CA2081462A1 - Five-membered ring alkanoic acid leukotriene antagonists - Google Patents
Five-membered ring alkanoic acid leukotriene antagonistsInfo
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- CA2081462A1 CA2081462A1 CA002081462A CA2081462A CA2081462A1 CA 2081462 A1 CA2081462 A1 CA 2081462A1 CA 002081462 A CA002081462 A CA 002081462A CA 2081462 A CA2081462 A CA 2081462A CA 2081462 A1 CA2081462 A1 CA 2081462A1
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- alkyl
- compound
- phenyl
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- acceptable salt
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- 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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- 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
- C07D409/06—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 carbon chain containing only aliphatic carbon atoms
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
This invention relates to alkanoic acid compounds having a 5-membered heterocyclic ring and a thio substituent which are useful as leukotriene antagonists.
Description
W0 91/16889 ~ . 2 ~ 8 ~ ~ 6 ~ Pcr/US9 l /02884 Five-Membered Ring Alkanoic Acid Leukotriene Antagonists This invention relates to heteroaromatic five-rnemembered ring S a3~anoic acid derivatives which are useful for ~eating diseases associated with leukotrienes.
"Slow Reacting Substanee of Anaphylaxis" (SRS-A) has been . shown to be a highly po~ent bronchoconst~icting substance which is 10 released pnmarily from mast cells and basophils on anLigeniC
challenge. SRS-A has been proposed as a primary mediator in human asthma. SRS-A, in addition to its pronounced effects on lung tissue.
also produces perrneability changes in skin and may be involved in acute cutaneous allergic reactions. Further, SRS-A has been shown to 15 effect depression of ventricular contraction and potentiation of the cardiovascular effects of histamine.
The dis~overy of the naturally occurring leukotrienes and their rela~ionship ~o SRS-A has reinforced interest in SRS-A and other arachidonate metabolites. SRS-A derived from mouse, rat, guinea pig 2 0 and man have all been characterized as mixtures of leukot~iene-C4 (LTC4), leukoeriene-D4 (LTD4) and leukotriene-E4 (LTE4).
As summarized by Lefer, A.M., BiQ~m~al Pharmacolo~v, 35, '~
123-127 tl986) both the peptide and non-peptide leukotrienes exert microcircula~ory actions, promoting leakage of fluid across Ihe 2 5 capillary endothelial membrane in most types of vascular beds. LTB~
has potent chemotactic actions and contribu~es to the recruitrnen~ and adherence of mobile scavenger cells to endothelial membrane. LTCl, LTD4 and LT'E4 s~imulate a variety of types of muscles. LTC4 and LTD4 are potent bronchoconstrictors and effec~ive stimulators of 3 0 vascular smooth muscle. This vasoconstrictor effect has been shown to occur in pulmonary, coronary, cerebral, renal, and mesenteric vascul atures .
Leuko~ienes have been implicated in a number of pulmonarv diseases. Leukotnenes are known to be potent bronchoconstrictors in 3 5 humans. LTC and LTD have been shown to be potent and selective peripheral airway agonists, being more active than histamine. [See Drazen, J.M. et al., roc. Nat'L. Acad. Sci USA, 77, 7, 4354-4358 (1980)1.
wo 91/16889 ; ~ 2 0 814 6 2 pcr/us91/o2884 LTC4 and LTD4 have been shown to increase the release of mucous from human airways in vitro. [See Marom, Z. et al., Arn Rev Respir.
~, 126, 449~51 (1982).] The leukotriene antagonists of ~he presen~
invention can be useful in the treatment of allergic or non-allergic 5 bronchial asthma sr pulmonary anaphylaxis.
Leukotrienes have also been directly or indirectly implicated in a variety of non-pulmonary diseases in the ocular, dermatologic.
cardiovascular, renal, trauma, inflamma~sry, carcinogenic and other areas.
Another area of utility for leukotriene antagonis~s is in the ~reatment of cardiovascular diseases. Since peptide leukotrienes are potent coronary vasoconstrictors, they are implicated in a variety of cardiac depression. Synthetic leulcotrienes have been shown to be powerful myocardial depressants, their effects consisting of a 15 de~rease i contractile force and coronary flow. The cardiac effects ot LTC4 and LTD4 have been shown to be antagonized by a specific leukotriene an~agonist. thus suggesting usefulness of leukotriene antagonists in the areas of myocardial depression and cardian anaphylaxis. [See Burke, J.A., et al., 20 ~ çs, 221, 1, 235-241 (1982).]
Leukot~iene antagonists can also be useful in the area of renal ischemia or renal failure. Badr et al. have shown that LTC4 produce~
signiticant elevation of mean arterial pressure and reductions in cardiac output and renal blood flow, and that such effects can be 2 5 abolished by a speci~lc leukotriene antagonist. [See Badr, K.F. et al..
~irçulation Research, 54, 5, 492-499 (1984). Leukotrienes have also been shown to have a role in endotoxin enduced renal failure and the effects of the leukotrienes selectively antagonized in this model of renal injury. [See Badr, K.F., et al., Kidnev InternatiQnal, 30, 474-48û
3 0 (1986).] LTD4 has been shown to produce local glomerular constrictor actions. which are prevented by trea~ment with a leuko~riene antagonist, [See Badr, K.F. et al., Kidnev Tnternational,'~9, 1, 32 (1986). LTC4 has been demonstrated to conlract rat glomerular mesangial cells in culture and thereby effect intraglomerular actions 35 to reduce filtration surface area. [see Dunn, M.J. et al., Kidnev Internationa!, 27, 1, 256 (1985). Thus another area of utility for leukotriene antagonists can be in the treatment of glomerulonephritis.
2081~62 W0 91/16889 ~ PCI/IJS91/02884 By antagonizing the effects of LTC4, LTD4 and LTE4 or other pharrnacologically active mediators at the end organ, for example airway smooth muscle, the compounds and pharmaceutical compositions of the i~stant invention are valuable in the treatment of S diseases in subjec~s, ineluding huma~n or animals, in which leukotrienes are a key factor.
Leukotriene antagonists based on 3-phenyl-3-thiopropionic acids are disclosed in U.S. paten2 4,820,719 and EPO application No.
0 202 759 published 26 November, 1986.
1 0 ~T~ LED DES~R~IIO~ OF l~ ~Q~
The compounds of this invention are represented by formula (I) X-R
~A~,~
Rl (I) wherein Rl is not subs~ituted Oll A or B;
X is O or S(O)q where q is 0, 1 or 2 with the proviso that R1 is not alkylthio or phenylthioaLkyl when q is 1 or 2;
Rl is C8 to C13 aL~cyl, C7 to C12 aLtcoxy, C7 to C12 alkylthio, Clo to C12 1-alkynyl, 10-undecynyloxy, ll-dodecynyl, phenyl-C~ to Cl o alkyl, phenyl-C3 to Cg alkoxy, phenylthio-C3 to Cg alkyl with each phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, Cl to C4 alkoxy, methylthio or trifluoromethylthio;
furyl-C4 to Clo alkyl, trifluoromethyl-C7 to C12 alkyl or cyclohexyl-C4 to Clo aLtcyl;
A is S, O, orN;
B is CH or NR2;
R2 is H, Cl to C13 aLkyl, Clo to Cl~-l-alkynyl, 1 l-docedynyl, phenyl-C4 tO Clo alkyl with phenyl optionally monosubstituted or ~Y;
3 0 the dotted line between A and B indicates a sin~le bond in one position and a double bond in the o~her;
wo 91/16889 2 0 81~ 6 2 PCI/US91/02~
Y is R3, CH(R4)tCH2)r"R3, CH(R~ tetr ol-~-yl, or tetrazol-5-yl;
R3 is -CORs where Rs is -OH or OX where X is a pharmaceutically acceptable cation or a pharmaceutically acceptable ester-forming group, -CN, -SO3H, -S02NH2, -NHSO2R~ I(NH2)CORs, or -NHcH2coR;t S or R3 is -N(R6)2 where R6 is H, Cl to C6 alkyl, phenylCI-C6alkyl, or the tWO R6 ~OUpS are combined to form a cyclic group having 3 to 5 carbons;
R4 is hydrogen, methyl, Cl to C4 alkoxy, fluoro or hydroxy;
R7 is Cl to Clo-alkyl, phenyl or substituted phenyl;
l 0 m is 0, 1, or 2;
R is -tCH2)nD. ~(cH2)nArD or ArD where n is 0-6, Ar is phenyl or subs~ituted phenyl, thienyl, pyridyl, imidazolyl, tetrazol-5-yl or thiazolyl and D is -(CH2)nR3, -COR3, ~etræol-5-yl, -CH(NH2)R3, -NHCH2CORs, -NHSO2R7, -SO3H, -CN, or-SO2NH2; or a pha~naceutically acceptable salt.
