, m), 0.84(3H, d, J~6Hz), 0.81(3H, d, J-6~z) Example 98 I Preparation of 3S-~4-(N-hydroxyamino)-2S-butoxymethyl-3S-methylsucc~.nyl3amino-3,4-dihydrocarbostyril Using a correspond~ng starting material, the captioned ~5 compound was obtained in the same manner as in Example 62.
WO94/21612 PCT/J~4/00434 NMR(270MHz, DMS0-d6)~ppm:10.48(lH, s), 10.26(lH, s), 8.77(lH, s), 8.35(1H, d, J=7Hz), 7.16(2H, t, J=8Hz), 6.93(1H, d, J=8Hz), 6.87(lH, d, J=8HZ), 4.40( lH, dt, J=12,7Hz), 3.10-3.50(4H, m), 2.80-3.10(2H, m), 2.74(1H, dt, J=4,10Hz), 2.10-2.30~1H, m), 1.20-1.50(4H, m), 0.98(3H, d, J=7Hz), 0.8$(3H, t, J-7Hz) Example 99 Preparation of 1-ethoxyethoxy-3S-t4-(N-hydroxyamino)-2R-isobuty}succinyl]amino-3,4-dihydrocarbostyril After conducting a reaction between the compound of Reference Example 88 and a corresponding s~arting material, the captioned compound was obtained in the same manner as in Example 1.
NMR(270MHZ, DMS0-d6)~ppm:10.38(1H, s), 8.72(1H, S), 8.36(1H, D,.J-8Hz), 7.32(2H, d, J~3Hz), 7.27tlH, d, J-7Hz), 7.00-7.10(1H, m), 4.60(1H, dt, J~13.7Hz), 4.15(1H, t, J-4Hz), 3.63(2H, dd, J-7.4Hz), 3.44(2H, g, J-7Hz), 2.~5-3.10(2H, m), ; 2.~5-2.85 ~lH, m), 2.17(1H, dd, J~14,7Hz), 2.01(1H, dd, J-14,8Hz), 1.40-1.75 (2H, m), 1.00-1.20(1H, m), 1.1~3H, t, J-7Hz), 0.89(3H, d, J-6Hz), 0.84(3H, d, J-6Hz) WO94/21612 PCTIJ~4/00434 ~:136108 Example 100 Preparation of l-ethoxy-3R-[4-(N-hydroxyamino)-2R
isobutylsuccinyl]amino-3,4-dihydrocarbostyril Using a corresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
NMR(270MHz, CDC13)8ppm:10.42(1H, s), 8.76(1H, s), 8.51(1H, d, J-8Hz~, 7.31(2H, dd, J-16,8Hz)~ 7.16(1H, d, J=8~z), 7.06(1H, t, J~8Hz), 4.56(1H, q, J-9Hz), 4.05(2H, q~ J-7Hz), 2.90-3.10(2H, m), 2.70-2.95(1H, m), 2.20(1H, dd, J=14,5Hz), 2.02(1H, dd, J-14,9Hz), 1.35-1.60(2H, m), 1.28t3H, t, J=7Hz), ~.95-1~20(1H, m), 0.85(3H, s), 0.83(3H, s) Example 101 Preparation of 3S-4~-(N-hydroxyamino)-2R-isobutylsucc~nyl~amino-1-methoxymethoxyethoxy-3,4-dihydrocarbostyril After conducting a reaction between the compound of Re~erence Example 89 and a correspondlng starting material, the captioned compound was obtained in the same manner as in Example 1.
MMR(270MHz, DMS0-d6)~ppm:10.38(lH, s), 8.70(lH, brs), 8.37tlH, WO94/21612 ~ 8 PCT/J~4/~0434 d, J=&Hz), 7.20-7.40~3H, m), 7.06(1H, td,J=7.2~z), 4.~2(2H, s), 4.50-4~70(1H, m), 4.15-4.25(2H, m~, 3.60-3.80(2H, m), 3.28(3H, s), 2.85-3.15(2H, m), 2.70-2.90(1H, m), 2.17(1H, dd, J=14.6Hz), 2.01(1H, dd, J=14.8Hz), 1.40-1.75(2H, m), 0.95-1.20(1H, m), 0.89(3H, d, J=6Hz), 0.85(3H, d, J=6Hz) Example 102 Preparatlon of 3S-~4-(N-hydroxyamino)-2R-lsobutylsuccinyl] amino-l, 7-dimethoxy-3,4-dihydrocarbostyril After conducting a reaction between the compound of Reference Example 90 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
NMR(270MHz, DMSO-d6)~ppm:10.39(1H, ~), 8.73(1H, s), 8.36(1H, d, J~8Hz), 7.19(1H, d, J~8Hz), 6.60-6.70(2H, m), 4.57(1H, q, J~lOHz), 3.82(3H, s), 3.77(3H, s), 2.89(2H, d, J=9Hæ), 2.70-2.90~1H,.m), 2.16(1H, dd, J-14,7Hz), 2.01(1H, dd, J=14,8Hz), 1.40-1.75(2H, m~, 1.00-1.20(1H, m), 0.89(3H, d, J-6Hz), 0.85(3H, d, J-6Hz) Example 103 W094/21612 PCT/J~4100434 ~ 13~10~ -196- I
Preparation of l-ethoxy-3S-t4-~N-hydroxyamino)-2R-iso~utylsuccinyl]amino-7-methoxy-3,4-dihydrocarbostyril After the compound of Reference Example 91 was allowed to react with a corresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
NMR(270MHZ, DMSO-d6)~ppm:10.37(1H, s), 8.71~1H, s), 8.32(1H, d, J~SHz), 7.19(1H, d, Js8Hz), 6.55-6.70~2H, m), 4.54(1H, q, J-lOHZ), 4.04(2H, ~, Js7~z)~ 3.77~3H, s), 2.70-3.99(3H, m), 0 2.16(1H, dd, J-14,7Hz), 2.01(1H, dd, J-14.8Hz), 1.35-1.70(2H, m), 1.28(3H, t, J-7Hz), 1.00-1.20($H, m), 0.89(3H, d, J=7Hz), 0.8S(3H, d, J~7Hz) - Example 104 ~reparat~on of 3S-~4-(N-hydroxyamino)-2R-isobutylsuccinyl]amlno-l-methoxyethyl-6,7-methylenedioxy-3,4-dihydrocarbostyril After conducting a reaction between the compound ; obtalned by treating the compound of Reference Example 92 with trifluoroac~t~c acid and a corresponding starting material, : the reaction was carr~ed out ~n the same manner as in Example and ! the reaction product was purified by high-performance liquid chromatography.
;: 25 NMR(270MHz, DMS0-d6)~ppm:10.37(1H, s), 8.71(1H, s), 8.17(1H, , WO94/21612 ~ 3 ~ PCT/J~4/00434 -197- , d, J=8Hz), 6.98(1H, s), 6.87(1H, s), 5.99(2H, s), 4.~0-4.37(1H, m), 4.00(2H, t, J=6Hz), 3.48(2H, t, J=6Hz), 3.23(3H, s), 2.80-2.75(3H, m), 2.17(1H, dd, J1=7Hz, J~=15Hz), 2.00(1H, dd, J1=8Hz, J2=14Hz), 1.63-1.61(1H, m), 1.47-1.44(1H, m), 1.12-1.06(1H, m), 0.87(6H, dd, J1=6Hz, J2=14Hz) Example 105 0 Preparatlon Of 3R-~4-(N-hydroxyamino)-2R-isobutylsuccinyl]am~no-l-methoxyethyl-6,7-methylenedioxy-3,4-dihydrocarbostyril After conducting a reaction between the compound obtained by treating the compound Of Reference Example 92 with trifl~sroacetic acid and a corresponding starting material, the reactlon was carried out in the same manner as in Example 1, and the reaction product was puri~led by high-performance li~uld chromatography.
NMR(270MHz, DMSO-d6)~ppm:10.40(1H, s), 8.74tlH~ s), 8.35(1H, d, J-8~z3, 6.98(1H, s), 6.88(1H, s), 5.99(2H, s), 4.40-4.32~1H, m), 4.01(2H, t, J-5Hz), 3.48(2H, t, J-5Hz), 3.23(3H, s), 2.83-2.75(3H, m), 2.20(1H, dd, J1~5Hz, 2-15Hz), 2.01(1H, dd, Jl-9Hz, J2-14Hz), 1.50-1~43(2H, m), 1.09-1.05(1H, m), 0.83(6H, dd, Jl,3Hz, J2~5Hz) WO94/21~12 PCT/J~4/00434 ~1361~8 -198- ' Example 106 Preparation of 3s-[4-(N-benzoyloxyamino)-2R-isobu~ylsuccinyl]amino-1-methoxyethoxymethyl-3, 4-dihydrocarbostyril Using a corresponding starting material, the cap~ioned compound was obtained in the same manner as in Example 8.
NMR(270MHz, DMSO-d6~ppm:11.95(lH, ~s), 8.35(lH, d, J=8Hz), 8.03(2H, d, J-7~z), 7.76(1H, t, J~7Hz), 7.60(2H, t, J=8Hz), 7.30-7.25(3H, m), 7.07(1H, dt, J1~2~z, J2=8Hz), 5.57tlH, d, J~llHz), 5.03(1H, d, J~llHz), 4.59-4.49(1H, m), 3.60(2H, dd, Jl-4Hz, J2-6Hz), 3.g4(2H, dd, Jl-4Hz, J2-6Hz), :
~ 15 3.22(3H, s~, 3.01-2.93(2H, m), 2.87-2.82(1H, m), 2.44(1H, dd, :~ Jl-7Nz, J2~15Hz), 2.27(1H, dd, Jl-7Hz, J2-lSHz), 1.71-1.53(2H ,m) 1.27-1.21(1H, m), 0.90(6H, dd, Jl=6Hz, J2-13HZ ) ~:20 Example 107 j Preparatlon of 3S-~4-(N-benzoyloxyamino)-2R-' isobutylsuccinyl]amino-l-methoxymethyl-3,4-dihydrocarbostyril ~:~ Using a corresponding starting material, the captioned :~ compound was obtained ln the same manner as in Example 8.
W094/21612 ~ PCTIJ~4/~34 NMR(270MHz, DMSO-d6)~ppm:11.95(1H, bs), 8.36(1H, d, J=8Hz), 8.03(2H, d, J=7Hz), 7.76(1H, t, J=7Hz~, 7.60(2H, t, J=8Hz), 7.32-7.22(3H, m), 7.07(1H, t, J=7Hz), 5.49(1H, d, J=llHz),5.01(1H, d, J=lOHz), 4.58-4.50(1H, m), 3.27(3H, s), 3.02-2.94(2H, m), 2.87-2.82(1H, m), 2.44(1H, dd, J1=7Hz, J2=lSHz)~ 2.27(lH, dd, J1=7Hz, J2=15Hz), 1.69-1.53(2H, m), $.27-1.17(1H, m), 0.902(6H, dd, Jl-6Hz, P2=13Hz) Example 108 Preparation of 3S-~4-(N-hydroxyamino)-2R-lsobutylsuccinyl~amino-6,7-dimethoxy-1-meth~xymethyl-3,4-dihydrocarbostyril After conducting a reaction between the compound of Reference Example 93 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
NM~(270M~z, DMSO-d6)~ppm:10.38(lH, s), 8.71~1H, s), 8.25(1H, d, J-8Hz), 6.91tlH, s), 6.86(1H, s), 5.48(1H, d, J-lOHz), 5.01(1H, d, J-lOHz), 4.48(1H, dt, J-11,8Hz), 3.75(3H, s), 3.74(3H, s), 3.26(3H, s), 2.80-2.91(3H, m),2.18~1H, dd, J~7,8Hz), 2.02(1H, dd, J-7,8Hz), 1.60-1.67(1H, m), 1.43-1.54(1H, m), 1.03-1.13(1H, m), 0.87(6H, dd, J=14,7Hz) WO94/21612 PCT/J~4100434 ~13~108 -200- !
Example 109 Preparation of 3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-6,7-dimethoxy 3,4-dihydrocarbostyril After conducting a reaction between the compound of Reference Example 94 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
NMR(~70MHz, DMso-d6)~ppm:lo.38tlH~ s), 9.97(1H, s), 8.74(1H, s), 8.12(1H, d, J-8Hz), 6.83(1H, s), 6.53(1H, s), 4.41(1H, dt, J-11,8Hz), 3.70(6H, s), 2.76-2.89(3H, m), 2.17(1H, dd, J-8,7Hz), 2.01(1H, dd, J~8,7Hz), 1.57-1.6S~lH, m), 1.42-~ l5 1.~2(1H, m), 1.03-1.13(1H, m~, 0.86t6H~ dd, Jal4,7Hz) : : Example llO
;~ Preparation of 3S-t4-(N-hydroxyamino)-2R-lsobutyls.uccinyl~amino-~-methoxY-l-methoxyethyl-3,4-dlhydrocar~ostyril After conducting a reaction between the compoundlof Reference Example 9S and a corresponding starting material, : ~ the captioned compound was obtained in the same manner as in ~5 Example 1.
; :
~ ' .
WO94/2l612 ~,~ 3 ~1 Q ~ PCT/J~4/00434 -201~
NMR(270MHz, DMS0-d6)~ppm:10.35(1H, s), 8.69(1H, s), 8.16(1H, d, J=8Hz), 7.12-7.01(2H, m), 6.88(lH, d, J=7Hz), 4.34-4.21(2H, m), 4.01-3.94(1H, m), 3.84(3H, s), 3.45-3.26(2H, m), 3.11(3H, s), 2.85-2.74(3H, m), 2.16(1H, dd, Jl-7Hz, J2=15Hz), 2.00~1H, dd, J1-8Hz, J2-14Hz), 1.64-1.59(1H, m), 1.52-1.42(1H, m), 1.13-1~03(1H, m), 0.87(6H, dd, J1a6Hz, J2=16Hz) 0 Example 111 Prepar~tion of 3S-[4-(N-benzoyloxyamino)-2~-isobutylsucclnyl]amino-l-methoxy-3,4-dlhydrocarbostyril Uslng a corresponding starting material, the captioned compound was obtained ln th~ same manner as in Example 8.
:
NMR(270MHz, DMS0-d6)~ppm:12.00(lH, brs), 3.46(lH, d, J=8Hz), 8.02t2H, d, J-7Hz), 7.75(lH, t, J-7Hz), 7.60(2H, t, J~7Hz), 7.35~1H, d, J-7Hz), 7.28(1H, d, J~7Hz), 7.16(1H, d, J~7Hz), 7.07(1H, t, J~7Hz), 4.64(1H, q, J~lOHz), 3.83t3H, s), 2.90-3.10(2H, m), 2.70-2.95~1H, m), 2.41(1H, dd, J-15,7Hz), 2.26(1H, dd, J~15,7Hz), 1.40-1.80(2H, m), 1.10-1.35(1H, m), 0.92(l3H, d, J~6Hz), `0.88(3H, d, J~6Hz) , .
Example 112 WO94/21612 PCTIJ~4l00434 ~136~Q8 -202- ~ ~
Preparation of 3-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxyethyl-6,7-methylendioxy-3,4-dihydrocarbostyril After conducting a reaction between the compound obtained by t~eating the compound of Reference Example 92 with trifluoroacetic acid and a corresponding starting material, the captioned compound was obtained (diastereomer, 1:1 mixtùre) in the same manner as in Example 1.
NMR(270MHZ, DMSO-d6)~ppm:10.39+10.36tlH, s), 8.73+8.70(1H, s), 8.35+8.16tlH, d, J-8Hz), 6.98(1H, s), 6.8~+6.86(1H, s), 5.99(2H, s),~4.40-4.35(1H, m), 4.01-4.00(2~, m), 3.48(2H, t, J-6Hz), 3.31~3.23(3H, s), 2.80-2.75(3H, m), 2.24-2.13(1H, m), 2.~05-1.97(1H, m), 1.73-1.40(2H, m), 1.07-1.05(1H, m), 0.91-0.82(6H, m) ~ ' .
Example 113 ~ Preparation of 3s-c4-(N-hydroxyamino)-2R--~ ~20 isobutylsuccinyl]amino-1-methoxyethoxy-3,4-dihydrocarbostyril After conducting a reaction between the compound of Reference Example g6 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
WO9412]612 ~.13 6 ~ ~ 8 PCT/J~4/0~34 -203- !
NMR(270MHz, DMS0-d6)~ppm:10.38(lH, brs), 8.72(lH, ~rs), 8.37(1H, d, J=8Hz), 7.26-7.36(3H, m), 7.06(1H, t, J=7Hz), 4.61(1H, dt, J=11,8Hz), 4.13-4.16(2H, m), 3.60-3.61(2H, m), 3.2~(3H, s), 2.99(1H, d, J=llHz), 2.92(1H, d, J=8Hz), 2~73-2.77(1H, mj, 2.~7(1H, dd, J=14,6Hz), Z.oltlH~ dd, J=14,8Hz), 1.61-1.67(1H, m), 1.43-1.53(1H, m), 1.06-1.15(1H, m), 0.87(6H, dd, J=13,7Hz) Example 114 Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-l-methoxyethoxymethoxyethoxy-3,4-d~hydrocarbostyril Ater conductlng a r8action between ~he compound of lS Reference Exampl~ 97 and a c~rresponding starting material, the captioned compou~d was obta~ ned ln the same manner as in ~xa~ple 1.
NMR(270MHz, DMS0-d6)~ppm:10.3~(lH, s), 8.72(lH, s), 8.37(lH, d, J-8Hz)^, 7.20-7.40(3H, m), 7.06(1H, td, J=7,2Hz), 4.68t2H, S), 4.50-4.80(1H, m), 4~18(2H~ t~ J-4Hz), 3.76(2H~ m), 3~60(2H~ m), 3.47(2H, m), 3~24t3H~ s)~ 2.85-3~10(2H, m), 2.70-2.85(1H, m), 2.17(1H, dd, Jsl4,7Hz), 2.01(1H, dd, J=lOr8Hz)~
1.35-1.75(2H, m), 1.00-1.20(1H, m), 0.89(3H, d, J=7Hz)~
0 85(3H, d, J-7Hz) WO94/21612 PCT/J~4/00434 ~1.36~ 04_ Example 115 Preparation of 3S-t4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino 1-methoxyethoxyethoxy-3,4-dihydrocarbos~yril After conducting a reaction ~etween the compound of Reference Example 98 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
NMR(270MHz, DMSQ-d6)~ppm:10.38(1H, s), 8.71(1H, s), 8.35(1H, ~:~ d, J-8Hz), 7.20-7.45(3H, m), 7.06(1H, t, J=7Hz), 4.61(1H, dt, ;~ J~13,8Hz), 4.15t2H~ dd, J-5,3Hz), 3.68(2H, d, J-3Hz), 3.40-~: 15 3.60(4H, m), 3.28(3H, s), 2.85-3.15(2H, m), 2.65-2.85(1H, m), 2.17(1H, dd, J-15,6Hz), 2.01(1H, dd, J~15,8Hz), 1.35-1.75(2H, m~, 0.95-1.20(1~, m), 0.89(3H, d, J-7Hz), 0.85(3H, d, J~7~z) Example t~6 Preparation of 35-~4-~N-hydroxyamino)-2R-hexylsuccinyl]amino-l-methoxy-3,4-dihydrocarbostyril After conducting a reaction of a corresponding start~ ng material t the captioned compound was obtained in the -same manner as in Example 1.
WO94121612 .~ PCT/J~4/00434 -~05-NMR~270MHz, DMS0-d6)~ppm:10.37(lH, s), 8.70(lH, s), 8.32(lH, d, J=8Hz), 7.35(1H, d, J=8Hz), 7.29(1H, d, J=8H~), 7.16(1H, d, J=8Hz), 7.07(1H, t, J=8Hz), 4.61(1H, dt, J=llr8Hz), 3.82(3H, s), 2.85-3.10(2H, m), 2.55-2.80(1H, m), 2.19(1H, dd, J=14,7Hz), 2.02(1H, dd, J=14,8Hz), 1.10-1.60(10H, m), 0.87(3H, t, J=7Hz) PHARMACOLOGICAL STUDIES
Test compounds were as follow:
l. 3S-~4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-3,4-dihydrocarbos~yr~l 2. 3S-~4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-7-methoxy-3,4-dihydrocarbostyril 3. 3S-~4-(N-hydroxyamlno)-2R-isobutylsuccinyl]amino-l-methoxy-3,4-dihydrocarbostyril 4. 3S-~4-(N-hydroxyamino)-2R-lsobutyl-3S-acetyl-thiomethylsucci~yl~amlno-3,4-dihydrocarbostyril 5. 3S-~4-(N-hydroxyamlno)-2R-isobutyl-3S-mercap.tomethylsuccinyl]amino-3,4-dihydrocarbo~tyril 6. 3S-t4-(N-hydroxyamlno)-2R-isobutyl-3S-(2-thlenylthiomethyl~succinyl]amino-3,4-dihydrocarbostyril 7. 3S-t4-(N-hydroxyamino)-2R-isobutyl-3(R or S)-WO94121612 PCT/J~4/00434 Q~
7. 3S-[4-(N-hydroxyamlno)-2R-isobutyl-3(R cr S)-phtnaiimidomethylsuccinyl]amino-3,4-dihydrocarbostyril 8. 1-ethoxycarbonylmethyl-3S-~4-(N-hydroxyamino)-2R-isobutylsuccinyl3amino-3,4-dihydrocarbostyril 9. 35-[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl-succinyl]amino-1-methoxy-3,4-dihydrocarbostyril 10. 1-aminocarbonylmethyl-3S-~4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-3,4-dihydrocarbostyril
~MR (2 7 OMHz. CDC 13 ) ~ ~ pm: 7. 2 0--7. 2 6 t2H, m 7 . O 5 ( 1 H . t . J = 7 H z ) ~ 6 . 8 1 ( 1 H . d , J = B H z ) 5 . 6 9 ( 1 H . b r s ) ~ 4 ~ 8 9 ( 1 H . d . J ~ 1 8 H z ) ~ 4 . 4 5 1 H. d. J=l 8Hz~ ~ 4. 3 1--4. 3 8 (lH, m) ~ 3. 3 7--3.
43 (lH? m) ~ 2. 86 tlH, t, J=l 5Hz~ ~ 1. 46 (9H, s 1- ) I
¦~ Reference Example 41 ¦ Preparation of 3S-t-butoxycarbonylamino-l-propoxy-carbonylmethyl-3,4-dihydrocarbostyril ~:~ 600 mg of 3S-t-butoxycarbonylamino-1-carboxymethyl-: 20 3,4-dihy~rocarbostyrll obtained ln Reference Example 40 was dissolved in 10 ml of dichloromethane, and 420 ~1 of propanol I
; was added and cooled in an lce bath, and 247 ~1 of N-methyl-morpholine, 430 mg of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimlde hydrochloride, and 11 mg of dimethylaminopyridine were add~d, and the mixture was stirred for 20 hours at room WO94/21612 ~ ;0; 8 PCT/~4/00434 temperature. The reaction solution was evaporated in vacuum, and 40 ml of ethyl acetate was added to the residue, which was sequentially washed with 15 ml of lN hydrochloric acid, 15 ml of aqueous solution of saturated sodium hydrogencarbonate, and 10 ml of saturated brine, and dried over magnesium sulfate, and evaporated in vacuum, and the captioned compound was obtained in a colorless oil form. Yield: 600 mg.
N M R (2 7 0 M ~ z. C D C 13 ~ ~ p p m : 7. 2 3 (2 H, d. J - 7 H
z)~7.06tlH.t.J-7Hz)~6.79(1H.d.J=7Hz) ~5.68(1H.brs)~4.87(1H.d.J=17Hz~4.50 (lH.d.J=17Hz)~4.35tl~,d t, J=14,5Hz)~4 .11(2H.t,J=7HZ)~3.45(1~.dd.J=14,5Hz) ~2.86(1H.t.J=14Hz)~1.63(2H.dq.J=7,7H
z)~1.48(9H.s)~0.86(3H.t.J-7Hz) , Reference Example 42 Preparatlon of 3S-t-butoxycarbonylamino-l-isopropoxy-carbonylmethyl-3,4-dihydrocarbostyril Using 2-propanol and a correæponding starting material, the captioned compound was obtained in the same manner as ln Reference Example 41~
NMR(27oMHz~cDcl3)~ppm:7~23t2H~d~J=8H
z)~7.06(1H.t,J=8Hz)~6.78(1H.d,J=8Hz) WO94/21612 ~ ~ 6 i~ ~ PCT/J~4/00434 . .
5. 6 9 (1 H. b r s) ~ 4. 9 5 - S. 1 5 (1 H. m) ~ 4. 8 1 (I
H. d. J = 1 7 H z) ~ 4. 4 7 ~1 H, d, J = 1 7 H z) ~ 4. 3 5 tl H. d t. J - 1 4, 5 H z) ~ 3. 4 5 (1 H. d d, J = 1 4, 5 H z) ! 2. 8 6 (1 H. t. J = 1 4 H z) ~ 1. 4 7 (9 H. s) ~ 1. 2 0 ~ 1.
3 0 ~6 H. m) Reference Example 43 Preparation of 3S-ben~yloxycarbonylamino-l=t-butoxy-- carbonylmethyl-3,4-dihydrocarbostyril ¦ Using t-butyl bromoacetate and a corresponding ¦ -starting material, the captioned compound was obtained in the 1~ same manner as in Reference Example 24.
N M R (2 7 O M ~ z. C D C 1~ ) ~ P ~ m : 7. 2 3 - 7. 3 9 (5 H, m 7. 7 (2 H, t. J = 8 H z) ~ 6. 7 9 (2 H, d. J = 8 H z) ~
¦ 5. 9 7 (1 H. b r s) ~ 5. 1 4 (2 H. s) ~ 4. 7 4 (1 H. d, J =
1 7 H z~ ~ 4. 3 4 - 4- 4 5 (2 H. m~ ~ 3. 4 7 (1 H. d d, J ~ 1 4, 6 H z) ~ 2. 8 8 (l H, t, J = 1 4 H z) ~ 1. 4 2 (9 H. s) :~-:~ Reerence Example 44 ~ Preparation of l-amlnocarbonylmethyl-3S-t-butoxy-¦ 2~ carbonylamino-3,4-dihydrocarbostyril Using iodoacetamide and a corresponding startlng material, the captioned compound was obtained in the same ~ manner as in Reference Example 24.
-: N M R (2 7 0 M H z. C D C l3 ) ~ ~ P m : 7. 1 5 - 7. 3 5 (2 H. m ~: 25 ) ~ 7. 0 5 - 7. 1 5 (2 H. m) ~ 6. 1 3 (1 H. b r s) ~ 5. 6 0 ( ;
~ wo94nl6l2 ~1 3 ~ PCT/~4/00434 .
1 H. b r s) ~ 5- 4 4 (1 H. b r s) ~ 4. 9 S (I H. d. J - l 6 H
z) ~ 4. 3 8 (l H. d t. J ~ 1 4, 6 H z) ~ 4. l 9 (1 H, d. J =
l 6 H z) ~ 3- 3 - 3- 5 0 (1 H, m) ~ 2. 8 8 (l H. t. J = 1 4 H z) ~ 1. 4 7 (9 H, s) Reference Example 45 Preparation of 3S-t-butoxycarbonylamino-l-(N-methyl-aminocarbonylmethyl)~3,4-dihydrocarbostyril 500 mg of 35-t-butoxycarbonylamino-1-carboxymethyl-3,4-dihydrocarbostyril was dissolved in lO ml of dichloromethane, and while stirring in ice-cooling, 240 mg of l-hydroxybenzotriazole, 0.21 ml of N-methylmorpholine, and 358 mg of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, and the mixture was s~irred for lO
minutes, and 0.34 ml of N-methylmorpholine and 210 mg of methylamine hydrochloride were added, and the mixture was ! st~rred ov~rnlght at room temperature. ~he reaction solution ~: was rioncentrated in ~acuo, and 30 ml of dichloromethane was ¦ added to the residue, and it was washed sequentially with 15 ¦ ml of lN hydrochloric acid, 15 ml of aqueous solution of saturated sodlum hydrogencarbonate, and 15 ml of saturated brine, and dried over magnes~um sulfate anhydride. Evaporated in vacuum, the captioned compound was o~tained in a white ~.
solid form. Yield: 540 mg.
I
W094nl612 ~ ~ 3 610 ~ PCT/nW410044 ~ M R (2 7 O M H z. C D C 13 ) ~ P P m : 7. 0 6 - 7. 3 2 (4 H, m ) ~ 6. 1 2 (1 H, b r s) ~ 5. 5 9 (1 H. b r 5) ~ 4. 9 4 (1 H, d. J = 1 6 H z) ~ 4- 3 4 ~ 4 4 4 tl H, m) ~ 4. 1 0 (1 H. d, J = 1 6 H z) ~ 3. 4 1 (1 H. d d, J - 1 5, 8 H z) ~ 2. 8 7 (1 H
, t. J = 1 5 H z) ~ 2. 8 2 (3 H. d. J = 5 H z) ~ 1. 4 8 (9 H,.m) Reference Example 46 Preparation of 3S-t butoxycarbonylamino-l-~N-propyl-aminocarbonylmethyl) 3,4-dihydrocarbostyril Us~ng 1-propylamine and a corresponding starting ~materlal, the captioned compound was obtained in the same manner as ln Reference Example 45.
N M R (2 7 0 M H z, C D C 13 ) ~ ~ P m : 7. 0 6 7. 3 2 t4 H, m ) ~ 6. 0 1 (1 H. b r s) ~ 5. 6 O (1 H, b r s) ~ A. 9 2 (1 H.
d, J = 1 6 H z) ~ 4- 3 4 - 4. 4 2 (1 H, m) ~ 4. 1 4 (1 H. d.
J = 1 6 H z) ~ 3. 4 3 tl H. d d, J - 1 5, 8 H z) ~ 3. 2 2 (2 H
. d~. 3 = 2~ 7 H z) ~ 2. 8 6 (l H, t, J = 1 5 H z) ~ 1. 4 2 -1. 5 3 (1 l~H~ m) ~ O. 8 6 (3 H, t, J ~ 7 H z) Reference Example 47 Preparat1on of 3S-t-butoxycarbonylamino-l-(N-methoxy-aminocarbonylmethyl~-3,4-dihydrocarbostyril Using methoxyamine and a corresponding starting material, the captioned compound was obtained in the same manner as in Reference Exampl~ 45.
N M R (2 7 O M H z. C D C 13 ) ~ p p m : 9. 0 6 (1 H. s) ~ 7. 1 `
5 - 7. 4 0 (3 H. m) ~ 7- 0 9 (1 H. t, J - 8 H z) ~ 5. 5 5 (1 W094~1612 PCT/~4/00434 ~1~61 ~8 H. b r s) ~ 4. 7 5 - 4. 9 5 ~l H, m) ~ 4. 3 6 (l H. d t,. J =
1 4, 6 H z) ~ 4- Q O - 4- 2 0 (1 H. m) ~ 3. 7 8 (3 ~. s) . 3 9 (1 H. d d. J = l 4, 5 H z) ~ ~. 8 6 (1 H, t, J = l 4 H z ) ~ 1. 4 8 (g H. s) Re~erence Example 48 Preparation of 3S-t-~utoxycarbonylamino-l-(N,N-dimethylaminocarbonylmethyl)-3,4-dihydrocarbostyril Using dimethylamine and a corresponding s~arting ~ material, the captioned compound was obtained in the same manner as in Reference Example 45.
~ M R (2 7 O M H Z. C D C 13 ) ~ P P m : 7. 2 0 - 7. 2 6 (Z H. m ) ~ 7. 0 3 (l H. t, J = 8 H z) ~ 6. 7 8 (1 H. d. J = 8 H z) ~
5. 7 8 (l H. b r s) ~ 4. 9 3 ~l H, d. J = l 7 H z) ~ 4. 5 0 ( 1 H. d. J = 1 7 H z) ~ 4. 3 4 - 4. 4 3 (1 Hl m) ~ 3. 3 9 - 3.
¦ 4 6 (1 H, m) ~ ~. 1 3 t3 H, s) ~ 2. 9 9 (3 H. s) ~ 2. 9 O ( l H, t, J - 1 4 H z) ~ 1. 4 7 (9 H, s) ~eference Exampl@ 49 Preparation of 3S-t-butoxycarbonylamino-l-morpholino-carbonylmethyl 3,4-dihydrocar~ostyril Using morpholine and a corresponding starting material, the captioned compound was obtained in the same manner as in Reference Example 45.
~ M R (2 7 O M H z. C D C 13 ) ~ p p m : 7. 2 2 (2 H. d, J = 7 H
z) ~ 7. O 5 (1 H~ t. J = 7 H z) ~ 6. 8 O tl H, d, J = 7 H z) ` wo 94nl6~2 ~ 1 3 6 1 0 8 PCT/~4/004~4 , . .
5. 6 6 (l ~. b r s) ~ 4. 9 2 (l H, d. J = 1 6 H z) ~ 4. 5 2 (1 H. d. J = 1 6 H z-3 ~ 4. 3 9 (1 H. d t. J = 1 4, 5 H z) ~ 3 ! 7 3 (4 H. d d. J = l 5, 4 H z) ~ 3. 6 1 (4 H, d d, J = 1 5, 4 H z) ~ 3. 4 3 (l H. d d. J - l 4, 5 H z) ~ 2. 9 0 (l H. t.
J~ J = 1 4 H z) ~ l. 4 7 (9 H. s) ! 5 Reference Example 50 ¦ Preparation of 1-allyl-3S-t-butoxycarbonylamino-3,4-dihydrocarbostyril Using allyl bromide and a corresponding starting ~material, the captioned compound was obtained in the same manner as ln Reference Example 24.