The term phenylthioalkyl is used to mean the thioether radical where phenyl is bonded to sulfur which is bonded ~o the alkyl moiety, the radical of the formula ~ } S--(CH2)n-2~
A preferred class of compounds of this inven~ion are the substituted alkanoic acid analogs of forrnula (I) where X is S(O)q where q is 0 and Y is -(CH2)0 3COOH represented by formula (II) X-R
~(CH2)0.3COOH
~1 I B
Rl (II) wherein R and Rl are the same as described above, A is S, O or ~ and B is CH or NR2. The most preferred class of these compounds are 3 0 those where X is S, R is -(CH2)nD, -(CH~)nArD or ArD. Y is -CH~COOH. A
~ U ~
WO 91/168~9 PCr/US91/02884 x-2 is S, O, or N, and B is CH or -NR2 where the group ~Y is no~ R2, and Rl is Cg ~o Cl3-alkyl or phenyl-C4 to Clo-alkyl. The most prefened compounds in this category are where J~Y is at the 2-position:
( 1 ) 3-~2-carboxyethylthio)-3 -(3-dodecylthien-2-yl)propionic S acid;
(2) 3-(2-carboxyethylthio)-3-[3-(8-phenyloctyl)~hien-2-yl]
propionic acid;
(3) 3-(2-carboxyethylthio)-3-(1-dodecyl-lH-imidazol-2-yl) propionic acid;
"Slow Reacting Substanee of Anaphylaxis" (SRS-A) has been . shown to be a highly po~ent bronchoconst~icting substance which is 10 released pnmarily from mast cells and basophils on anLigeniC
challenge. SRS-A has been proposed as a primary mediator in human asthma. SRS-A, in addition to its pronounced effects on lung tissue.
also produces perrneability changes in skin and may be involved in acute cutaneous allergic reactions. Further, SRS-A has been shown to 15 effect depression of ventricular contraction and potentiation of the cardiovascular effects of histamine.
The dis~overy of the naturally occurring leukotrienes and their rela~ionship ~o SRS-A has reinforced interest in SRS-A and other arachidonate metabolites. SRS-A derived from mouse, rat, guinea pig 2 0 and man have all been characterized as mixtures of leukot~iene-C4 (LTC4), leukoeriene-D4 (LTD4) and leukotriene-E4 (LTE4).
As summarized by Lefer, A.M., BiQ~m~al Pharmacolo~v, 35, '~
123-127 tl986) both the peptide and non-peptide leukotrienes exert microcircula~ory actions, promoting leakage of fluid across Ihe 2 5 capillary endothelial membrane in most types of vascular beds. LTB~
has potent chemotactic actions and contribu~es to the recruitrnen~ and adherence of mobile scavenger cells to endothelial membrane. LTCl, LTD4 and LT'E4 s~imulate a variety of types of muscles. LTC4 and LTD4 are potent bronchoconstrictors and effec~ive stimulators of 3 0 vascular smooth muscle. This vasoconstrictor effect has been shown to occur in pulmonary, coronary, cerebral, renal, and mesenteric vascul atures .
Leuko~ienes have been implicated in a number of pulmonarv diseases. Leukotnenes are known to be potent bronchoconstrictors in 3 5 humans. LTC and LTD have been shown to be potent and selective peripheral airway agonists, being more active than histamine. [See Drazen, J.M. et al., roc. Nat'L. Acad. Sci USA, 77, 7, 4354-4358 (1980)1.
wo 91/16889 ; ~ 2 0 814 6 2 pcr/us91/o2884 LTC4 and LTD4 have been shown to increase the release of mucous from human airways in vitro. [See Marom, Z. et al., Arn Rev Respir.
~, 126, 449~51 (1982).] The leukotriene antagonists of ~he presen~
invention can be useful in the treatment of allergic or non-allergic 5 bronchial asthma sr pulmonary anaphylaxis.
Leukotrienes have also been directly or indirectly implicated in a variety of non-pulmonary diseases in the ocular, dermatologic.
cardiovascular, renal, trauma, inflamma~sry, carcinogenic and other areas.
Another area of utility for leukotriene antagonis~s is in the ~reatment of cardiovascular diseases. Since peptide leukotrienes are potent coronary vasoconstrictors, they are implicated in a variety of cardiac depression. Synthetic leulcotrienes have been shown to be powerful myocardial depressants, their effects consisting of a 15 de~rease i contractile force and coronary flow. The cardiac effects ot LTC4 and LTD4 have been shown to be antagonized by a specific leukotriene an~agonist. thus suggesting usefulness of leukotriene antagonists in the areas of myocardial depression and cardian anaphylaxis. [See Burke, J.A., et al., 20 ~ çs, 221, 1, 235-241 (1982).]
Leukot~iene antagonists can also be useful in the area of renal ischemia or renal failure. Badr et al. have shown that LTC4 produce~
signiticant elevation of mean arterial pressure and reductions in cardiac output and renal blood flow, and that such effects can be 2 5 abolished by a speci~lc leukotriene antagonist. [See Badr, K.F. et al..
~irçulation Research, 54, 5, 492-499 (1984). Leukotrienes have also been shown to have a role in endotoxin enduced renal failure and the effects of the leukotrienes selectively antagonized in this model of renal injury. [See Badr, K.F., et al., Kidnev InternatiQnal, 30, 474-48û
3 0 (1986).] LTD4 has been shown to produce local glomerular constrictor actions. which are prevented by trea~ment with a leuko~riene antagonist, [See Badr, K.F. et al., Kidnev Tnternational,'~9, 1, 32 (1986). LTC4 has been demonstrated to conlract rat glomerular mesangial cells in culture and thereby effect intraglomerular actions 35 to reduce filtration surface area. [see Dunn, M.J. et al., Kidnev Internationa!, 27, 1, 256 (1985). Thus another area of utility for leukotriene antagonists can be in the treatment of glomerulonephritis.
2081~62 W0 91/16889 ~ PCI/IJS91/02884 By antagonizing the effects of LTC4, LTD4 and LTE4 or other pharrnacologically active mediators at the end organ, for example airway smooth muscle, the compounds and pharmaceutical compositions of the i~stant invention are valuable in the treatment of S diseases in subjec~s, ineluding huma~n or animals, in which leukotrienes are a key factor.
Leukotriene antagonists based on 3-phenyl-3-thiopropionic acids are disclosed in U.S. paten2 4,820,719 and EPO application No.
0 202 759 published 26 November, 1986.
1 0 ~T~ LED DES~R~IIO~ OF l~ ~Q~
The compounds of this invention are represented by formula (I) X-R
~A~,~
Rl (I) wherein Rl is not subs~ituted Oll A or B;
X is O or S(O)q where q is 0, 1 or 2 with the proviso that R1 is not alkylthio or phenylthioaLkyl when q is 1 or 2;
Rl is C8 to C13 aL~cyl, C7 to C12 aLtcoxy, C7 to C12 alkylthio, Clo to C12 1-alkynyl, 10-undecynyloxy, ll-dodecynyl, phenyl-C~ to Cl o alkyl, phenyl-C3 to Cg alkoxy, phenylthio-C3 to Cg alkyl with each phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, Cl to C4 alkoxy, methylthio or trifluoromethylthio;
furyl-C4 to Clo alkyl, trifluoromethyl-C7 to C12 alkyl or cyclohexyl-C4 to Clo aLtcyl;
A is S, O, orN;
B is CH or NR2;
R2 is H, Cl to C13 aLkyl, Clo to Cl~-l-alkynyl, 1 l-docedynyl, phenyl-C4 tO Clo alkyl with phenyl optionally monosubstituted or ~Y;
3 0 the dotted line between A and B indicates a sin~le bond in one position and a double bond in the o~her;
wo 91/16889 2 0 81~ 6 2 PCI/US91/02~
Y is R3, CH(R4)tCH2)r"R3, CH(R~ tetr ol-~-yl, or tetrazol-5-yl;
R3 is -CORs where Rs is -OH or OX where X is a pharmaceutically acceptable cation or a pharmaceutically acceptable ester-forming group, -CN, -SO3H, -S02NH2, -NHSO2R~ I(NH2)CORs, or -NHcH2coR;t S or R3 is -N(R6)2 where R6 is H, Cl to C6 alkyl, phenylCI-C6alkyl, or the tWO R6 ~OUpS are combined to form a cyclic group having 3 to 5 carbons;
R4 is hydrogen, methyl, Cl to C4 alkoxy, fluoro or hydroxy;
R7 is Cl to Clo-alkyl, phenyl or substituted phenyl;
l 0 m is 0, 1, or 2;
R is -tCH2)nD. ~(cH2)nArD or ArD where n is 0-6, Ar is phenyl or subs~ituted phenyl, thienyl, pyridyl, imidazolyl, tetrazol-5-yl or thiazolyl and D is -(CH2)nR3, -COR3, ~etræol-5-yl, -CH(NH2)R3, -NHCH2CORs, -NHSO2R7, -SO3H, -CN, or-SO2NH2; or a pha~naceutically acceptable salt.
The term phenylthioalkyl is used to mean the thioether radical where phenyl is bonded to sulfur which is bonded ~o the alkyl moiety, the radical of the formula ~ } S--(CH2)n-2~
A preferred class of compounds of this inven~ion are the substituted alkanoic acid analogs of forrnula (I) where X is S(O)q where q is 0 and Y is -(CH2)0 3COOH represented by formula (II) X-R
~(CH2)0.3COOH
~1 I B
Rl (II) wherein R and Rl are the same as described above, A is S, O or ~ and B is CH or NR2. The most preferred class of these compounds are 3 0 those where X is S, R is -(CH2)nD, -(CH~)nArD or ArD. Y is -CH~COOH. A
~ U ~
WO 91/168~9 PCr/US91/02884 x-2 is S, O, or N, and B is CH or -NR2 where the group ~Y is no~ R2, and Rl is Cg ~o Cl3-alkyl or phenyl-C4 to Clo-alkyl. The most prefened compounds in this category are where J~Y is at the 2-position:
( 1 ) 3-~2-carboxyethylthio)-3 -(3-dodecylthien-2-yl)propionic S acid;
(2) 3-(2-carboxyethylthio)-3-[3-(8-phenyloctyl)~hien-2-yl]
propionic acid;
(3) 3-(2-carboxyethylthio)-3-(1-dodecyl-lH-imidazol-2-yl) propionic acid;
(4) 3-(2-carboxyethylthio)-3-[1-(8-phenyloctyl)-lH-imida~ol-2-yl]propionic acid, (S) 3-(2-oarboxyethylthio~-3-[3-(8-phenyloctyl)fur-2-yl]
propionic acid, and (6) 3-(2-carboxyethylthio)-3-(3-dodecylfur-2-yl)propionic 1 5 acid.
A further particular group of compounds of ~his. inven~ion are those where X is S, Y is -C(OH)HCOR3, R is -(CH2)nD, -(CH2)nArD or ArD, Rl is Cg to C13-aIkyl or phenyl-C4 to Clo-alkyl, A is S, O, or N and B is X-R
CH or -NR2 where ~he group ~Y is not R2. The most preferred X-R
compounds of this group are those where ~Y is at the 2-position:
3 -(2-carboxyethylthio)-3-(3-dodecylthien-2-yl)-~ -hydroxypropionic acid;
3-(2-carboxyethylthio)-3 -(3 -(8-phenyloc tyl)thien-~ -yl)-2-hydroxypropionic acid, 2 5 3-(2-carboxyethylthio)-3-( 1 -dodecyl- 1 H-imidazol-~ -yl)-~ -hydroxypropionic acid, 3-(2-carboxyethylthio)-3-( 1 -(~8~phenyloctyl)- 1 H-imidazol-~ -yl)-2-hydroxypropionic acid, 3-(2-carboxyethylthio)-3-(3 -dodecylfur-~ -yl)-~ -3 0 hydroxypropionic acid; and 3-(2-carboxyethylthio)-3-(3-(8-phenyloctyl)fur-~ -vl)-~-hydroxypropionic acid.
WO 91/16889 PCI/~ IS9l/02884 ~
2 0 ~ 2 Another preferred class of compounds of this inven~ion are the compounds where Y is (CH2)0- l -tetrazol-S-yl or -CH(OH)-tetrazol-~ -vl .
X is S, R is -(CH2)nD, -(CH~)nArD or A~D, A is O, S or N, B is -CH- or ~TR~
where the group ~Y is not R2, and Rl is C8 to C13-aLIcyl or phenyl-C~
X-R
S to C~lo-alkyl. The most preferred compounds are those where ~Y is at the 2-position,: ¦
4-thia-5-(3-dodecyl~hien-2-yl)-6-(tetrazol-5-yl)hexanoic acid;
4-thia-5 (1-dodecyl-lH-imidazol-2-yl)-6-(tetrazol-5-yl)hexanoic acid;
I 0 4-thia-5-(3-( 8 -phenyloctyl)thien-2-yl )-6-( tetrazol-S -yl)hexanoic acid;
4-thia-5-(1-(8~phenyloctyl)-lH-imidazol-2-yl)-6-(tetrazol-5-yl)hexanoic acid 4-thia-5-(3-dodecylfur-2-yl)-6-(tetrazol-5-yl)hexanoic acid;
l $ 4-thia-5-(3-(8-phenyloctyl)fur-2-yl)-6-(tetrazol-5-yl)hexanoic a id;
4-thia-5-(3-dodecylthien-2-yl)-6-hydroxy-6-(teIra~
yl)hexanoic acid;
4-thia-S-(-1 -dodecyl- 1 H-imidazol-2-yl)-6-hydroxy-6-(tetrazol -2 0 5-yl)hexanoic acid;
4-thia-S-(3-(8-phenyloctyl)thien-2-yl)-6-(te~razol-5-yl)hexanoic acid;
4-thia-5 (1-(8-phenyloctyl)-lH-imidazol-2-yl)-6-hydroxy-6-(~etrazol-S-yl)hexanoic acid ' 2 5 4-thia-5-(3-dodecylfur-2-yl)-6-hydroxy-6-(te~razol-5-yl)-hexanoic acid; and 4-~hia-5-(3-(8-phenyloctyl),fur-2-yl)-6-hydroxy-6-(tetrazol-5 -yl)hexanoic acid.
A second class of preferred compounds are those where X is O~
3 0 particularly those p ~alleling the preferred and most preferTed defi~i~ions for the case where X is S given above. Most preferred compounds of this group are the following compounds: .
3-(2-carboxyethyloxy)-3-(3-dodecylthien-~-yl)propionic acid:
3-~2-carboxyethyloxy3-3-[3-(8-phenyloctyl)thien-2-yl]-3 5 propionic acid;
XV~1~62 WO 91/16889 ~ j PCr/US91/02884 3-(2-carboxyethyloxy)-3-( 1 -dodecyl- 1 H-imidazol-2-yl) propionic acid;
3-(2-carboxyethyloxy)-3-[1-(8-phenyloctyl)-lH-imidazol-~-yl]propionic acid.
3 -(2-carboxyethyloxy)-3 -(3 -dodecylthien -2-yl)-2 -hydro~ypropionic acid;
3-(2-carboxye thyloxy)-3 -(1 dodecyl- 1 H-imidazol- 2 -yl) -2 -hydroxypropionic acid;
4-oxy-5-(3-dodecylthien-2-yl)-6-(tetrazol-5-yl)hexanoic acid;
1 0 4-oxy-5-(3 -(8 -phenylsctyl)thien-2-yl)-6-(tetrazol-5 -yl?hexanoic acid;
4-oxy-5-(1 -(8-phenyloctyl)-lH-imidazol-2-yl)-6-(tetrazol-5-yl)hexanoic acid; and 4-oxy-5-( 1 -dodecyl- 1 H-imidazol-2-yl)-6-(tetrazol-5 -yl)hexanoic acid.
AIl compounds of this invention have at least one assymetric center due to X being sulfur or oxygen. Some of the compounds of the fo~nula ~I) contain two asymmetric centers, such as ~hen Ra in the Y
sustituent is other than hydrogen, such as is n~ethyl, methoxy, fluoro 2 0 or hydroxy. Osher asymetric centers may also be present in these molecules depending on the selection of subsùtuents in any given compound. In practice, these compounds are prepared as a mixture ot stereoisomers. all steroisomers, as mixtures or resolved isomers, are included in this invention. Resolution procedures employing, for example, optically active amines furnish the separa~ed enantiomers.
Pharmaceutically acceptable esters may be formed from those compounds having a carboxylic acid function ie when R has the -C(:R~
tenninal groupO Such an ester, or di-ester as the case may be will be - any ester which, as with pharmacuetically acceptable salts, gives an 3 0 ester which retains tbe activity of the parent compound and does not impart to the parent acid any unacceptable untoward pharmacologic~l or toxic affects in the context of its intended use and application.
While it is expected that any carboxylic acid ester may be used. it is preferred to employ certain esters derived from the following - 3 5 radicals: Cl to C6 a]kyl, cycloalkyl, aryl, arylalkyl, alkylaryl.
alkylaryla~kyl, arninoalkyl, indanyl, pivaloyloxyn ethyl, 1' ~ t. ~' ',,' 1~
wo 91/16889 2 0 814 6 2 PCr/USg1/02884 ~
acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, or thienylglycyloxymethyl.