N M R t2 7 0 M H z. C D C l3 ) ~ ~ ~ m : 7. 2 3 (l H. d. J 3 8 H
z) ~ 7. 2 l (l H. d. J = 7 H z) ~ 7. 0 6 - 6. 9 9 (2 H. m) ~
5. g 4 ~ S. 8 2 (l H. m) ~ 5. 7 5 tl H. b s) ~ 6. 2 3 - 5. l ¦ 2 (2 H. m) ~ 4. 8 8 - 4. 7 8 (l H. m) ~ 4. 3 5 - 4. 2 6 (2 H
, m) ~ 3. 4 4 (l H. d d. Jl = 5 H Z~ J2 = l 5 H z) ~ 2. 8 1 ( l H. t. J = 1 S H z3 ~ l. 4 8 (9 H. s) ~: .
Reference Example 51 Preparation of 3S-t-hutoxycarbonylamino-1-cinnamyl- 1 2~ 3,4-dihyd~ocarbostyril Uslng a starting material corresponding to cinnamyl bromide, the captioned compound was obtained in the same ~1~manner as in Ref~rence Example 24. .
M R (2 7 0 M H z. C D C l3 ) ~ ~ ~ m : 7. 3 6 - 7. 1 9 t7 H. m 7. 1 0 - 7. 0 l (2 H. m~ ~ 6. 5 4 (l H. d. J = 1 6 ~ z) .
Wo94/21612 ~ 1 3 ~10 8 PCT/J~4/00434 . . i 6. 2 4 (1 H. t d. Jl ~ 1 6 H Z J2 = 6 H z) ~ 5. 7 6 (1 H, b ) 4 9 9 (1 H. d d d, J1 = 2 H Z J2 3 ) ~ 4. 4 6 (1 H. d d d. J1 = 1 H Z J2 = 6 H z. J3 = 1 6 H z) ~ 4. 3 7 - 4. 3 1 (1 H. m) ~ 3. 4 5 (1 H. d d. J1 = 5 H z. I
2 = 1 5 H z) ~ 2. 8 3 (1 H. t, J ~ 1 5 H z) ~ 1. 4 8 (9 H. s) Reference Example 52 Preparation of 3S-t-butoxycarbonylamino-1-methyl-3,4-dihydrocarbostyril Using iodomethane and a corresponding starting ~ material, the captioned compound was obtained in the same manner as in Reference Example 24.
~ M R (2 7 O M ~ z. C D C 13 ) ~ P P m : 7. 2 0 - 7. 3 2 (2 H. m ) ~ 6. 9 8 - 1. O 8 t2 H. m) ~ 5. 7 1 (1 H. b r s) ~ 4. 1 9 -4. 2 8 (1 H. m) ~ 3. 4 8 - 3. 5 0 (1 H. m) ~ 2. 7 8 (1 H. t , J = 1 5 H z) ~ 1. 4 8 t9 H. s) Reference Example 53 Preparation of 3S-t-butoxycarbonylamino-1-ethyl-3,4-dlhydrocarbostyrll Uslng iodoethane and a corresponding starting materlal, the captioned compound was obtained in the same manner as in Reference Example 24.
W094/21612 -~ 13 6 1~ 8 pcTl~4looa4 ~g8-~ M R (2 7 O M H z. ~ D C 13 ) ~ P P m : 7. 1 5 - 7. 3 5 (2 H. m ) ~ 7. 0 3 (2 H. t, J = 7 H z) ~ 5. 7 4 (l H, b r s) ~ 4. 2 4 (1 H. d t. J - l 4. 5 H z) ~ 3. 8 5 ~ 4. 2 0 (2 H, m) ~ 3. 4 l (l H. d d. J - l 4- 5 H z) ~ 2. 7 5 (1 H. t, J = 1 4 H z) 1. 4 7 (9 K, s) ~ l. 2 6 (3 H. t, J - 7 H z) Reference Example 54 Preparation of 1-benzyloxyethyl-3S-t-butoxyoarbonyl-amino-3,4-dihydrocarbostyril Uslng 1-benzyloxy-2-iodoethane and a corresponding starting material, the captioned compound was obtained in the same manner as in Reference Example 24.
N M R (2 7 O M H z. C D C l3 ) ~ ~ p ~ : 7. l 5 - 7. 4 0 (8 H, m ¦ ) ~ 6. 9 5 - 7. l O (l H, m) ~ 5. 7 1 (l H, b r s) ~ 4. 5 2 ( 2 H. s~ ~ 4. l 5 - 4. 3 5 (2 H. ~) ~ 3. 9 5 - 4. 1 5 tl H, m ) ~ 3. 7 3 (2 H. t~ J = 6 H z) ~ 3. 3 9 (l H. d d. J - l 4, 6 I H z) ~ 2. 7 6 ~L H, t, J = l 4 H z) ~ 1. 4 7 (9 H. s) ~-- Reference Example 55 Preparation of 3S-t-butoxycarbonylamino-1-(2-hydroxy-ethyl)-3,4-dlhydrocarbo tyril 1.50 g of 1-benzylo~yethyl-3S-t-butoxycarbonylamino-3,4-dihydrocarbostyril was dissolved in 10 ml of ethanol, and 100 mg of 20% palladium hydrox$de-on-carbon ( wet ) was added, and the mixture was saturated with hydrogen. After s~irring I for 1 day at ordinary pressure, the catalyst was filtered away, the filtra~e was concentrated in vacuo, and the captloned compound was obtained. Yield: 1.05 g.
W094121612 ~ 13 6 1 Q 8 PCT/nW4100434 _99_ i N M R (2 7 O M H z. C D C 13 ~ S p P m : 7. 0 0 - 7. ~ O (4 H, m ) ~ 5. 7 0 (1 H. b r s) ~ 4. 1 5 - 4. 4 0 (2 H, m) ~ 3. 8 0 -4. 1 5 (3 H. m) ~ 3~ 4 0 (1 H, d d. J = 1 5. 7 H z) ~ 2. 8 1 (1 H. t. J = 1 5 H z) ~ 2- 2 3 (1 H. b r s) ~ 1. 4 7 (9 H. s ) Reference Example 56 Preparation of 3S-t butoxycarbonylamino-l-(2-propynyl)-3,4 dihydrocarbostyril Using propalgyl bromide and a corresponding starting material, the captioned compound was ob~ained in the same manner 2S in Re~erence Example 24.
N M R (2 7 O M H z. C D C 13 ) ~ P P m : 7. 2 1 7. 3 S (~ H, m ) ~ 7. 0 8 (1 H~ d t, J = 1, 7 H z) ~ 5. 6 8 tl H. b r s) ~ 4 . 9 5 (1 H. d d. J = 1 7, 2 H z) ~ 4. 4 7 (1 H. d d, J ~ 1 7, 2 H z) ~ 4. 2 5 - 4. 4 4 (1 H. m) ~ 3. 4 2 (1 H. d d, J = 1 5 t 5 H z~ ~ 2. 8 0 (l H, t, J = 1 S H z) ~ 2. 2 4 (l H. t, J =
2 H z) ~ 1. 4 7 t9 H. s) Reference Example 57 Preparation of 7-chloro-3S-phthalimido-3,4-dlhydrocarbostyril 2~82 g of 3S-amlno-7-chloro-3, 4-dihydrocarbostyril was suspended in 40 ml of dimethylformamide, and 3.46 g of N-carboethoxyphthallmide and 1. 52 g of sodium carbonate were added, and the mixture was stirred overnight at room tsmperature. The reaction solution was concentrated in ~racuo, and 50 ml of water was added to the residue, and the WO94/21612 PCTIJ~4/00434 ~ 1 3 6 1 0 ~ f r --1~) 0 ~ precipitates were filtered. The crude product was washed with 5' 30 ml of ethyl acetate and 30 ml of methanol, and the ~, captioned compound was obtained in a pale brown powder form.
Yield: 4.02 g.
MMR(270MHz, DMSO-d6)~ppm:10.69(1H, brs), 7.89-7.97~4H, m), 7.25(1H, d, Js8Hz), 7.04(1H, dd, J=8,2Hz), 6.95(1H, d, J=2Hz), 5.06(lH, dd, J=15,7Hz)~ 3.66(lH, t, J=15Hz), 3.15(lH, dd, Jal5,7Hz) .
Reference Example 58 Preparation of 3S-triphenylmethylamino-3,4-dihydrocarbostyril 2.26 g of 3S-amino-3,4-dlhydrocarbostyril was suspended in ~0 ml of dimethyl formamide, and while stirring ln ice-cooling, 5.03 g of triphenylmethyl chloride was added, and the pH was ad~usted to 8 by triethylamine. After stlrring for 1 hour at 0~, returnlng to room temperature, the pH was adJusted again to 8 by triethylamine, and the solution was stirred for 1 hour. The reaction solution was concentrated in vacuo, and 100 ml of ethyl acetate was added, and it was washed seguentlally with lN hydrochloric acid (80 ml), aqueous solution of saturated sodium hydrogencarbonate (50 ml x 2 times), and saturated brine (S0 ml x 2 times), and dried over magneslum sulfate anhydr~de, and evaporated in vacuum. To the ;, ' ~:
W094/21612 ~ 1~ 610 8 PCT/~4/00434 .
-101~
residue, n-hexane was added, precipitates were filtered, and the captioned compound was obtained. Yield: 5.34 g.
NMR(270MHz, CDC13)~ppm:7.52-7.57(6H, m), 7.44(lH, br), 7.19-7.32(9H, m), 7.10(1H, t, J=8Hz), 6.87(1H, t, Ja8Hz), 6.69(lH, d, J-8Hz), 6.64(1H, d, J-8Hz), 3.41(lH, dd, J-6~15Hz), 2.46(1H, t, J=15Hz), 1.65(1H, dd, J=6.15Hz) Reference Example 59 Preparation of 3S-(tert-butoxycarbonyl)amino-7-chloro-1-methoxy-3,4-d~hydrocarbostyri~
Using ~odomethane and a corresponding starting material, the captioned compound was obtained in the same ,,~
~ 15 manner as ln Reference Example 21.
,~
NMR(270MHz, CDC}3)8ppm:7.22tlH, d, J-2Hz), 7.14(1H, d, ~-8Hz), 7.05~1H, dd, J-2~8Hz), 5.55(1H, br), ~ 4.34(1H, dt, J-14,6Hz), 3.94t3H, 5), 3.42(1H, dd, J~14,6Hz), ; ~20 2.77(1H, t, J-14Hz), 1.48~9Hr s) Reference Example 60 't`
: Preparation o~ 3~-(4-hydroxy-ZR-isobutyl-3S-methyl-succlnyl)amino-1-methoxymethyl-3,4-dihydrocarbostyril W094/2l612 ~ U ~ PCT/J~4/OW4 -10~-3S-(4-hydroxy-2R-isobutyl-3-ethenysuccinyl)amino-l-methoxymethyl-3,4-dihydrocarbostyril (800 mg, 2.14 mmol) obtain~d in the same manner aS in Reference Example 4 was dissolved in ethanol (10 ml), and 10% palladium-carbon (100 mg~ was added, and the mixture was saturated with hydrogen.
After stirring for 1 day at ordinary pressure, the catalyst was filtered off, and the solvent was evaporated in ~acuo, and the captioned compound was obtained. Yield: 790 mg.
NMR(270MHz, DMSO-d6)~ppm:8.50( lH, d, J~8Hz ), 7.15-7.35(3H, m), 7.06(1H, t, J-7Hz), 5.48(1H, d, J=lOHz), 5.02(lH, d, J-lOHz), 4.57(lH, dt, J-14~7Hz), 3.26(3H, s), 3.05~1H, t, J-14Hz), 2.94(1H, dd, J-14,7Hz), 2.80-3.20(1H, m), 2.20-2.45(1H, m), 1.4o-l.7ot2H~ m), 0.90-1.20(1H, m), 1.04(3H, d, J-7Hz), 0.90(3H, d, J-7Hz), 0.83(3H, d, J=7Hz) .:
Reference Exampls 61 Preparation of 3S-benzyloxycarbonylamino-1-methoxy- `
~: 20 e~hoxymethyl-3,4-dihydrocarbostyril Using methoxyethoxymethyl chloride and a corresponding starting materiàl, the captioned compound was obtained in the same manner as in Reference Example 24.
MMR(270MHz, CDC13)~ppm:7.20-7.50(7H, m), 7.20(1H, d, WOg4nl612 PCTtJ~4100434 ~ 1 3 6 1 0 8 J=7Hz), 7.09(1H, t, J=7Hz), 5~92~1H, brs), 5.82(1H, d, J=llHz), 5.15(2H, s), 5.01(lH, d, J=llHz), 4.40~lH, dt, J=14,6Hz3, 3.72(2H, dd, J=5.3Hz), 3.53(2H, t, J=5Hz~, 3.41~1H, dd, J-14,6Hz~, 3.37(3H, s), 2.83(1H, t, J=14Hz~
~eference Example 62 Preparation of 4-t-butoxy-2R-isobutyl-3-propyl-succinic acid Using aryl bromide and a corresponding starting material, the capt~oned compound was obtained in the same manner as in Reference Example 8.
NMR(270MHz, CDCl3)~ppm:2.68~1H, dt, Jl-3Hz, J2-9Hz), 2.50(1H, dt, Jl-2Hz, J~lOHz), 1.74-1.12(16H, m), 1.45(9H, s), 0.96-0.87(9H, m) ,- .
Reference Example 63 Preparation of 3-benzyl-4-t-butoxy-2R-isobutyl-~: succlnic acld U.sing benzyl bromide and a corresponding starting material, the captioned compound was obtained in the same ! ~ m?nner as in Reference Example 8.
NMR(270MHz, CDCl3)~ppm:7.26-7.16(5H, m), 2.91-2.74~4H, m), $ 1.77-1.60t2H, m), 1.29-1.18(10H, m), 1.26(9H, s), 0.91(6H, dd, WO94/~1612 PCT/J~4/00434 ~ 1 3 6 1 0 ~ - 104- !
Jl=3HZ, J2=7Hz) Reference Example 64 Preparation of 4-t-butoxy-2R-isobutyl-3-(4-methoxy-benzyl)succini~ acid Using 4-methoxybenzyl chloride and a corresponding - starting matexial, the captioned co~pound was o~tained in the same manner as in Reference Exampla 8.
MMR(270MHz, CDC13)~ppm:7OO9(2H, d, Js9Hz), 6.79(2H, d, J-9Hz), 3.77(3H, s), 2.87-2.72(4H, m), 1.7~-1.59(2H, m), 1.33-1.21(10H, m), 1.28(9H, s), Q.90(6H, dd, Jl~3Hz, J237Hz) I !
Reference Example 65 Preparation of benzyl 2-benzyloxycarbonyl-3S-tert-butoxycar~onyl-5-methylhexanoate U~ing L-leucin, the captioned compound was obtained in the same manner as in Reference Example 1.
25 Re~erence Example 66 ~' WO 94/21612 PCTlJP94/Oû434 l D 8 1os Preparation of 3S-benzyloxycarbonylamino-1-methoxy-methoxyethyl-3,4-dihydrocarbostyril Using l-iodo-2-methoxymethoxyethane and a corresponding starting material, the captioned compound was obtained in the same manner as in Reference Example 24.
NMR(270MHz, CDC13)~ppm:7.15-7.45(8H, m), 7.06(1H, t, J=7Hz), 6.01(1H, brs), 5.15(2H, s), 4.59(2H, q, J=6Hz), 4.25 4.40(1H, ^ m~, 4.25(1H, dt, J-14r5Hz), 4.08(1H, dt, J=14,7Hz), 3.78(2H, 10t, J-5Hz), 3~44(1H, dd, J-15,6Hz), 3.29(3H, s), 2.81(1H, t, J-15~z) Reference Example 67 15Preparation of 4-t-butoxy-2R-lsobutyl-3-(3-ph~nylpropyl)succintc acid Uslng cinnamyl bromide and a corresponding starting material, the eaptloned compound was obtained in the same manner as ln Reference Example 8.
NM~(270MHz, CDC13)~ppm:7.29-7.13(5H, m), 2.71-2.50 (4H, m), 1.74-1.42(15H, m), 1.43(9H, s), 1.20-1.12(1H, m), 0.90(6H, d, J-7Hz) WOg4nl6~ PCT/p~4/00434 Reference Example 68 Preparation of 4-t-butoxy-2R-isobutyl-3-(2-methyl-benzyl)succinic acid Using a-bromo-o-xylene and a corresponding starting ¦ 5 material, the captioned compound was obtained in the same ¦ manner as in Reference Example 8.
NMR(270MEz, CDCl3)6ppm:7.lZ-7.06(4H, m), 2.9l-2.79(4H, m), ~ 2.29(3H, s), 1.77-1.60(2H, m), 1.29-1.17tlOH, m), 1.25(9H, m), 0.92(6H, dd, J1~lHz, J2~6HZ) Reference Example 69 Preparation of 4-t-butoxy-2R-isobutyl-3-(3-methyl--~ 15 benzyl)succinic acld ~: Using -bromo-m-xylene and a corresponding starting mat~r~al, the captloned compound wa~ obtained in the same manner a~ ~n Reference Exa~ple 8.
:
NMR(270MHz, CDCl3)~ppm:7.17-6.95(4H, m), 2.89-2.73(4H, m), 2.29(3H, s), 1.79-1.54(2H, m), 1.31-1.20(10H, m), 1.27(9H, s), 0.9l(6H~ dd, Jl-3Hz, J2-7HZ) ~: ~ .
.
Reference Example 7~
W094/21612 .~ 1 3 ~ 1 0 8 Preparation of 4-t-butoxy-2R-isobutyl-3-(4-methyl-benzyl)succinic acid Using a-bromo-p-xylene and a corresponding starting material, the captioned ~ompound was obtained in the same 5 manner as in Reference Example 8.
NMR(270MHz, CDC13)~ppm:7.05(4H, s), 2.88-2.70(4H, m), - 2.29(3H, s), 1.76-1.59(2H, m), 1.33-1.17(10H, m), 1.28(9H, s), 0.90(6H, dd, J1~4Hz, J2-7Hz) Reference Example 71 Preparation of 4S-isopropyl-3~ oxononyl)-2-oxazolidinone 4S-Isopropyl-2-oxazolidinone (1.02 g, 7.90 mmol) was dlssolved in tetrahydrofurane (25 ml) in nitrogen atmosphere, and cooled to -78~. Dripp$ng n-butyl lithium (1.63M hexane solutlon) (5.09 ml, 8.30 mmol), the solution was stirred for 30 minutes. Adding pelargonyl chloride (5.09 ml, 8.67 mmol), ~he solution was stlrred for 1.5 hours at -78C. The reaction solution was poured into 5~ aqueous solution of ammonium chloride (30 ml), and extracted with ethyl acetate (30 ml x 2 times), and the organic layer was washed with water (10 ml) and saturated brine (20 ml), and dried over magnesium sulfate.
The solvent was evaporated in vacuo, and the captioned .. W094n1612 PCTI~4/00434 s, hl361 08 .~
compound was obtained in a colorless oily form. -Yield: 2.10 g MMR(270MXZ, CDC13)~ppm:4.40(1H, dt, J=8.4Hz), 4~26tlH~ t, J-9Hz), 4.19(1H, dd, J39.3Hz~, 2.7 -3.05(2H, m), 2.25-2.50(1H, m), 1.50-1.75(2H, m), 1.15-1.50(10H, m), 0.91(3H, d, J=7Hz), 0.86(3H, d, J-7Hz), 0.80-l.OO(.~H, m) Reference Example 72 ¦ Preparation of 4S-isopropyl-3-(2~-t-butoxycarbonyl-methyl-l-oxononyl)-2-oxazolidinone Tetrahydrofurane t2.5 ml) was added to diisopropyl-amine (1.~8 ml, 9.85 mmol), being i~e-cooling, n-bu~yl lithium (1.63 M hexane solution) (5.50 ml, 8.97 mmol) was dripped, and the solutlon was stirred for 15 minu~es, and cooled to -78C, and tetrahydrofurane (5 ml) solution of 4S-isopropyl-3-(1-oxononyl)-2-oxazolldinone (2.30 g, 8~54 mmol) was dripped, and the solution was stlrred for 30 minutes at -78~C. Adding t-butylbromoacetate (1.66 ml, 10.28 mmol), the temperature was gradually raised to -5~ while stirring for 7 hours. The I reaction solution was poured into 5~ aqueous solution of ~.`
~mmo~ium chloride, and extracted with ethyl acetate (20 ml x 2 times), and the organic layer was washed sequentially with WO94/21612 PCT/p~4/00434 1361~
los water (~0 ml) and saturated brine (20 ml), and dried over magnesium sulfate. The s~lvent was evaporated in vacuo, and purified by silica gel chromatography (eluted in hexane:ethyl acetate - 14:1), and the captioned compound was obtained.
Yield: 2.19 g.
NMR(270MHz, CDCl3)~ppm:4.43(lH, dt, J-8,4Hz), 4.10-4.35(3H, m), 2.74(1H, dd, J-16,10Hz), 2.42(1H, dd, J-16,4Hz), 2.30-- 2.55tlH, m), 1.41(9H, s), 1.10-1.75(12H, m), 0.93(3H, d~
J~6Hz), 0.88(3H, d, J-6Hz), 0.80-1.10(3H, m) Reference Exa~ple 73 Preparat~on of 3S-t(2R-t-butoxycarbonylmethyl)-(l-oxononyl)]amino-1-methoxy-3,4-dihydrocarbostyril 4S-Isopropyl-3-(2R-t-butoxycarbonylmethyl~l-oxononyl)-2-oxazolldinone (2.19 5, 5.71 mmol) was dissolved in a mixed solvent of tetrahydrofurane-water (3:1, 120 ml~, and ~- cooled to 0~. Adding sequentlally lithium hydroxide hydrate ~79 mg, .11.42 mmol) and 30~ aqueous solution of hydrogen peroxide (2.94 ml), the solutlon was stirred for 1.5 hours at 0~. Adding 1.5N aqueous solution of sodium sulfite (21.5 ml), the solution was stirred for several minutes, and the mixture was poured into methylene chloride (150 ml), and washed sequentially with lN hydrochloric acid (50 ml) and ~. WO94/21612 PCT/~4/00434 ~13610~ " -., -110--saturated brine (20 ml), and dried over magnesium sulfate.
After evaporating the solvent in vacuo, adding dimethyl formamide (10 ml), the solution was ice-cooled, and 3S-amino-1-methOxy-3,4-dihydrOCarbostyril hydrochloride (1.30 g, 5.71 mmol), N-methylmorpholine (628 ~1, 5.71 mmol~, 1-~ hydroxybenzotriazole (873 mg, 5.71 mmol), and dicyclohexyl-¦ carbodiimide (1.18 g, 5.71 mmol) were sequentially added, and ¦ the mixture was stirred for 15 hours at room temperature. The ~ solvent was evaporated in vacuo, ethyl acetate (50 ml) was added, and the mixture was sequentially washed with lN
hydrochloric acid (20 ml), saturated aqueous solution of sodium hydrogen~arbonate (20 ml x 2), and saturated brine (30 ml), and dried over magnesium sulfate. After evaporating the I ~olven~ ln vacuo, ~t was purlfied by silica gel column r 15 chromatography teluted in hexane:ethyl ace~ate o 3:1), and the captioned compound was obtained. Yield: 2.70 g.
NMRt270MHz, CDCl3)~ppm:7~15-7040(3H, m), 7.08(1H, t, J-7Hz) : 6.63(1H, d, J~6Hz), 4.60(1H, dt, J~14,6Hz), 3.94(3H, s), 3-49tlH, .dd, J-15,6Hz), 2.76(1H, t, J~15.Hz), 2.55-2.80(2H, m), 2.30-2.50(1H, m), 1.45t9H, s), 1.20-1.&0(12H, m), 0.87(3H, t, J~7Hz) Reference Example 74 . WO94~1612 PCT/~4/0~34 ;-136~ Q~
Preparation of 7-chloro-1-methoxymethyl-3S-phthalimido-3,4-dihydrocarbostyril Using methoxymethyl chloride and a corresponding ~.
starting material, the captioned compound was obtained in the same manner as in Reference Example 24.
i ~ NMR(270MHz, CDC13)~ppm:7.86-7.93~2H, m), 7.73-7.79(2H, m), ¦ 7.39(1H, d, J-2Hz), 7.06-7.14(2H, m), 5.68(1H, d, J=llHz), - 5.15(1H, dd, J-15,6Hz), 4.99(1H, d, J=llHz), 4.02(1H, t, J-6Hz), -~.41(3H, s), 2.97(lH, dd, J~14,6Hz) Reference Example 75 Preparation of 3(R,S)-benzyloxycarbonylamino-l-tert-butoxyethyl-3,4-dlhydrocarbostyril Uslng l-iodo-2-tert-butoxyethane and a corresponding starting material, the captioned compound was obtained in the same manner as in Reference Example 24.
NMR(270MHz~ CDC13)~ppm:6.99-7.40(9H, m), 6.00(1H, br), 5.12-5.17(2H, m), 4.08-4.35(2H, m), 3.87(1H, dt, J-14,7Hz), 3.55-3.64t3~, m), 2.80(lH, t, J-14Hz), 1.12(9H, s) Re~erence Example 76 WO94/21612 ~ 13 61~ 8 PCT/~4/00434 ; .
Preparation of l-methoxyethyl-3S-triphenylme~hyl-am~no-3,4-dihydrocarbostyril Using l-iodo-2-methoxyethane and a corresponding starting material, the captioned compound was obtained in the same manner as in Reference Example 24.
NMR(270MHz, CDC13)~ppm:7.49-7.54(6H, m~, 7.08-7.~1(11H, m), - 6.88(1H, dt, J~2,8Hz), 6.66(1H, d, J-8Hz), 4.20(1H, dt, J~14,5Hz), 3.98(1H, dt, J-14,7Hz), -~.59(1H, dd, J-7,5Hz)~, 3.37(1H, dd, J~14,5Hz), 3.34(3H, s), 2.36(1H, t, J=14Hz), I.56tlH, dd, J~14,SHz) Reference Example 77 Preparation of 3~R,S)-benzyloxyamlno-l-methoxyethyl-3,4-dihydrocarbostyril Using 1-iodo-2-methoxyethane and a corresponding starting material, the captioned compound was obtained in the 2~ same manner as in Refere~c~ Example 24.
NMR(270MHz, CDC13)~ppm:7.19-7.40(8H, m), 7.05(1H, t, J=7Hz), 5.99(1H, br), 5.15(2H, s), 4.33(1H, dt, ~14,5Hz), 4.25(1H, dt, J~14,5Hz), 4.00(1H, dt, J-14,7Hz), 3.59-3.68(2H, m), 3.44(1H, dd, J-14,5Hz), 3.35(1H, s), 2.81(1H, t, J=14Hz), ~ WO94~1612 .~13 610 g PCT/J~4/00434 -: , i 1~12(9H, s) i Reference Example 78 Preparation of 4-t-butoxy-2R-isobutyl-3-(4-methoxy-carbonylbenzyl)succinic acid ,. Using 4-methoxycarbonylbenzyl bromide and a '~ corresponding starting material, the captioned compound was obtained ln the same manner as in Reference Example 8.
', 10 NMR~270MHz, CDC13)~ppm:7.94(2H, d, J~8Hz), 7.25~2H, d, 3-8Kz)~ 3.90(3H, s), 2.97-2.74(AH, m~, 1.78-1.60(2H, m), 1.29-j 1.18(10H, ~, 1.26(9H, s), 0.91~6H, dd, Jl=3Hz, J2~6HZ) ;
Reference Example 79 Preparation of 4-t-butoxy-3-hexyl-2R-isobutylsuccinic ¦ acid j 20 Usin~ l-iodohexane and a corresponding starting material, the captioned compound was ob~ained in the same ! manner as in Reference Example 8.
¦~ NMR(270MH , CDC13)~ppm:2.71(1H, dt, Jl-4Hz, J2-9Hz), 25 2.52(1H, dt, J1~4Hz, J2-9Hz), 1.76-1.55(2H, m), W0~4121612 PCT1~4/00434 ~136108 1.49(9H, s), 1.30-1.15(11H, m), 0.99-0.88(9H, m) Reference Example 80 Preparation of benzyl 2-benzyloxycarbonyl-3R-t-butoxycarbonyl-pentanoate ¦ Using D-norleucine and a corresponding starting material, the captioned compound was obtained in the same - manner as in Reference Example 1.
Reference Example 81 Preparation of 4-t-butoxy 2R-isobutyl-3-(3,4-methylenedioxybenzyl)succinic acid Us~ng 3,4-methylenedioxybenzyl chloride and a corresponding startlng material, the captioned compound was obtained ln the same manner as in Re~arence Example 8.
.
NMR(270MHz, CDC13)~ppm:6.71-6.60(3H, m), 5.91(2H, s), 2.83-2.69.~4H, m), 1.75~1.56(2~, m), 1.32(9H, s), 1.25-1.16(1H, m), 0.90(6H, dd, Jl-3Hz, J2-7Hz) !
Reference Example 82 Zs Preparation of 4-t-butoxy-3-(3-ethoxycarbonylpropyl)-W094/21612 ~ 0 8 PCT/J~4/0~34 2R-isobutylsuccinic acid Using e~hyl 4-bromocrotonate and a corresponding starting material, the captioned compound was obtained in the same manner as in Referenc~ Example 8.
s NMRt270MHz, CDC13)~ppm:4.12(2H, q, J-?Hz), 2.73-2.63 (lH, m), 2.53-2.46(1H, m), 2.34-2.29(2H, m), 1.73-1.51(6H, m~, 1.46(9H, s), 1.28-1.16(4H, m), 1.25(3H, t, J~7Hz), 0.90(6H, d, J-6Hz) Reference Example 83 Preparation of l-ethoxymethyl-3S-triphPnylmethyl-amino-3,4-dihyd~ocarbostyrll - 15 Using ethoxymethyl chloride and a corresponding , ~, starting material, the captioned compound was obtained in the same manner as in Reference Example 24.
NMR(270MHz, CDCl3)~ppm:7.52(6H, d, J~7Hz), 7.10-7.40(11H, m), 6.93(lH, dt, J-1.7Hz), 6.68(lH, d, J-7Hz), 5.76(lH, d, ~-~ - J~lOHz), 4.94(1H, d, J~lOHz), 3.45-3.60~2H, m), 3.43(1H, dd, J-14.5Hz), 2.44(1H, t, J-14Hz), 1.67(1H, dd, J-14.5Hz), ~- . . , i ~ .
1.19(3H, t, J-17Hz) -~ 25 ': ~
' ,-WO94121612 ~ 1 ~ C1 ~ ~ PCT/J~4100434 / Reference Example 84 j Preparation of 0-butyl-D-serine To a mixed solution of 60~ sodium hydride (28.8 g), imidazole (1.08 g, 15.9 mmol), and dry tetrahydrofurane (270 ml), a mixed solution of N-trityl-D-serine (25.0 g, 72.0 mmol) ~ and dry tetrahydrofurane (150 ml) was dripped in 15 minutes at ¦ -15C, and the mixture was stirred for 45 minutes at -15C.
Further, butyl iodide (65.5 ml, 576 mmol) was added, and the mixture was stirred for 2 hours at -15~. Moreover, at -15C, addin~ 60% sodium hydr~de (12.0 g) and butyl iodide (129 ml, 1.13 mol), the mixture was stirred for 1 day at -20C. Adding water (1 liter) to the reaction solution, it was extracted wlth ether (300 ml x 2), and the organic layer was washed with 5~ aqueous solution of citric acid (200 ml) and sa~urated IS brine (100 ml), and dried over magnesium sulfate. The solvent was evaporated in vacuo, and 50% acetic acid-ethanol solution (100 ml) was added to the obtained oily matter, and the ~lxture was stirred for lS hours at room temperature. The sediment was filtered, and washed with ethanol and ether, and 0-butyl-D.-serine (6.11 g, 53~) was ob~ai~ed.
MMR(270MHz, D20)~ppm:3.75-4.00(3H, m), 3.50-3.70(2H, m), . ~ I .
1.57(2H, dt, J-14.7Hz), 1.33(2H, dtt J-14.7Hz), 0.90(3H, t, J~7Hz ) , 25 WO94/21612 ~13 61~ 8 PCT/J~4/00434 Reference Example 85 Preparation of benzyl 2-benzyloxycarbonyl-3s-tert-butoxycarbonyl-4-butoxy-butylate Using O-butyl-D-serine and a corresponding starting m~terial, the captioned compound was obtained in the same manner as in Ref~rence Example l.
Reference Example 86 Preparat~on of O-nitrophenyl-L-alanine To N-acetyl-O-nitrophenyl-DL-alanine (324 g, l~28 mol), aqueous solution (l.8 li'ers) of lN sodium hydroxide was .~ added to dissolved, and acylase (9.0 g) and cobalt (II) chlor~de hexahydrate (lO0 mg) were se~uentlally added, and the mixture was stirred for 2 days at 37~. After filtering the insoluble matter, the flltrate was evaporated in vacuo, and preclpitatlng crystals were filtered and washed with a small , -:
~ amount of water, and the captioned compound t99.6 g, 37%) was - obtained.
-: 20 ~- Reference Example 87 Preparation of 3S-(4-hydroxy-2-isobutyl-3-methylthiomethylsuccinyl)amino-3,4-dihydrocarbostyril A mixsd liquid of 3S-(4-hydroxy-2-isobutyl-3-;~ 25 acetylthiomethylsuccinyl)amino-3,4-dihydrocarbostyril , W094/21612 PCT/J~4/00434 ~ ~361~
-118- !
(800 mg, 1.97 m mol) and methanol (lO ml) was chilled in ice.
An aqueous solution (8 ml) of lN sodium hydroxide was added, and the mixture was stirred for 40 minutes in ice-cooling.