The compounds of the present invention, depending on their s~ucture, are capable of forming pharmaceutically acceptable salts 5 with acids and bases according ~o procedures well known in the arn Such salts are those which match the-activity of the parent compound and do not exhibit untoward or deliberous activity. Acceptable acids include inorganic and organic acids, such as hydrochloric, sulfuric, methanesulfonic, benzenesulfonic, p-toluenesulfonic acid and acetic 10 acid. Bases include organic and inorganic bases, such as ammonia, arginine, organie amines, alkali metal bases and alkaline earth metal bases. Pipera~ine and ethylenediamine salts are particularly useful in this invention. Also preferred are the dipotassium, disodium, dimagnesium, dizinc, and dicalcium salts of the diacid compounds of 15 forrnula (I). Pharmaceut.ically acceptable cations are the same as rhe just recited base-derived pharmaceutically acceptable salts.
The compounds of the formula ~1) wherein Y is CH2C02H are prepared by reacting the appropriate aldehydes of the formula VI or VII, wherein Rl, R2 and A are as described above and an esterified 2 0 bromoacetate, conveniently t-butyl bromoacetate, with a mixture of diethyl aluminum chloride, zinc dust and a catalytic amount of cuprous bromide at low temperatures in an inert solvent to give the esterified 3-hydroxypropionate derivative which is reacted directlv with a substituted thiol in ~rifluoroacetic acid. Alternatively. a 2 5 mixture of trimethyl borate and zinc in tetrahydrofuran may be used to prepare the 3-hydroxypropionate derivative. Preferably, compounds of formula (I) are prepared from the aldehydes VI or VII
by reaction with lithium diisopropylamide and t-butyl acetate at -78C to 25C in a suitable solvent such as, for example, THF, to provide 3 0 ~he precursor es2erified 3-hydroxypropionate derivatives which are converted to the thiol acids with ~ mercaptan in trifluoroacetic acid.
By employing an esterified 2-b,omopropionate in the above reaction with an aldehydes VI or VII, the compounds of the formula (I) wherein Y is CH(~H3)C02H are obtained.
WO 91/16889 PCl /US91/02884 .. ~'I; ' ' .~
~A~CE~O ~N~C~IO
.2iQ ~ R2iQ~
Rl (VI) Rl (VII) .
To prepare the compounds of formula (I) wherein q is l or 2, the appropriate thio product is conveniently oxidized with sodium 5 period~te or metachloroperben~oic acid to obtain ~he sulfoxide or sulfone product.
The aldehydes of the forrnula (VI) and (VI1) are known or readily prepared utilizing the general procedures described as follows.
The aldehyde precursors to the compounds of the formula (I) 10 wherein R1 is, for exarnple, an aL~cyl radical containing 8 to 13 carbon atoms are prepared from the appropriate 2-methoxyphenyl-4,4-dimethyloxazoline [see Meyers e~ al. J. Qr~. ~hem., ~, 1372 (1973)].
The aldehyde precursors to the compounds of the formula (I) wherein R 1 is a 1 -alkynyl radical con~aining 10 to 12 carbon atoms 15 are prepar~d by coupling a halobenzaldehyde with the: appropriate l-aL~;yne in the presence of cuprous iodide and (P03)2PdC12. [See Eigahara et al., Svnthesi_. 627 (1980)]. The catalytic hydrogenation of these alkynyl containing precursors under standard conditions affords the aldehyde precursors of the compounds of the formula (I) wherein 20 Rl is an alkyl or phenylalkyl radical.
Alternatively, ~he compounds of ~he formula (I) wherein Y is CH2C02H are prepared from a propionate precursor of Ihe following structural formulas ~VIII) and (IX).
2~¦~ R,,,~ COORI6 2 5 Rl (VIII) Rl (IX) wherein R1, R2 and A are described above, and R16 is an es~er protective group, such as t-butyl. A compound of formula (VIII) or (IX) is reacted with a mix~ure of alkali metal alkoxide. such as sodium 6~89 2 0 8 1 ~ 6 2 Pc-r/uss1/02884 "_~
methoxide, and substituted thiol to give, after removal of the ester protective group, products of formula (I).
The propionate precursors of formula (VIII) or (IX) are prepared from the corresponding aldehydes of formulas (VI) and S (VII) by general procedures such as reaction with an alkyl (triphenylphosphoranylidene)aceta~e or by conversion of the aldehyde to a 3-hydroxypropionate derivative, as described above, followed by an elimina2ion reaction to form the double bond.
Additionally, the propenoate precursor is obtained from a 3-me~hane-sulfonyloxypropionate derivative by treatment with triethylamine or from a 3-acetoxypropionate derivative by treatment with 1,8-diazabicyclo-[5,4,0]undec-7-ene at elevated temperature, eg. about 90C.
The compounds of the forrnula tI) wherein Y is CH(OH)(CH2)mCO2H are prepared ~rom an epoxide precursor of ~he following stmctural formulas (X) and (XI) R2~l ~COOR I \N;~, R~ (X) Rl (XI) wherein Rl, R2, A and m are the sarne as described above, and Rl6 is - C1 to C6aLIcoxy. A compound of forrnula (X) or (XI) is reacted in an inert solvent with triethylamine and a substituted thiol selected to give, after removal of ester protecti~e groups, a product of formula (I).
The epoxide precursors of fonnula (X) or (XI) where m is 0 are prepared by reaction of an aldehyde of the formula (VI) or (VII) wi~h a lower alkyl chloroacetare and an alkali metal alkoxide, such as sodium methoxide.
Alternatively, the compounds of the formula (I) wherein Y is CH(OH)COR16 are prepared from a propenoate precursor of formula (VIII) or (IX) wherein R16 is lower all;yl.
The 2-thioimidazole precursors necessary ~o prepare the R-heterocyclic derivatives of formula (I) are known compounds or are wo 9~/16889 P~r/u~ 2l~ fi 2 conveniently prepared employing standard chemical reactions.
Preferably these reactants bearing a carboxyl or carboxymethyl substituent as set forth in R8 and R~ above are employed as the corresponding carboalkoxy derivatives wherein the alkoxy radical contains from one to six carbon atoms. When pr~sent, the alkoxy subs~ituent is subsequently hydrolyzed to give the free carboxyl or carboxymethyl substituted products.
Appropriate modifications of the general processes disclosed, and as further described iD the Examples provided hereinbelow, furnish thc various compounds defined by formula (I).
l~ie leuko~iene antagonist activity of the compounds of this invention is measured by the ability of the compounds to inhibit the leukotriene induced contraction of guinea pig tracheal tissues in vitro.
The following methodology was employed: In vitrQ: Guinea pig (adul~
male albino Hartley strain) tracheal spiral strips of approximate dimensions 2 to 3 mm cross-sectional width and 3.5 cm length were ba~hed in modified Krebs buffer in jacketed 10 ml tissue ba~h and continuously aeratcd with 95% 0~15% C02. The tissues were connected via silk suture to force displacement transducers for 2 0 reeording isometric tension. The tissues were equilibrated for 1 hr, prctreated for 15 minutes with meclofenamic acid (1 mM) to remove intrinsic prostaglandin responses1 and then pretreated for an additional 30 minutes with either the test compound or vehicle control. .9 cumulative concentration-response curve for LTD4 on 2 5 triplicate tissues was generated by successive increases in the bath concentration of.the LTD4. In order to minimize intertissue variabiIity, the contractions elicited by LTD4 were standardized as percentage of the maximum rcsponse obtained to a reference agonist.
carbachol ( I O mM) .
3 0 Calcula~ions: The averages of the ~riplicate LTD4 concentration-response curves both in the presence and absence of the test compound w~,re plotted on log graph paper. The concentration of LTD4 needed to elicit 30% of the contraction elicited by car~achol measured and defined as ~he EC30. The -log KB value for the ~est 3 5 compound was determined by the following equations:
I. ~30 (presence of test compound? = dose ratio = X
EC30 (presence of vehicle control) t;
WO 9l;168~9 2 ~ 8 ~ ~ ~ 2 Pc~rtUS9l/02884 ~
2. KB = concentration of test compound/(X-1) The compounds of this invention possess an~agonist activity against leukotrienes, primarily leukotriene D4. The antagonist 5 aetivity of represen~ative compounds of this invention is ~abula~ed below. The -log KB Yalues were calculated from the above test protocols. Where compounds were tested more than once, the -log KB
~ralues given herein represent the current average da~a. Compound 3-(2-carboxyeth~lthio-3-~3-dodecylthien-2-yl)propionic acid at a molar 10 concentration of 10-5 showed a pKB of 6.5 in comparison lo a pKg of 7.3 for a 10-6 molar concen~ation of 2-hydroxy-3(R)-2-carboxyethylthio)-3-[2-(8-phenyloctyl)phenyl]propionic acid, a known leukotriene antagonist. Likewise, methyl 2-hydroxy-3-(2-carboxyethylthio)-3-(3-dodecylimidazol-2-yl)propionate was tes~ed 15 against the afore men~ioned phenylpropionic acid, the imidazole ha~ing a pKg of 5.9 at a molar concentration of 10-5 and the phenylpropionic acid having a pKg of 8.3 at a molar concentration of The specificity of the antagonist acti~i~y of a number of the 2 0 compounds of this invention is demonstrated by relatively low levels of antagonism toward agonists such as potassium chloride, carbachol.
histamine and PGF2-Pharmaceutical compositions of the present inven~ion comprisea pharmaceutical carrier or diluent and an amount of a compound of 2 5 the formula (I) or a pharmaceutically acceptable salt, such as an alkali me~al salt thereof, sufficient to produce the inhibition of the effects of leukotrienes .