Methyl iodide (430 ~1, 6.91 m mol) was added, and further the i 5 mixture was stirred for 2 hours in ice-cooling. Then, lN-hydrochlolic acid (10 ml) was added, the precipitating crystals were filtered, and the captioned compound was obtained in a yellow solid (330 mg, 44%).
f 10 NMR(270MHz, DMS0-d6~ppm:10.22(1H, s), 8.47~lH, d, J-8Hz), 7.18(2H, q, J-8Hz), 6.89(2H, dd, J~11,8Hz), 4.43(lH, dt, J~14.7Hz), 2.80-3.20(3H, m), 2.40-2.80(3H, m), 2.04(3H, s), 1.35-1.70(2H, m), 0.90-1.05(1H, m), 0.87(3H, d, J=7Hz);
0.83(3H, do J~7Hz) ~- Reference Example 88 Preparation of 3S-amino-l-ethoxyethoxy-3,4-dlhydrocarbostril ! 20 Sod$um hydrlde, o~lness (186 mg) was washed twice with ¦~ hexane (2 ml), suspended in dimethyl formamide (14 ml), and 3S-amino-1-hydroxy-3,4-dihydrocarbostyril hydrochloride (500 mg, 2.33 m mol) was added. The mixture was stirred for 20 minutes ln lce-cooling and then for l hour in room temperature~
WO94/21612 ,~ U(~ PCT/J~4/00434 The mixture was chilled in ice again, and 2-iodo-ethylethylether (513 mg, 256 m mol) was added. The mixture was stirred for 20 minutes in ice-cooling and for 1 hour in room temperature. The solvent was evaporated in vacuo, and to the obtained residue, water (30 ml) was added. The mixture was extracted twice with dichloromethane (30 ml), and the organic layers were combined, washed with saturated saline water ~30 ml) and dried over magnesium sulfate. The solvent was evaporated in vacuo to obtained the captioned compound (522 mg, go~) NMR(270MHz, CDCl3)~ppm:7.40(1H, t, J-8Hz), 7.1a-7.~5(2H, m), 7.05(1H, t, J-8Hz), 4.20-4.35(2H, m), 3~60-3.80(t2H, m), 3.65(lH, dd, J-13,6~z), 3.53(2H, q, J-7Hz), 3.10(1H, dd, J-15,6Hz), 2.86(lH, t, J~15Hz), 1.23(3H, t, J-7Hz) Re~erence Example 89 Preparatlon of 3S-amino-1-methoxymethoxyethoxy-3,4-2Q dihydrocarbostyrll Using l-iodo-2-methoxymethoxyethane, the captioned compound was obtained in the same manner as in Reference .
Example 88.
MMR(270MHz, CDCl~)~ppm:7.37tlH, d, J-7Hz), 7.33(1H, d, J=7Hz), WO 94/21612 i r ~ O ~ PCT/J~4/00434 -1~0- 1 7.20(1H, d, J=7Hz), 7.05(1H, td, J=7.1Hz), 4.68(2H, s), 4.20-4.40(2H, m), 3.75-3.95(2H, m), 3.64(1H, dd, J=13,6Hz), 3.38(3H, s), 3.11(1H, dd, J=15,6Hz), 2.85(1H, t, J=15Hz) Reference Example 90 Preparation of 3S-t-butoxyc rbonylamino-l-methoxy-7-methoxy-3,4-dihydrocarbostyril Using a corresponding starting material, the captioned 1 10 compound was obtained in the same manner as in Reference Example 21.
NMR(270MHz, CDC13)~ppm:7.11(lH, d, J~8~z), 6.79(lH, d, J=2Hz), 6.60(1~, dd, J~8~2Hz), 5.57~lH, brs), 4.33(lH, dt, ~314,6Hz),.
3.92(3H, s), 3-82(3H, s), 3~36(1H, dd, J~14,4Hz), 2.73(1H, t, ¦ J~14Hz), 1.48(9H, s) , ~
Reference Example 91 Preparatlon of 3S-t-butoxycarbonylamino-l-ethoxy-7-methoxy-3,4-dihydrocarbostyrll Using ethyl lodide and a corresponding startin~
material, the captioned compound was obtained in the same manner as in Reference Example 21.
WO94/21612 ;.~ 61 0~ PCT/J~4/00434 NMR(270MHz, CDCl3)~ppm:7.11(lH, d, J=8Hz), 6.79tlH, d, J=3Hz), 6.59(1H, dd, J=8,3Hz), 5.57(1H, brs), 4.31(1H, dt, J=14,6Hz), 4.05-4.25t2H, m), 3.82(3H, s), 3.37(1H, dd, J=15,6Hz), 2.72(1H, t, J=15Hz), 1.49(9H, S), 1.38(3H, t, J-7Hz) s Reference Example 92 Preparation of 3S-t-butoxycarbonylamino-l-methoxyethyl-6,7-methylenedioxy-3,4-dihydrocarbostyr~l Using l-iodo-2-methoxyethane and a corresponding starting material, the captloned compoun~ was obtained in the same manner as ~n Reference Example 24.
,~ .
: NMR(270MHz, DMS0-d6)~pp~:6.89(1H, s), 6.65(1H, s), 5.94(2H, , -~ ~
~ : dd, J1-lHz, J2~2Hz), 5.70(1H, bs), 4.25-4.14(2H, m), 3.93-.
~ 15 3.82tlH, m), 3.62-3.60(2H, m), 3.34(3H, s), 3.29-3.23(lH, dd, , ~ J1-5Hz, J2-14Hz), 2.67(lH, t, J~15~z), 1.47(9H, s) ''~
, ~ , :~
Reference Exampl- 93 ~;; 20 Preparation of 3-benzyloxycarbonylamino-6,7-~- dimethoxy-1-methoxymethyl-3,4-dihydrocarbostyril~
Using methoxymethyl chloride and a corresponding start~ng materlal, the captioned compound was obtained in the same manner as in Reference Example 24.
~ 25 :
WO94/21612 PCT/J~4/00434 3610~
-122- ~
NMR(270MHz, CDC13)~ppm:7.30-7.34(5H, m), 6.96(1H, s), 6.71(1H, s)j 5.96(1H, brs), 5.71(1H, d, J=llHz), 5.15(2H, s), 4.89(1H, d, J=llHz), 4.38(1H, dt, J=14,5Hz), 3.88(3H, s), 3.86(3H, s), 3.40(3H, s), 3.36(1H, dd, J=14~5Hz), 2.76(1H, t, J=14Hz) s Reference Example 94 Preparation of 3-amino-6,7-dimethoxy-3,4-dihydrocarbostyril hydrochloride Using 2-nitro-4,5-d~methoxybenzyl chloride, the captioned compound was obtained in accordance with a method descrlbed in J. Med. Chem. 1972, 15, 325.
NMR(270MHz, DMS06~)~ppm:10.49(1H, s), 8.52(3H, s), 6.92(1H, s), 6.56~1H, s), 4.06-4.16(1H, m), 3.72(3H, s), 3.70(3H, s), 3.12(1H, dd, J-14,7Hz), 2.98(1H, t, Jsl4.Hz) Reference Example 95 Prep ration of 8-methoxy-1-methoxyethyl-3S-tritylamino-3,4-dihYdrOCar~OStYrll Us~n~ l-iodo-2-methoxyethane and a corresponding start~ ng mater~ al, the captioned compound was obtained in the same manner as in Reference Example 24.
.
~ ~ NMR(270MHz~ CDC13)~ppm:7.49-7.45(6H, m), 7.30-7.18(9H, m), WO94/21612 PCT/J~4/00434 !
6.90(1H, t, J=8Hz), 6.74(1H, d, J=8Hz), 6.25(~H, d, J=8Hz), `~
, 4.45(2H, m), 4.14-4.0~(1H, m), 3.80(3H, s), 3.49-3.41(2H, m), '' 3.28(1H, dd, Jl-5Hz, J2=14Hz), 3.23(3H, s), 2.36(1H, t, J=14Hz), 1.28(1H, dd, Jl-5Hz, J2=15Hz) S
I Reference Example 96 ¦ Preparation of l-methoxyethoxy-3S- -triphenylmethylamino-3,4-dihydrocarbostyril ¦ Uslng l~iodo-2-methoxyethane and a corresponding ¦ 10 starting material, the captioned compound was obtained in the ! same manner as in Reerence Exampla 24.
NMR(270MHz, CDC13)~ppm:7~51-7.56~6~, m), 7.22-7.32(11H, m), 6.91(1H, dt, J~2.7Hz), 6.66(1H, d, J-7Hz), 4.23-4.30(1H, m), 15 4.08-4.20~lH, m), 3.95(lH, d, J-3H~), 3.63-3.76(2H, m), ; 3.44(1H, ddd, J-14,5, 3Hz), 3-39t3H, s), 2.33(1H, t, J-14Hz), 1.56(lH, dd, J-14.5Hz) .
¦~ 20 Reference Example 97 Preparation of 3S-amino~l-methoxyethoxymethoxyethoxy-3,4-dihydrocarbostyril -Using l-iodo-2-methoxyethoxymethoxyethane and a correspondlng startlng material, the captioned compound was obtained in the sama manner as in ~eference Example 88.
, WO94/21612 PCT/J~4/00434 i~l3~108 --NMR(270MHz, CDC13)~ppm:7.10-7.45(3H, m), 7.06(1H, td, J=7.2Hz), 4.77(2H, s), 4.20-4.40t2H~ m), 3.7S-3.95(2H, m), 3.45-3.75(5H, m), 3.38(3H, s), 3.11(1H, dd, J=15.6Hz), , 5 2.86(lH, t, JY15Hz3 j Reference Example 98Preparation of 3S-amino-l-methoxye~hoxyethoxy-3,4-dihydrocarbostyril Us~ng 1-~odo-2-methoxyethoxyetane and a corresponding starting material, the captioned compound was obtained in the same manner as in Reference Example 88.
NMR(270MHz, CDC13)~ppm: 7.39(1H, t, J~7~z), 7.10-7.35(2H, m), i 7.05(1H, t, J-7Hz), 4.20-4.40(2H, m), 3.70-3.90(2H, m), 3.50-3.70(5H, m), 3.40(3H, s), 3.1~(1H, dd, J~15.6Hz), 2.86(1H, t, J-15Hz) !
2Q Example l Preparatlon of 3S-t4-(N-hydroxyamino)-2R-isobutyl-succinyl]amino-3~4-dihydrocarbostyril 240 mg of 3S-~4-(N-benzyloxyamino)-2R-isobutyl-~- succinyl]amino-3,4-dihydrocarbostyril was dissol~ed in 10.8 ml of ethanol, and 1.2 ml of cyclohexene and 60 mg of 10%
WO94/21612 ~ PCT/J~4/00434 -125- , palladium-carbon wexe added, and the mixture was stirred for 20 minutes in reflux. Filtering off the catalyst, the filtrate was concentrat~d in vacuo. The residue was purified by column chromatography (silica gel 20 g, chloroform/methanol = 20~1 v/v), and the captioned compound was obtained in a white solid form. Yield: llO mg.
a ]D - -49 ~c~l, methanol) N M R (2 7 O M H z. D M S O - d~ ) ~ p p m : 1 O. 3 8 (1 H. b r s ) ~ 1 O. 2 O (1 H, s) ~ 8. 7 O (1 H. b r s) ~ 8. 1 5 (1 H. d , J = 8 H z) ~ 7. 1 6 (2 H, t, J = 7 H z) ~ 6. 9 O t2 H, d d.
J = 1 6, 8 H z) ~ 4. 4 4 (1 H. d t, J - 1 2, 8 H z) ~ 2. 7 O -3. O O (3 H, m) ~ 2. 1 7 (1 H, d d. J = 1 4, 6 H z) ~ 2. O 4 (1 H. d d. J = 1 4, 7 H z) ~ 1. 4 O - 1. 7 O (2 H. m) ~ 1. O
O - 1. 3 O (1 H. m) ~ O. 8 6 (6 H. d d. J = 1 2, 6 H z) Exampl~ 2 Uslng a corresponding starting material, 3S~ ( N-hydroxyamino)-2R-isobutylsuccinyl~amino-7-methoxy-3,4-d~hydrocarbostyrll was obtained in the same manner as in Example 1.
M R (2 7 O M H z. D M S O - d3 ) ~ p p m : 1 O. 3 6 (1 H, b r s ) ~ 1 O. 1 4 (1 H. s) ~ 8. 7 O tl H. s) ~ 8. 1 3 (1 H. d. J
- 8 H z) ~ 7. O 8 (1 H, d. J = 8 H z) ~ 6. 5 1 (1 H, d d, J =
, WO94/21612 PCT/J~4/00434 61~8 . 8, 2 H z) ~ 6. 4 6 ~1 H, d. J = 2 H z) ~ 4. 4 2 (l H. d t. J
` = 1 3, 8 H ~) ~ 3. 7 0 (3 H, s) ~ 2. 6 5 - 3. 0 0 (3 H, m) ~
2. 1 7 (1 H. d d, J = 1 4, 6 H z) ~ 2. 0 1 (1 H. d d. J = 1 4 , 7 H z) ~ 1. 2 0 - l. 7 0 (2 H, m) ~ l. 0 0 - l. 2 0 (1 H. m ) ~ 0. 8 6 (6 H t d d. J = 1 3, 6 H z) Example 3 Using a corresponding starting material, 3S- r 4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-l-methoxy-3,4-dlhydrocarbostyr~l was obtained in the same manner as in 10 Exampla 1.
t a ] D - -19 ( c~1, methanol ) ~MR (2 7 OMHz. 3MS O--d~ p pm: 1 O. 4 5 (1 H, b r s 8 . 7 1 ( 1 H. b r s ) ~ 8 . 3 6 ( 1 H. d, J = 8 H z ~ ~ 7 . 3 1 ( 2 H. d d, J--1 6, 8 H z ) ~ 7 . 1 6 ( 1 H. d, J = 8 H z ) ~ 7 .
15 O 7 (1 H. t. J=8Hz) ~ 4. 6 O (lH, d t, J- 1 3, 8 Hz) ~
3. 8 2 (3H. s) ~ 2. 8 5--3. 1 5 (2H, m) ~ 2. 7 Q--2. 8 5 ( 1 H . m ) ~ 2 . 1 8 t 1 H . d d . J--1 4 , 6 H z ) ~ 2 . O 1 ( 1 H .
t t. J= 1 4, 8H z) ~ 1. 4 O~ l. 7 5 (2H. m) ~ 1. O O--1.
1 5 (1 ~ O. 8 7 (6 H, t d~ J ~; 1 3, 6 H z) 20 Example 4 Preparatlon of 3S- t 4- ( N-hydroxyamino ) -ZR-isobutyl-3S-acetyLthiomethylsuccinyl]amlno-3,4-dihydrocarbostyril 330 mg of 3S-(4-hydroxy-2R-isobutyl-3S-acetyl-thiomethylsuccinyl)amino-3,4-dihydrocarbostyril was dissol~ed in a mixed solvent of 1 ml of dimethyl formamide and 3.5 ml of WO 94/21612 w 13 610 ~ PCT/J~4100434 -127- ~ ~
dichloromethane, and cooled in an ice bath, and 110 mg of l-hydroxybenzotriazole, 107 ~l of N~methylmorpholine~ and 186 mg of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, and the mixture was further stirred for 1 hour in an ice bath, and a solution of 57 mg of hydroxylamine hydrochloride and 89 ~1 of N-methylmorpholine dissolved in O.S
ml of dimethyl formamide was added. After stirring for l hour in an ice bath, the reaction solution was concentrated in vacuo. The residue was dissolved in lO ml of butanol, and washed in 5 ml of water, and evaporated in vacuum. The residue was purified by column chromatography (silica gel 20 g, chloroform/methanol ~ 20/1 v/v), and the captioned compound was obtain~d in a white solid form. Yield: 45 mg.
t a JD - -49 (c-1, methanol) N M R (2 7 O M H z, D M S O - tB ) ~ P p m : l 0. 6 l (l H, s) ~
l 0. 2 3 (l H, s) ~ 8. 9 2 (l H. s) ~ 8. 5 1 (l H, d. J = 8 H z) ~ 7. 1 0 - 7. 2 0 (2 H, m) ~ 6. 9 1 (2 H. d d, J = l S, 8 H z) ~ 4. 5 1 (l H. C. J = 9 H z) ~ 2. 8 0 - 3. 2 O (4 H. m ) ~ 1. 4 0 - l. 6 0 (2 H. m) ~ O. 8 0 - 1. 0 0 (1 H, m) ~ O.
8 3 (6 H. t d. J = l 2~ 6 H z) Example 5 Preparation of 3S-r4-(N-hydroxyamlno)-2R-lsobutyl-3S-~ mercaptomethylsuccinyl]amino-3,4-dihydrocarbostyril 14 mg of 3S-C4-(N-hydroxyamino)-2~-isobutyl-3S-acetyl-thiomethylsuccinyl]amino-3~4-dhydrocarbos~yril was dissolved in l ml of methanol, and 200 ~l of methylamine 40~-methanol , WO 94121612 PCT/J~4/00434 `~J ~6~0S
solution was dripped. After stirring for 1 hour at room temperature, precipitating crystals were filtered, and the captioned compound was obtained in a white solid form. Yield:
4 mg.
NM R ( 2 7 O MH z . DM S O--d 6 ) ~ P p m: 1 0 . 5 9 ( 1 H , s ) ~
1 O. 1 1 (1 H. s) ~ 8. 9 5 (1 H. s) ~ 8. 5 4 (1 H. d. J=8 H z) ~ 7. 0 5--7. 2 5 (2H, m) ~ 6. 8 2 (2 H. d d, J = 1 6.
8 H z ) ~ 4 . 4 0--4 . 6 0 ( 1 H . m ) ~ 2 . 6 0--3 . 3 0 ( 4 H . m ) ~ 1. 4 5--1. 7 0 t2H. m) ~ O. 8 O--1. 1 0 (1 H. m) ~ û. 8 4 (6H. dd. J=l 2t 6Hz) Example 6 Using a correspondlng starting material, 3S-~4-(N-: hydroxyamlno)-2R-lsobutyl-3S-(2-thienyl~hiomethyl)succinyl]
~ amino-3,4-dihydrocarbostyril was obtained in the same manner j as in Exampla 4.
a ]D ~ 52- (c-l, methanol) N M R (2 7 O M H z. D M S O - d~ ~ ~ p p m : 1 O. 7 0 tl H, s) ~
1 O. 2 2 (1 H. s) ~ 8. 9 5 (1 H, s) ~ 8. 4 7 (1 H. d, J = 7 . ~ H z) ~ 7. 6 0 (1 H. d, J = 4 H z) ~ 7. 1 0 - 7. 2 0 (3 H. m) 7. 0 5 (l H. d d, J = 3. 5 H z) ~ 6. 9 0 (2 H. d d. J = 1 7 . 8 ~ z) ~ 4. 3 7 (1 H. d t. J = 1 4. 7 H z) ~ 2. 8 0 - 3. 2 0 (4 H. m) ~ 1. 4 0 0 1. 6 0 (2 H, m) ~ O. 8 0 - 1. 0 0 (l H.
m) ~ O. 8 2 (6 H. d d, J = 1 O. 6 H z) ' WO94/21612 PCT/J~4/00434 Example 7 Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-3(R
or s)-phthalimidomethylsuccinyl]amino-3,4-dihydrocarbostyril To a 20 ml suspension of dimethyl formamide of 320 mg of 3S-[4-(N-benzyloxyamino)-2R-isobutyl-3(R or S)~phthalimido-methylsuccinyl]amino-3,4-dihydrocarbostyril, 200 mg of 10%
palladium-carbon was added, ~nd hydrogen gas was i~troduced in vacuo, and the mixture was stirred for 2 days. The catalyst was filtered away from the reaction solu~ion by using celite, lO and the flltrate was concentrated in vacuo. Adding 200 ml of methano~ to the cry5talline residue, it was heated and dissolved, and the remaining catalyst was filtered off by uslng cellte. The f iltrate was concentrated in vacuo, and the .
pr~cipitatlng sediment was f iltered and dried, and the ::aptioned compound was obta~ned in a whlte solid form. Yield:
172 mg.
NMR t2 7 OMHz. DMSO--dB ) ~ ~ Pm: 1 O. 4 7 (lH. s) ~
1 O. 1 2 ( 1 H. s ) ~ 8 . 6 B ( 1 H, s ) ~ 8. 5 0 ( 1 H, d. J = 8 H z) ~ 7. 8 8--7. 8 0 (4H. m) ~ 7. 1 6 (2H. t, J=8H z) 6 9 0 ( 2 H. d d . J 1 = 8 H Z . J 2 3 (LH. m) ~ 3. 9 0--3. 8 5 (1 H. m) ~ 3. 50--3. 4 3 llH
, m) ~ 2. 9 7 (2H. d, J~ 1 1 H z) ~ 2. 6 3--2. 5 9 (2H. m ) ~ 1. 6 2--1. 5 3 (2H, m) ~ O. 9 5--0~ 8 1 (7H. m) ~ WO94/21612 PCT/~4/00434 ~ 1~610~
Example 8 Preparation of 3S-[4-(N-benzoyloxyamino)-2R-isobutyl-succinyl]amino-3,4-dihydrocarbostyril 180 mg of 3S-~4-(N-hydroxyamino)-2R-isobutylsuccinyl]
amino-3,4-dihydrocarbostyril was dissolved in a mixed solvent of 2 ml of dimethyl formamide and 2 ml 9f dichloromethane, cooled in a water bath, 220 ~1 of pyridine and 88 -~1 of benzoyl chloride were added, and the mixture was stirred for 30 minutes in an ice bath. The reaction solution was concentrated in vacuo, 30 ml of chloroform was added, and it was washed by lO ml of lN hydrochloric acid and lO ml of water, and dried over magnes$um sulfate, and evaporated in vacuum. To the resldue, lO ml of diethyl ether was added, precipitating crystals were filtered, and the captioned compound was obtained in a white solld form. Yield: llO mg.
N M R (2 7 O M H z. C D C 13 ) ~ ~ p m : 1 O. 4 8 (1 H. b r s) 8. O 8 (2 H. d, J = 7 H z) ~ 7. 7 4 (l H. s) ~ 7. 6 2 (l H.
t, J = 7 H z) ~ 7. 4 6 t2 H, t, J = 7 H z) ~ 7. 1 O - 7. 2 5 ( 2 H. m) ~~7. O l (2 H. t, J = 7 H z) ~ 6. 7 4 (l H. d. J = 7 H z) ~ 4. 5 5 (l H. d t, J = l 4, 7 H z) ~ 3. 4 O ~l H. d d, J = 1 5, 6 H z) ~ 2. 6 5 - 3. 3 O (3 H, m) ~ 2. 4 9 (l H. d d , 3 = 1 5, 3 H z) ~ l. O O - 1. 8 O (3 H. m) ~ O. 9 6 (6 H. d d. J - 1 2, 6 H z) ~ W094/21612 r~l,Jr~,u~
!l .
Example 9 . Preparation of 3-[4-(N-hydroxyamino)-2-piperonyl-succinyl]amino-3,4-dihydxocarbostyril To 10 ml of methanol solution of 49 mg of ~ hydroxylamine hydrochloride, while stirring in ice-cooling, 10 ¦ ml of methanol solution of 66 m~ of potaSsium hydroxide was ¦ added and stirred for 5 minutes, and 3 ml solution of dimethyl formamlde of 100 mg of 3-(4-ethoxy-2-piperonyls~ccinyl) amino-3,4-dihydrocarbostyril was added, and s~irred overnight at r~om temperature. The reaction solution was neutralized with acetic ac~d, the insoluble matter was filtered off, and the filtrate was concentrated in vacuo. The residue was extracted wlth 2Q ml of n-butanol. After washing ~he organic layer three times by water, it was concentrated in ~acuo. The residue was puri~ied by sillca gel preparation ~chloroform:
methanol ~ 7:1), and the capt~oned compound was obtained.
~-~ Yield: 4.47 mg.
,~
- : 20 N M R ( 2 ? O M ~ z . D M S Q--t B ) ~ P p m : 1 0 . 4 0 t 1 H , b r s 1 0. 2 9: (1H. b r s) ~ 8. 7 0 (1H. b r s) ~ 8. 1 7 (1 H
, d. J=8Hz) ~ 7. 1 7 (2H, t, J--7Hz) ~ 6. 9 6--6. 6 1 ~- (SH. m) ~ S. 9 7 (2H, s) ~ 4. 5 1--4. 4 2 (1 H. m) ~ 3.
1 0--2. 6 2 (4H, m) ~ 2. 4 9--1. 9 3 (3H. m) ~ , WU~ O~ PCT/J~4/00434 I Example 10 Preparation of 3S-r4-(N-benzyloxyamino)-2R-isobutyl-3 i 5 (R or S)-phthalimidomethylsuccinyl] amino-3,4-j dihydrocarbostyril 99O mg of 3S-(4-tert-butoxy-2R-isobutyl-3 (R or S)-¦ phthalimidomethylsuccinyl)amino-3,4-dihydrocarbostyril was dissolved in 5 ml of dichloromethane, and 10 ml of 4N hydrogen chloride/dioxane was added, and let stand at room temperature for 2 hours. The reaction solution was concentrated in vacuo, ¦ and the residue was dissolved in 50 ml of ethyl acetate. The ethyl acetate layer was wasAed by saturated brine (2 ti~es), and dried by sodium sulfate anhydride, and concentrated in IS vacuo. The obtalne~ residue was dried and powdered (660 mg).
To 10 ml solutlon o~ tetrahydrofurane of 660 mg of the obtained powder, N-methylmorpholine was added by 1~0 ~1 while cooling and stirring in ice-salt, and 240 ~1 of isobutyl chloroormate was added and stlrred ~or 5 minutes. In ~; 20~ successiQn, addlng lO ml o~ dimethyl formamide of 573 mg of benzyloxyamine, the solution was stirred for 1 hour at room ` temperature whlle maintaining at p~ 8. The reaction solution was con'centratediln vacuo, and 20 ml of water was added to the residue to solidlfy and filter. The crude product was washed t with ethyl acetate and diethyl ether, and the cap~ioned ,' ' .
, : :, : ,:
,~
.
~.
WO94/21612 136~0~
compound was obtained in a white solid form. Yield: 330 mg.
M R (2 7 O M H z, D M S O - d6 ) ~ P P m : 1 1. 1 8 (l H. s) 1 O. 2 4 (l ~.. s) ~ 8. 5 7 (1 H, d, J = 8 H z) ~ 7. 9 2 - 7.
8 4 (4 ~. m) ~ 7. ~ 2 - 7. l 5 (7 H. m) ~ 6. 9 7 - 6. 9 l (2 H. m) ~ 4. 6 7 - 4. 3 7 (3 H, m) ~ 4. O O - 3. 8 5 (1 H. m) ¦ ~ 3. 6 O - 3. 5 O (l H. m) ~ 3. O 3 ~2 H. d, J ~ l O H z) ~ 2 . 7 2 - 2. 6 9 (2 H. m) ~ 1. 5 9 - l. 5 4 (2 H. m) ~ O. 9 8 -I O. 8 3 t7 H. m) t 10 Example 11 ,~
Preparation of 3S-~4-(N-benzyloxyamino)-2R-isobutyl-succinyl]amino-3,4-dihydrocarbostyril 500 mg of S-(3-carboxy-2R-isobutylpropionyl)amino-3,4-dihydrocarbostyril was dissol~ed in 5 ml o dimethyl 15 formam~de, and 329 mg of O-benzylhydroxylamine was added, and I cooled in an ice bath, and 213 mg of l-hydroxybenzotriazole, j - 259 ~1 of N-methylmorphollne, and 368 mg of 1-ethyl-3-t3-dimethylaminopropyl)carbodiimide hydrochloride were added, and the m~xture was stirred for 3 hours in an ice bath and 15 20 hours at room t~mperature. The reaction solution was concentrated in vacuo, and 50 ml of ethyl acstate was added to the resid~e, and it was washed by lO ml of water, lO ml of lN
hydrochloric acid, saturated aqueous solution of sodium hydrogencarbonate (lO ml x ~ times), ànd lO ml of brine, and 25 dried over magnesium sulate, and evaporated in vacuum. The v~ V~ U~ PCT/J~4/00434 residue was purified by column chromatography (silica gel SO
g, chloroform/methanol - 40/1 v/~), and the captioned compound was obtained in a white solid form. Yield: 300 mg.
~JMR (2 7 OMHz, CDC 13 ) ~ P P m : 8. 5 7 (1 H. b r s) ~ 7 . 7 9 (1 H. b ~ s) ~ 7. 3 8 (5H, s) ~ 7. 1 8 t2H. d d! J=
1 4. 7Hz) ~ 7~ 0 1 (1 H. t. J=7Hz) ~ 6. 7 8 ~1 H. d. J
= 7 H z ) ~ 4 . 9 0 ( 2 H. s ) ~ 4 . 4 S--4 . 6 0 ( 1 H. m) ~ 3 . 3 5--3. 5 0 (1 H. m) ~ 2. 8 0--2. 9 8 (1 H. m) ~ 2. 8 0 (1 H
, t, J--1 4Hz) ~ 2. 20--2. 50 (2H, m) ~ 1. 20--1..40 (3H. m) ~ O. 94 (6H, dt, J=16, 6Hz) ::, Example 12 Us~ng a corresponding starting mat~rial, 3S-t4-(N-bensyloxy~mino)-2R-isobutylsuccinyl]amlno 7-methoxy-3,4--d$hydrocarbostyril was obtained in the same manner as in ExamplQ 11.
~ -s, ~
NMR (270M~Hz.: CDC13 ) ~ppm: 8. 90 (lH. s) ~ 8. 4 Z~ 9 ~ 1 H . s ) ~ 7 . 3 4 ( 5 H . s ) ~ 7 . 0 5--7 . 1 5 ( 1 H . m ) ~ 6 . 9~ 9 t l N. d . J = 8 H.z ) ~ 6 . S 1 t l H . d d . J = 8, 2 H z ) ~
- 6. 4 1 (1}~. s) ~ 4. 8 8 ~2H. s) ~ 4. 4 0--4. 5 5 (1 H. m 3 . ? 3 ( 3 H . s ) ~ 3 . 2 5--3 . 4 s t l H, m ) ~ 2 . 9 0 ~ 3 .
1 0 ( 1 H . m ) ~ 2 . 6 6 t l ~I, t, J
~ 1 4 E~ z ) ~ 2 . 1 5--2 . 5 0 ( 2 H . m ) ~ 1 . 5 0--1 . 8 0 ( 2 H .
25 - m) ~ 1. 2 0--1. 4 0 ( l H. m) ~ O . 9 4 ( 6 H. d d . J--1 9, 6 ~:~ H z) '''~'~',:
., ,; - . .
, i ~ , , - ~ ~
wos4nl612 ~ PCT/J~4/00434 Example 13 Using a corresponding starting material, 3S-[4-(N-benzyloxyamino)-2R-isobutylsuccinyl]amino-1-methoxy-3,4-dihydrocarbostyril was obtained in the same manner as in Example 11~
N M R (2 7 O M ~ z. C D C 1.3 ) ~ p p m : 8. 6 9 (l H. s) ~ 7. 3 7 ~5 H. s) ~ 7. 1 5 - 7. 3 5 (~ H. m) ~ 7. 0 7 (1 H. t. J =
7 H z) ~ 6. 6 7 (1 H. d. J = 6 H z) ~ 4. 9 0 t2 H, s) ~ 4. 4 O - 4. 6 0 (1 H. m) ~ 3. 9 2 ~3 H. s) ~ ~. 2 5 - 3. 4 5 (l H
, m) ~ 2. 7 5 - 2. 9 5 (2 ~. m) ~ 2. 2 0 - 2. 5 0 (2 H. m) ~
l. 5 0 - 1. 8 0 (2 H. m) ~ l. 2 0 - 1. 3 5 (2 H, m) ~ O. ~ 3 (6 H, d d. J ~ l 6, 6 H z) ; 15 EXample 14 Preparation of l-hexyloxy-3S-[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsucclnyl]amino-3,4-dihydrocarbostyrll ~; To a lS ml solutlon of tetrahydrofurane of 400 mg of 3S-t4-(N-benzyloxyamino)-ZR-lsobutyl-3S-methylsuccinyl]amino-1-hexyloxy-3,4-dihydrocarbostyril, 150 mg of 10~ palladium-carbon and 1.0 ml of cyclohexene were added and stirred for 30 minutes while refluxing. The catalyst was filtered off from the reaction solutlon by using celite, and the filtrate was concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (eluted in 3~
W094/21612 ~ PCTI~4/00434 methanol/chloroform), and the captioned compound was obtained.
Yield: 250 mg.
M R t2 7 O M H z. D ~ S O - d~ ) ~ p p m : l 0. 4 8 (l H, s) ~
8. 7 6 (1 H. s) ~ 8- 5 5 (l H, d. J - 8 H z) ~ 7. 3 S - 7. 2 7 (2 H. m) ~ 7. l 4 (l H, d, J - 7 H z~ ~ 7. 0 6 (l H, t, J
7 ~ 2) ~ 4. 6 3 - 4- 5 8 (1 H, m) ~ 4. 0 0 (1 H, d, J = 7 H
z) ~ 3. 9 7 (1 H. d. J = 7 H z) ~ 3. 0 6 (1 H. t, J = 1 3 H z ) ~ 2. 9 4 (1 H. d d. Jl ~ 7 H Z~ J2 = 1 6 H z) ~ 2. 5 l - 2.
4 5 tl H. m) ~ 2~ 2 0 - 2. 1 3 (l H. m) ~ l. 7 1 - l. 2 7 tl O H. m) ~ O. 9 7 (3 H. d. J - 7 H z) ~ O. 9 2 - O. 8 0 (l O H
, m) I Example 15 ¦ Preparat$on of 1-(4-cyanobenzyl)-3S-[4-(N-hydroxy-I:~ amino~-2R-isobutyl-3S-methylsucrinyl]amino-3,4-dihydrocarbostyril ¦ After conducting a reaction between the compound of Reference Example 24 and a corresponding staring material, the capt~oned compound was obtained in the same manner as in Example 16.