When the pharmaceutical composition is employed in the form of a solution or suspension, examples of appropria~e pharmaceutical 3 0 carriers or diluents include: for aqueous systems, water; for non-aqueous systems, ethanol, glycerin, propylene glycol, corn oil, cot~onseed oil, peanut oil, sesame oil, liquid parafins and .nixtures thereof with water; for solid systems, lactose, kaolin and mannitol;
and for aerosol systems, dichlorodifluoromethane, 35 chlorotrifluoroe~hane and compressed carbon dioxide. Also. in addition to the pharmaceutical carrier or diluent, the instant compositions may include other ingredients such as stabilizers.
. i i ~ 08~ ~ 6~
wo 91/16889 ; ~ -~ Pcr/~lssl/o2884 .
- antioxidants, preserva~ives, lubricants, suspending agents, viscosity modifiers and the like, provided that the additional ingredients do no~
have a detrimental effect on the therapeutic action of the instant compositions .
S The nature of the composition and the pharmaceutical carrier or diluent will, of course, depend upon the intended roote of administration, for example parenterally, topically, orally or by inhalation.
In general, particularly for the prophylactic ~reatment of asthma, the compositions will be in a form sui~able for administra~ion by inhalation. Thus the compositions will comprise a suspension or solution of the ac~ive ingredien~ in wa~er for administration by means of a conventionaI nebulizer. Alternatively the compositions will comprise a suspension or solution of the active ingredient in a conventional liquified propellant or compressed gas to be administered from a pressurized aerosol container. The compositions may also comprise the solid active ingredient diluted with a solid diluent for administration from a powder inhalation device. In the above compositions, the amount of carrier or diluent will vary but preferably. ~ill be the major proportion of a suspension or solution of the ac~ive ingredient. When the diluent is a solid it may be presen~ in lesser, equal or greater amounts than the solid active ingredient.
For parenteral administra~ion the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampul or an ? 5 aqueous or nonaqueous liquid suspension.
For topical administration the pharmaceutical composition will be in the form of a cream, ointment, liniment, Ic~ion, pastes, and drops ~uitable for administration to the eye, ear, or nose.
For oral administlation the pharmaceutical composition will be 3 0 in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syrup liquid, or emulsion.
Usually a compoun~l of formula I is administered to a subject in - a composition comprising a nontoxic amount sufficient to produce an inhibition of the symptoms of a dise~se in which leukotrienes are a 3 5 factor. When employed in this manner. the dosage of the composi~ion is selected from the range of from 350 mg to 1000 mo of active ingredient for each administration. For convenience, equ~l doses will wo 91/168X9 2 ~ 8 1 4 ~ 2 Pcr/US91/02884 ~
l 4 be administered l ~o 5 ~imes daily with the daily dosage regimen being selected from about 350 mg to about 5000 mg.
The pharrnaceutical preparations thus described are made following the conventional techniques of the phamaceutical chemist as 5 appropriate to the desired end product.
Included within the scope of this disclosure is the method of treating a disease which comprises administering to a subject a therapeutically effective amount of a compound of formula L
preferably in the form of a pharmaceutical composition. For example, 10 inhibiting the symptoms of an allergic response resulting frorn a mediator release by administration of an effective amount of a compound of formula I is included within the scope of this disclosure.
The administration may be carried out in dosage units at suitable intervals or in single doses as needed. Usually this method will be 15 practiced when relief of symptoms is specifically required. However, the me~hod is also usefully camed out as continuous or prophylactic treatmenl. It is within the skill of the art to determine by routine experimentation the effectiYe dosage to be administered ~rom the dose range set forth above, taking into consideration such factors as 2 0 the degree of severity of the condition or disease being treated, and so forth.
Compounds of this invention, alone and in combination with a histamine Hl-receptor antagonist, inhibi~ antigen-induced conrrac~ion of isolated, sensitized guinea pig ~rachea (a model of respiralory 5 anaphy1axis as described by Weichman, B.M., Wasserman, M.A., Holden, D.A., Osborn, R.R., Woodward, D.F., Ku, T.W., and Gleason, J.G.. J
Ph~macol. Exp. Ther., 227, 700-705, l 983.
Pharmaceutical compositions, as described hereinaoove, of the present invention also comprise a pharmaceutical carrier or diluent 30 and a combina~ion of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, and an histamine Hl-receptor antagonist in amounts sufficient to inhibit antigen- induced respiratory anaphylaxis. The above-defined dosage of a compound of formula I is conveniently employed for this purpose and the kno~ n 3 5 effective dosage for the histamine Hl -receptor antagonist. The methods of administration described above for the single active wo 91/16889 Pcr/ussl2o0 l S
ingredient can similarly be employed for ~he combination with a histamine Hl-receptor anta~onist.
The following examples illustrate the preparation of the compounds of this invention and their incorporation into S pharma~eutical composi~ions and as such are not to be considered as limiting the invention se~ forth in the claims appended hereto.
;E~xam~
>~ ~
2-yl2~rol2ionic acid (i), ~ ~
A mixture of 3-methyl-2-thiophenecarboxylic acid (lO g, 0.07 mole) and thionyl chloride (20 rnL) was hea~ed a~ 50C for 2 hours. IR
analysis indicated l~omplete conversion to ~he acid chloride. Excess l 5 thionyl chloride was evaporated and the residue was azeotroped with dry toluene (3 times). The crude product was dissolved in ether, s~irred with activated charcoal, filtered and concentrated to provide 3-methyl-2-thiophenecarboxylic acid chloride as an oil: which was not purified further.
2 0 (ii) ~
A solution of 3-methyl-2-thiophenecarboxylic acid chloride (9 g.
0.056 mole) in di~hloromethane (50 mL) was treated dropwise below 20C with a solution of 2-amino-2-methyl-l-propanol (9.98 g, O.l l~
mole) in dichloromethane (20 mL). The resulting solution was lhen 2 S stirTed at ambient temperature for 2 hours, extrac~ed with water and the organic phase was dried tMgSO4) and concentrated. This concentrate was suspended in toluene (lO0 mL), and ~hionyl chloride (l35 mL, 0.18 mole) was added dropwise to the st~lTed suspension below 30C. After being sti~red at 25C for l 8 hours, the solvent was 3 0 removed and the residue was partitioned between water and ether.
The aqueous layer was extracted with additional ether, and the combined organic layer was washed ~ h brine, dried tMgSO4) and concen~rated to 11.9 g of crude ma~erial. This was purified by Qash chromatography over silica gel with 9: l petroleum ether/ether to 3 5 provide 4,4-dimethyl-2-[2-(3-methylthienvl)]oxazoline as an oil; 90 MHz lH NMR (CDC13): 1.3 ppm (s, 6H), 2.55 (s, 3H), 4.05 ~s. 2H?, 6.~5 (d, lH), 7.25 (d, lH).
?wo ~ s889 pcr/us~l/o2884 ,_ 2081~62 (iii) 4~ ~2 ~ Qdecvl th ie~Lox azoline ~, To a solution of 4,4-dimethyl-2-E2-(3-methylthienyl)]oxazoline (2 g, 10.2 mmole) in ethyl ether (15 mL) cooled to -78C was added dropwise n.-butyl lithiurn (8.8 mL of 2.5 M in hexanes). The resulting solution was stirred an additional 20 minutes at -78C, and then stirred for 30 to 40 minutes at 0C. The reaction mixture was recooled to -78C, and a solution of l-bromodecane (2.58 g, 11 mmole) in ether (10 rnL) was added slowly. l~e coolant was removed, and the mixture was stirred at ambient temperature for 18 hours. The reaction was quenched with saturated NH4Cl solution. The product was extracted with additional ether, and the organic phase was then washed with brine, dried and was concentrated. Chromatography over silica gel with 5% e~hyl ether in petroleum ether afforded the 4,4-dimethyl~2-~2-(3-dodecylthienyl)]oxazoline as an oil; 90 MHz I H
NMR tCDC13): 9.4-1.8 ppm (m, 23H), 1.32 (s, 6H), 2.95 (broad t. 2H), 4.1 (s, 2H), 6.9 (d, lH), 7.3 (d, lH).
(iv) ~ ~-dQdecvlthis~ ~ethYlo~Yazolinium iodide.
A mixture of 4,4-dimethyl-2-[2-(3-dodecylthienyl)]oxazoline (6.2 g, 31.7 mmole) and methyl iodide (70 rnl,) was refluxed for 24 2 ~ hours under an argon atmosphere. Excess methyl iodide was evaporated, the semi-solid residue was suspended in petroleum ether and filtered. The solid was stirred in diethyl ether and filtered to obtain solid 2-[2-~3-dodecylthienyl)]-3,4,4-trimethyloxazolinium iodide; mp 148-154C; 90 MHz lH NMR (CDC13): 0.65-1.75 ppm (m~
23H), 1.75 (s, 6H), 2.95 ~broad t, 2H), 3.65 (s, 3H), 5.1 (broad s, ~H), 7.2 (d, lH), 8.1 (d, lH).
(v) 3-dodecy~ ~ thiophenecarboxa~ehvde.
A solution of sodium bis-(2-methoxyethoxy)aluminum hydride ~ in toluene (15 rnL of 0.34 M solution, 5.1 mmole) was cooled to -70C3 0 under an argon atmosphere, and was treated dropwise with a solution of 7-~2-(3-dodecylthienyl)]-3,4,4-trimethyloxazolinium iodide (4 g, 8.1 mmole) in THF (20 mL) while maintaining the temperature belo~
-~C. ~hen the mixture was stirred at -SC to 10C for 4 hours. E.Yces hydride reagent was quenched by the slow addition of dilute HCI. and the mixture was then stirred at 25C fo}- 18 hours. The separated organic layer was washed wi~h sodium sulfite solution and wa~er, and the co.~.centrated, dried product was flash chromatographed over silica wo 91/16889 . , pcr/us91/o2884 . .
gel with 5 % ether in petroleum ether to afford 3-dodecyl-2-thiophenecarboxaldehyde as an oil; 90 MHz lH NMR (CDC13): 0.75-1.9 ppm (m, 23H), 3.0 (broad t, 2~), 7.0 (d, lH), 7.65 (d, lH), 10.1 (s, lH).
(vi) ~DL~-Lithium diisopropyl amide was prepared by ~he ad~ition of n-butyl lithium (1.1 mL of 2.5 M in hexanes) to a solution of diisopropylamine (288 mg, 2.85 mmole) in THl: (5 rnL) held at -78C
under an argon atmosphere. After being stirred for S minutes, t-butyl acetate (330 mg, 2.85 mmole) in TX~ (5 rnL) was then added dropwise, and the resulting solution was stirred at -78C for 15 minutes. Then a solution of 3-dodecyl-2-thiophenecarboxaldehyde (799 mg, 2.85 mmole) in THF (5 m7 ) was added slowly, and the resulting mixture was stirred an additional hour at -78C. The mixture was allowed to slowly warm to ambient tempera~ure, and stirring was ~hen continued for another hour. Saturated NH4C 1 solution and ether were added, and the organic phase was washed wi~h brine, dried, concentrated and flash chromatographed over silic~
gel with an elu~on system of 15% of ethyl ether and 85% of petroleum ether to afford t-butyl 3-[2-(3-dodecylthienyl)]-3-hydroxypropionate as an oil;
270 MHz lH NMR (CDC13): 0.89 ppm (t,3H), 1.5 (broad s, 18H), 1.49-1.65 (m and s~ llH), 2.55-2.85 (m,4H); 3.44 (s,lH), 5.4 (dd, lH), 6.88 (d,lH), 7.19 (d,lH).
(Yii) ~L2-carboxvethvlthio)~ -dodecvlthien-2-vl~propioniç acid.
2 5 A solution of t-butyl 3-[2-(3-dodecylthienyl)]-3-hydroxypropionate (400 mg, 1 mmole) in dichloromethane (6 mL) was cooled to -10C and 3-mercaptopropionic acid (634 mg, 6 mmole was added. Then tri~uoroacetic acid (8 mL) was added dropwise a~
-10C. After being stirred at -10C for 45 minutes and a~ 0C for 5 3 0 hours, the mixture was partitioned between dichloromethane and water. The organic extract was washed with water, dried, concentrated and chromatographed over silica gel with a solution of 80:20 hexaneslethyl ~cetate containing 0.25% of formic acid to provide 3-(2-carboxyethylthio)-3-(3-dodecylthien-2-yl)propionic ~cid (oily); 270 MHz lH NMR (CDC13): 0.86 ppm (t.3H), 1.25 (broad s~ 18H~.
1.54 (m,2H), 2.42 (t,2H), 2.46-2.65 (m,4H), 2.68 (dd, 1 H), ~.8~ (dd, I H`).
:! - ` 2 0 81 a~ 6 2 pcr/us9l/o2884 3.34 (s,2H), 4.61 (t,lH), 6,82 (d,lH), 7.32 (d,lH). Anal. Calcd. for C22H36O4S2:C, 61.64; H, 8.47. ~ound: C, 62.03; H, 8.14.
, ~mJ~1~2 ~ ~rbQxvethvl~hio)-(i) ~
A mixture of 1 8-crown-6 (0.8 g) and potassium t-butoxide (3.9 g, 0.035 mmole) in benzene (50 mL) was stirred for 15 minutes. Then 10 imidazole (2.04 g, 0.03 mole) was added, and, after 30 minutes at 2~C, the mixture was heated to 60C and dodecyl bromide (8.71 g~
0.035 mole) in benzene (20 mL) was added over 15 minutes. This mixture was heated at 60C for one hour, then cooled, diluted with water, and the layers were separated. The wa~er-washed, dried 15 organic layer was concentra~ed and the residue was flash chromatographed over silica gel with 4:1 ethyl acetate/methanol to provide 1-dodecylimidazole.
lH NMR tCDC13): 0.82-1.02 ppm (m,3H), 1.16-1.54 (m,18H), 1.7 (t,2H), 3.96 (t,2H), 6.92 (s,lH), 7.06 (s,1H), 7.46 (s,lH).
2 0 (ii) ~Q~c~limida~le-2-carboxaldehvde.
A solution of l-dodecylimidazole (~.77 g, 11.7 mmole) in ethyl ether (100 mL) was cooled to -50C and n-butyl lithium (5 mL of 2.6 M in hexanes) was addPd. After one hour of stirrin" at -50C, dimethylformamide (2 mT ) was then added and the mixture .was 2 5 allowed to warm to ambient temperature over 30 minutes. The reaction was diluted wi~h satura~ed NH4CI solution, the ether layer was separaled and washed with brine, dried and concentrated. This crude product was chromatographed over silica gel with 50% ethyl acetate in hcxanes to afford l-dodecylimida~ole-2-carboxaldehyde as 30 an oil; lH NMR (CDC13): 0.78-0.96 ppm (m,3H), 1.15-1.50 (m,18H), 1.58-2.02 (m,2H), 440 (t,2H), 7.16 (s,lH), 7.26 (s,lH), 9.85 (s,lH).
(iii) ~
A solution of l-dodecylimidazole-2-carboxaldehyde (1.4 g, 5 3 mmole) in dichloromethane (25 mL) was cooled to -~0C and tre~ted 3 5 with methyl chloroacetate (763 mg, 7.03 mmole) followed by sodium methoxide in methanol (1.27 mL of 25% I` aOMe). The temperature 20~62 WO 91/1688g PCr/uSslto2884 .. .. ..
was raised to 0C, stirred for 2.5 hours at 0C, and then poured into cold O.SN HCI. The layers were se:parated, and the organic phase was dried, concentrated and the residuc was flash chromatographed over silica gel with ethyl acetate to yield of the oily ~rans-2-carbomethoxv 3-(1-dodecylimidazol-2-yl)-oxirane; lH NMR (CDC13): 0.72-0.90 ppm (m,3H), 1.05-1.40 (m,l 8H), 1.54-1.94 (m,2H), 3.67 (s,lH), 3,82 (s.3H), 3.92 (s,1H), 4.10 (t72H), 6.88 (s,lH), 6.92 (s,lH).
~odeçvlimida~ Y~S~a~e~
A~ ~olution of trans 2-carbomethoxy-3-( 1 -dodecylimidazol-2-yl)oxirane (1.06 g, 3.16 mmole), methyl 3-mercaptopropionate (4.16 mg, 3.47 mmole), triethylamine (0.47 mL, 3.47 mmole) in methanol (10 mL) was stirred at ambient temperature for 16 hours. The sol~cnt was evaporated and the residue was chromatographed over silica gel with 7:3 hexanes/ethyl aeetate to give methyl 2-hydroxy-3-(2-carbomethoxyethylthio-3-(1-dodecylimidazol-2-yl)propionate (oil).
lH NMR (CDC13): 0.80-0.94 ppm (t,3H), 1.10-1.50 (m,14H), 1.60-1.92 (m.2H), 2.22-2.50 (m,2H), 2.72-2.96 (m,2H), 3.67 ~s,6H), 3.88-4.20 (m,2H), 4.40 (d,lH), 4.75 (d,lH), 6.57 (broad s, lH), 6.88 (s,2H).