20 N M R ~ ~ 7 O M H z, D M S O--d ~ p m : l O . 4 9 ( l H . s ) 8 . 7 7 ( 1 H. s ) ~ 8 . 5 4 ( 1 H, d . J = 9 H z ) ~ 7 . 8 O ( 2 H, : d. J--8 H z) ~ 7. 4 3 (2H, d, J=8 H z) ~ 7. 2 9 tl H. d.
J = 7 H z ) ~ 7 . 1 7 ( 1 H. t . J = 8 H z ) ~ 7. 0 0 (l H. t. J -7H z) ~ 6. 9 O (1 H. d. J=8H z) ~ 5. 3 O (l H. d. J= l 7 Hz) ~ 5. 1 9 (lH, d. J--1 7E~z) ~ 4. 7 5--4. 7O (1H. m 3 . 1 5 ( 1 E~ , ~ , J = 1 5 H z ) ~ 3 . O O ( 1 H . d d ~ J 1 = 6 H
Z~ J2 =1 5Hz) ~ 2. 5 5--2~ 4 9 (l H~ m) ~ 2. 2 l--2. l 5 WO 94/21612 ~'~ 13 ~ PCT/JP94/00434 (1 H. m) ~ 1. 5 8 - 1 ~ 4 3 ( 2 H . m ) ~ 0 . 9 9 ( 3 H , d . J = 7 H ~) ~ 1. 0 1 - 0. 7 9 (1 H. m) ~ 0. 8 3 ( 6 H . d d . J 1 = 7 H
z J - 1 8 ~ z) Example 16 Preparation of 1-(5-chloro-2-thienylmethyl)-3S-t4-~N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]amino-3,4-dihydrocarbostyril To 920 mg of 3S-(4-t-butoxy-2R-isobutyl-3S-methyl-succinyl~amino-l-(5-chloro-2-thienylmethyl)-3,4-dihydrocarbostyril obtained in the same manner as in Reference Example 22 by using a corresponding starting material, 5 ml of tr~fluoroacet~c acid was added to dissolve, and let stand at room temperature for 90 minutes. The reac~ion solution was : concentrated in vacuo, and the obtained oily residue was extracted in ~0 ml of ethyl acetate. The ethyl acetate layer : was washed three times ~n saturated brlne, dried over .~ .
magnesium sulfate anhyd~ide, and concentrated in vacuo. The obtalned resldue was drled (790 mg). To a 10 ml solution of ~ tetrahydrofurane of 390 mg of the obtained compaund, while : 20 cooling and stirring in ice/salt, 126 ~1 of N-methyl-morpholine and 111 ~1 of isobutyl chloroformate were added, and the mixture was stirred for 15 minutes. To the reaction solution, 195 mg of 0-(t-butyld~methyl5ilyl)hydroxyamine was added, and stirred overnight at room temperature. The in oluble matter was filtered off from the reaction solution, WO94/21612 PCT/J~4/00434 ; ~3~;~G~
and 4 ml of acetic acid and 4 ml of water were added to the filtrate, and stirred for 3 hours at room temperature. The reaction solution was concentrated in vacuo, and the obtained residue was dissolved and extracted in 50 ml of ethyl acetate.
The ethyl acetate layer was washed three times in saturated brine and two times in water, and concentrated in ~acuo. The obtained resldue was purified by silica gel column chromatography (eluted in 3~ methanol/chloroform), and ~he captioned compound was obtained in a white solid form. Yield:
170 mg.
NMR (2 7 OMHt. DMSO--d6 ) ~ P Pm: 1 O. 4 8 ~l H. s) ~
8. 7 6 (l H. s) ~ 8. 5 2 (l H. d. J=8 H z) ~ 7. 2 g--7. 2 5 ( 3 H. m) ~ 7 . 0 6--7 . 0 0 ( 2 H, m) ~ 6 . 9 4 ( l H. d . J =
4 H z) ~ 5. 2 3 t2H. d. J ~ 3 ~I z) ~ 4. 6 2--4. 5 7 (l H. m ) ~ 3 . 0 4 ~t 1 H. t . J = 1 4 H z ) ~ 2 . 9 3 ( 1 H. d d J 1 = 6 E~
Z ~ J 2 = l 5 H z ) ~ 2 . 5 4--2 . 4 7 t l H . m ) ~ 2 . 2 0--2 . l 4 - ( 1 H. m) ~ 1. 6 0--l 4 2 ( 2 H, r~) ~ O . 9 8 ( 3 H, d, J _ 7 z) ~ l. O 0--0. 8 0 (1 H. m) ~ O. 8 5 (6 H. d d. Jl = 6 H
Z' J2 = 1 7H z) Example 17 Preparation of 3s-t4-(N-hy`droxyamino)-2R-isobutyl-3 methylsuccinyl]amlno-3,g-dihydrocarbostyril Using a correspondlng starting material, the captioned compound wa9 obtalned in the 9~me manner as in Example 14.
WO 94/Z1612 ~ ~ PCT/JP94/00434 NM R ( 2 7 0 MH z, DM S O--d 6 ) ~ P P m: l 0 . 4 8 ( 1 H. s ) ~
1 0. 1 8 (l H. s) ~ 8- 7 5 (I H. s) ~ 8~ 3 7 ( 1 H, d . J = 8 H z) ~ 7. 2 0--7. 1 3 (2 H~ m) ~ 6. 9 5--6. 8 6 (2 H. m) ~
4 . 5 l --4 . 4 6 ( 1 H. m) ~ 2 . 9 9--2 . 9 3 ( 2 H, m) ~ 2 . S 1 --2. 4 4 (I H, m) ~ ~. 2 0--2. 1 4 (l H. m) ~ 1 . 6 0--! . 4 0 ( 2 H. m) ~ 0. 9 7 ( 3 H. d . J = 7 ~ z ) ~ 0 . 9 8--0 . 8 0 ( 1 H, m) ~ O. 8 4 (6 H. d d. Jl ~ 6 H Z~ J2 = l 5 H z) Example 18 Preparation of 1-hydroxy-3S-~4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]amino-3,4-dihydrocarbostyril After conducting a reaction between the compound of Reference Example 26 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 14.
N M R (2 7 O M H z, D M S O - dB ) 8 P P m : l 0. 4 g (2 H. b s) . 7 6 (1 H. s) ~ 8. 5 4 (1 H. d. J = 8 H zj ~ 7. 3 2 - 7.
2 0 (3 H. m~ ~ 7. 0 l (l ~, e d. J1 = 2 H Z~ J2 - 7 H z) ~ 4 . 6 4 - 4. 5 4 (1 H. m) ~ 3. 0 6 (l H, t, J = l 5 H z) ~ 2. 9 3 (1 H. d d. il ~ 7 H Z~ J2 = l 6 H z) ~ ~. 5 l - 2. 4 5 (L H
, m~ ~ 2. 2 0 - 2. l 4 ~1 H. m) ~ l. 6 5 - 1. 4 2 (2 H. m) ~
9 8 (3 ~- d- J = 7 H z) ~ l. O O 0.... 8 0 tl H. m) ~ O- 8 5 (6 H~ d d, Jl = 7 ~ Z' J2 ~ l 6 H Z) Example 19 Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-3S-m~thylsuccinyl]amino-l-methoxy-3,4-dihydrocarbostyril Using a corresponding starting material, the captioned W094121612 PCT/J~4/00434 ~36 1~8 -140- . I
compound was obtained in the same manner as in Example 14.
M R (2 7 O M H z. D M S O - d6 ) ~ P p m : 1 O. 4 8 (1 ~, s) 8. 1 6 tl H. s) ~ 8. 5 5 (1 H, d, J = 8 H z) ~ 7. 3 6 - 7. 2 B (2 H. m) ~ 7. 1 6 t1 H. d, J = 8 H z) ~ 7. 0 7 tL H, t. J
= 7 H z) ~ 4. 6 6 - 4. 6 1 tl H. m) ~ 3. 8 3 (3 H, s) ~ 3. 0 6 2. 9 3 (2 H. m) ~ 2. 5 2 - 2. 4 4 (1 H. m) ~ 2. 2 0 - 2.
L 3 (1 H. m) ~ 1. 5 7 - 1. 4 2 ~2 ~. m) ~ O. 9 7 (3 K. d, J
= 7 H z) ~ O. 9 8 - O. 8 1 (1 H. m) ~ O. 8 4 (6 H. d d. J1 =
10 6 H z, J2 = 1 4 H z) Example 20 Preparation of 7-chloro-1-ethoxy-3S-~4-(N-hydroxy-amino)-2R-isobutyl-3S-methylsuccinyl]am~no-3,4-dihydrocarbostyril After conducting a reactlon between the compound of Reference Example 27 and a corresponding starting material, the captloned compound was obtalned in the ~ame manner as in Exampl~ 14.
N M R (2 7 O M H z. D M S O - d~ p m : 1 O. 4 8 (l H. s) 8. 7 7 (1 H. s) ~ 8- 5 8 (1 H, d, 3 = ~ H z) ~ 7. 3 2 (1 H.
d. J = 8 H z) ~ 7. 1 3 - 7- 0 9 t2 H, m) ~ 4~ 6 3 - 4. 5 9 tl H, m) ~ 4. 0 6 (2 ~. q. J = 7 H z) ~ 3. 0 4 - 2. 9 5 (2 H. m ) ~ 2. 5 1 - 2. 4 3 (1 H. m) ~ 2. 1 9 - 2. 1 2 (1 H, m) ~ 1.
6 9 - 1. 4 1 (2 H. m) ~ 1. 2 8 (3 H, t, J = 7 H z) ~ O. 9 7 ( 3 H. d. J . 7 ~ z) ~ O. 9 8 - O. 8 0 (1 H, m) ~ O. 8 3 (6 H.
d d. J1 = 7 H Z~ J2 = 1 2 H 2) WOg4/21612 ~.~ <~ PCTIJ~4/00434 Example 21 Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-succinyl]amino-1-isobutoxy-3,4-dihydrocarbostyri.l After conducting a reaction between the compound of Reference Example 28 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
NMR (2 7 OMH z. DMS --d6 ) ~ ~ Pm: l 0. 3 8 ~ l H. s) ~
8. 7 l (l H. s) ~ 8. 3 5 ( l H, d. J--8 H z) ~ 7. 2 5--7. 4 - O (2H, m) ~ 7. 1 5 (1 H. d. -J=7H z) ~ 7. 0 6 (1 H. t. J
=7Hz) ~ 4. 50--4. 70 (1H, m) ~ 3. 7 8 (2H, d t. J=2 2, 7Hz) ~ 2. 70--3. l O (3H. m) ~ 2. l 7 (1 H. d d. J=
l 4, 6 H z ) ~ l . 9 0--2 . l 5 ( 2 H, m) ~ l . 4 O--l . 7 5 ( 2 H
, m) ~ l . O O--l . 2 0 ( l H, m) ~ O. 9 9 ( 6 H. d d, J = 6, 3 1~ }Iz) ~ O. 87 (6H. td. J 81 2, 6Hz) ; ~ Example 22 ~reparation of l-ethoxy-3S-t4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]amino-3,4-dihydrocarbostyril After conducting a reaction between the compound of - Referencs Example 29 and a correspondlng starting material, the captloned compound was obtained ln the same manner as in Example 14.
.
wos4nl6l2 PCT/J~4/00434 0 ~ -142-M R (Z 7 O M H z, D M S O - dB ) ~ P p m : 1 O. 4 9 (! H, s) 8. 7 7 (I H. s) ~ 8- 5 7 (l H. d, J = 8 H z) ~ 7. 3 l (2 H.
t. J = 8 ~ z) ~ 7. 1 6 (1 H, d, J - 8 H z) ~ 7. 0 6 (l H. ~.
J = 8 H z) ~ 4. 5 4 - 4. 6 6 (1 H. m) ~ 4. 0 5 (2 H. q, J = t H z) ~ 2- 9 6 - ~- 0 7 (2 H. m) ~ 2. 4 9 - 2. 5 2 (l H. m) 2. 1 Z - 2. 2 0 (l H. ~) ~ 1. 4 0 - 1. 5 8 (2 H. ~) ~ 1. 2 8 (3 H. t, J = 7 H z) ~ O. 9 8 (3 H. d. J = 7 H z) ~ O. 9 8 - O
. 8 4 (1 H. m) ~ O. 8 4 (6 ~. d d. J = 1 3, 6 H z) Example 23 Prepa~ation of 3R-t4-(N-hydroxyamino)-2R isobutyl- .-succinyl]amino-l-methoxy-3,4-d~hydrocarbostyril Us~ng a corresponding starting material, the captioned compound was obta~ned in the ~ame manner as in Example l.
~ M R (2 7 Q M H z, D M S O - d~ ) ~ P P m : l 0. 4 2 (l H, s) 8. 7 6 (l H. s) ~ 8- 5 1 tl H. d. J = 8 H z) ~ 7. ~ 2 (2 H, d d. J = 1 6, 8 H z) ~ 7. 1 6 (l H. d. J = 8 H z) ~ 7. 0 7 (l H, ~, J = 8 H z) ~ 4- 5 8 (1 H. q. J - 8 H z) ~ 3. 8 3 (3 H, s) ~ 2. 7 0 - 3- 1 0 (3 H, m) ~ 2. 2 2 (1 H, d d. J = l 5, 5 H z) ~ 2. 0 2 (l H. d d. J = 1 5, 9 H z) ~ 1. 4 0 - l. 6 0 (2 ~, m) ~ O. 9 5 - l. 2 0 (l H, m) ~ O. 8 4 (6 H. d, J = 6 H z) Example 24 Preparation of 3R-t4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]amino-l-methoxy-3,4-dihydrocarbostyril Using a corresponding starting material, the captioned WO94/21612 ,~ o PCT/J~4100434 compound was obtained in the same manner as in Example 14.
M R (2 7 O M H z, D M S O - d3 ) ~ P P m : 1 0. 4 8 (1 H, s) 8. 7 6 (l H. s) ~ 8- 6 1 (1 H, d. J = 8 H z) ~ 7. 2 5 - 7. 4 0 (2 H. m) ~ 7. 1 6 (1 H. d, J = 8 H z) ~ 7. 0 7 (1 H. t, J
= 8 H z) ~ 4. 6 6 tl H. d t, J = 1 3, 8 H z) ~ 2. 8 0 - 3. 1 0 (2 H. m) ~ 2. 4 0 - 2- 6 0 (L H, m) ~ 2. O 5 - 2. 3 0 (1 H, m) ~ l. 3 0 - l. 6 0 (2 H. m) ~ l. 0 1 (3 H. d, J = 7 H z) O. 7 5 - 1. 0 5 (1 H, m) ~ 0. 8 1 (6 H, d d, J = 6, 4 H z) Example 25 Preparat~on of l-ethoxymethyl-3(R or S)-~4-(N-~: hydroxyamino)-2R-~sobutylsucclnyl]amino-3,4-dihydrocarbostyrilAfter conducting a reaction between the compound obtained by catalytic reductlon treatmen~ of ~he compound of Ref~rence Example 30 and a corresponding starting material, the captioned compound (dlastereomer l.l mixture) was obtained - ln the qame manner as in Exampl~ 1.
NMR (2 7OMHz. DMSO--d~ ) ~ PPm: 1 O. 4O (1H. b s) :~ 20 ~ 8. 7 6 * 8. 7 2 (1 H. s) ~ 8. 4 4 + 8. 2 8 (l H. d, J = 8 H
.
-- ~ z ) ~ 7 . 2 9--7 . 2 6 (3 H. m~ ~ 7 . O 9--7 . O 3 ( 1 H, m) ~ S
5 6 + 5 . 5 4 ( l H. d . J = I 1 H z ) ~ 5 . O 2 + 5 . O 1 t 1 H, d.
, J = 1 1 H z) ~ 4. 5 3 - 4. 4 8 (1 H . m ) ~ 3 . 5 1 ( 2 H . ~ . J
= 7 H z) ~ 3. 0 0 - 2 . 8 2 ( 3 H, m) ~ 2 . 2 5 - 1 . 9 8 ( 2 H, m ) ~ 1 . 7 O - 1 . 4 5 ( 2 H. m) ~ l. l l (3 H. t, J = 7 H z ) ~ 1 . 1 4 - 1. 0 7 ~l H. m) ~ 0. 9 l - 0. 8 3 (6 H. m) W~94/21bl2 PCT/J~4/00434 ~ ~ 3 6 ~ 144-Example 26 Preparation of l-hexyloxymethyl-3S-~4-(N-hydroxy- c 5 amino)-~R-isobutylsuccinylJamino-3,4-dihydrocarbostyril After conducting a reaction between the compound obtained by ca~alytic reduction treatment of the compound of Reference Example 31 and a corresponding starting material, the captionad compound was obtained in the same manner as in 1~ Example 1.
N M ~ (2 7 O M H z. D M S O - d~ ) ~ p p m : l 0. 3 8 (1 H. s) 8. 7 1 (1 H. s) ~ 8~ 2 8 (l H. d. J = 8 H z) ~ 7. 2 7 (3 H, t. J - 6 H z) ~ 7. 0 6 (l H. t d. Jl = 2 H Z~ J2 = 8 H z) ~ 5 . 5 4 (1 H. d. J = 1 1 ~ z) ~ 5. 0 2 ~1 H, d, J = l 1 ~ z) ~ 4 . 5 6 - 4. 4 S (1 H. m) ~ 3. 4 5 (2 H. t, J = 6 H z) ~ 3. 0 0 - 2. 8 0 (3 H. m) ~ 2. l 8 (1 H. d d. Jl = 6 H Z~ J2 = l 4 z) ~ 2. 0 2 (1 H. d d, Jl = 8 H Z~ J2 ~ 1 5 H 2~ ~ l. 7 5 - l . 5 5 (l H. m) ~ 1. 5 4 - l. 4 5 t3 H. m) ~ l. 2 0 - 1. 0 7 ( 7 H. m3 ~ O. 9 1 - O. 7 8 (9 H, m) 20 EXample 27 Preparatlon of 3S-[4 (N-hydroxyamino)-2R-isobutyl-succinyl]amino-1-methoxymethyl-3,4-dihydrocarbostyril Af~er conducting a reaction between the compound obtained by catalytic reduction treatment of the compound of 25 Reference Example 32 and a corresponding starting materia~, WO 94t21612 PCT/JW4/00434 the captioned compound was obtained in the same manner as in Example 1.
N M R (2 7 O M H z. D M S O - d~ ) ~ P P m : 1 O. 3 9 tl H. b r s ) ~ 8. 7 1 (1 H. b r s) ~ 8. 2 9 (1 H. d. J = 7 H z) ~ 7. i 5 - 7. 3 5 (3 H. m) ~ 7. 0 7 (1 H. ~, J = 7 H z) ~ 5. 4 9 (1 H
, d. J = 1 0 H z) ~ 5. 0 0 (1 H, d, J ~ 1 0 H z) ~ 4. 5 2 (1 H
, d t. J = 1 4, 7 H z) ~ 3- 2 6 (3 H. s) ~ 2. 7 0 - 3. 1 0 (3 H. m) ~ 2. 1 8 (1 H. d d. J = 1 4, 6 H z) ~ 2. 0 2 (l H. d d , J =.1 4, 8 H z) ~ 1. 3 5 - 1. 7 5 (2 H, m) ~ 1. 0 0 - 1. 2 0 (1 H. m) ~ O. 8 8 t6 H. d t. J = 1 4, 6 H z) Example 28 Preparation of l-benzyl-35-t4-(N-hydroxyamino)-2R-~sobutylsuccinyl]amino-3,4-dihydrocarbostyr~l After conductlng a react~on between the compound obtained by trlfluoroacetlc acid treatment of the compound of Reference Example 33 and a corresponding starting material, the captioned compound was obtalned in the same manner as in ~xample 1.
N M R (2 7 0 M H z. D M S O ~ d~ ) ~ p p m : 1 O. 3 9 (1 H. s) ~
~- ~ 8. 7 2 tl H. s) ~ 8. 3 1 (1 H, d. J = 8 H z) ~ 7. 3 4 - 7- 1 4 (8 ~. m) ~ 6. 9 8 (1 H. t, J - 8 H z) ~ 5. 2 2 (1 H. d, J
= 1 6 H z~ ~ 5. 1 0 (1 H. d . J = 1 6 H z) ~ 4. 6 9 - 4. 5 9 (1 - H. m) ~ 3. 0 7 D 2. 9 7 t2 H. m) ~ 2. 8 1 - 2. 7 5 (1 H. m) ~ 2. 2 0 (1 H. d d ~ J 1 = 7 H Z ~ J 2 = 1 5 H z ) ~ 2. 0 3 (1 H.
t d. Jl - 8 H z, J~ = 1 5 H z) ~ 1. 6 5 - 1. 4 5 (2 H. m) ~ 1 , 1 4 - 1. 0 7 (1 H, m) ~ O. 8 7 1 (6 H. d d. il = 7 H Z~ J2 - 1 6 H z) wO94n1612 PCT/J~4/00434 ~.361~
Example 29 Preparation of 3S-[4-(N-hydroxyamino)-2R-isobutyl-succinyl]amino-1-(4-methoxycarbonylbenzyl)-3,4-dihydrocarbostyril Using the compound obtained by trifluoroacetic acid treatment of the compound of Reference Example 34 and a corresponding starting material, the captioned compound was obta~ned in the same manner as in Example 1.
N M R (2 7 0 M H z. D M S 0 - d~ ) ~ p P m : l 0. 3 9 tl H, s) 10 8. 7 2 ~1 H. s) ~ 8. 3 3 (1 H. d. J = 7 H z) ~ 7. 9 1 (2 H.
d. J = 8 H z) ~ 7. 3 7 t2 H, d. J = 8 H z) ~ 7. 2 7 (1 H. d.
J = 7 H z) ~ 7. 1 6 (l H. t, J = 7 H z) ~ 7. 0 0 (l H. t, J =
7 H z) ~ 6. 9 1 (1 H. d. J = 8 ~ z) ~ 5. 3 0 (l H. d. J = l 7 l5 H z) ~ 5. l 7 (1 ~. d. J = 1 7 H z) ~ 4. 7 3 - 4. 6 3 (l H. m ) ~ 3. 8 3 (3 H. s) ~ 3. 0 9 - 2. 9 9 (2 H. m) ~ 2. 8 8 - 2.
7 3 (1 H, ~) ~ 2. 2 0 (1 H. d d. Jl = 7 H Z- J2 = l 5 H ~) ~
2. 0 3 (1 H. d d. Jl = ~ ~ 2, J 2 - 1 5 H z ) ~ 1 . 6 5 - 1 . 4 6 :~ (2 H. m) ~ 1. 1 3 - l- 0 7 (l H. m) ~ 0. 8 7 (6 H. d d, Jl : 20 6 H Z~ J2 = 1 5 H z) Example 30 Preparation of 1-(4-carboxybenzyl)-3(R or S)-[4~(N-hydroxyamino)-2R-isobutylsuccinyl~amino-3,4-dihydrocarbostyril To a mixed solut~on of 5 ml of methanol and 5 ml of 25 tetrahydrofurane of 200 mg of 3S-~4-(N-benzyloxyamino)-2R-W094/21612 "l.5 n 1 ~ ~ PCT/J~4/00434 isobutylsuccinyl]amino-l-(4-methoxycarbonylbenzyl)-3,4-dihydrocarbostyril, 2.0 ml of lN sodium hydroxide was added at room temperature, and stirred overnight. The reaction solution was neutralized by adding lN hydrochloric acid, and concentrated in vacuo. To the obtained residue, 20 ml of e~hyl acetate and 20 ml of water were added, and the solution was shaken to separate the water layer, and the ethyl acetate layer was washed once ~n saturated agueous solution of sodium hydrogencarbonate. The water layer and saturated aqueous s~lution of sodium hydrogencarbonate were put together, stirred in ice-cooling, and the pH was ad~usted to 2 by lN
hydrochloric acid, and the solution was extracted in 30 ml of ethyl acetate. The ethyl acetate layer was washed twice in ¦ saturated brine, dried over sodium sulfat~ anhydride, and concentrated in vacuo. To the obtalned crystalline residue, diethyl ether was added, flltered and dr~ed. Yield: llO mg.
Thu-~ obtalned compound was operated by the same manner ; as in Example l, and the captloned compound (diastereomer l:l ¦ mixture~ was obtaln~d.
N M R (2 7 O M H z. D M S O - d~ ) ~ P P m : I 2. 8 5 (1 H. b s) ~ I 0. 4 I + I 0. 3 9 (I H. s) ~ 8. 7 5 + 8. 7 2 tl H. s) ~ 8 ; . 4 9 + 8. 3 3 (l H. d. J = 8 H z) ~ 7. 8 8 (2 H. d. J = 8 H z ) ~ 7. 3 4 t2 H. d. J = 7 H z) ~ 7. 2 8 (I H. d. J = 8 H z) ~
7. I 1 (l H. t. J = 7 H z) ~ 7. 0 2 - 6. 9 I (2 H, m) ~ S. 3 I (I H, d. J = 1 1 H z) ~ 5- I 6 (l H. d. J = I 7 H z) ~ 4. 7 O - 4. 6 2 (l H. m) . 3- 0 8 - 2- 8 I (3 H. m) ~ 2. 2 2 (I H
WO94/21612 ,~ lU ~ PCT/~4/00434 , d d. Jl = 5 H Z~ J2 = l S H z) ~ 2. 0 3 (1 H, d d. il - 9 H
Z~ J2 = 1 S H z) ~ 1. 5 4 - l. 4 4 (2 H, m) ~ 1. 1 2 - 1. 0 3 (1 H. m) ~ 0. 9 0 - 0, 8 2 (6 H, m) Example 31 Preparation of 3S-t4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl~amino-1-(4-methoxybenzyl)-3,4-dihydrocarbostyril After conducting a reaction between the compound of Reference Example 35 and a corresponding starting material, the captioned ~ompound was obtained in the same manner as in Example 14.
~IMR (2 7 OMHz. DMSO--d3 ) ~ ~ ~m: 1 O. 4 8 (1 H. s) 8. ~ 6 (lH. s) ~ 8. 5 1 (lH, d. J=8Hz) ~ 7. 2 6 (1 H.
d . J = 8 ~I z ) ~ 7 . 1 9--7 . 1 4, ( 3 H, m) ~ 7 . O L--6 . 9 5 ( 2 H. m) ~ 6 . 8 7 ( 2 H, d . J = 9 EI z ) ~ 5 . 1 0 ( 2 H, b s ) ~ 4 .
6 8--4 . 6 3 ( 1 H. m) ~ 3 . 7 0 ( 3 H. s ) ~ 3 . 0 9 ( 1 H, t . J
= 1 5 H z ) ~ 2 . 9 6 ( 1 H. d d . J 1 = 6 ~ Z ~ J 2 1 5 - ~ 5 6--2 . 4 9 ( 1 H . m ) ~ 2 . 2 2--2 . 1 6 ( 1 H . ra ) ~ 1 . 5 8--1 . 44 (2H. m) ~ 1. 0 1--O. 80 (lH, m) ~ O. 9 9 (3H. d, J=7Hz) ~ O. 8 5 (6H. t d. Jl =6 H z. J~ --1 9Hz) Example 32 Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-succinyl]amlno-l-phthalimidomethyl-3,4-dihydrocarbostyril After conducting a reaction between the compound WO94/21612 ~ PCT/J~4/00434 ob~ained by trifluoroacetic acid treatment of the compound of Reference Example 36 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
N M R t2 7 O M H z, D M S O - d6 ) ~ P P m : 1 0. 3 6 (1 H, s) ~-8. 7 l (1 H. s~ ~ 8- 3 6 (1 H. d. J = 8 H z) ~ 7. 8 4 (4 H.
s) ~ 1. 2 5 (3 H. s) ~ 6. 9 0 - 7. l O (1 H. m) ~ 6. 0 5 (1 H. d. J = 1 4 H z) ~ 6. 6 6 (l H, d. J = 1 4 H z) ~ 4. 4 7 (l - H. q, J = 8 H z) ~ 2. 7 0 - 3. 0 O (3 H. m) ~ 2. 1 8 (l H. d 0 d. J = l 4, 7 H z) ~ 2. 0 l (l H, d d. J = l 4, 7 H z) ~ l. 4 O--1 . 8 0 t 2 H . m ) ~ 1 . O O--1 . 2 5 ( 1 H , sn ) ~ O . 8 8 ( 6 H
, d d. J = l 7, 6 H z) -~ Example 33 ~ Preparation of l-ethoxycarbonylmethyl-3S-~4-( N-1~ ~
1~ 15 hydroxyamino)-2R-isobutylsuccinyl~amino-3,4-dihydrocarbostyril 1, After conducting a reactlon between the compound obtalned by trifluoroac-tic acld treatment of the compound of Reference Ex~ample 37 and a corresponding starting materiait the captioned compound was obtained in the same manner as in 20- Exampl~ 1.
NM:R (2 70MHz. DMS O--d~P pm: 1 0. 3 7 (1 H, s) 8. 7 1 tlH. s) ~ 8. 2 9 (1 H.d, J--8H z~ ~ 7. 2 6 (2H, ~ 1 ,-, i .
. ~ t. J=7Hz) ~ 7. 0 6 (1 H. t.J=7 H z) ~ 6. 9 7 (1 H. d.
J=7H z) ~ 4. 8 0 (1 H. d. J= 1 7H z3 ~ 4. 5 6 (1 H. d. J
= 1 7 H z ) ~ 4 . 4 2--4 . 6 5 ( 1 H . m ) ~ 4 . 1 4 ( 2 H . ~ . J = 7 [~ H z ) ~ 2 . 7 0--3 . 1 0 ( 3 H. m) ~ 2 . 1 9 ( 1 H. d d, J = 1 4, ",, ~ ~ , WO94/21612 !'i; PCTtJ~4/00434 ~15Q-7 H z) ~ 2. O 1 (1 H, d d. J = 1 4, 7 H z) ~ 1. 4 O - 1. 7 8 ( 2 H. m) ~ 1. 2 0 (3 H. t. J - 7 H z) ~ 1. 0 0 ~ 1. 2 5 (1 ~.
m) ~ O. 8 7 (6 H, d d. J - I 5, 6 H z) Example 34 Preparation of 3S-[4-(N-hydroxyamino)-2R-isobutyl-succinyl]amino-1-carboxymethyl-3,4-dihydrocarbostyril Using 3S-~4-(N-benzyloxyamino)-2R-isobutylsuccinyl]
amino-l-ethoxycarbonylmethyl-3,4-dihydrocarbostyril obtained in the same manner as in Example 11 by using a corresponding starting material, the captioned compound was obtained in the same manner as in Example 30.
N M R (2 7 O M H z~ D M S O - d~ ) ~ P P m : 1 O. 4 O tl H. s) ~
8. 7 5 (1 H. b r s) ~ 8. 2 1 (1 H. d. J - 7 H z~ ~ 7. 2 1 (2 H. t. J - 7 H z) ~ 6. 9 8 (1 H, t. J = 7 H z) ~ 6. 8 8 (1 H.
d. J = 7 H z) ~ 4. 5 6 ~1 H. d, J = 1 7 H z) ~ 4. 4 7 (1 H, d t. J = 1 4, 7 H z) ~ 4- O 6 (1 H. d. J = 1 7 H z) ~ 2. 6 5 - 3 . O 5 (3 H, m) ~ 2. 1 8 tl H, d d. J = 1 4, 7 H z) ~ 2. O 1 ( 1 H. t d. J = 1 4, 8 H z) ~ L. 4 O - 1. 7 S (2 ~. m) ~ 1. 0 O
', - 1. 2 0 (1 H. m) ~ O. 8 7 (6 H, d d, J = 1 6r 7 H z) 2~
Example 35 Preparation of 7-chloro-1-ethoxycarbonylmethyl-3S-~4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-3,4-dihydrocarbostyr~l After conducting a reaction between the compound W094121612 ' I ~ 6 I Q 8 PCT/J~4/00434 obtained by trifluoroacetic acid treatment of the compound of Reference Example 38 and a corresponding s~arting material, the captioned com~ound was obtained in the same manner as in Example 1.
S N M R (2 7 O M H z. D M S O ~ d6 ) ~ P P m : 1 O. 3 8 (1 H. s) 8. 7 1 (1 H. s) ~ 8- 3 3 (1 H. d, J = 8 H z) ~ 7. 3 1 (1 H, d. J = 7 H z) ~ 7. 1 0 - 7. 2 0 (2 H, m) ~ 4. 7 9 (1 H, d, J
= 1 8 H z) ~ 4. 6 3 (1 H. d, J = 1 8 H z) ~ 4. 4 5 - 4. 6 0 (1 H. m) ~ 4. 1 4 (2 H. q. J = 7 H z) ~ 2. 6 0 - 3. 1 0 (3 H. m ) ~ 2. 1 7 (1 H. d d. J ~-1 4, 6 H z) ~ 2. 0 1 (1 H, d d. J =
1 4, 7 H z) ~ 1. 2 0 - 1. 7 5 (2 H. m) ~ 1. 2 1 (3 H, t, J -7 H z) ~ 1. 0 0 - 1. 2 0 (1 H. m) ~ O. 8 6 (6 H. d d, J = 1 4 I` ~
~ , 6 H ~) : :
Example 36 Preparatlon of 3S-~4-(N-hydroxyamino)-2R-isobutyl-succlnylJa~lno-l-propoxycarbonylmethyl-3,4-dihydrocarbostyril - After conductlng a reactlon between the compound .: ~ o~tained by trifluoroacetlc acld treatment of ~he compound of Reference Example 41 and a correspondlng starting material, the captioned compound was o~tained in the same manner as in Example 1.
.