2 0 ~v! ~f~.S~-hvdrQxy-3~$.R)-(~-c~r~QxYethYlthioi-3-(1-A solution of methyl 2-hydroxy-3-(2-carbomethoxyethyl~hio)-3-(1-dodecylimidazol-2-yl)propionate (400 mg, 0.88 mmole) in methanol (12 mL) was ~eated with a solution of sodium hydroxide (96 mg, 2.4 mmole) in water (4 mL). This mixture was stirred at ambient temperature for 28 hours. The solvents were evaporated, the residue was dissolved in water (20 mL) and the aqueous solution was acidified with 3.0 N HCl (0.8 mL). The product was extracted into 1:1 methyl ethyl ketone and ethyl acetate. The washed extrac~s were 3 0 dried, and the solvent was evaporated to afford homogeneous, oily 2(R,S)-hydroxy-3(S ,R)-(2-carboxymethylthio)-3 -(1 -dodecylimidazol -2-yl)propionic acid;
lH NMR (Me2CO-D6): 0.70-1.01 ppm (m,3H), 1.06-1.60 (m,l~H).
1.67-2.13 (m,2H), 2.36-3.06 (m,4H), 4.20 (t,2H), 4.68 (d,lH), 4.78 3 5 (d,IH), 7.21 (s,1H), 7.36 (s,lH), 10.18 (broad, 3H).
WO`91/16889 2 0 8 ~ ~ 6 2 PCI`/US91/02884 ~
~ .
~ .' The title compound is prepared by the method described in Example 1 (i-vii) by using 2-methyl-3-~hiophenecarboxylic acid in 5 place of 3-methyl-2-thiophenecarboxylic acid.
~lç ~
The title compound is prepared by the method described in 10 Exarnple l(i-vii) by using 2-me~hyl-3-furancarboxylic acid in place of 3-methyl-2-thiophenecarboxylic acid.
~mple 5 3-('~-Carbo~xvethYl~hio!-3-~3-~8-pheny!Qctyl)thien-2-vllpropionic acid 1~ The title compound is synthesized from 3-(8-phenyloctyl)-2-thiophenecarboxaldehyde, prepared from 4,4-dimethyl-2-[2-(3-methoxythienyl]oxazoline and 8-phenyloctyl bromide following ~he procedure given in EPO application No. 0 202 759 published 26 November, 1 986.
Examp~_6 ~-(2-C.arboxYeth~ ~ L~dodecvl-lH-~imidazol-2-vl~propionic ~cid The title compound is prepared by using 1-dodecylimidazol-~-carboxaldehyde [Example 2(ii)] in the method outlined in Example 2 5 1 (vi-vii) for 3-dodecyl-2-thiophenecarboxaldehyde.
xamp~
3-(2-carboxvethvlthio-~-rl -f 8-~henvl~ctYI~- I H-imidazol-~-3 0 The title compound is prepared by the method described in Example 1 (vi-vii) by using I -(8-phen.yloctyl)- 1 H-imidazole-2-~,arboxaldehyde ~whieh is Frepared by the methods outlined in Example 2(i-ii) using 8-phenyloctyl bromide] in place of dodecyl bromide in place of 3-dodecyl-2-thiophenecarboxaldehyde.
Examp!e 8 3-(2-Carhoxvethvlthio)-3-(3 -dodecvlthien-~ -vl-~0~1~62 wo 91/16889 ~ Pcr/uss1/o2884 .
~-hvdr~x~r~ionic acid The title compound is prepared by the method described in Example 2(iii-Y) by using 3-dodecyl-2-thiophenecarboxaldehyde in place of 1-dodecylimidazole-2-carboxaldehyde.
~2!Q2 ~-(2-~boxYethylthio~ dQ
~hvdroxv~Q~
l~e ~tle compound is prepared by the method described in 10 Ex~mple 2(iii-v) by using 3-dodecyl-2-furancarboxaldehyde in place of l-dodecylimidazole-2-carboxaldehyde.
E~am~2~
l 5 ¢tetrazol-5-vl~hexanQlc acid The title compound is prepared from 3-dodecyl-2-thiophenecarboxaldehyde by condensation with ethyl 2-(tetrazol-5-yl) acetate (as per EPO application No. 0 2Q2 759 published 26 November, 1986) after which the condensation product is oxidized to 2 0 méthyl 3-(3-dodecylthien-2-yl-3-keto-2-(~etrazol-5-yl)propionate by manganese dioxide in refluxing toluene. This B-keto acid is decarboxylated in hot acetic acid/hydrochloric acid as described in the above reference, the resulting (3-dodecylthien-2-yl)-5-methyltetrazolketone is reduced with sodium borohydride in 2 5 methanol to provide the 3-hydroxy derivative, and the ti~le compound is obtained on treatment with 3-mercaptopropionic acid in trifluoroacetic acid as described in Example 1 ~vii).
~ample 1, 1 30 4-Thia-5-(1-dodecvl-1~-imidazol-2-yl)-6-(tetrazol-5-vl~hexanoic acid The title compound is prepared by tke method described in Example 10 by using 1-dodecylimidazole-2-carboxaldehyde in place of 3-dodecyl-2-~hiophenecarboxaldehyde.
3 5 Example 12 2-(4-Carbosvphenoxv)-2-(3-dodecvlthien-2-vl)acetic acid (i) methyl 2-chloro-2-(3-dodecylthien-2-yl)acetate.
WO 9~/16X89 2 0 8 1 ~L 6 2 PCr/US91/02884 ~
i The title compound is prepared from 3-dodecyl-2-thio-phenecarboxaldehyde 1 (v) following the procedure given in U.S .
Patent No. 4,820,719 for the preparation of methyl 2-chloro-2-(2-dodecyl-phenyl)acetate frorn 2-dodecylbenzaldehyde.
5 (ii) 2-~4-Carboxyphenoxy)-2-(3-doclecylthien-2-yl)acetic acid The title compound is prepared from methyl 2-chloro-2-(3-dodecylthien-2-yl)acetate by reaction with methyl 4-hydroxy-benzoate and potassium carbonate in dimethylformamide followed by saponi~lcation of the diester.
ExamR~
Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forrns and with numerous exeipients. Examples of such formularions are given below.
n~redients Per Tabiet Per 10,000 I~ets:
1. Ac~ive ingrediont 2 0 (Cpd of Forrn. I) 40 mg 400 g 2. Corn Starch 20 mg 200 g 3. Alginic acid 20 mg 200 g 4. Sodium alginate 20 mg 200 g 5. Mg stearate 1.3_rng~
101.3 mg 1013 g Procedure for tablets:
Step 1 Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitabl~ mixer/blender.
3 0 Step 2 Add sufficient water portion-wise to the blend from Step 1 with careful mixing after each addition. Such addirions of water and mixing until the mass is of a consistency to permit its conversion to wet granules.
Step 3 The we~ mass is converted tO granules by passing it 3 5 through an oscillating granulator using a ~o. 8 mesh (.3S
mm) screen.
propionic acid, and (6) 3-(2-carboxyethylthio)-3-(3-dodecylfur-2-yl)propionic 1 5 acid.
A further particular group of compounds of ~his. inven~ion are those where X is S, Y is -C(OH)HCOR3, R is -(CH2)nD, -(CH2)nArD or ArD, Rl is Cg to C13-aIkyl or phenyl-C4 to Clo-alkyl, A is S, O, or N and B is X-R
CH or -NR2 where ~he group ~Y is not R2. The most preferred X-R
compounds of this group are those where ~Y is at the 2-position:
3 -(2-carboxyethylthio)-3-(3-dodecylthien-2-yl)-~ -hydroxypropionic acid;
3-(2-carboxyethylthio)-3 -(3 -(8-phenyloc tyl)thien-~ -yl)-2-hydroxypropionic acid, 2 5 3-(2-carboxyethylthio)-3-( 1 -dodecyl- 1 H-imidazol-~ -yl)-~ -hydroxypropionic acid, 3-(2-carboxyethylthio)-3-( 1 -(~8~phenyloctyl)- 1 H-imidazol-~ -yl)-2-hydroxypropionic acid, 3-(2-carboxyethylthio)-3-(3 -dodecylfur-~ -yl)-~ -3 0 hydroxypropionic acid; and 3-(2-carboxyethylthio)-3-(3-(8-phenyloctyl)fur-~ -vl)-~-hydroxypropionic acid.
WO 91/16889 PCI/~ IS9l/02884 ~
2 0 ~ 2 Another preferred class of compounds of this inven~ion are the compounds where Y is (CH2)0- l -tetrazol-S-yl or -CH(OH)-tetrazol-~ -vl .