NMR (2 7 OMH Z. DMS O--d6 ) ~ P Pm: 1 O. 3 8 (1 H. s) ~
8. 7 1 (1 H. S) ~ 8- 3 1 (1 H, d. J=8H z) ~ 7. 2 7 (2H, ~, J = 8 H z) ~ 7. 0 5 (1 H. t, J = 8 H z) ~ 6. 9 8 ( 1 H, d .
J = 8 H z) ~ 4. 8 1 (l H. d. J = 1 7 H z) ~ 4. 5 9 (1 H. d. J
-' :
~13610~
-152- ~
= 1 7 H z) ~ 4. 4 0 4. 5 S (1 H, m) ~ 4. 0 4 (2 H, c. J - 7 H z) ~ 2. 6 5 - 3. 1 0 (3 H, m) ~ 2. l 8 (l H. d d. J = l 4, 6 H z) ~ 2. 0 l (l H. d d. J = l 4, 7 H z) ~ l. 4 0 - 1. 7 5 ( 4 H. m) ~ 1. 0 0 - 1. 2 0 tl H, m) ~ O. 7 5 - I. O O (9 H. m ) Example 37 Prepara~ion of 3S-r4-(N--hydroxyamino)-2R-isobutyl-succinyl~amino-l-isopropoxycarbonylmethyl-3,4-dihydrocarbostyril After conducting a reaction between the compound obtained by trifluoroacetic acid treatment of ~he compound of 1~ Reference Example 42 and a corresponding starting material, the captioned rompound was obtained in the same manner as in Example 1.
N M R t2 7 O M H z, D M S O - dB ) ~ P p m : 1 O. 3 8 (1 H. s) 8. 7 l tl H. s~ ~ 8. 3 1 (l H. d, J = 8 H z) ~ 7. 2 7 (2 H.
t. J - 8 H z) ~ 7. 0 5 (1 H. t, J = 8 H z) ~ 6. 9 4 (l H. d.
J = 8 H z) ~ 4. 9 3 (l H. t t, J = 7, 7 H z) ~ 4. 7 7 tl H. d , J - 1 8 H z) ~ 4. 5 4 (l H. d. 3 = 1 8 ~ z) ~ 4. 4 S - 4. 6 5 ;~ (l H. m) ~ 2. 7 0 - 3. l S (3 H, m) ~ 2. 1 8 (1 H. d d. J =
l 4, 6 H z) ~ 2. 0 1 (1 H, d d. J = 1 4, 7 H z) ~ l. 4 0 - 1.
7 S (2 H, m) ~ l. 2 1 (3 H. d. J = 2 H z) ~ 1. 1 9 (3 H. d.
J = 2 ~ l. O O - 1. 2 0 (l H. m~ ~ O. 8 7 (6 H. d d. J -l 5, 6 H z) Example 38 Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-succinyl]amlno-1-t-butoxycarbonylmethyl-3,4-dihydrocarbostyril WO94/21612 ~ v~ PCT/J~4/00434 -153- ~ , After conducting a reaction betweien the compound obtained by catalytic reduction treatment of the compound of Reference Example 43 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example l.le 43 and a corresponding starting material, the captioned compound wa~ obtained in the same manner as in Example 1.
N M R (2 ~ O M H z. D M S O - d8 ) ~ P P m : 1 O. 3 8 (1 H. b r s ) ~ 8. 7 1 (1 H. b r s) ~ 8. 3 0 (1 H. d. J = 8 H z) ~ 7. 2 S
- 7~ 3 0 t2 H. m) ~ 7. 0 6 (l H, t, Ji-i7 H z) ~ 6. 9 3 (l H
:~ , d, J ~ 7 H z) ~ 4. 7 0 (1 H. d, J = 1 7 H z) ~ 4. 4 4 - 4. 5 4 (2 H. m) ~ 2. 7 S - 3. 0 2 (3 H, m) ~ 1. 9 8 - 2. 2 6 (~ H
~: 15 ~ m) ~ 1. 6 1 - 1. 7 1 (1 H. m) ~ 1. 4 2 - 1. 5 1 (1 H. m) ~
1. 3 9 ~9 H. s) ~ 1. 0 1 - 1. 1 1 (1 H, m) ~ 0. 8 7 (6 H, d d, J-= 1 5, 1 H z~
Example 39 Preparat$on of 1-amlnocarbonylmethyl-3S-~4-(N-hydroxy-~: amino)-2R-isobutylsuccinyl~amino-3,4-dlhydrocarbostyril After conducting a reactlon between the compound obtained by trifluoroacetic acid treatment of the compound of : Reference Example 44 and a correspondlng starting material, the captioned compound was obtained in the same manner as in ','~
f',l i3~
-15~L-Example 1.
N M R (2 7 0 M H z. D M S O - d6 ) ~ P P m : 1 O. 3 9 (1 ~. s) 8. 7 3 (1 H, s) ~ 8- 2 4 (I H. d. J = 8 H z) ~ 7. 5 8 (1.~, s) ~ 7. 1 0 - 7. 3 0 (3 H. m) ~ 7. 0 2 (1 H. t. J = 8 H z) ~
6. 8 4 (1 H. d. J = 8 H z) ~ 4. 6 4 (1 H. d. J = 1 7 H z) ~ 4 . 5 0 4. 7 0 (1 H. m) ~ 4. 1 9 (1 H. d. J = 1 7 H z) ~ 2. 7 O - 3. 1 Q (3 H. m) ~ 2. 1 8 (1 H. d d. J = 1 4, 6 H z) ~ 2.
O 1 (1 H. d d. J = 1 4, 8 H z) ~ 1. 4 0 - i. 7 S (2 H, m) ~ O
. 9 5 - 1. 2 0 (1 H. m) ~ O. 8 7 (6 H, d d. J - 1 S~ 6 H z) Example 40 Preparation of 3S-C4-(N-hydroxyamLno)-2R-isobut succinyl]amlno-l-(N-methylaminocarbQnylmethyl)-3,4-lS dihydrocarbostyril Af~er conducting a reactlon between ~he compound : obtained by trifluoro~c~tic acid treatment of the compound of Reference Example 45 and a corresponding starting material, the captioned ~ompound was obtained in the same manner as in Exampl~ 1.
N M R ~2 7 O M H z. D M S O - d~ p m : 1 O. 3 8 (1 H. b r s ) ~ 8.1 7 1 (1 H. b r s) ~ 8. 2 4 (1 H. d. J = 8 H z~ ~ 8. 0 0 (1 ~. d. J = 5 H z) ~ 7, 2 3 - 7. 2 ? (2 H. m) ~ 7. 0 3 tl H
. ~, J - 7 H z) ~ 6. 8 4 (1 H. d. J = 8 H z) ~ 4. 5 7 - 4. 6 9 (2 H, m) ~ 4. 2 0 (1 H. d. J = 1 7 H z) ~ 2. 9 2 - 3. 0 S (2 H. m) ~ 2. 7 4 - 2. 8 O (l H. m) ~ 2. 6 0 (3 H, d. J = S H z WO94/21612 PCT/J~4100434 -155- ~
) ~ 1. g 8 - 2. 2 S (2 H. m) ~ l. 4 2 - l. 6 8 (2 H. m) ~ l.
0 1 - 1. l 2 (l H. m) ~ 0. 8 7 (6 H. d d, J = 1 5, 7 H z) Example 41 Preparation of 3S-[4-(N-hydroxyamino)-2R-isobutyl-succinyl]amino~ N-propylaminocarbonylmethyl)-3,4-d~hydrocarbostyril After conducting a reaction between ~he compound obtained by trifluoroacetic acid treatment of the compound of Reference Example 46 and a corresponding starting materi.al, the captioned compound was obtained in the same manner as in Example 1.
¦~ ~MR ( 2 7 O MH z . DM S O - d3 ~ ~ P P m : 1 0. 3 8 (l H. b r s ) ~ 8. 7 2 (1 H. b r s3 ~ 8. 2 4 tl H. d. J=8H z) ~ 8. O 8 (1 H. b r s) ~ 7. 2 2 - 7. 2 7 (2 H. m) ~ 7. 0 2 (l H. t. J
= 7 H z) ~ 6. B 4 (l H. d. J - 8 H z~ ~ 4. 5 4 - 4. 6 8 (2 H.
m) ~ 4. 2 5 tl H. d. J ~ 1 7 H z) ~ 2. 9 4 - 3. 0 5 (3 H, m) ~ 2. 7 5 ~ 2. 8 0 (1 H, m) ~ 1. 9 6 - 2. 2 5 (2 H. m~ ~ l. 4 2--1. 6 8 (2 H. m) ~ 1. O 1--1. 1 2 ( 1 E~. m) ~ O. 8 O--O .
9 1 (9 H. m) Exampl~ 42 Preparation of 3S-[4-(N-hydroxyamino)-~R-isobutyl-succinyl]am~no-l-(N-methoxyam~nocarbonylmethyl)-3,4-dihydrocarbostyril WO94/21612 PCT/J~4/00434 ~ 1 3 ~ 156-After conducting a reaction between the compound obtained by trifluoroacetic acid treatment of the compound of Reference Example 47 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
~MR (2 7 OMHz. DMSO--d6 ) ~ P pm: 1 1. 4 O (1 H, s) ~
1 O . 3 9 ( l H. s ) ~ 8 . 7 2 ( l H, s ) ~ 8 . 2 7 ( l H. d . J = 8 H z ) ~ 7 . 2 O--7 . 4 O ( 2 H , m ) ~ 7 . O 4 ( 1 H , t , J = 8 H z ) ~ 6 . 9 1 ( 1 H, d . J = 8 H z ) ~ 4 . 5 9 ( 1 H. d, J = 1 6 H z ) 4 . 4 O--4 . 7 O ( 1 H . m ) ~ 4 . 2 5 ( 1 H . d . J = 1 6 H z ) ~ 3 .
S 9 (~, s) ~ 2. 7 0--3. 1 O (3H. m) ~ 2. 1 9 (1 H. d d, J = 1 4. 7 H z) ~ 2. O 2 ( 1 H. d d, J = 1 4, 7 H z) ~ 1 . 3 O--1 . 8 O ( 2 H . m ) ~ O . 9 O--1 . 2 O ( 1 H . m ) ~ O . 8 7 ( 6 H, d 15 d, Jzl 5, 6H~) j:
~ Example 43 " ~
:~ Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-succinyl}amlno-1-(N,N-dlmethylaminocarbonylmethyl)-3,4-d~hydrocarbostyr~l :
~ After conducting a reaction between ~he compound I
obtalned by trlfluoroacetic acid treatment of the compound of ~^ Reference Example 48 and a corre~pondlng starting material, ~:~ 25 the captioned compound was obtalned in the same manner as in Example 1.
.
wog4nl612 ~ t~ pcTlJ~4loa434 N ~ R (2 7 O M H z, D M S O - d8 ) ~ P P m : 1 O. 3 8 (1 H. b r s ) ~ 8. 7 2 (1 H, b r s) ~ 8. 2 6 (1 H. d. J = 8 H z) ~ 1. 2 O
- 7. 2 6 (2 H. m) ~ 7. O O (1 H. t, J = 8 H z) ~ 6. 8 4 (1 H
. d. J = 8 H z) ~ 4. 9 3 (1 H. d~ J = 1 7 H z) ~ 4. 4 6 - 4. 5 6 (2 H. m) ~ 3- O 9 (3 H, s) ~ 2- 7 3 - 3 O 2 (6 H. m) ~ 1 . 9 ~ - 2. 2 S ~2 H. m) ~ 1- 4 2 - 1. 7 O (2 H, m) ~ 1. O 1 -1 5 L . 1 2 ~1 H. m) ~ O- 8 7 t6 H. d d. J 1 5, 7 H x) ¦ Example 44 I Preparation of 3S-~4-(N-hydroxyamino)-2R-iso~utyl-I succinyl~amino-1 morpholinocarbonylmethyl-3,4-dihydr~carbostyr~l ~ fter conducting a react~on between the compound obtained by trifluoroacetic a id treatment of the compound of Reference Example 4g and a correspondin~ starting material, the capt~oned compound was obtain~d in the same manner as ~n Example 1.
NMR (2 7 OMKz. DMSO--dB ) ~ P P~: 1 O. 3 8 (1 H. s) 8 . 1 1 ~ 1 H . s ) ~ 8 . 2 7 ( 1 H . d . J ~ 8 H z ) ~ 7 . 2 4 ( 2 H .
t, J=8H z) ~ 7. 0 1 (1 H. t. J=8 ~ z) ~ 6. 8 6 ~ 1 H. d, J = 8 H z) ~ 4. 9 7 (1 H. d. J--1 7 H z) ~ 4. 5 7 ( 1 H. d, =1 7Hzl ~ 4. 40--4. 60 (lH, m) ~ 3. 50--3. 7 5 (8H, m ) ~ 2 . 7 0--3 . 2 0 ( 3 H . m ) ~ Z . 1 9 ( 1 E~ . d d . J = 1 4 , 7 Hz) ~ 2. 0 1 (lH. dd. J=l 4. 7Hz) ~ 1. 40--1. 8 0 (2 H. m) ~ O. 95--1. 20 (lH, m) ~ O. 87 (6H, dd. J=l 5 , 6 ~ z) 25 Example 4 5 WO94J21612 'i 13 6 l~ ~ PCT/J~4/00434 Preparation of l-allyl-3S-[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]amino-3,4-dihydrocarbostyril After conducting a reaction between the compound of ~ ReferenCe Example 50 and a corresponding starting material, I . 5 the captioned compound was obtained in the same manner as in Example 16.
NMR (2 7 OMHz. DMSO--d6 ) ~ P pm: 1 O. 4 8 (1 H. s) 8 . 7 7 ( 1 H. s ) ~ 8 . 4 5 ( 1 H. d . J = 8 H z ) ~ 7 . 2 S ~ 2 H, t, J=7Hz) ~ 7. 0 6--6. 9 9 t2H, m) ~ 5. 9 0--5. 8 0 (1 H. m) ~ S . 1 5--5 . 0 6 ( 2 H. m) ~ 4 . 6 9 - 4 . S 3 ( 2 H. m~
4 . 4 1 ( 1 H, d . J--1 7 H z ) ~ 3 . 0 4 ( l H, t, J = 1 5 ~ z ) 2 . 9 3 ( 1 H. d d, J 1 = 6 E~ Z . J 2 = 1 5 H z ) ~ 7 . 5 4--2 . 4 7 (1 H. m) ~ 2. 2 0--2. 1 4 (1 H. n) ~ 1. 6 O--L. 4 2 (2 H
- ~: , m ) ~ O . 9 7 ( 3 H . t . J = 7 H z ) ~ O . 9 8 - O . 8 0 ( 1 H . m ) :~
~ 15 ~ 0. 8 4 t6 H. d t, Jl = 6 H Z~ J a = 1 7 H z) : :
Example 46 . Prepara~on of l-clnnamyl-3S-~4-(N-hydroxyamino)-2~-; lsobutyl-3S-methylsucc~nyl~amino-3,4-dihydrocarbostyril After c~nducting a reactlon between the compound of Reference Example 51 and a correspond~ng material, the c~ptloned compound was obtaln~d ln the same manner as in Example 16.
!~ I , .
~ M R ( 2 7 0 M H z , D M S O--d ~ ) ~ P p m : 1 0 . 4 9 t l H . s ) ; :~ 8. 7 7 (1 H. s) ~ 8. 4 7 (1 H. d, J = 8 H z) ~ 7. 4 0 (2 H.
~.-~:~ d. J=7Hz) ~ 7. 3 2--7. 2 1 (S H. m) ~ 7. 1 6 tl H. t. 3 = 8 H z), 7 . 0 2 ( 1 H. t . J = 8 H z) ~ 6 . 5 2 ( 1 H. d . J = 1 6 H ) 6 3 0 ( l H. t t . J 1 = 5 H Z . J 2 WO94/21612 ~ i. 3 6 1 0 ~ PCTIJ~4100434 -15g-tl H, d d. Jl = 4 H Z~ J2 = 1 7 H z) ~ 4. 6 7 ~ 4. ~ Z (2 ~.
m) ~ 3. O 7 (1 H. ~. J = 1 5 H z) ~ 2. 9 6 (1 H. d d. Jl = 6 H ~ J2 = 1 5 H z) ~ 2- 5 6 - 2- 4 9 (1 H. m) ~ 2. 2 1 - 2. I
5 (1 H. m) . 1. 6 1 - 1- 4 3 (2 H. m) . O. 9 8 (3.~. d. J =
7 H z) ~ - 9 9 - O. 7 9 (1 H, m) ~ O. 8 4 (6 H. d d, Jl = 6 H Z~ J2 = 1 8 H z~
Example 47 Preparation of 3S-[4-(N-hydroxyamino)-2R-isobutyl-succinyl~amino-l-methyl-3,4-dihydrocarbostyril After conducting a reaction between the compound obtained by trifluoroacetic acid treatment of the compound of Reference Example 52 and a corresponding starting material, the capt~oned compound was obtained in the same manner as in ; Example 1.
I5 N M R t2 7 O M H z, D M S O - d~ ) ~ P P m : 1 O. 3 7 (1 H. s) ~
8. 7 1 (1 H. s) ~ 8- 2 O (I H. d. J - 8 H z~ ~ 7. 3 3 - 7. 2 4 t2 H. m~ ~ 7. 1 1 (1 H. d, J - 8 H z) ~ 7. O 4 ~1 H, t, J
-- = 8 H z) ~ 4. 4 9 - 4. 3 9 (1 H, m) ~ 3. 2 8 (3 H. s) ~ 2. 9 ~; 7 - 2. 8 9 (2 H. m) ~ 2. 8 5 - 2. 7 3 (1 H. m) ~ 2. 1 7 (1 H
20 ~ d d. Jl = 6 H Z~ J2 = 1 4 H z) ~ 2. O 1 (1 H. d d, Jl = 7 H
Z' J2 ~ 1 4 H z~ ~ 1. 7 3 - 1. 6 2 (1 H. m) ~ 1. 5 4 - 1. 4 2 (1 H. m) ~ 1. 1 5 - 1. O O (1 H, m) ~ O. 8 7 (6 H. d d. Jl ' ' = 6 H Z~ J2 = 1 5 H z) Example 48 Preparation of l-ethyl-3S-~4-(N-hydroxyamino)-2R-W094121612 PCT/J~4/00434 f. l 3 ~
isobutylsuccinyl]amino-3,4-dihydrocarbostyril After conducting a reaction between the compound obtained by trifluoroacetic acid treatment of the compound of Reference Example 53 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example lo M R (2 7 O M H z. D M S O - d8 ) ~ P P m : I 0. 3 7 (1 H. s) ~
8. 7 1 (1 H. s) ~ 8- 2 0 (1 H, d, J = 8 H z) ~ 7. 2 0 - 7. 3 5 (2 H. m) ~ 7. 1 5 (1 H. d. J = 8 H z) ~ 7. 0 3 tl H. t. J
= 8 H z) ~ 4. 3 5 - 4- 5 0 (1 H. m) ~ 3. 8 0 - 4. 1 0 (2 H, m ) ~ 2. 9 1 (2 H. d. J = 9 H z) ~ 2. 7 0 - 2. 9 0 (1 H. m~ ~ 2 . 1 7 (1 H. d d. J = 1 4, 7 ~ z) ~ 2. 0 1 (1 H. d d. J = 1 4.
8 H z) ~ 1. 4 0 - 1. 8 0 (2 H, m) ~ 1. 1 3 (3 H, ~, J = 7 H z ) ~ 1. 0 0 - 1. 2 5 (1 H. m) ~ O. 8 7 (6 H. d d, J = 1 4, 6 H
Z) Example 49 Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-3S-methylsucclnyl]amino-l-propyl-3,4-dihydrocarbostyril After conducting a reaction between the compound of ~:~ 20 Reference Example 50 and a corresponding starting material, ; the captioned compound was obtained in the same manner as in Example 14.
N M R ( 2 7 O M H z , D M S O--d ~ P P m : 1 O . 4 7 t ~ H . s ) ~
8 . 7 6 ( 1 H. s ) ~ 8 . 4 1 ( 1 H. d . J = 8 H z ) ~ 7 . 2 8--7 . 2 5 t 2 H. m) ~ 7 . 1 4 ( 1 H. d . J = 8 H z ) ~ 7 . O 2 ( 1 H. ~ . J
_ 7 ~ z ) ~ 4 . 5 2--4 . 4 7 ( 1 H. m) ~ 3 . 8 4 ( 2 H. t . J = 8 H
W094t~1612 h1. 3 610 8 PCT/J~4/00434 z) ~ 3. 0 5--2. 8 0 (2 H. m) ~ 2. 5 1--2. 4 6 ( 1 H. m) ~ 2 2 0--2 . 1 6 ( 1 H. m) ~ 1 . 5 9--1 . 4 6 ( 4 H. m) ~ O . 9 6 ( }1, d, J = 7 H z ) ~ O . 9 1 --O . 8 0 ( 1 0 H, m ) Example 50 Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-3S-I methylsuccinyl]amino-l-(3-phenylpropyl~-3,4-dihydrocarbostyril I After conducting a reaction between the compound of Reference Example 5l and a correspond~ng starting ma~erial, ~ the captioned compound was obtained in the same manner as in ¦ Example 14.
¦ ~ M R (2 7 O M H z. D M S O - d6 ) ~ ~ P m : l 0. 4 7 (1 H. s) ~
¦ 8. 7 6 (1 H. s) ~ 8- 4 l (l H, d. J = 8 H z) ~ 7. 3 0 - 7. 1 5 ~ H. m) ~ 7. 0 7 - 6. 9 ~ (2 H. m) ~ 4. 5 1 - 4. 4 6 tl H
, m) ~ 3. 9 2 (2 H. t) ~ 2- 9 8 - 2. 8 8 (2 H. m) ~ 2. 6 4 ( 2 H. t, J = 8 H z) ~ 2. 5 1 - 2. ~ 6 (l H. m) ~ 2. Z 0 - 2. 1 3 (1 H. m) ~ 7 - 1. 7 8 (2 H. m) ~ 1. 6 5 - 1. 3 8 (2 H
. m) ~ O. 9 6 (3 H. d, J = 7 H z) ~ O. 9 8 - O. 8 0 (1 H. m) O ~ O. ~ 4-(6 H. d d. Jl = 6 H Z~ J2 = 1 7 ~ Z) Example 51 ~ Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-¦ succinyl]amino-1-(2-hydroxyethyl)-3,4-dihydrocarbostyril ¦ 25 After conducting a reaction between the compound W094/21612 ~ 3 ~ PCT/J~4/00434 obtained by trifluoroacetic acid treatment of the compGund of ReferenCe Example 55 and a ccrresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
~MR (2 7 O M H z, D M S O - d~ ) ~ P P m : 1 O. 4 9 (1 H, s) 8 . 7 0 (1 H. s) ~ 8- 1 9 (1 H, d, J = 8 H z) ~ 7. 1 5 - ~. 3 5 ~3 K. m) ~ 6. 9 0 - 7- 1 0 (1 H, m) ~ 4. 8 5 (1 H. t. J =
6 H z) ~ 4. 4 6 (l H. d t, J = 1 3~ 8 H zj ~ 3. 9 0 4. 0 5 ( 1 H. m) ~ 3. 8 4 (1 H. d t. J= 1 4, 7 H z) ~ 3. 4 5 - 3. 6 5 (2 H. m) ~ 2. 7 0 - 3- 0 0 (3 H, m) ~ 2. 1 8 (1 H, d d. J =
1 4, 7 H z) ~ 2. 0 4 tl H. d d, J = 1 4, 7 H z) ~ 1. 3 5 - 1.
7 5 t2 H. m) ~ O- 9 5 - 1- 2 0 (1 H. m~ ~ O. 8 7 (6 H. d d, J = 1 5, 7 H z) Example S2 Preparation of 3S-t4-(N-hydroxyamino)-2R-isobutyl-3 methylsuccinyl~ami~o-1-methyl-3,4-d~hydrocarbastyril After conductlng a reaction between th~ compound of Reerence Example 52 and a corresponding starting material, the captlPned compound was obtained in the same manner as in Example 16.
~ M R (2 7 O M H z. D ~ S O - t~ ) ~ P ~ m : 1 O. 4 8 (1 H, b r s ) ~ 8. 7 6 (1 H. b r s) ~ 8. 4 1 (1 H, d. J = 8 H z) ~ 7. 2 5 - 7. 3 3 (2 H. m) ~ 7. 1 1 (1 H. d. J = 8 H ~) ~ 7. 0 3 (1 H
, d. J = 7 H z) ~ 4. 4 4 - 4- S 4 (1 H. m) ~ 3. 2 8 t3 H. s) ~ 2. 8 9 - 3. 0 7 (2 H. m) ~ Z. 4 9 - 2. S 3 (1 H. m) ~ 2. 1 6 ~1 H. d d. J = 1 1, 7 H z) ~ 1. 4 1 - 1. 6 2 (2 H. m) ~ O.
9 6 t3 H. d. J = 7 H z) ~ O- 8 4 - O. 9 6 (1 H. m) ~ O. 8 4 ( 6 H. d d. J = 1 7, 6 H z) WO94/21612 i-~ .3 6 ~ 0 8 PCT/J~4/UO434 Example 53 Preparation of 3S-~4-(N-acPtoxyamino)-2R-isobutyl-succinyl]amino-1-methoxy-3,4-dihydrocarbostyril Using acetic anhydride and a corresponding starting m~terial, the captioned compound was obtained in the same manner as in Example 8.
N M R (2 7 O M H z, D M S O - d~ P m : 1 1. 6 O (1 H. s) ~
8. 3 4 (1 H. d. J - 8 H z) ~ 7. 2 O - 7. 4 O (2 n, m) ~ 7. 1 6 (1 H. d. J a 8 H z~ ~ 7. O 7 (1 H. t, J = 8 H z) ~ 4. 6 1 ( 1 H. d t, J = 1 2, 8 H z) ~ 3~ 8 2 t3 H. s) ~ 2. 6 O - 3. 1 O
(3 H. m) ~ 2. 3 4 (1 H. d d. J = 1 5, 7 H z) ~ 2. 1 1 (1 H.
¦: d d. J = 1 5, 7 H z) ~ 2- 1 5 (3 H. s) ~ 1. 4 O - 1. 8 O (2 H
¦ . , m) ~ 1. O 5 - 1. 4 O (1 H. m) ~ O. 8 7 (6 H. d d, J = 1 5, 6 H z) ¦ Example 54 ¦~ Preparation of 3S-t4-(N-benzoyloxyamino)-2R-isobutyl-:~ 3S-methylsuccinyl~mlno-1-methoxy-3,4-dihydrocarbostyril . Using a correspond~ng startl~g material, the captioned ~: : 20 compound ~as obtained in the same manner as in Example 8.
:' .NM R t 2 7 0 MH z . DM S O--d ~ ) ~ p ~ m: 1 2 . 0 8 ( 1 H. s ) j 8 . 6 4 ( 1 H. d . J = 8 }I z ) ~ 8 . 0 4 ( 2 H, d . J = 7 H z ) ~ 7 .
7 6 (1 H . t, J = 8 H t ) ~ 7 . 6 0 ( 2 H . t, J--8 H 2 ) ~ 7 . 3 7 --7. 29 (2H. m) ~ 7. 1 6 (lH, d. J=7Hz) ~ 7. 0 7 (1 H
, t, J=8Hz) ~ 4. 6 8--4. 6 3 (1 H. m) ~ 3. 8 3 t3 H. s) 3. 0 8 (1 H. t. J=l 3Hz) ~ 2. 9 7 (1 H. d d. Jl =7 H z J2 - 1 6 H z) . 2. 5 5 - 2. 4 1 (2 H. m) ~ 1. 6 O - 1. 5 3 ( WO94/21612 PCT/J~4/00434 ~ 13Glo~
-164- , 2 H. m) ~ 1. 2 1 - 1. 1 5 (1 H, m) ~ 1. 1 0 (3 H, d. J = 6 H
z) ~ 0. 8 7 (6 H. t. J = 7 H z) Example 55 Preparation of 3S-[4-(N-hydroxyamino)-2R-isobutyl-3(R
or S)-phthalimidomethylsuccinyl3amino-l-methoxy-3~4 dihydrocarbos~yril Using a corresponding starting material, the captioned compound was obtained in the same manner as in Example 7.
M R (2 7 O M ~ z, D M S O - d6 ) ~ P P m : 1 O. 4 7 (1 H. s) 8. 6 8 (1 H. s~ ~ 8- 6 5 (1 H. d. J - g ~ z) ~ 7. 8 8 - 7.
O (4 H. m) ~ 7. 3 3 (1 H. t, J = 8 H z) ~ 7. 2 6 tl H. d. J
= 7 H z) ~ 7. 1 6 (1 H. d. J = 7 ~ z) ~ 7. 0 6 tl H. t. J = 7 z) ~ 4. 6 1 - 4. 5 6 (1 H, m) ~ 3. 8 9 (1 H. d d. il = 3 H
~: Z' J2 = 1 5 H z) ~ 3. 8 2 (3 H. s) ~ 3. 4 8 (1 H. d d. Jl ~
Z~ J2 = 1 4 H z) ~ 3- 0 6 - 2- 8 9 (2 ~. m) ~ 2. 7 9 - 2.
6 3 ~2 H. m) ~ 1. 6 7 - 1. 5 4 (3 H, m) ~ O. 8 6 (6 H, d d, Jl = 6 ~ Z~ J2 = 1 5 ~ ~) ' Example 56 P~eparatlon of 3-~4-(N-hydroxyamino)-~R-isobutyl-3(R
or S)-phthalimldemethyl~uccinyl]amino-l-methyl-3,4-i d~hydrocarbostyril - : After conducting a reaction between the compound obtained by trifluoroacetic acld treatment of the compound of Reference Example 52 and a corresponding starting material, . , .
~ ~ .
1 ~ .
W094/21S12 ~ U~lv~ pcr/J~4l~4~4 the captioned compound (diastereomer 1:1 mixture) was obtained in the same manner as in Example 7.
N M R (2 7 O M H z. D M S O - d6 ) ~ P P m : 1 O. S O + 1 O. 4 5 ( 1 H, s) ~ 8~ 7 1 + 8- 6 8 (1 H, s) ~ 8. 6 6 + 8. S 3 (1 H, d , J - 8 H z) ~ 7. 8 8 - 7. 8 O (4 H, m) ~ 7. 3 2 - 7. 2 O (2 H
, m) ~ 7. 1 4 - 6. 9 9 (2 H, m) ~ 4. S 6 - 4. 4 O (1 H, m) ~
4, O 5 + 3. 8 9 (1 H, d d, Jl = 1 O H Z~ J2 = 1 3 H z) ~ 3. 7 O ~ 3. 4 7 (l H. d d. Jl = 4 H Z~ J2 = 1 3 H z) ~ 3. 2 8 (3 H
, 5) ~ 3. O 1 - 2. 8 9 (2 H. ~) ~ 2. 8 2 - 2. 6 S t2 H, m) 1. 7 O - 1. 4 9 (3 H. m) ~ O. 9 1 - O. 8 2 (6 H, m) Example 57 Preparatlon of 3S-~4-( N-hydroxyamino) 2R-isobutyl-3S-methylsuccinyl]amino-1-(2-propynyl)-3,4-dihydrocarbostyril After c~nductlng a reaction between the compound of Re~erence Example 56 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 16.
NMR (2 7 0MH z. DMS C)--d~ P p m : 1 0. 4 9 ( 1 H. b r s .) ~ 8. 7 7 (l H. b r s) ~ 8. 4 8 (1 H, d, J = 8 H ~) ~ 7. 2 O
- 7. 3 6 (3 H. m) ~ 7. O 7 (1 H, t, J = 8 H z) ~ 4. 7 9 (1 H
, d d. J = 1 8. 2 H z) ~ 4. 6 2 (1 H, d d, J = 1 8. 2 H z) ~ 4 . 4 8 - 4. S 8 (1 H. m) ~ 3. O O (1 H, t, J = 1 S H z) ~ 2. 9 1 (1 H. d d. J ~ 1 5. 6 H Z) ~ 2. 4 6 - 2. 5 4 (2 H, m) ~ 2.
: WO94/21612 ) PCT/J~4/00434 ~13~1~3~
1 4 - 2. 2 0 (1 H. m) ~ 1. 5 8 - l. 6 6 (1 H, m) ~ l. 4 6 (!
H. d ~, J = 3. 1 5 H z) ~ 0. 9 7 (3 H. d. J = 7 H z) ~ 0. 9 7 - 0. 8 5 (1 H. m) ~ 0. 8 5 (6 H. d d. J = l 4. 7 H z) Example 58 Preparation of 3S-t4-(N-hydroxyamino)-3S-aminomethyl-2R-isobutylsuccinyl]amino-1-methoxy-3,4-dihydrocarbostyril 50 mg of 3S-~4-(N-hydroxyamino)-2R-isobutyl-3S-- phthalimidomethylsuccinyl]amino-1-methoxy-3,4-dihydrocarbostyril was dissol~ed in 3 ml of dim2thyl ~ormamide, and 19 ~1 of hydrazine monohydrate was added and stirred for 1 hour at room temperature~ The reaction solution ~ was concentrated in vacuo, 1 ml of methanol was added, ~he -~ insoluble matter was filtered away, and the filtrate was ~: 15 evaporated in vacuum, and 3 ml o~ diethyl e~her was added to : the precipitating cryætals to filter, and the captioned compound was obtained t n a white solid form. Yield: 7 mg.
~: : ~ M R ~2 7 O M H 2, D M S O - d ) ~ P P m : 1 0. 5 6 (l H, b r s ) ~ 9- S B (l H, s) ~ 8. 6 0 (1 ~, d, .J = 8 H z) ~ 7. 3 2 (2 ~: H, d d. J ~ 1 5, 7 H z) ~ 7. 1 6 (1 H, d, J = 7 H z) ~ 7. 0 7 tl H, t, J - 7 H z) ~ 4. 6 8 (l H, d t, J = 1 2, 8 H z) ~ 3.
8 2 (3 H, s~ ~ 2. 4 0 - 3. 2 0 t6 H, m) ~ 0. 9 0 - l. 8 0 (3 ~ H, m) ~ 0. 8 7 ~6 H. d d, J = l 8, 6 H z) :~ , -:
-WO9~/21612 PCT/J~4/0~34 Example 59 Preparation of l-aminocarbonylmethyl-3S-[4-(N-hydroxy-amino)-2R-isobutyl-3S-acetylthiomethylsuccinyl]amino-3,4-di~ydrocarbostyril After conducting a reaction between the compound of Reference Example 44 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 4.
NMR(270MHz, DMS0-d~)~ppm:10.62(1H, s), 8.92(1H, s), 8.55~1H, d, J~8Hz), 7.57(1H, s), 7.10-7.35(3H, m), 7.03(1H, t, J-7Hz), 6.86(1H, d, J-7Hz), 4.55-4.75(1H, m), 4.66(1H, d, J=17~z), 4.20(lH, d, J=17Hz), 2.80-3.20(4H, m), 2.40-2.65(lH, m), l5 2.31(3H, s), 2.20-2.40(1H, m), 1.40-1.70(2H, m), 0.80-l.OO(lH, m), 0.87(3H, d, J=7Hz), 0.81(3H, d, J-7Hz) ~:~ Example 60 Preparation.of 7-chloro-3S-~4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-l-methoxy-3,4-dihydrocarbostyril , After conducting a reaction between the compound obtained by trifluoroacetic acid treatment of the compound of Re~erence Example 59 and a corresponding start~ng material, `
the captioned compound was obtained in the same manner as in WO94/21612 PCT/n~4/00434 ~ 1 3 ~ 168-Example 1.
NMR~270MHz, DMSO-d6)~ppm:10.38(lH, brs), 8.72(1~, brs), 8.38(1H, d, J=8Hz), 7.31(1H, d, J-8Hz), 7.11-7.16(2H, m), 4.63(1H, dt, J=11,8Hz), 3.84(3H, s), 2.98(1H, d, J=llHz), 2.97(1H, d, J=8Hz), 2.75-2.76(1H, m), 2.16(1H, dd, J=6,14~z), 2.01(1H, dd, J-8,14Hz), 1.6o-l~65tlH~ m), 1.42-1.49tlH, m), 1.02-1.12(1H, m), 0.87(6H, dd, J36,12Hz) Example 61 Preparation of l-carboxyme~hyl-3S-~4-(N-hydroxy-amino)-2R-isobutyl-3S-methylsuccinyl]amino-3,4-d~hydrocarbostyril After conductlng a reactlon between the compound of :~ :
- ~ ~ : Reference Example 39 and a corresponding starting material, -~ the captioned compound was obtalned in the same manner as in -~ Example 14.
~:~
~ ~ ZO
~: : NMR(270MHz, DMS0-d6)~ppm:10.49(1H, s), 8.75(1H, brs), 8.46(1H, d, J-8Hz), 7.28-7.22(2H, m), 7.02(1H, t, J~8Hz), 6.93(1~,! d, ¦- J~8Hz), 4.69(1H, d, J-l?Hz), 4.57-4.52(1H, m), 4.34tlH, d, ~-~ J~17Hz), 3.05(1H, t, J-lSHz), 2.91tlH, dd, Jl=6Hz, J2-15Hz), 2.51-2.47(1H, m), 2.21-2.15(1H, m), 1.63-1.42t2H, m), 0.99-:
W094/2161? h ~t)~ ~ PCTIJ~4100434 0.80(10H, m), 0.98t3H, d, J=8Hz), 0.85(6H, dd, Jl=6Hz, J2=18HZ ) Example 62 5Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]amino-l-methoxymethyl-3,4-dihydxocarbostyril After conducting a reaction between the compound of Reference Example 60 and a corresponding starting material, I the captloned compound was obtained ln the same manner as in Example 14.
NMR(270MHz, DMSO-d6)~ppm:10.49(1H, s), 8.77(1H, s), 8.49(1H, d, J-8Hz), 7.15-7.35(3H, m), 7.06(1H, t, J-7Hz), 5.47(1H, d, J~lOHz), 5.02(1H, d, 3-lOHz), 4.57'1H, dt, JY14~ 7Hz), 3.27(3H, s), 3.07(lH, t, J~14Hz), 2.91(lH, dd, J-14,6Hz), 2.40-2.60(1H, m), 2.10-2.30(1H, m), 1.50-1.70(1H, m), 1.46(1H, t, J=llHz), 0.80-l.OO(lH, m), Q.98(3H, d, JY7~Z), 0~88~3H, d, J-7Hz), 0.81(3H, d, J-7Hz) ~-~ ~ .
Example 63 Preparation of 3S-t4-(N-hydroxyamino)-2R-isobutyl-3S-acetylthiomethylsuccinyl]amino-1-methoxymethyl-3,4-dihydrocarbostyril ~- : 25After conducting a reaction between the compound of W094/21612 PCTI~4/00434 ~ 1 361~
-170- !
Reference Example 32 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 4.
NMR(270MHz, DMSO-d6)~ppm:10.61(1H, s), 8.91(1H, s), 8.60(1H, d, Js8Hz), 7.15-7.35(3H, m), 7.07(1H, t, J=7Hz), 5.47(1H, d, JSlOHz), 5.03(1H, d, J=lOHz), 4.60(1H, dt, J-13,7Hz), 3.27(3H, s), 2.80-3.20(4H, m), 2.40-2.70(1H, m), 2.20-2.40(1H, m), 2.30t3H, s), 1.4Q-1.70(2H, m), 0.80-l.OO(lH, m), 0.87(3H, d, J-6Hz), 0.81(3H, d, J-6Hz) xample 64 Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl--~S-mercaptomethylsucclnyl~am~no-l-methoxymethyl 3,4-dihydrocarbostyril Using a corresponding start~ng material, the captioned compound was obtained in the same manner as in Example 5.
NMR(270MHZ, DMSO-d6)~ppm:8.55(1H, d, J-~Hz), 7.15-7.30(3H, m), 7.06(1H, t, J-8Hz), 5-47tlH, d, J-lOHz), 5.01tlH, d, J310Hz), 4.53~1~, dt, J~1;4,7Hz), 3.27(3H, s), 3.09(1H, d, J-15Hz), 2.97(1H, dd, J~15,7Hz), 2.40-2.70(3H, m), 2.20-2.40~1H, m), 1.40-1.70(2H, m), 0.80-l.OO(lH, m), 0.~6(3H, d, J-7Hzl, -: 25 o.g2(3H, d, J-7Hz) ::' WO94/21612 ~i ~J ~ PCT/J~4100434 Example 65 Preparation of l-ethoxy-3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-3,4-dihydrocarbostyril After conducting a reaction between the compound obtained by trifluoroacetic acid treatment of the compound of Reference Example 29 and a corresponding starting material, the captioned~ ompound was obtained in the same manner as in Example 1-NMR(270MHz, DMS0-d6)~ppm:10.37(1H, s), 8.71(1~, s), 8.35(1H, d, J~8Hz), 7.35-7.26(2H, m~, 7.16(1H, d, J=8Hz), 7.06(1H, t, 3. J~7Hz), 4.63-4.53(1H, m), 4.04t2H, q, J~7Hz), 3.01-2.92(2H, Z 15 m), 2.80-2.72~1H, m), 2.17(1H, dd, Jl-6Hz, J2=14Hz), 2.01(1H, dd,Jl-8Hz, J2-15Hz), 1.64-1.43(2H, m), 1.28(3H, t, J=7Hz), - 1.12-l.Q4(lH, m), 0.87(6H, dd, J1~6Hz, J2-12Hz) Example 66 Preparation of 3S-t4-(N-hydroxyamino)-2~-isobutyl-~ succlnyl]amino-l-methoxyethoxymethyl-3,4-dihydrocarbostyril j After conducting a reaction between the compo~nd i obtained by catalytic reduction treatment of the compound of Reference Example 61 and a corresponding starting material, W094/21612 PCT/~4100434 _ ~3~
-17~-the captioned compound was obtained in the same manner as in Example 1.
NMR(270MHz, DMS~-d6)~ppm:10.41(1H, s~, 8.73(1H, s), 8.29(1H, d, J=8Hz), 7.25-7.40(3H, m), 7.00-7.15(1H, m), 5.57(1H, d, J-lOHz), 5.02(lH, d, J=lOHz), 4.51(lH, dt, J=14, 7Hz), 3.60(2H, t, J~4Hz), 3.44(2H, t, J=4Hz), 3.22(3H, s), 2.70-3.10(3H, m), 2.18(1H, dd, JS14,7Hz), 2.02(1H, dd, J=14,7Hz), 1.40-1.80(2H, m), 1.00-1.30(1H, m), O.90t3H~ d, J~7Hz), 0.85(3H, d, J=7Hz) Example 67 : Preparation of 3S-t4-(N-hydroxyamino)-2R-isobutyl-3-propylsuccinyl]amino-l-methoxy-3,4-dihydrocarb~styril ~ After conduct~ng a reaction between the compound of ,~
~ Refer~nce Example 62 and a corresponding starting material, ~ :
: the capt~oned compound was obtalned ~n the s~me manner as in :~
Example 14.
20 NMR(270MHz, DMSO-d6)~ppm:10.49(lH, s), 8.78(1H, s), 8.52(1H, d, J-8Hz), 7.36-7.29(2H~ m), 7.16(1H, d, J=8Hz), 7.07(1H, t, J~7Hz)l, 4.67-4.62(1H, m), 3.83(3H, s), 3.04(1H, t, J=16Hz), 2.94(1H, dd, ~1-7Hz, J2~16Hz), 2.52-2.43(1H, m), 2.11-2.09(1H, m), 1.58-1.41(2H, m), 1.24-1.03(4H, m), 0.96-0.80(10H, m) -~ 25 ::
WO94/21612 PCT/J~4100434 Example 68 Preparation of 3S-[3-benzyl-4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-l~methoxy-3,4-dihydrocarbostyril After conducting a reaction between the compound of Reference Example 63 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 14.
NMR(270MHz, DMSO-d6)~ppm:lO.28(~H, s), 8.69-8.65(2H, m), 7.36-7.03(9H, m), 4.68-4.63(lH, m), 3.84(3H, s), 3.12(1H, t, J315Hz), 2.98(1H, dd, Jl-7Hz, J2~l6Hz), 2.75-2.7I~2H, m), 2.58-2.55(1H, m), 2.45-2.39(1~, m), 1.62-1.48(2~, m), 1.03-0.97(lH, m), 0.87(6H, dd, Jl-6Hz, J2-l6Hz) Example 69 ~ Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-¦~ 3-~4-methoxybenzyl)succinyl]amino-l-methoxy-3,4-::20 dihydrocarbostyril After conducting a reaction between the compound of Reference Example 64 and a corresponding starting material, the captioned compound wzs obtained in the same manner as in Example 14.
I WO94/21612 PCT/J~4/00434 ~ ~3~i10 ~
-174- !
NMRt270MHz, DMS0-d6)~ppm:10.25(lH, s), 8.65(1H, d, J=8Hz), ~ 8.64(1H, s), 7.36-7.27(2H, m), 7.16(1H, d, J=7Hz), 7.05(1H, i dt, Jl=lHz, J2-7Hz), 6.99(2H, d, J=9Hz), 6.79(2H, d, J=9Hz), t 4.68-4.63(1H, m), 3.84(3H, s), 3.71(3H, s), 3.11(1H, t, ¦ 5 J=15Hz), 2.98(1H, dd, Jl=7Hz, J2=16Hz), 2.68-2.56(3H, m), 2.39-2.34(1H, m), 1.64-1.54(2H, m~, 1.00-0.96(1H, m), 0.86(6H, dd, Jl=7Hz, J2=16Hz) Example 70 Preparation of l-carboxymethyl-3S- r 4-(N~-hydroxy-am~no)-2R-isobutyl-3(R or S)-phthalimidomethylsuccinyl]amino-~ : 3,4-dihydrocarbostyril :: After conducting a rea~tion between the compound of Reference Example 39 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 14.
: , :
:: NMR(270MHz, DMS0-d6)~ppm:10.50(1H, s), 8.70(lH, bs), 8.57(lH, d, J~8Hz), 7.88-7.80(4H, m), 7.28-7.23(2H, m), 7.02~1H, t, J-7Hz), 6.94(1H, d, J-8Hz), 4.71(1H, d, J-18Hz), 4.50-4.37t2H, m), 3.90(lH, dd, Jl=lOHz, J2=14Hz), 3.48(lH, dd, Jl=5Hz, J2~14Hz), 3.17-2.92(2H, m), 2.84-2.65(2H, m), 1.71-1.54(2H, m), 1.00-0.96~1H~ m), 0.86(6H, dd, J1~7Hz, J2=19Hz) W094/21612 ~ ~ LU ~ PCT/J~4/00434 Example 71 Preparation of 3S-[4-tN-hydroxyamino)-2R-iso~utyl-3S-methylsuccinyl]amino-l-methoxyethoxymethyl-3,4-dihydrocarbostyril After conducting a reaction between a corresponding starting material and the compound obtained by catalytic reduction treatment of the compound of ~eference Example 61, the captioned compound was obtained in the same manner as in Example 62.
NMR(27CMHz, DMSO-d6~ppm:10.49(1H, s), 8.78(1H, s), 8.48(1H, d, J~8Hz), 7.20-7.35(3H, m)! 7.00-7.10(1H, m), 5.56(1H, d, J~lOHz), 5.04(1H, d, J=lOHz), 4.55(1H, dt, J=14,7Hz), 3.60(2H, dd, J-6,3Hz), 3.44(2H, dd, J-6,3Hz), 3.22(3H, s), 3.06(1H, t, J-14Hz), 2.91(1H, dd, J-14,6Hz), 2.45-2.60(1~, m), 2.10-2.30(1H, m), 1.50-1.70(1H, m), 1.47(1H, t, J=13Hz), 0.80-l.lO(lH, m), 0.98~3H, d, J~7Hz), 0.88t3H, d, J~7Hz), 0.81(3H, d, J-7Hz~
Example 72 ~ I Preparation of 3S-~4-(N-hydroxyamino)-2S-isobutyl-succinyl]amino-l-methoxy-3,4-dihydrocarbostyril After conducting a reaction between the compound of Reference Example 65 and a corresponding starting material, WO94/21612 PCT/J~4/00434 .
3~ 10~
the captioned compound was obtained in the same manner as in Example 1.
NMR(270MHz, D~so-d6)~ppm:lo~4ltlHr brs), 8.75(1H, brs), `~
8.50(1H, d, J=8Hz), 7.32(2H, t, J=BHz), 7.16(1H, d, J=8Hz), 7.07(1H, t, J-8Hz), 4.06(1H, dt, J=11,8Hz), 3.83(3H, s), .
2.98(lH, d, J=llHz~, 2.97(1H, d, J-8Hz), 2.79-2.84( lHr m), 2.21(1H, dd, J=5,14Hz), 2.02(1H, dd, J=g,14Hz), 1.42-1.51(2H, .
m), 1.02-1.12(1H, m), 0.84(6H, d, Js6Hz) Example 73 Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-succ~nyl]amlno-l-methoxymethoxyethyl-3,4-dihydrocarbostyril After conducting a reaction between the compound obtained by catalytic reduction treatment of the compound of :~ Reference Example 66 and a correspond~ng starting material, the captioned compound was obtained in the same manner a~ in Example 1.
NMR~270MHz, ~MSO-d6)~ppm:10.37(1H, s), 8.70(1H, s), a.23(1H, . d, J-8Hz), 7.20-7.35(3H, m), 7.03tlH, t, J38Hz), 4.52(2H, q, J~6Hz), 4.40-4.60(1H, m), 4.09(2H, t, J-6Hz), 3.63(2H, t, J-6Hz), 3.17~3H, s), 2.70-3.00(3H, m), 2.18(1H, dd, J=15,6Hz), 2.~1(1H, dd, J~15,7Hz), 1.40-1.80(2H, m), 1.00-1.20(1H, m), WO94/21612 .~ b 10 8 PCTIJ~4/00434 0.90(3H, d, J=7Hz), 0.84(3H, d, J=7~z) Example 74 Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-3-(3-phenylpropyl)succinyl]amino-l-methoxy-3,4-dihydrocarbostyril After conducting a reaction between ~he compound of Reference Example 67 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 14.
NMR(270MHz, DMSO-d6)~ppm:10.52(1H, s), 8.80~lH, s), 8~52(lH, d, J=8Hz), 7.35(1H, t, J~7Hz), 7.30-7.15(7H, m), 7.lO(lH, t, J~7Hz), 4.66-4.61(1H, m), 3.83(3H, s), 2.96(1H, t, J=16Hz), 2.82(1H, dd, Jl~6Hz, J2~l6Hz), 2.56~2.43(3H, m), 2.14-2.09(1H, m), 1.57-1.29(6H, m), 0.95-0.92(lH, m), 0.83(6H, dd, Jl-6Hz, J2~l2Hz) Example 75 ~reparat~on of 35-~4-(N-hydroxyamino)-2R-isobutyl-3-(2-methylbenzyl3succinyl~amino-l-methoxy-3,4-dihydrocarbostyril After conducting a reaction between the compound of WO94/21612 PCT/J~4/00434 ~-~ 1 3 ~ ~ 3 ~ 178~
Reference Example 68 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 14.
NMR(270MHz, DMSO-d6)~ppm:10.21(lH, s), 8.70(lH, d, J=8Hz), 8.60(1H, s~, 7.33(1H, t, J=8Hz), 7.28(1H, d, J=7Hz), 7.16(1H, d, J=8Hz), 7.07-6.56(5H, m), 4.68-4.62(1H, m), 3.84(3H, s), 3.15(1H, t, J=15H ), 2.98~1H, dd, J1=6Hz, J2-16Hz), 2.75-2.71(2H, m), 2.61~2.55(1H, m), 2.42-2.37(1H, m), 2.22(3H, s), 1.63-1.47(2H, m~, 1.00-Q.96(1H, m), 0.87(6H, dd, Jl=6Hz, J2 ' 1 7HZ ) Example 76 Preparation of 3S-r4-(N-hydroxyamino)-2R-isobutyl-3-( 3-methylbenzyl)succinyl]amino-1-methoxy-3,4-dihydrocarbostyrll After conducting a reaction between the compound of ~eferenc~ Example 69 and a corresponding starting material, the capt~oned compound was obtained in the same manner as in Example 14.
, MMR~270MHz, DMS0-d6)~ppm:10.27(1H, s), 8.67-8~64(2H, m), 7.36-7.27(2H, m), 7.~8-6.85(6H, m), 4.68-4.63~1H, m), 3.84(3H, s), 3.12(1H, t, J~15Hz), 2.98(1H, dd, J1=7Hz, J2=16Hz), 2.7S-WO94/21612 PCT/J~4/00434 ~13G~08 2.49(3H, m), 2.44-2.38(1H~ m), 2.26(3H, s), 1.64-1.47(2H, m), 1.01-0.97(1H, m), 0.87(6H, dd, J1=6Hz, J2=16Hz) Example 77 Preparation of 3S-r4-(N-hydroxyamino)-2R-isobutyl-3-(4-methylbenzyl)succinyl]amino-1-methoxy-3,4-dihydrocarbostyril After conducting a reaction between the compound of Reference Example 70 and a corresponding starting material, the captioned compound was obtained ~n ~he same manner as in Example 14.
, .
NMR(270MHz, DMSO-d6)~ppm:10.25(1H, s), 8.66-8.63(2H, m), 7.36-7.27(2H, m), 7.16(1H, d, J-8Hz), 7.08-7.02(3H, m), 6.96(2H, d, J-8Hz), 4.68-4.63(1H, m), 3.84(3H, s), 3.11tlH, t, J-13Hz), 2.98(i~, dd, J1-6Hz, 32~15Hz), 2.75-2.49(3H, m), 2.41-2.35(1H, m), 2~25(3H, s~, 1.61-1.47(2H, m), 1.00-0.82(7H, m), 0.86(6H, dd, J1~6Hz, J2-15Hz) Eyampls 7B
Preparation of ~S-t4-(N-hydroxyamino)-2R-heptyl-succinyl]amino-l-methoxy-3,4-dihydrocarbostyril After conducting a reaction between the compound of Reference Example 73 and a corresponding starting material, the captioned compound was obtained in the same manner as in W094/tl612 PCTtJ~4/Q0434 ~
~.136~
Example 14.
NMR(270MHz, DMSO-d6)~ppm:10.38(lH, s), 8.71(lH, s), 8.32(lH, d, J=8Hz), 7.32(2H, dd, J=16,8Hz), 7.16(1H, d, J=8Hz), 7.07(1H, t, J=8Hz), 4.61(1H, dt, J=12~8Hz), 3.82(3H, s), 2.85-3.10(2H, m), 2.55-2.89(1H, m), 2.20(1H, dd, J=14,7Hz), 2.02(1H, dd, J=14.7Hz), 1.05-1.60(12H, m), 0.87(3H, t, J=6Hz) Example 79 Preparation o~ 3S-~4-(N-acetylhydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxymethyl-3,4-dihydrocarbostyril Using acetic anhydride and a corresponding starting 15 ma~erial, the captioned compound was obtained in ~he same manner as in Example 8.
NMR(270MHz, DMSO-d6)~ppm:11.63(1H, s), 8.33(1H, d, J-8Hz), 7.20-7.35(3H, m), 7.07(1H, t, J~7Hz~, 5.49(1H, d, J=lOHz), 5.00(1H, ~, J~lOHz~, 4.53(1H, dt, 3-13,8Hz), 3.26(3H, s), 2.90-3.10~2H, m~, 2.70-2.90(lH, m), 2.35tlH, dd, J=15,6Hz), 2.18(1H, dd, J-15,8Hz), 2.15(3H, s), 1.40-1.80(2H, m), 1.10-1.35(1H, m), 0.90(3X, d, J-7Hz), 0.85t3H, d, J=7Hz) WO94/21612 ~ l 3 ~ 1 0 8 PCT/J~4/00434 Exampl~ 80 Preparation of 7-chloro-3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-l-methoxymethyl-3,4-dihydrocarbostyril After conducting a reaction between the compound obtained by hydrazine treatment of the compound of Reference ~xample 74 and a oorresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
NMR(270MHz, DMSO-d6)~ppm:10.38(1H, brs), 8.72(lH, brs), 8.32(1H, d, J-8Hz), 7.30(1H, d, J-8Hz), 7.28(1H, d, J-2Hz), 7.13(1H, dd, J=2,8Hz), 5.47(1~, d, J-llHz), 5.06(1H, d, J~llHz), 4.55(lH, dtr J-11,8Hz), 3.26(3H, s), 2.98(1H, d, J~llHz), 2.97(1H, d, Js8Hz~, 2.75-2.84(1H, m), 2.17(1H, dd, J~7, 15Hz ), 2 . Ol(lH, dd, J-8,15Hz), 1.51-1.59(lH, m), 1.43-1.53(1H, m), 1.02-1.12(1H, m), 0.87(6H, dd, J-6,13Hz) Example 81 Preparation of l~tert-butoxyethyl-3S-t4-(N-hydroxy-amino),-2R-isobutylsuccinyl]amino-3,4-dihydrocarbostyril After conducting a reaction be~ween the compound obtained by catalytic reduction treatment of the compound of Reference Example 75 and a corresponding starting material, WO94t21612 PCT/P~4/00434 t 3 ~ - 182- ! .
the captioned compound was obtained in the same manner as in Example 1.
NMR(270MHz, DMSO-d6)~ppm:10.37tlH, brs), 8.70(1H, brs~, 8.20(1H, d, J-8Hz), 7.22-7.31(3H, m), 6.99-7.05(1H, m), 4.43(1H, dt, J~11,8Hz), 4.04(1H, dt, J=14,6Hz), 3.85(1H, dt, J=14,7Hz), 3.45-8.50(1H, m), 2.92(1H, d, J-llHz), 2.91(1H, d, J=8Hz), 2~76-2.82(1H, m), 2.18(1H, dd, J=7,15Hz), 2.01(1H, dd, J~8,15Hz), 1~59-l.67tlH~ m), 1.45-1.54(1H, m), 1.06-1.13(1H, I m), 1.06(9H, s~, 0.87(6H, dd, J=7,14Hz) Example 82 Prepara~ion of 3S-t4-~N-hydroxyamino)-2R-isobutyl-succinyl~amino-1-methoxyethyl-3,4-dihydrocarbostyril After conduct~ng a reactlon between the compound obtained by trifluoroacetic acid treatmant of the compound of Rererence Example 76 and a corresponding starting material, the ca~tioned compound wa obtalned ln the same manner as in Example 1.
NMR(270MHz, DMSO-d6)~ppm:10.37(1H, brs), 8.71(1H, brs), 8.23(1H, d, J-8Hz), 7.23-7.31(3H, m), 7.00-7.06(1H, m), 4.45(1H, dt, J-11,8Hz), 4.01-4.11(2H, m), 3.45-3.54(2H, m), 3.23(3H, s), 2.92(1H, d, J=llHz), 2.91(1H, d, J-8Hz), 2.75-W094121612 ~ ~ 6 ~ ~ ~ PCTIJ~4100434 -1~3-2.79(lH, m), 2.17(lH, dd, J=7,14Hz), 2.01~1H, dd, J=8,14Hz), 1.62-1.66(1H, m), 1.43-1.54(1H, m), 1.08-1,15~1H, m), 0.87(6H, dd, J=7,14Hz) Example 83 Preparation of 3R-~4-(N-hydroxyamino)-2R-isobutyl-succinylJamino-1-methoxymethyl-3,4-dihydrocarbostyril After conductlng a reaction between the compound obtain2d by catalytic reduction treatment of the compound of Reference Example 77 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
NMR(270MHz, DMS0-d6~6ppm:10.40(1H, brs), 8.74(lH, brs), 8.39(1H, d, J-8H2), 7.22-7.31(3H, m), 7.00-7.05(1H, m), 4.43(1H, dt, J-8,11Hz~, 4.02-4.12(2H, m3, 3.49-3.53(2H, m), 3.24(3H, s), 2.91tlH~ d, J-8Hz), 2.90(lH, d, J-llHz), 2.83-2.88tlH, m), 2~11(1H, dd, J-5,14Hæ), 2.01(1H, dd, Js9,14Hz), 2~ 1.44-1.47(2H, ~), 1.05-1.07(1H, m), 0.84t6H, ~d, J=6,2Hz) .
.
Example 84 Preparation of 3S-t4~(N-hydroxyamino)-2R-ethoxye~hyl-succinyl]amlno-1-methoxy-3,4-dihydrocarbostyril W094/21612 PCT/J~4/00434 3 6 1 0~ -184-Transforming 4-ethoxypropionic acid ~Vlado Prelog, Ber. 72B, 1103 6 (1939)] into 4-ethoxypropionyl chloride by using oxalyl chloride, and af~er allowing to react with a corresponding starting material, the captioned compound was obtained in the same manner as in Example 78.
MMR(270MHz, DMSO-d6)~ppm:10.39~1H, brs), 8.71(lH, s), 8.30(lH, d, J=8Hz~, 7.32(2H, dd, J316,8Hz), 7.16(lH, d, J=8Hz), 7.08(1H, t, J-8Hz), 4.61(1H, dt, J~12,8Hz), 3.82(3H, s), 3.41(2H, q, J-8Hz), 3.25-3.50(2H, m), 2.90-3.10(2H, m), 2.70-2.90(1H, m), 2.23(1H, dd, J-15,7Hz), 1.50-1.80(2H, m), 1.11(3H, t, J-7Hz) Example 85 Preparation of 3R-t4-(N-hydroxyamino)-2R-is~butyl-succinyl]am~no-l-methoxymethyl-3,4-dihydrocarbostyril After conducting a reactlon between a corresponding ~tarting material and using a compound obtained by the method of J. Med. Chem. 1972, 15, 325, the capt~oned compound was obtained in the same manner as in Example 27.
NMR(270MHz, DMSO-d6)~ppm:10.41(1H, s), 8.75(1H, s), 8.44(2H, d, J~8Hz), 7.2o-7.35t3H~ m), 7.06(1H, t, J-7Hz), 5.50(1H, d, J-lOHz), 5.01(1H, d, J~lOHz), 4.51(1H, dt, J=lZ,8Hz), 3.26(3H, W094/21S12 PCT/~4l00434 ~1361~8 s), 2.75-3.10(3H, m), 2.22(1H, dd, J=15.5Hz), 2.02(1H, dd, J=15.~Hz), 1.40-1.60(1H, m), 0.95-1.35(2H, m), 0.85(~H, t, J=SHz) Example 86 Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutyl-3S-acetylthiomethylsuccinyl]amino-1-methoxy-3,4-dihydrocarbostyril Using a correspond~ng starting material, the captioned i compound was o~tained in the same manner as in Example 4.
.
; NMR(270MHz, DMS0-d6)~ppm:10.61(lH, s), 8.91(lH, s), 8.67(lH, d, J;-8Hz), 7-34tlH, t, J-8~z), 7.27(lH, d, J-8Hz), 7.17(1~, d, 5~ J-~8Hz), 7.07(lH, t, J~7Hz), 4.67(lH, dt, J=12,8Hz), 3.83~3H, s~, 2,80-3~15(4H, m), 2.25-2.65(1H, m), 2.20-2.40(1H, m), 2.30(3H, s), 1.50-1.70(1H, m), 1.51(1H, t, J~llHz), 0.~3~1H, t, J~llHz), 0.86(3H, d, J-7Hz), 0.82(3H, d, J-7Hz) ~, , 20~-Example 87 Preparation o~ 3S-t4-~N-hydroxyamino)-2R-isobutyl 3S-~ mercaptomethylsuccinyl]amino-l-methoxy-3,4-dihydrocarbostyril -~ Using a corresponding starting material, the captioned ~ -25 compound was obtained in the same manner as in Example 5.
,~' ,~
~ . .
,, ,., W094/21612 PCT/J~4100434 ~2 ~ a s ~ -186-NMR(270MHz, DMSO-d6)~ppm:8.62(1H, d, J=8Hz), 7.32(2H, dd, J=14.7Hz), 7.15(1H, d, J=8Hz), 7.07~1H, t, J-7Hz), 4.58(1H, dt, J=14,7~z), 3.B2(3H, s), 3.10(lH, t, J=15Hz), 2.98(lH, dd, J=15,7Hz), 2.40-1.65(3H, m), 2.20-2.40(1H, m), 1.45-1.70(1H, S m), 1.50(1H, t, J=12Hz), 0.94(1H, t, J=12Hz~, 0.86(3H, d, J-7Hz), 0.82(3H, d, J-7Hz) Example 88 Preparation of 3S-t4-(N-hydroxyamino)-2R-isobutyl-3-(4-methoxycarbonylbenzyl)succinyl~amlno-1-methoxy-3,4-dihydrocarbostyrll After ~onducting a react~on between the compound of Reference Example 78 and a correspondi~g starting material, lS the captioned compound was obtained in the same manner as in - ~ Example 14.
' NMR(270MHz, DMSO-d6)~ppm:10.29(1H, s), 8.70(1H, d, J-8Hz), : 8.66(1H, s), 7.85(2H, d, J-8Hz), 7.36-7.27(2H, m), 7.22(2H, d, J-8Hz), ~.16(1H, d, J~7Hz3, 7.05(1H, t, J37Hz), 4.66-4.61(1H, m), 3.84(6H, s), 3.14(1H, t, J~lSHz), 2.99(1H, dd, J1~7Hz, ~, J2-16Hz), 2. 81-2. 78( 2H, m), 2.60-2.57(lH, m), 2. 46-2.40(1`H, m), 1.62-1.48(2H, m), 1.01-0.97(1H, m), 0.87(6H, dd, Jl-6Hz, J2-16HZ ) -S,-~&
Example 89 Preparation of 3S-[3-hexyl-4-(N-h~droxyamino)-2R-isobutylsuccinyl]amino-l-methoxy-3,4-dihydrocarbostyril After conducting a reaction between the compound of Reference Example 79 and a corre~ponding starting material, the captioned compound was obtained in the same manner as in Example 14.
NMR(270MHz, DMSO-~6)~ppm:10.48~lH, s), 8.77~1H, s), 8.53(lH, d, J-8Hz), 7.34(1~, t, J-8Hz), 7.28~1H, d, J-7Hz), 7.16(1H, d, ~;~ J-8Hz), 7.06(1H, t, J-8Hz), 4.66-4.61(1H, m), 3.83(3H, s), 2.99(1~, t, J313Hz), 2.90(1H, dd, ~1~9Hz, J2-12~z), 2.51-2.4211H, m), 2.09-2.05(1H, m), 1.57-1.41(2H, m), 1.22-1.05(10H, m), 0.95-0.80(10H, m) .
' Example 90 ~: Preparation of 3S-~4-(N-hydroxyamino)-2R-butyl-3S-m~thylsuccinyl]amino-1-methoxy-3,4-dihydrocarbostyril Ater conducting a reaction between the compound of ,~. Reference Example 80 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 62.
WO 94t21612 PCT/~P94/00434 .3~
NMR( 270MHz, DMSO-d6 ) ~ppm: 10 . 49 ( lH, s ), 8 . 76 ( lH, s ), 8 . a2 ( lH, d, J=8Hz), 7.32(2H, dd, JD16,8HZ), 7.16(1H, d, J=8HZ), 7.07(lH, t, J=8Hz), 4.62(lH, dt, J=14,7Hz), 3.83(3H, s), 2.30-2 . 50 ( lH , m ) , 2 . 10- 2 . 30 ( lH , m ) , 1 . 00 - 1 . 50 ( 6H , m ) , 0 . 9 5 ( 3H , d , J=7Hz ), 0 . 85( 3H, t, J=7Hz ) Example 9 1 Preparation of 3S-~4-(N-hydroxyamino)-2R-butyl-succinyl]amino-1-methoxy-3,4-dihydrocarbostyril After conducting a reaction between the compound of Ref rence Example 80 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
NMR(270MHz, DMS0-d6)~ppm:10.38~lH, s), 8.70(lH, s), 8.31(lH, d, J~7Hz), 7.32(2H, dd, J-16,8Hz), 7.16(1H, d, J-8Hz), 7.07(1H, t, J-8Hz), 4.61(1H, dt, J-13,8Hz), 3.82~3H, s), 2.80-3.10(2H, m), 2.55-2.80(lH, m), 2.20~lH, dd, J-14,7Hz), 2.03(1H, dd, J-14,8Hz), 1.10-1.60(6H, m), 0.87(3H, t, J-7Hz) Example 92 Preparat~on of 3S-~4-(N-hydroxyamino)-2R-isobutyl-3-(3,4-methylenedioxybenzyl)succinyl]amino-1-methoxy-3,4-WO94/21612 . PCTIJ~4/00434 dihydrocarbostyril After conducting a reaction between the compound of Reference Example 81 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 14.
NMR(270MHz, DMSO-d6)~ppm:10.28(1H, s), 8.68(1H, s), 8.65(1H, d, JD8Hz), 7.36-7.27t2H, m), 7.16(1H, d, J=7Hz), 7.05(1H, dt, Jl-lHz, J2-7Hz), 6.77(1~, d, J-8Hz), 6.60(lH, d, J-2Hz), 6.52(1H, dd, J1~2Hz, J2~8Hz~, S.95(2H, s), 4.66-4~61(1H, m), 3.84(3H, s), 3.12(lH, t, J-lSHz), 2.98(1H, dd, J~-7Hz, J2-16HZ), 2.66-2.49(3H, m), 2.38-2.32(1H, m), 1.60-1.46(2H, m), 0.99-0.95(1H, m), 0.86(6H, dd, Jl-6Hz, J2=lSHz) ~15 Example 93 ~reparation of 3S-~3-(3-ethoxycarbonylpropyl)-4-(N-hydroxyamlno)-2R-~sobutylsuccinyl3amino-1-methoxy-3,4-dihydrocarbostyr'l After conductln~ a re~ctlon between the compound of Reference Example 82 and a corre~pondlng starting material, ; the capt1oned compound was obtained ln the same manner as in Example 14 NMR(270MHz, DMSO-d6)~ppm:10.53(1H, s), 8.83(1H, s), 8.54(1H, WO94/21612 PCT/3~4/0~34 ~ ~ 1 3 6 1 ~ ~
--190-- ! ~
d, J=8Hz), 7. 4(1H,t, J=8Hz), 7.~8(1H, d, J=8Hz), 7.16(1H, d, J=8Hz), 7.07(1H, t, J=8Hz), 4.69-4.59(1H, m), 4.05~2H, q, J=7Hz), 3.83(3H, s), 3.08-2.93(2H, m), 2.51~2.43tlH, m), 2.32-2.22(2H, m), 2.10-2.06(1H, m~, 1.56-1.31(6H, m), 1.18(3H, t, J 7Hz) 0 95-0 80~7H, m), 0.84(6H, dd, Jl=6~z, J2=12Hz) Example 94 Prepara~ion of 1-ethoxymethyl-35-~4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-3,4-dihydrocarbostyril After conducting a reaction between the compound obtained by catalytic reduct$on treatment of the compound of Reference Example 83 and a corresponding starting material, the captloned compound was obtained in the same manner as in Example 1.
NMR(270MHz, DMSO-d6)~ppm:10~39(1H, s), 8.72(1H, s), 8.28(1H, d, J-8Hz), 7.20-7.35(3H, m), 7006(1H, t, J=7Hz), 5.54(1H, d, J-lOHz), 5~00(lH, d, J~lOHz), 4.50(lH, dt, J-14,7Hz~, 3.51(2H, q, J~7Hz), 2.70-3.10(3H, m), 2.15(1H, dd, J=14,7Hz), 2.01(1H, dd, J-14,7Hz), 1.40-1.80(2H, m), 1.10(3H, t, J~7Hz), 1.00-1.20(1H, m), O.90t3H~ d, J~7Hz), 0.85(3H, d, J-7Hz) W094121612 ~ ~ 3~ 10 8 PCT/JW4/00434 Example 95 ;
Preparation of 3S-[4-(N-hydroxyamino~-2S-butoxymethylsuccinyl]amino-1-methoxy-3,4-dihydrocarbostyril After conducting a reaction between the compound of Reference Example 85 and a corresponding starting material, ~he captioned campound was obtained in the same manner as in Example 1.
NMRt270MHz, DMS0-d6)~ppm:10.37(lH, s), 8.69(1H, s), 8.34(lH, d, J-8Hz), 7.34(1H, t, J~8Hz), 7.28(1H, d, J 8Hz), 7.16(1H, d, J-8Hz), 7.08(1H, t, J-8Hz), 4.58(1H, dt, J~12.8Hz), 3.83(3H, s), 3.30-3.60(4H, m), 2.90-3.10(3H, m), Z,27(1H, dd, J~15.8Hz), 2.11(1H, dd, J-15.~Hz), 1.20-1.60(4H, m), 0.88(3H, t, J~7Hz) Example 96 .
Preparation of 3S-~4-(N-hydroxyamino)-2-isobutyl-3-methyl-thiomethylsuccinyl~amino-3,~-dlhydrocarbostyri~
Using the compound of Reference Example 87 and a corresponding starting materiai, the captioned compound was obtaimed in the same as in Example 4.
NMR(270MHz, DMSO-d6)~ppm:10.61(1H, s), lO.l9(1H, s), 8.87(1H, s), 8.45(1H, d, J~8Hz), 7.18(2H, dd, J-16,8Hz), 6.90(2H, dd, WO94/21612 PCT/J~4/00434 __ 610~
-192- ~
J=16,8Hz), 4.41(1H, dt, J=14.7Hz), 2.80-3.30(3H, m), 2,25-2.70(3H, m), 2.00(3H, s), 1.30-1.70(2H, m), 0.80-l.lO(lH, m), 0.86(3H, d, J=7Hz), 0.82(3H, d, J-7Hz) Example 97 Preparation of ~S-t4-(N-hydroxyamino)-2R-isobutyl-3S-(2-thienylthiomethyl)succinyl]amino-1-methoxy-3,4-dlhydrocarbostyril A~ter conducting a reaction of a corresponding starting material, the captioned compound was obtained in the same manner as in Example 4.
NMR(270MHz, DMS0-d6)~ppm:10.70(1H, s), 8.96(1H, s), 8.64(1H, d, J-8Hz), 7.60(1H, dd, J~5.1Hz), 7.33(1H, t, J38Hz), 7.99-7.30(5H, m), 4.54(1H, dt, J~14,7Hz), 3.81t3H, s); 2.80-3.20(5H, m), 2.30-2.50(1H, m), 1.40-1.6S~2H, m), 0.80-l.OO(lH, m), 0.84(3H, d, J~6Hz), 0.81(3H, d, J-6~z) Example 98 I Preparation of 3S-~4-(N-hydroxyamino)-2S-butoxymethyl-3S-methylsucc~.nyl3amino-3,4-dihydrocarbostyril Using a correspond~ng starting material, the captioned ~5 compound was obtained in the same manner as in Example 62.
WO94/21612 PCT/J~4/00434 NMR(270MHz, DMS0-d6)~ppm:10.48(lH, s), 10.26(lH, s), 8.77(lH, s), 8.35(1H, d, J=7Hz), 7.16(2H, t, J=8Hz), 6.93(1H, d, J=8Hz), 6.87(lH, d, J=8HZ), 4.40( lH, dt, J=12,7Hz), 3.10-3.50(4H, m), 2.80-3.10(2H, m), 2.74(1H, dt, J=4,10Hz), 2.10-2.30~1H, m), 1.20-1.50(4H, m), 0.98(3H, d, J=7Hz), 0.8$(3H, t, J-7Hz) Example 99 Preparation of 1-ethoxyethoxy-3S-t4-(N-hydroxyamino)-2R-isobuty}succinyl]amino-3,4-dihydrocarbostyril After conducting a reaction between the compound of Reference Example 88 and a corresponding s~arting material, the captioned compound was obtained in the same manner as in Example 1.
NMR(270MHZ, DMS0-d6)~ppm:10.38(1H, s), 8.72(1H, S), 8.36(1H, D,.J-8Hz), 7.32(2H, d, J~3Hz), 7.27tlH, d, J-7Hz), 7.00-7.10(1H, m), 4.60(1H, dt, J~13.7Hz), 4.15(1H, t, J-4Hz), 3.63(2H, dd, J-7.4Hz), 3.44(2H, g, J-7Hz), 2.~5-3.10(2H, m), ; 2.~5-2.85 ~lH, m), 2.17(1H, dd, J~14,7Hz), 2.01(1H, dd, J-14,8Hz), 1.40-1.75 (2H, m), 1.00-1.20(1H, m), 1.1~3H, t, J-7Hz), 0.89(3H, d, J-6Hz), 0.84(3H, d, J-6Hz) WO94/21612 PCTIJ~4/00434 ~:136108 Example 100 Preparation of l-ethoxy-3R-[4-(N-hydroxyamino)-2R
isobutylsuccinyl]amino-3,4-dihydrocarbostyril Using a corresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
NMR(270MHz, CDC13)8ppm:10.42(1H, s), 8.76(1H, s), 8.51(1H, d, J-8Hz~, 7.31(2H, dd, J-16,8Hz)~ 7.16(1H, d, J=8~z), 7.06(1H, t, J~8Hz), 4.56(1H, q, J-9Hz), 4.05(2H, q~ J-7Hz), 2.90-3.10(2H, m), 2.70-2.95(1H, m), 2.20(1H, dd, J=14,5Hz), 2.02(1H, dd, J-14,9Hz), 1.35-1.60(2H, m), 1.28t3H, t, J=7Hz), ~.95-1~20(1H, m), 0.85(3H, s), 0.83(3H, s) Example 101 Preparation of 3S-4~-(N-hydroxyamino)-2R-isobutylsucc~nyl~amino-1-methoxymethoxyethoxy-3,4-dihydrocarbostyril After conducting a reaction between the compound of Re~erence Example 89 and a correspondlng starting material, the captioned compound was obtained in the same manner as in Example 1.
MMR(270MHz, DMS0-d6)~ppm:10.38(lH, s), 8.70(lH, brs), 8.37tlH, WO94/21612 ~ 8 PCT/J~4/~0434 d, J=&Hz), 7.20-7.40~3H, m), 7.06(1H, td,J=7.2~z), 4.~2(2H, s), 4.50-4~70(1H, m), 4.15-4.25(2H, m~, 3.60-3.80(2H, m), 3.28(3H, s), 2.85-3.15(2H, m), 2.70-2.90(1H, m), 2.17(1H, dd, J=14.6Hz), 2.01(1H, dd, J=14.8Hz), 1.40-1.75(2H, m), 0.95-1.20(1H, m), 0.89(3H, d, J=6Hz), 0.85(3H, d, J=6Hz) Example 102 Preparatlon of 3S-~4-(N-hydroxyamino)-2R-lsobutylsuccinyl] amino-l, 7-dimethoxy-3,4-dihydrocarbostyril After conducting a reaction between the compound of Reference Example 90 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
NMR(270MHz, DMSO-d6)~ppm:10.39(1H, ~), 8.73(1H, s), 8.36(1H, d, J~8Hz), 7.19(1H, d, J~8Hz), 6.60-6.70(2H, m), 4.57(1H, q, J~lOHz), 3.82(3H, s), 3.77(3H, s), 2.89(2H, d, J=9Hæ), 2.70-2.90~1H,.m), 2.16(1H, dd, J-14,7Hz), 2.01(1H, dd, J=14,8Hz), 1.40-1.75(2H, m~, 1.00-1.20(1H, m), 0.89(3H, d, J-6Hz), 0.85(3H, d, J-6Hz) Example 103 W094/21612 PCT/J~4100434 ~ 13~10~ -196- I
Preparation of l-ethoxy-3S-t4-~N-hydroxyamino)-2R-iso~utylsuccinyl]amino-7-methoxy-3,4-dihydrocarbostyril After the compound of Reference Example 91 was allowed to react with a corresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
NMR(270MHZ, DMSO-d6)~ppm:10.37(1H, s), 8.71~1H, s), 8.32(1H, d, J~SHz), 7.19(1H, d, Js8Hz), 6.55-6.70~2H, m), 4.54(1H, q, J-lOHZ), 4.04(2H, ~, Js7~z)~ 3.77~3H, s), 2.70-3.99(3H, m), 0 2.16(1H, dd, J-14,7Hz), 2.01(1H, dd, J-14.8Hz), 1.35-1.70(2H, m), 1.28(3H, t, J-7Hz), 1.00-1.20($H, m), 0.89(3H, d, J=7Hz), 0.8S(3H, d, J~7Hz) - Example 104 ~reparat~on of 3S-~4-(N-hydroxyamino)-2R-isobutylsuccinyl]amlno-l-methoxyethyl-6,7-methylenedioxy-3,4-dihydrocarbostyril After conducting a reaction between the compound ; obtalned by treating the compound of Reference Example 92 with trifluoroac~t~c acid and a corresponding starting material, : the reaction was carr~ed out ~n the same manner as in Example and ! the reaction product was purified by high-performance liquid chromatography.
;: 25 NMR(270MHz, DMS0-d6)~ppm:10.37(1H, s), 8.71(1H, s), 8.17(1H, , WO94/21612 ~ 3 ~ PCT/J~4/00434 -197- , d, J=8Hz), 6.98(1H, s), 6.87(1H, s), 5.99(2H, s), 4.~0-4.37(1H, m), 4.00(2H, t, J=6Hz), 3.48(2H, t, J=6Hz), 3.23(3H, s), 2.80-2.75(3H, m), 2.17(1H, dd, J1=7Hz, J~=15Hz), 2.00(1H, dd, J1=8Hz, J2=14Hz), 1.63-1.61(1H, m), 1.47-1.44(1H, m), 1.12-1.06(1H, m), 0.87(6H, dd, J1=6Hz, J2=14Hz) Example 105 0 Preparatlon Of 3R-~4-(N-hydroxyamino)-2R-isobutylsuccinyl]am~no-l-methoxyethyl-6,7-methylenedioxy-3,4-dihydrocarbostyril After conducting a reaction between the compound obtained by treating the compound Of Reference Example 92 with trifl~sroacetic acid and a corresponding starting material, the reactlon was carried out in the same manner as in Example 1, and the reaction product was puri~led by high-performance li~uld chromatography.
NMR(270MHz, DMSO-d6)~ppm:10.40(1H, s), 8.74tlH~ s), 8.35(1H, d, J-8~z3, 6.98(1H, s), 6.88(1H, s), 5.99(2H, s), 4.40-4.32~1H, m), 4.01(2H, t, J-5Hz), 3.48(2H, t, J-5Hz), 3.23(3H, s), 2.83-2.75(3H, m), 2.20(1H, dd, J1~5Hz, 2-15Hz), 2.01(1H, dd, Jl-9Hz, J2-14Hz), 1.50-1~43(2H, m), 1.09-1.05(1H, m), 0.83(6H, dd, Jl,3Hz, J2~5Hz) WO94/21~12 PCT/J~4/00434 ~1361~8 -198- ' Example 106 Preparation of 3s-[4-(N-benzoyloxyamino)-2R-isobu~ylsuccinyl]amino-1-methoxyethoxymethyl-3, 4-dihydrocarbostyril Using a corresponding starting material, the cap~ioned compound was obtained in the same manner as in Example 8.
NMR(270MHz, DMSO-d6~ppm:11.95(lH, ~s), 8.35(lH, d, J=8Hz), 8.03(2H, d, J-7~z), 7.76(1H, t, J~7Hz), 7.60(2H, t, J=8Hz), 7.30-7.25(3H, m), 7.07(1H, dt, J1~2~z, J2=8Hz), 5.57tlH, d, J~llHz), 5.03(1H, d, J~llHz), 4.59-4.49(1H, m), 3.60(2H, dd, Jl-4Hz, J2-6Hz), 3.g4(2H, dd, Jl-4Hz, J2-6Hz), :
~ 15 3.22(3H, s~, 3.01-2.93(2H, m), 2.87-2.82(1H, m), 2.44(1H, dd, :~ Jl-7Nz, J2~15Hz), 2.27(1H, dd, Jl-7Hz, J2-lSHz), 1.71-1.53(2H ,m) 1.27-1.21(1H, m), 0.90(6H, dd, Jl=6Hz, J2-13HZ ) ~:20 Example 107 j Preparatlon of 3S-~4-(N-benzoyloxyamino)-2R-' isobutylsuccinyl]amino-l-methoxymethyl-3,4-dihydrocarbostyril ~:~ Using a corresponding starting material, the captioned :~ compound was obtained ln the same manner as in Example 8.
W094/21612 ~ PCTIJ~4/~34 NMR(270MHz, DMSO-d6)~ppm:11.95(1H, bs), 8.36(1H, d, J=8Hz), 8.03(2H, d, J=7Hz), 7.76(1H, t, J=7Hz~, 7.60(2H, t, J=8Hz), 7.32-7.22(3H, m), 7.07(1H, t, J=7Hz), 5.49(1H, d, J=llHz),5.01(1H, d, J=lOHz), 4.58-4.50(1H, m), 3.27(3H, s), 3.02-2.94(2H, m), 2.87-2.82(1H, m), 2.44(1H, dd, J1=7Hz, J2=lSHz)~ 2.27(lH, dd, J1=7Hz, J2=15Hz), 1.69-1.53(2H, m), $.27-1.17(1H, m), 0.902(6H, dd, Jl-6Hz, P2=13Hz) Example 108 Preparation of 3S-~4-(N-hydroxyamino)-2R-lsobutylsuccinyl~amino-6,7-dimethoxy-1-meth~xymethyl-3,4-dihydrocarbostyril After conducting a reaction between the compound of Reference Example 93 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
NM~(270M~z, DMSO-d6)~ppm:10.38(lH, s), 8.71~1H, s), 8.25(1H, d, J-8Hz), 6.91tlH, s), 6.86(1H, s), 5.48(1H, d, J-lOHz), 5.01(1H, d, J-lOHz), 4.48(1H, dt, J-11,8Hz), 3.75(3H, s), 3.74(3H, s), 3.26(3H, s), 2.80-2.91(3H, m),2.18~1H, dd, J~7,8Hz), 2.02(1H, dd, J-7,8Hz), 1.60-1.67(1H, m), 1.43-1.54(1H, m), 1.03-1.13(1H, m), 0.87(6H, dd, J=14,7Hz) WO94/21612 PCT/J~4100434 ~13~108 -200- !
Example 109 Preparation of 3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-6,7-dimethoxy 3,4-dihydrocarbostyril After conducting a reaction between the compound of Reference Example 94 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
NMR(~70MHz, DMso-d6)~ppm:lo.38tlH~ s), 9.97(1H, s), 8.74(1H, s), 8.12(1H, d, J-8Hz), 6.83(1H, s), 6.53(1H, s), 4.41(1H, dt, J-11,8Hz), 3.70(6H, s), 2.76-2.89(3H, m), 2.17(1H, dd, J-8,7Hz), 2.01(1H, dd, J~8,7Hz), 1.57-1.6S~lH, m), 1.42-~ l5 1.~2(1H, m), 1.03-1.13(1H, m~, 0.86t6H~ dd, Jal4,7Hz) : : Example llO
;~ Preparation of 3S-t4-(N-hydroxyamino)-2R-lsobutyls.uccinyl~amino-~-methoxY-l-methoxyethyl-3,4-dlhydrocar~ostyril After conducting a reaction between the compoundlof Reference Example 9S and a corresponding starting material, : ~ the captioned compound was obtained in the same manner as in ~5 Example 1.
; :
~ ' .
WO94/2l612 ~,~ 3 ~1 Q ~ PCT/J~4/00434 -201~
NMR(270MHz, DMS0-d6)~ppm:10.35(1H, s), 8.69(1H, s), 8.16(1H, d, J=8Hz), 7.12-7.01(2H, m), 6.88(lH, d, J=7Hz), 4.34-4.21(2H, m), 4.01-3.94(1H, m), 3.84(3H, s), 3.45-3.26(2H, m), 3.11(3H, s), 2.85-2.74(3H, m), 2.16(1H, dd, Jl-7Hz, J2=15Hz), 2.00~1H, dd, J1-8Hz, J2-14Hz), 1.64-1.59(1H, m), 1.52-1.42(1H, m), 1.13-1~03(1H, m), 0.87(6H, dd, J1a6Hz, J2=16Hz) 0 Example 111 Prepar~tion of 3S-[4-(N-benzoyloxyamino)-2~-isobutylsucclnyl]amino-l-methoxy-3,4-dlhydrocarbostyril Uslng a corresponding starting material, the captioned compound was obtained ln th~ same manner as in Example 8.
:
NMR(270MHz, DMS0-d6)~ppm:12.00(lH, brs), 3.46(lH, d, J=8Hz), 8.02t2H, d, J-7Hz), 7.75(lH, t, J-7Hz), 7.60(2H, t, J~7Hz), 7.35~1H, d, J-7Hz), 7.28(1H, d, J~7Hz), 7.16(1H, d, J~7Hz), 7.07(1H, t, J~7Hz), 4.64(1H, q, J~lOHz), 3.83t3H, s), 2.90-3.10(2H, m), 2.70-2.95~1H, m), 2.41(1H, dd, J-15,7Hz), 2.26(1H, dd, J~15,7Hz), 1.40-1.80(2H, m), 1.10-1.35(1H, m), 0.92(l3H, d, J~6Hz), `0.88(3H, d, J~6Hz) , .
Example 112 WO94/21612 PCTIJ~4l00434 ~136~Q8 -202- ~ ~
Preparation of 3-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxyethyl-6,7-methylendioxy-3,4-dihydrocarbostyril After conducting a reaction between the compound obtained by t~eating the compound of Reference Example 92 with trifluoroacetic acid and a corresponding starting material, the captioned compound was obtained (diastereomer, 1:1 mixtùre) in the same manner as in Example 1.
NMR(270MHZ, DMSO-d6)~ppm:10.39+10.36tlH, s), 8.73+8.70(1H, s), 8.35+8.16tlH, d, J-8Hz), 6.98(1H, s), 6.8~+6.86(1H, s), 5.99(2H, s),~4.40-4.35(1H, m), 4.01-4.00(2~, m), 3.48(2H, t, J-6Hz), 3.31~3.23(3H, s), 2.80-2.75(3H, m), 2.24-2.13(1H, m), 2.~05-1.97(1H, m), 1.73-1.40(2H, m), 1.07-1.05(1H, m), 0.91-0.82(6H, m) ~ ' .
Example 113 ~ Preparation of 3s-c4-(N-hydroxyamino)-2R--~ ~20 isobutylsuccinyl]amino-1-methoxyethoxy-3,4-dihydrocarbostyril After conducting a reaction between the compound of Reference Example g6 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
WO9412]612 ~.13 6 ~ ~ 8 PCT/J~4/0~34 -203- !
NMR(270MHz, DMS0-d6)~ppm:10.38(lH, brs), 8.72(lH, ~rs), 8.37(1H, d, J=8Hz), 7.26-7.36(3H, m), 7.06(1H, t, J=7Hz), 4.61(1H, dt, J=11,8Hz), 4.13-4.16(2H, m), 3.60-3.61(2H, m), 3.2~(3H, s), 2.99(1H, d, J=llHz), 2.92(1H, d, J=8Hz), 2~73-2.77(1H, mj, 2.~7(1H, dd, J=14,6Hz), Z.oltlH~ dd, J=14,8Hz), 1.61-1.67(1H, m), 1.43-1.53(1H, m), 1.06-1.15(1H, m), 0.87(6H, dd, J=13,7Hz) Example 114 Preparation of 3S-~4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-l-methoxyethoxymethoxyethoxy-3,4-d~hydrocarbostyril Ater conductlng a r8action between ~he compound of lS Reference Exampl~ 97 and a c~rresponding starting material, the captioned compou~d was obta~ ned ln the same manner as in ~xa~ple 1.
NMR(270MHz, DMS0-d6)~ppm:10.3~(lH, s), 8.72(lH, s), 8.37(lH, d, J-8Hz)^, 7.20-7.40(3H, m), 7.06(1H, td, J=7,2Hz), 4.68t2H, S), 4.50-4.80(1H, m), 4~18(2H~ t~ J-4Hz), 3.76(2H~ m), 3~60(2H~ m), 3.47(2H, m), 3~24t3H~ s)~ 2.85-3~10(2H, m), 2.70-2.85(1H, m), 2.17(1H, dd, Jsl4,7Hz), 2.01(1H, dd, J=lOr8Hz)~
1.35-1.75(2H, m), 1.00-1.20(1H, m), 0.89(3H, d, J=7Hz)~
0 85(3H, d, J-7Hz) WO94/21612 PCT/J~4/00434 ~1.36~ 04_ Example 115 Preparation of 3S-t4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino 1-methoxyethoxyethoxy-3,4-dihydrocarbos~yril After conducting a reaction ~etween the compound of Reference Example 98 and a corresponding starting material, the captioned compound was obtained in the same manner as in Example 1.
NMR(270MHz, DMSQ-d6)~ppm:10.38(1H, s), 8.71(1H, s), 8.35(1H, ~:~ d, J-8Hz), 7.20-7.45(3H, m), 7.06(1H, t, J=7Hz), 4.61(1H, dt, ;~ J~13,8Hz), 4.15t2H~ dd, J-5,3Hz), 3.68(2H, d, J-3Hz), 3.40-~: 15 3.60(4H, m), 3.28(3H, s), 2.85-3.15(2H, m), 2.65-2.85(1H, m), 2.17(1H, dd, J-15,6Hz), 2.01(1H, dd, J~15,8Hz), 1.35-1.75(2H, m~, 0.95-1.20(1~, m), 0.89(3H, d, J-7Hz), 0.85(3H, d, J~7~z) Example t~6 Preparation of 35-~4-~N-hydroxyamino)-2R-hexylsuccinyl]amino-l-methoxy-3,4-dihydrocarbostyril After conducting a reaction of a corresponding start~ ng material t the captioned compound was obtained in the -same manner as in Example 1.
WO94121612 .~ PCT/J~4/00434 -~05-NMR~270MHz, DMS0-d6)~ppm:10.37(lH, s), 8.70(lH, s), 8.32(lH, d, J=8Hz), 7.35(1H, d, J=8Hz), 7.29(1H, d, J=8H~), 7.16(1H, d, J=8Hz), 7.07(1H, t, J=8Hz), 4.61(1H, dt, J=llr8Hz), 3.82(3H, s), 2.85-3.10(2H, m), 2.55-2.80(1H, m), 2.19(1H, dd, J=14,7Hz), 2.02(1H, dd, J=14,8Hz), 1.10-1.60(10H, m), 0.87(3H, t, J=7Hz) PHARMACOLOGICAL STUDIES
Test compounds were as follow:
l. 3S-~4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-3,4-dihydrocarbos~yr~l 2. 3S-~4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-7-methoxy-3,4-dihydrocarbostyril 3. 3S-~4-(N-hydroxyamlno)-2R-isobutylsuccinyl]amino-l-methoxy-3,4-dihydrocarbostyril 4. 3S-~4-(N-hydroxyamino)-2R-lsobutyl-3S-acetyl-thiomethylsucci~yl~amlno-3,4-dihydrocarbostyril 5. 3S-~4-(N-hydroxyamlno)-2R-isobutyl-3S-mercap.tomethylsuccinyl]amino-3,4-dihydrocarbo~tyril 6. 3S-t4-(N-hydroxyamlno)-2R-isobutyl-3S-(2-thlenylthiomethyl~succinyl]amino-3,4-dihydrocarbostyril 7. 3S-t4-(N-hydroxyamino)-2R-isobutyl-3(R or S)-WO94121612 PCT/J~4/00434 Q~
7. 3S-[4-(N-hydroxyamlno)-2R-isobutyl-3(R cr S)-phtnaiimidomethylsuccinyl]amino-3,4-dihydrocarbostyril 8. 1-ethoxycarbonylmethyl-3S-~4-(N-hydroxyamino)-2R-isobutylsuccinyl3amino-3,4-dihydrocarbostyril 9. 35-[4-(N-hydroxyamino)-2R-isobutyl-3S-methyl-succinyl]amino-1-methoxy-3,4-dihydrocarbostyril 10. 1-aminocarbonylmethyl-3S-~4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-3,4-dihydrocarbostyril
11. 3S-~4-(N-hydroxyamino)-2R-isobutylsuccinyl]
amino-1-(4-methoxycarbonylbenzyl)-3,4-dihydrocarbostyril
amino-1-(4-methoxycarbonylbenzyl)-3,4-dihydrocarbostyril
12. 1-ethyl-3S-[4-(N-hydroxyamino)-2R-isobutyl-succinyl~amlno-3,4-dihydrocarbo tyril
13. 1-allyl-3S-t4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]amino-3,4-dihydrocarbostyril
14. 35-~4-(N-hydroxyamino)-2R-isobutylsuccinyl~
amino-l-methoxymethyl-3,4-dihydrocarbostyril
amino-l-methoxymethyl-3,4-dihydrocarbostyril
15. 3S-~4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]amino-1-(2-propynyl)-3,4-dihydrocarbostyrll
16. 1-carboxymethyl-3S-C4-(N-hydroxyamino)-2R-isobutyl-.3S-methylsuccinyl]amino-3~4-dihydrocarbostyril
17. 1-ethoxy-3S-t4-(N-hydroxyamino)-2R-isobutylsuccinyl]amlno-3,4-dihydrocarbostyril
18. 3S-[4-(N-hydroxyamino)-2R-isobutyl-succinyl]amino-1-methoxyethoxymethyl~3,4-dihydrocarbostyril : 25 19. 3S-t4-(N-hydroxyamlno)-2R-lsobutyl-W094/21612 ~ ~ PCT/3~4/00434 succinyl]amlno-l-methoxymethoxyethyl-3~4-diAydrocarbostyril 20. 3S-[4-(N-hydroxyamino)-2R-heptylsuccinyl]amino-l-methoxy-3,4-dihydrocarbostyril 21. 3S-~4-(N-hydroxyamino)-2R-isobutyl-succinyl]amino-l-methoxyethyl-3,4-dihydrocarbostyril 22. 3S-t4-(N-hydroxyamino)-2R-ethaxye~hyl-succinyl~amino-l-methoxy-3,4-dihydrocarbostyril 23. 3S-~4-(N-hydroxyamino)-2R-isobutyl-3-(3,4-methylenedioxybenzyl)succ~nyl]amino-l-methoxy-3,4-dihydrocarbostyril 24. 3S-~4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-l-methoxyethyl-6,7-methylenedioxy-3,4-diAydrocarbostyril 25. 3R-~4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-l-methoxyethyl-6,7-methylenedioxy-3~4-dihydrocarbostyril 26. 3-~4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-l-methoxyethyl-6,7-methylendioxy-3,4-dihydrocarbostyril 2~ :
(l). Measuring method of Stromelysin inhibiting activity Inhibiting of Stromelysin refined from the culture supernatant of mouse colon cancer cell (Colon 26 cell) was ~5 measured by using fluorescence labeled casein, according to i 3 ~ ' -S~
the method proposed by Miyazaki et al. ( J. Biochem., lQ~, 537-543~ l99O), and S. S. Twining LFed. Proc., ~2, 1951 (1984)].
The enzyme was activated by incubating for 2 hours at 37C in 1 mM mercury (II) p~aminophenylacetate. The test compound was used by dissolving in dimethyl sulfoxide. The enzyme reaction was started by adding the activated enzyme in .
a solution of 50 mM TRIS-hydrochloric acid ~pH 7.5), 10 mM
CaC12, and 0.1 % (v/v) dimethyl sulfoxide containins the test compound and 0.25% (wSv) of fluorescence labeled casein as substrate. The reactlon was conducted for 3 hours a~ 37-C, and stopped by adding an equivalent amount of 5% (w/v~
trichloroacetic ac~d solution. Afterwards, by centrifugal '~
~ separation for 15 minutes at 3000 rpm, 4~, the undigested i~.
: substrate was precipitated, and to 1 part by ~olume of the , obtalned supernatant, 4 parts by volume of 0.3M phosphate buffer (pH 8.5) was added, and the fluorescence intensity was measured at 520 nm (Em)/495 nm (Ex), and the decomposition volume was quantitatively determined.
The enzyme lnhlbiting actlvlty was expressed by the concentra-tion (IC50) of the test compound wherein the enzyme act~vity of known amount was inhibited till 50%. The results ~`
- are shown in Table 1.
~5 , w094/t1612 ~ U ~ PCT/J~4/00~34 --;~09-- !
Table 1 .
Test compound Stromelysin IC50(M) . .
1 5.7 x 10-7 2 4.9 x 10-7 3 1.3 x 10-6 4 ~.5 x 1~-7 1.$ x 10-7 6 2.7 x 10-8 7 2.3 x 10-~
8 3.8 x 10-7 0 3.6 x 10-8 2.0 x 1~-7 11 2.9 x 10-7 12 7.0 x 10-7 13 2.8 x 10-8 14 3.7 x 1~-8 (2) Measuring method of interstitial collagenase inhibiting activity Inhibiting of interstitial collagenase refined from tne culture supernatant of human fibroblast cell (Detroit 551 cell) was measured by using fluorescence labeled collagen, according to the method proposed by Nagai et al.
tInflammation, 4 (2), 123 ~1984)].
The enzyme was actlvated by incubating for 3 hours at 25 37~ 1n 1 mM mercury (II) p-aminophenylacetate. The test W~94/21612 ~.1 3 ~ ~ ~ 8 PCT/~4/00434 -210- `
comp~und was used by dissolving in dimethyl sulfoxid~. The enzyme reaction was started by adding the activated enzyme in - 50 mM TRIS-hydrochloric acid ~pH 7.5), 0.2M NaCl, 5 mM CaC12, 0.02 ~ (w/v) Na~3, 2.5 mM acetic acid, and 0.1% (v/v) dimethyl 5 sulfoxide solution containing the test compound and 0.025 (w/v? of fluorescence labeled collagen as substrate. The reaction was conducted for 2 hours at 35C, ànd stopped by `
adding ice-chilled 80 mM 0-phenanthroline, 5Q~ (v/v) ethanol solution by 1/20 amount. To this, moreover, an e~uivalent volume of 50 mM TRIS-hydrochloric acid (pH 7.5), 0.2 M NaCl, 5 mM CaC12, 0.02% (w/v) NaN3 solution was added to incubate :~
further for 1 hour at 35C to degenerate specifically only the digestion product, and the digestion product was extracted by adding 0.17 M TRIS-hydrochloric acid (pH 9.5), 0.67 M NaCl solution including an equivalent amount of 70% (v/v) ethanol, and afterwards, by centrifugal separatlon for 15 minutes at 3000 rpm, 4~, the undigested substrate was precipitated. The fluorescsnce intenslty of the obta~ned supernatant was measured at 520 nm ( Em )/495 nm (Ex~, and the decomposition volume was quant~tat vely determined.
The enzyme inhibitlng actlvlty was expressed by the i~ concentration (ICsO) of the test compound wherein the enzyme aCtivity of known amount was inhibited till S0%. The results are shown in Table 2.
WO 94/21612 r; ~ 3 6 1~ PCT/J~4/00434 Table 2 Test compound Interstitial collagenase IC50(M) 1 2.1 x 10-7 2 4.5 x 10-7 3 6.9 x 10-7 4 2.9 x 10-6 3.6 x 10-7 6 2.~ x 10-9 7 2.5 x 10-12 8 1.6 x 10-7 ~ 2.2 x 10-8 3.1 x 10-8 11 7.5 x 10-7 12 2.9 x 10-7 13 1.0 x 10-8 14 2.2 x 10-~
2.0 x 10-8 16 6.9 x 10-8 17 4.1 x 10-8 18 8.8 x 10-8
(l). Measuring method of Stromelysin inhibiting activity Inhibiting of Stromelysin refined from the culture supernatant of mouse colon cancer cell (Colon 26 cell) was ~5 measured by using fluorescence labeled casein, according to i 3 ~ ' -S~
the method proposed by Miyazaki et al. ( J. Biochem., lQ~, 537-543~ l99O), and S. S. Twining LFed. Proc., ~2, 1951 (1984)].
The enzyme was activated by incubating for 2 hours at 37C in 1 mM mercury (II) p~aminophenylacetate. The test compound was used by dissolving in dimethyl sulfoxide. The enzyme reaction was started by adding the activated enzyme in .
a solution of 50 mM TRIS-hydrochloric acid ~pH 7.5), 10 mM
CaC12, and 0.1 % (v/v) dimethyl sulfoxide containins the test compound and 0.25% (wSv) of fluorescence labeled casein as substrate. The reactlon was conducted for 3 hours a~ 37-C, and stopped by adding an equivalent amount of 5% (w/v~
trichloroacetic ac~d solution. Afterwards, by centrifugal '~
~ separation for 15 minutes at 3000 rpm, 4~, the undigested i~.
: substrate was precipitated, and to 1 part by ~olume of the , obtalned supernatant, 4 parts by volume of 0.3M phosphate buffer (pH 8.5) was added, and the fluorescence intensity was measured at 520 nm (Em)/495 nm (Ex), and the decomposition volume was quantitatively determined.
The enzyme lnhlbiting actlvlty was expressed by the concentra-tion (IC50) of the test compound wherein the enzyme act~vity of known amount was inhibited till 50%. The results ~`
- are shown in Table 1.
~5 , w094/t1612 ~ U ~ PCT/J~4/00~34 --;~09-- !
Table 1 .
Test compound Stromelysin IC50(M) . .
1 5.7 x 10-7 2 4.9 x 10-7 3 1.3 x 10-6 4 ~.5 x 1~-7 1.$ x 10-7 6 2.7 x 10-8 7 2.3 x 10-~
8 3.8 x 10-7 0 3.6 x 10-8 2.0 x 1~-7 11 2.9 x 10-7 12 7.0 x 10-7 13 2.8 x 10-8 14 3.7 x 1~-8 (2) Measuring method of interstitial collagenase inhibiting activity Inhibiting of interstitial collagenase refined from tne culture supernatant of human fibroblast cell (Detroit 551 cell) was measured by using fluorescence labeled collagen, according to the method proposed by Nagai et al.
tInflammation, 4 (2), 123 ~1984)].
The enzyme was actlvated by incubating for 3 hours at 25 37~ 1n 1 mM mercury (II) p-aminophenylacetate. The test W~94/21612 ~.1 3 ~ ~ ~ 8 PCT/~4/00434 -210- `
comp~und was used by dissolving in dimethyl sulfoxid~. The enzyme reaction was started by adding the activated enzyme in - 50 mM TRIS-hydrochloric acid ~pH 7.5), 0.2M NaCl, 5 mM CaC12, 0.02 ~ (w/v) Na~3, 2.5 mM acetic acid, and 0.1% (v/v) dimethyl 5 sulfoxide solution containing the test compound and 0.025 (w/v? of fluorescence labeled collagen as substrate. The reaction was conducted for 2 hours at 35C, ànd stopped by `
adding ice-chilled 80 mM 0-phenanthroline, 5Q~ (v/v) ethanol solution by 1/20 amount. To this, moreover, an e~uivalent volume of 50 mM TRIS-hydrochloric acid (pH 7.5), 0.2 M NaCl, 5 mM CaC12, 0.02% (w/v) NaN3 solution was added to incubate :~
further for 1 hour at 35C to degenerate specifically only the digestion product, and the digestion product was extracted by adding 0.17 M TRIS-hydrochloric acid (pH 9.5), 0.67 M NaCl solution including an equivalent amount of 70% (v/v) ethanol, and afterwards, by centrifugal separatlon for 15 minutes at 3000 rpm, 4~, the undigested substrate was precipitated. The fluorescsnce intenslty of the obta~ned supernatant was measured at 520 nm ( Em )/495 nm (Ex~, and the decomposition volume was quant~tat vely determined.
The enzyme inhibitlng actlvlty was expressed by the i~ concentration (ICsO) of the test compound wherein the enzyme aCtivity of known amount was inhibited till S0%. The results are shown in Table 2.
WO 94/21612 r; ~ 3 6 1~ PCT/J~4/00434 Table 2 Test compound Interstitial collagenase IC50(M) 1 2.1 x 10-7 2 4.5 x 10-7 3 6.9 x 10-7 4 2.9 x 10-6 3.6 x 10-7 6 2.~ x 10-9 7 2.5 x 10-12 8 1.6 x 10-7 ~ 2.2 x 10-8 3.1 x 10-8 11 7.5 x 10-7 12 2.9 x 10-7 13 1.0 x 10-8 14 2.2 x 10-~
2.0 x 10-8 16 6.9 x 10-8 17 4.1 x 10-8 18 8.8 x 10-8
19 1.4 x 10-7 2.2 x 10-7 21 1.1 x 10-7 22 3.7 x 10-6 23 6.4 x 10-24 7.4 x 10-7 4.1 x 10-6 26 1.0 x 10-6 (3) Measuring method of type IV collagenase inhibiting activlty WO94/21612 ~ b ~ 0 8 PCT/J~4/00434 -21~-Inhibiting of type IV collagenase refined ~rom the culture supernatant of human lung fibroblast cell (HT-1080 cell) was measured by using fluorescence labeled gelatin, according to the method proposed by Haris et al. ~Haris, E.D., and Krane, S.M., Biochim. Biophys. Acta., 258, 566~576 (1972)].
The enzyme was activated by incubating for 22 hours at 37C in l mM mercury (II) p-aminophenylacetate. The test compound was used by dissolving in dimethyl sulfoxide. The enzyme reaction was 5tarted by adding the ac~ivated enzyme in 50 mM TRIS-hydrochloric acid (pH 7.5), lO mM CaC12, O.Ol %
(w~v) "Bridge 35" (tradename, available from Wa~o Pure Chemical Industries, Ltd.), 0.1% (~/v) dime~hyl sulfoxide solution containing the test compound and 0.1% (w/v) of fluorescence labeled gelatin as substrate. The reaction was conducted for 6 hours at 37C, and stopped by adding 30~ (w/v) trichloroacetic acid solution by l/2 amount. AXter letting stand at 4C for 30 minutes, by ~entrifugal separation for lO
minutes at lO000 rpm, 4~, the ~ndigested substrate was precipitated~ To l part by volume of ~he obtain~d supernatant, 50 parts by volume of 0.3M phosphate buffer (pH
8.5) was added, and the fluorescence intensity was measured at 520 nm (Em)/495 nm (Ex), and the undigested amount was quantitatively determined.
The enzyme inhi~iting activity was expressed by the WO94/21612 ~ b 1 ~ ~ PCT/J~4/00434 _ ~213- , concentration (ICso) of the test compound wherein the enzyme activity of known amount was blocked till 50%. The results are shown in Table 3.
Table 3 Test compound Type IV
collagenase IC50(M) l 1.7 x lO-6 2 5.l x 10-7 3 5.3 x 10-7 4 l.9 x lO-6 5.4 x lO-7 6 5.8 x lO-8 7 l.8 x lO-8 8 2.3 x 10-7 9 5.6 x lO-9 8.7 x lO-9 ll 5.6 x 10-7 12 3.4 x 10-7 13 4.0 x lO-8 14 3.7 x lO-8 4.6.x lO-8 16 l.7 x 10-7 17 3.4 x 10-7 18 l.9 x lO-6 l9 ~.8 x lO-6 2.0 x lO-8 21 3.4 x 10-7 22 > lO-6 I ~ 23 5.7 x lO-8 :
WO 94/21612 PCTIJ~4/00434 '. tl * ~ 2 1 4 -The following ingredients were blended by ordinary method, and tableted, and 100 tablets containing 50 mg of active ingredient per tablet were obtained.
3S-t4-(N-hydroxyamino)-2R-isobutyl-3S-acetyl-thiomethylsuccinyl]amino-3,4-dihydrocarbostyril ................. 5g Sodium lauryl sulfate .... ~.............................. 0.2g Magnesium stearate ....... ~.............................. 0.2g Crystalline cellulose ........................ ........... 4.6g 3S-~4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-car~oxymethyl-3,4-dihydrocarbostyril...................... lg Polyethylene slycol (molecular weight: 4000)........ 0.3g Sodlum chloride .................................... O.9g Polyoxy ethylene sorb~tan mono oleate .............. 0.4g Sodium metablsulflte ............................... O.lg Methyl paraba~e ..........................~...... 0.18g Propyl parabane ................................ . 0.02g Di~tilled water for ~n~ectlon .................. lO.Oml Whil e stirring parabanes, sodium metabisulfite and sodlum chloride, they are dissolved ln distilled water in about half volume of the specified amount at 80C. ~he obtalned solution was cooled to 40C, and active ingredient WO94121612 ~ 8 PCT/J~4/00434 _ compounds of the invention, and polyethylene glycol and polyoxy ethylene sorbitan mono oleate were dissolved in the solution. Distilled water for injection was added to the solution to adjust to a final volume, and the solution was sterilized and fiLtered through a proper filter paper to sterilize, thereby preparing an injection.
; 20 .
The enzyme was activated by incubating for 22 hours at 37C in l mM mercury (II) p-aminophenylacetate. The test compound was used by dissolving in dimethyl sulfoxide. The enzyme reaction was 5tarted by adding the ac~ivated enzyme in 50 mM TRIS-hydrochloric acid (pH 7.5), lO mM CaC12, O.Ol %
(w~v) "Bridge 35" (tradename, available from Wa~o Pure Chemical Industries, Ltd.), 0.1% (~/v) dime~hyl sulfoxide solution containing the test compound and 0.1% (w/v) of fluorescence labeled gelatin as substrate. The reaction was conducted for 6 hours at 37C, and stopped by adding 30~ (w/v) trichloroacetic acid solution by l/2 amount. AXter letting stand at 4C for 30 minutes, by ~entrifugal separation for lO
minutes at lO000 rpm, 4~, the ~ndigested substrate was precipitated~ To l part by volume of ~he obtain~d supernatant, 50 parts by volume of 0.3M phosphate buffer (pH
8.5) was added, and the fluorescence intensity was measured at 520 nm (Em)/495 nm (Ex), and the undigested amount was quantitatively determined.
The enzyme inhi~iting activity was expressed by the WO94/21612 ~ b 1 ~ ~ PCT/J~4/00434 _ ~213- , concentration (ICso) of the test compound wherein the enzyme activity of known amount was blocked till 50%. The results are shown in Table 3.
Table 3 Test compound Type IV
collagenase IC50(M) l 1.7 x lO-6 2 5.l x 10-7 3 5.3 x 10-7 4 l.9 x lO-6 5.4 x lO-7 6 5.8 x lO-8 7 l.8 x lO-8 8 2.3 x 10-7 9 5.6 x lO-9 8.7 x lO-9 ll 5.6 x 10-7 12 3.4 x 10-7 13 4.0 x lO-8 14 3.7 x lO-8 4.6.x lO-8 16 l.7 x 10-7 17 3.4 x 10-7 18 l.9 x lO-6 l9 ~.8 x lO-6 2.0 x lO-8 21 3.4 x 10-7 22 > lO-6 I ~ 23 5.7 x lO-8 :
WO 94/21612 PCTIJ~4/00434 '. tl * ~ 2 1 4 -The following ingredients were blended by ordinary method, and tableted, and 100 tablets containing 50 mg of active ingredient per tablet were obtained.
3S-t4-(N-hydroxyamino)-2R-isobutyl-3S-acetyl-thiomethylsuccinyl]amino-3,4-dihydrocarbostyril ................. 5g Sodium lauryl sulfate .... ~.............................. 0.2g Magnesium stearate ....... ~.............................. 0.2g Crystalline cellulose ........................ ........... 4.6g 3S-~4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-car~oxymethyl-3,4-dihydrocarbostyril...................... lg Polyethylene slycol (molecular weight: 4000)........ 0.3g Sodlum chloride .................................... O.9g Polyoxy ethylene sorb~tan mono oleate .............. 0.4g Sodium metablsulflte ............................... O.lg Methyl paraba~e ..........................~...... 0.18g Propyl parabane ................................ . 0.02g Di~tilled water for ~n~ectlon .................. lO.Oml Whil e stirring parabanes, sodium metabisulfite and sodlum chloride, they are dissolved ln distilled water in about half volume of the specified amount at 80C. ~he obtalned solution was cooled to 40C, and active ingredient WO94121612 ~ 8 PCT/J~4/00434 _ compounds of the invention, and polyethylene glycol and polyoxy ethylene sorbitan mono oleate were dissolved in the solution. Distilled water for injection was added to the solution to adjust to a final volume, and the solution was sterilized and fiLtered through a proper filter paper to sterilize, thereby preparing an injection.
; 20 .
Claims (23)
1. A carbostyril derivative of the formula (1):
(1) [where R1 is a hydrogen atom or a group -A-R1a (where A is a lower alkylene group, and R1a is a hydrogen atom, an amino group, a phthalimido group, a thienylthio group, a lower alkanoylthio group, a mercapto group, a phenyl group which may possess one to three groups selected from the group consisting of a halogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group and a lower alkylenedioxy group as substituent, a carboxy group, a lower alkoxycarbonyl group, phenylthio group, or a lower alkylthio group);
R2 is a hydrogen atom or a lower alkyl group;
R3 is a hydrogen atom, a hydroxy group, a lower alkoxy group, a lower alkoxy-lower alkoxy group, a lower alkoxy-lower alkoxy-lower alkoxy group, a lower alkoxy-lower alkoxy-lower alkoxy-lower alkoxy group, or a group -B-R3a {where B is a lower alkylene group, a lower alkenylene group or a lower alkynylene group, R3a is a hydrogen atom, a hydroxy group, a lower alkoxy group, a lower alkoxy-lower alkoxy group, a phenyl group which may possess one to three groups selected from the group consisting of a halogen atom, a cyano group, a hydroxy group, a lower alkyl group, a lower alkoxy group, a carboxy group and a lower alkoxycarbonyl group as substituent, a thienyl group which may possess a halogen atom as substituent, a phthalimido group, a carboxy group, a lower alkoxycarbonyl group or a group -CO-N(R3b)-R3C (where R3b is a hydrogen atom or a lower alkyl group, and R3c is a hydrogen atom, a lower alkyl group or a lower alkoxy group, and a group -N(R3b)-R3c may form a saturated heterocyclic ring with five or six members which may further possess one hetero atom selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom)};
R4 is a hydrogen atom, a halogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, or a lower alkylenedioxy group;
R5 is a hydrogen atom, a benzoyl group, a lower alkanoyl group, or a phenyl-lower alkyl group;
R6 is an alkyl group with 1 to 12 carbon atoms, a lower alkoxy-lower alkyl group, or a phenyl-lower alkyl group which may possess a lower alkylenedioxy group as substituent on the phenyl ring; and n is 1 or 2 ], or its salt.
(1) [where R1 is a hydrogen atom or a group -A-R1a (where A is a lower alkylene group, and R1a is a hydrogen atom, an amino group, a phthalimido group, a thienylthio group, a lower alkanoylthio group, a mercapto group, a phenyl group which may possess one to three groups selected from the group consisting of a halogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group and a lower alkylenedioxy group as substituent, a carboxy group, a lower alkoxycarbonyl group, phenylthio group, or a lower alkylthio group);
R2 is a hydrogen atom or a lower alkyl group;
R3 is a hydrogen atom, a hydroxy group, a lower alkoxy group, a lower alkoxy-lower alkoxy group, a lower alkoxy-lower alkoxy-lower alkoxy group, a lower alkoxy-lower alkoxy-lower alkoxy-lower alkoxy group, or a group -B-R3a {where B is a lower alkylene group, a lower alkenylene group or a lower alkynylene group, R3a is a hydrogen atom, a hydroxy group, a lower alkoxy group, a lower alkoxy-lower alkoxy group, a phenyl group which may possess one to three groups selected from the group consisting of a halogen atom, a cyano group, a hydroxy group, a lower alkyl group, a lower alkoxy group, a carboxy group and a lower alkoxycarbonyl group as substituent, a thienyl group which may possess a halogen atom as substituent, a phthalimido group, a carboxy group, a lower alkoxycarbonyl group or a group -CO-N(R3b)-R3C (where R3b is a hydrogen atom or a lower alkyl group, and R3c is a hydrogen atom, a lower alkyl group or a lower alkoxy group, and a group -N(R3b)-R3c may form a saturated heterocyclic ring with five or six members which may further possess one hetero atom selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom)};
R4 is a hydrogen atom, a halogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, or a lower alkylenedioxy group;
R5 is a hydrogen atom, a benzoyl group, a lower alkanoyl group, or a phenyl-lower alkyl group;
R6 is an alkyl group with 1 to 12 carbon atoms, a lower alkoxy-lower alkyl group, or a phenyl-lower alkyl group which may possess a lower alkylenedioxy group as substituent on the phenyl ring; and n is 1 or 2 ], or its salt.
2. A carbostyril derivative or its salt as claimed in claim 1, wherein R2 is a hydrogen atom, R5 is a hydrogen atom.
3. A carbostyril derivative or its salt as claimed in claim 1, wherein R5 is a benzoyl group, a lower alkanoyl group, or a phenyl-lower alkyl group.
4. A carbostyril derivative or its salt as claimed in claim 2, wherein R4 is a hydrogen atom, a halogen atom, a lower alkoxy group, or a lower alkylenedioxy group, and R6 is an alkyl group with 1 to 12 carbon atoms.
5. A carbostyril derivative or its salt as claimed in claim 2, wherein R6 is a lower alkoxy-lower alkyl group, or a phenyl-lower alkyl group which may possess a lower alkylenedioxy group as substituent on the phenyl ring.
6. A carbostyril derivative or its salt as claimed in claim 4, wherein R1 is a hydrogen atom or a group -A-R1a (where A is a lower alkylene group, and R1a is a hydrogen atom, a phthalimido group, a thienylthio group, a lower alkanoylthio group, or a phenyl group which may possess one to three groups selected from the group consisting of a halogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group and a lower alkylenedioxy group as substituent.
7. A carbostyril derivative or its salt as claimed in claim 4, wherein a group -A-R1a (where A is a lower alkylene group, and R1a is an amino group, a mercapto group, a carboxy group, a lower alkoxycarbonyl group, a phenylthio group, or a lower alkylthio group).
8. A carbostyril derivative or its salt as claimed in claim 4, wherein R3 is a hydrogen atom, or a group -B-R3a {where B is a lower alkylene group, a lower alkenylene group or a lower alkynylene group, R3a is a hydrogen atom, a lower alkoxy group, a lower alkoxy-lower alkoxy group, a carboxy group, or a group -CO-N(R3b)-R3c (where R3b is a hydrogen atom or a lower alkyl group, and R3c is a hydrogen atom, a lower alkyl group or a lower alkoxy group)}.
9. A carbostyril derivative or its salt as claimed in claim 8, wherein R1 is a hydrogen atom or a group -A-R1a (where A is a lower alkylene group, and R1a is a hydrogen atom, a phthalimido group, a thienylthio group, a lower alkanoylthio group, or a phenyl group which may possess one to three groups selected from the group consisting of a halogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group and a lower alkylenedioxy group as substituent).
10. A carbostyril derivative or its salt as claimed in claim 9, wherein R3 is a group -B-R3a (where B is a low er alkylene group, and R3a is a lower alkoxy group, lower alkoxy-lower alkoxy group).
11. A carbostyril derivative or its salt as claimed in claim 10, wherein R1 is a hydrogen atom or a group A-R1a (where A is a lower alkylene group, and R1a is a hydrogen atom).
12. A carbostyril derivative or its salt as claimed in claim 9, wherein R3 is a hydrogen atom, or a group -B-R3a (where B is a lower alkylene group, and R3a is a hydrogen atom, a carboxy group, or a group -CO-N(R3b)-R3c (where R3b and R3c are same meanings as defined in claim 8)}.
13. A carbostyril derivative or its salt as claimed in claim 12, wherein R1 is a hydrogen atom or a group -A-R1a (where A is a lower alkylene group, and R1a is a hydrogen atom).
14. A carbostyril derivative or its salt as claimed in claim 9, wherein R3 is a group -B-R3a (where B is a lower alkenylene group or a lower alkynylene group, R3a is same meanings as defined in claim 8)}.
15. A carbostyril derivative or its salt as claimed in claim 4, wherein R3 is a hydroxy group, a lower alkoxy group, a lower alkoxy-lower alkoxy group, a lower alkoxy-lower alkoxy-lower alkoxy group, or a lower alkoxy-lower alkoxy-lower alkoxy-lower alkoxy group.
16. A carbostyril derivative or its salt as claimed in claim 15, wherein R1 is a hydrogen atom or a group -A-R1a (where A is a lower alkylene group, and R1a is a hydrogen atom, a phthalimido group, a thienylthio group, a lower alkanoylthio group, or a phenyl group which may possess one to three groups selected from the group consisting of a halogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group and a lower alkylenedioxy group as substituent).
17. A carbostyril derivative or its salt as claimed in claim 16, wherein R1 is a hydrogen atom or a group -A-R1a (where A is a lower alkylene group, and R1a is a hydrogen atom).
18. A carbostyril derivative or its salt as claimed in claim 17, wherein R3 is a lower alkoxy group.
19. A carbostyril derivative or its salt as claimed in claim 4, wherein R3 is a group -B-R3a {where B is a lower alkylene group, a lower alkenylene group or a lower alkynylene group, R3a is a hydroxy group, a phenyl group which may possess one to three groups selected from the group consisting of a halogen atom, a cyano group, a hydroxy group, a lower alkyl group, a lower alkoxy group, a carboxy group and a lower alkoxycarbonyl group as substituent, a thienyl group which may possess a halogen atom as substituenet, a phthalimido group, a lower alkoxycarbonyl group or a group -CO-N(R3b)-R3c (where a group -N(R3b)-R3C forms a saturated heterocyclic ring with ive or six members which may further possess one hetero atom selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom)}.
20. A carbostyril derivative selected from 3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxy-3,4-dihydrocarbostyril, 3S-[4-(N-hydroxyamino)-2R-isobutyl-3S-acetylthiomethyl-succinyl]amino-3,4-dihydrocarbostyril, 3S-[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]-amino-1-methoxy-3,4-dihydrocarbostyril, 3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxymethyl-3, 4-dihydrocarbostyril, 1-carboxymethyl-3S-[4-(N-hydroxyamino)-2R-isobutyl-3S-methylsuccinyl]amino-3,4-dihydrocarbostyril, 3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxyethoxymethyl-3,4-dihydrocarbostyril, 3S-[4-(N-hydroxyamino)-2R-heptylsuccinyl]amino-1-methoxy-3,4-dihydrocarbostyril, 7-chloro-3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]-amino-1-methoxymethyl-3,4-dihydrocarbostyril, 3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxyethyl-3,4-dihydrocarbostyril, 3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxyethyl-6,7-methylenedioxy-3,4-dihydrocarbostyril, and 3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxyethyl-6,7-methylenedioxy-3,4-dihydrocarbostyril, or its salt.
21. A method of preparlng a carbostyril derivative of the formula (1) defined in claim 1, which comprises (a) reacting a carboxylic acid of the formula (2):
(2) with an amine of the formula (3):
R5ONH2 (3) to provide a compound of the formula (1):
(1) in the above formulas, R1, R2, R3, R4, R5, R6 and n are the same meanings as defined in claim 1, (2) reducing or saponifying a compound of the formula (1-A):
(1-A) to provide a compound of the formula (1-B):
(1-B) in the above formulas, R1, R2, R3, R4, R6 and n are the same meanings as defined in claim 1, R5 is a benzoyl group, a lower alkanoyl group or a phenyl-lower alkyl group, (3) reacting a compound of the formula (1-B):
(1-B) with a compound of the formula: R5' -X or (R5')2O to provide a compound of the formula (1-A):
(1-A) in the above formulas, R1, R2, R3, R4, R6 and n are the same meanings as defined in claim 1, R5 and X are the same meanings as defined above), or (4) reacting a compound of the formula (2):
(2) with a compound of the formula (3') R21R22R23SiONH2 (3) .
to provide a compound of the formula (42):
(42) and then introducing the obtained compound (42) into the compound of formula (1-B):
(1-B) by de-silylation, in the above formula, R1, R2, R3, R4, R6 and n are the same meanings as defined in claim 1, R21, R22 and R23 are lower alkyl groups),
(2) with an amine of the formula (3):
R5ONH2 (3) to provide a compound of the formula (1):
(1) in the above formulas, R1, R2, R3, R4, R5, R6 and n are the same meanings as defined in claim 1, (2) reducing or saponifying a compound of the formula (1-A):
(1-A) to provide a compound of the formula (1-B):
(1-B) in the above formulas, R1, R2, R3, R4, R6 and n are the same meanings as defined in claim 1, R5 is a benzoyl group, a lower alkanoyl group or a phenyl-lower alkyl group, (3) reacting a compound of the formula (1-B):
(1-B) with a compound of the formula: R5' -X or (R5')2O to provide a compound of the formula (1-A):
(1-A) in the above formulas, R1, R2, R3, R4, R6 and n are the same meanings as defined in claim 1, R5 and X are the same meanings as defined above), or (4) reacting a compound of the formula (2):
(2) with a compound of the formula (3') R21R22R23SiONH2 (3) .
to provide a compound of the formula (42):
(42) and then introducing the obtained compound (42) into the compound of formula (1-B):
(1-B) by de-silylation, in the above formula, R1, R2, R3, R4, R6 and n are the same meanings as defined in claim 1, R21, R22 and R23 are lower alkyl groups),
22. An extracellular matrix metalloproteinases inhibitor containing, as an effective ingredient, a carbostyril derivative defined in claim 1 or its salt.
23. A prophylactic or therapeutic agent for metastasis, infiltration or proliferation of various cancer cells, rheumatoid arthritis, periodontal diseases, corneal ulcer, osteoporosis, other bone absorption diseases, multiple sclerosis, hypomyelination, diseases accompanied by vascularization, dermal and gastrointestinal ulceration, and wound healing and postoperative symptoms, colonanastomosis caused by elevation of collagenase level, increase of collagen destruction caused in relation with diabetes mellitus, atherosclerosis, proliferation due to suture of blood vessels, or nephritis, which contains, as an effective ingredient, a carbostyril derivative defined in claim 1 or its salt.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5/58264 | 1993-03-18 | ||
| JP5826493 | 1993-03-18 | ||
| JP25687393 | 1993-10-14 | ||
| JP5/256873 | 1993-10-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2136108A1 true CA2136108A1 (en) | 1994-09-29 |
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ID=26399315
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002136108A Abandoned CA2136108A1 (en) | 1993-03-18 | 1994-03-17 | Carbostyril derivatives as matrix metalloproteinases inhibitors |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0641323A1 (en) |
| KR (1) | KR950704257A (en) |
| CN (1) | CN1105799A (en) |
| AU (1) | AU672888B2 (en) |
| CA (1) | CA2136108A1 (en) |
| TW (1) | TW290541B (en) |
| WO (1) | WO1994021612A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB9423914D0 (en) * | 1994-11-26 | 1995-01-11 | British Biotech Pharm | Polyether derivatives as metalloproteinase inhibitors |
| US5672598A (en) * | 1995-03-21 | 1997-09-30 | The Procter & Gamble Company | Lactam-containing hydroxamic acids |
| US5917090A (en) * | 1995-06-30 | 1999-06-29 | British Biotech Pharmaceuticals Ltd. | Matrix metalloproteinase inhibitors |
| AR004214A1 (en) * | 1995-10-12 | 1998-11-04 | Otsuka Pharma Co Ltd | A PREPARATION OF OPHTHALMIC DROPS FOR THE CURE OF OPHTHALMIC DISEASES |
| EP0873304B1 (en) | 1995-11-23 | 2001-09-05 | British Biotech Pharmaceuticals Limited | Metalloproteinase inhibitors |
| JP4358908B2 (en) * | 1996-01-02 | 2009-11-04 | アヴェンティス ファーマシューティカルズ インコーポレイテッド | Substituted (aryl, heteroaryl, arylmethyl or heteroarylmethyl) hydroxamic acid compounds |
| WO1997037658A1 (en) * | 1996-04-04 | 1997-10-16 | F.Hoffmann-La Roche Ag | Use of derivatives of tetrahydro-beta-carbolines as antimetastatic agents |
| US6462023B1 (en) | 1996-09-10 | 2002-10-08 | British Biotech Pharmaceuticals, Ltd. | Cytostatic agents |
| JP4238334B2 (en) | 1996-09-10 | 2009-03-18 | ヴァーナリス （アールアンドディー） リミテッド | Cytostatic hydroxamic acid derivatives |
| US5985911A (en) * | 1997-01-07 | 1999-11-16 | Abbott Laboratories | C-terminal ketone inhibitors of matrix metalloproteinases and TNFα secretion |
| US5952320A (en) * | 1997-01-07 | 1999-09-14 | Abbott Laboratories | Macrocyclic inhibitors of matrix metalloproteinases and TNFα secretion |
| US6288261B1 (en) | 1998-12-18 | 2001-09-11 | Abbott Laboratories | Inhibitors of matrix metalloproteinases |
| US6858598B1 (en) | 1998-12-23 | 2005-02-22 | G. D. Searle & Co. | Method of using a matrix metalloproteinase inhibitor and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia |
| US6833373B1 (en) | 1998-12-23 | 2004-12-21 | G.D. Searle & Co. | Method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia |
| BR0210422A (en) | 2001-06-15 | 2004-08-17 | Vicuron Pharm Inc | Bicyclic Pyrrolidine Compounds |
| AR036053A1 (en) | 2001-06-15 | 2004-08-04 | Versicor Inc | N-FORMIL-HYDROXYLAMINE COMPOUNDS, A PROCESS FOR PREPARATION AND PHARMACEUTICAL COMPOSITIONS |
| PE20030701A1 (en) | 2001-12-20 | 2003-08-21 | Schering Corp | COMPOUNDS FOR THE TREATMENT OF INFLAMMATORY DISORDERS |
| US7879877B2 (en) | 2003-07-30 | 2011-02-01 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives for accelerating salivation |
| CN108285469B (en) * | 2018-03-15 | 2020-07-24 | 遵义医学院 | A kind of antibacterial quinolone derivative and preparation method and application thereof |
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| GB8827308D0 (en) * | 1988-11-23 | 1988-12-29 | British Bio Technology | Compounds |
| GB9107368D0 (en) * | 1991-04-08 | 1991-05-22 | Smithkline Beecham Plc | Novel compounds |
-
1994
- 1994-03-17 CN CN94190137A patent/CN1105799A/en active Pending
- 1994-03-17 WO PCT/JP1994/000434 patent/WO1994021612A1/en not_active Application Discontinuation
- 1994-03-17 AU AU62637/94A patent/AU672888B2/en not_active Ceased
- 1994-03-17 CA CA002136108A patent/CA2136108A1/en not_active Abandoned
- 1994-03-17 TW TW083102314A patent/TW290541B/zh active
- 1994-03-17 EP EP94910035A patent/EP0641323A1/en not_active Ceased
- 1994-11-18 KR KR1019940704126A patent/KR950704257A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| TW290541B (en) | 1996-11-11 |
| AU672888B2 (en) | 1996-10-17 |
| AU6263794A (en) | 1994-10-11 |
| WO1994021612A1 (en) | 1994-09-29 |
| CN1105799A (en) | 1995-07-26 |
| KR950704257A (en) | 1995-11-17 |
| EP0641323A1 (en) | 1995-03-08 |
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