X is S, R is -(CH2)nD, -(CH~)nArD or A~D, A is O, S or N, B is -CH- or ~TR~
where the group ~Y is not R2, and Rl is C8 to C13-aLIcyl or phenyl-C~
X-R
S to C~lo-alkyl. The most preferred compounds are those where ~Y is at the 2-position,: ¦
4-thia-5-(3-dodecyl~hien-2-yl)-6-(tetrazol-5-yl)hexanoic acid;
4-thia-5 (1-dodecyl-lH-imidazol-2-yl)-6-(tetrazol-5-yl)hexanoic acid;
I 0 4-thia-5-(3-( 8 -phenyloctyl)thien-2-yl )-6-( tetrazol-S -yl)hexanoic acid;
4-thia-5-(1-(8~phenyloctyl)-lH-imidazol-2-yl)-6-(tetrazol-5-yl)hexanoic acid 4-thia-5-(3-dodecylfur-2-yl)-6-(tetrazol-5-yl)hexanoic acid;
l $ 4-thia-5-(3-(8-phenyloctyl)fur-2-yl)-6-(tetrazol-5-yl)hexanoic a id;
4-thia-5-(3-dodecylthien-2-yl)-6-hydroxy-6-(teIra~
yl)hexanoic acid;
4-thia-S-(-1 -dodecyl- 1 H-imidazol-2-yl)-6-hydroxy-6-(tetrazol -2 0 5-yl)hexanoic acid;
4-thia-S-(3-(8-phenyloctyl)thien-2-yl)-6-(te~razol-5-yl)hexanoic acid;
4-thia-5 (1-(8-phenyloctyl)-lH-imidazol-2-yl)-6-hydroxy-6-(~etrazol-S-yl)hexanoic acid ' 2 5 4-thia-5-(3-dodecylfur-2-yl)-6-hydroxy-6-(te~razol-5-yl)-hexanoic acid; and 4-~hia-5-(3-(8-phenyloctyl),fur-2-yl)-6-hydroxy-6-(tetrazol-5 -yl)hexanoic acid.
A second class of preferred compounds are those where X is O~
3 0 particularly those p ~alleling the preferred and most preferTed defi~i~ions for the case where X is S given above. Most preferred compounds of this group are the following compounds: .
3-(2-carboxyethyloxy)-3-(3-dodecylthien-~-yl)propionic acid:
3-~2-carboxyethyloxy3-3-[3-(8-phenyloctyl)thien-2-yl]-3 5 propionic acid;
XV~1~62 WO 91/16889 ~ j PCr/US91/02884 3-(2-carboxyethyloxy)-3-( 1 -dodecyl- 1 H-imidazol-2-yl) propionic acid;
3-(2-carboxyethyloxy)-3-[1-(8-phenyloctyl)-lH-imidazol-~-yl]propionic acid.
3 -(2-carboxyethyloxy)-3 -(3 -dodecylthien -2-yl)-2 -hydro~ypropionic acid;
3-(2-carboxye thyloxy)-3 -(1 dodecyl- 1 H-imidazol- 2 -yl) -2 -hydroxypropionic acid;
4-oxy-5-(3-dodecylthien-2-yl)-6-(tetrazol-5-yl)hexanoic acid;
1 0 4-oxy-5-(3 -(8 -phenylsctyl)thien-2-yl)-6-(tetrazol-5 -yl?hexanoic acid;
4-oxy-5-(1 -(8-phenyloctyl)-lH-imidazol-2-yl)-6-(tetrazol-5-yl)hexanoic acid; and 4-oxy-5-( 1 -dodecyl- 1 H-imidazol-2-yl)-6-(tetrazol-5 -yl)hexanoic acid.
AIl compounds of this invention have at least one assymetric center due to X being sulfur or oxygen. Some of the compounds of the fo~nula ~I) contain two asymmetric centers, such as ~hen Ra in the Y
sustituent is other than hydrogen, such as is n~ethyl, methoxy, fluoro 2 0 or hydroxy. Osher asymetric centers may also be present in these molecules depending on the selection of subsùtuents in any given compound. In practice, these compounds are prepared as a mixture ot stereoisomers. all steroisomers, as mixtures or resolved isomers, are included in this invention. Resolution procedures employing, for example, optically active amines furnish the separa~ed enantiomers.
Pharmaceutically acceptable esters may be formed from those compounds having a carboxylic acid function ie when R has the -C(:R~
tenninal groupO Such an ester, or di-ester as the case may be will be - any ester which, as with pharmacuetically acceptable salts, gives an 3 0 ester which retains tbe activity of the parent compound and does not impart to the parent acid any unacceptable untoward pharmacologic~l or toxic affects in the context of its intended use and application.
While it is expected that any carboxylic acid ester may be used. it is preferred to employ certain esters derived from the following - 3 5 radicals: Cl to C6 a]kyl, cycloalkyl, aryl, arylalkyl, alkylaryl.
alkylaryla~kyl, arninoalkyl, indanyl, pivaloyloxyn ethyl, 1' ~ t. ~' ',,' 1~
wo 91/16889 2 0 814 6 2 PCr/USg1/02884 ~
acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, or thienylglycyloxymethyl.
The compounds of the present invention, depending on their s~ucture, are capable of forming pharmaceutically acceptable salts 5 with acids and bases according ~o procedures well known in the arn Such salts are those which match the-activity of the parent compound and do not exhibit untoward or deliberous activity. Acceptable acids include inorganic and organic acids, such as hydrochloric, sulfuric, methanesulfonic, benzenesulfonic, p-toluenesulfonic acid and acetic 10 acid. Bases include organic and inorganic bases, such as ammonia, arginine, organie amines, alkali metal bases and alkaline earth metal bases. Pipera~ine and ethylenediamine salts are particularly useful in this invention. Also preferred are the dipotassium, disodium, dimagnesium, dizinc, and dicalcium salts of the diacid compounds of 15 forrnula (I). Pharmaceut.ically acceptable cations are the same as rhe just recited base-derived pharmaceutically acceptable salts.
The compounds of the formula ~1) wherein Y is CH2C02H are prepared by reacting the appropriate aldehydes of the formula VI or VII, wherein Rl, R2 and A are as described above and an esterified 2 0 bromoacetate, conveniently t-butyl bromoacetate, with a mixture of diethyl aluminum chloride, zinc dust and a catalytic amount of cuprous bromide at low temperatures in an inert solvent to give the esterified 3-hydroxypropionate derivative which is reacted directlv with a substituted thiol in ~rifluoroacetic acid. Alternatively. a 2 5 mixture of trimethyl borate and zinc in tetrahydrofuran may be used to prepare the 3-hydroxypropionate derivative. Preferably, compounds of formula (I) are prepared from the aldehydes VI or VII
by reaction with lithium diisopropylamide and t-butyl acetate at -78C to 25C in a suitable solvent such as, for example, THF, to provide 3 0 ~he precursor es2erified 3-hydroxypropionate derivatives which are converted to the thiol acids with ~ mercaptan in trifluoroacetic acid.
By employing an esterified 2-b,omopropionate in the above reaction with an aldehydes VI or VII, the compounds of the formula (I) wherein Y is CH(~H3)C02H are obtained.
WO 91/16889 PCl /US91/02884 .. ~'I; ' ' .~
~A~CE~O ~N~C~IO
.2iQ ~ R2iQ~
Rl (VI) Rl (VII) .
To prepare the compounds of formula (I) wherein q is l or 2, the appropriate thio product is conveniently oxidized with sodium 5 period~te or metachloroperben~oic acid to obtain ~he sulfoxide or sulfone product.
The aldehydes of the forrnula (VI) and (VI1) are known or readily prepared utilizing the general procedures described as follows.
The aldehyde precursors to the compounds of the formula (I) 10 wherein R1 is, for exarnple, an aL~cyl radical containing 8 to 13 carbon atoms are prepared from the appropriate 2-methoxyphenyl-4,4-dimethyloxazoline [see Meyers e~ al. J. Qr~. ~hem., ~, 1372 (1973)].
The aldehyde precursors to the compounds of the formula (I) wherein R 1 is a 1 -alkynyl radical con~aining 10 to 12 carbon atoms 15 are prepar~d by coupling a halobenzaldehyde with the: appropriate l-aL~;yne in the presence of cuprous iodide and (P03)2PdC12. [See Eigahara et al., Svnthesi_. 627 (1980)]. The catalytic hydrogenation of these alkynyl containing precursors under standard conditions affords the aldehyde precursors of the compounds of the formula (I) wherein 20 Rl is an alkyl or phenylalkyl radical.
Alternatively, ~he compounds of ~he formula (I) wherein Y is CH2C02H are prepared from a propionate precursor of Ihe following structural formulas ~VIII) and (IX).
2~¦~ R,,,~ COORI6 2 5 Rl (VIII) Rl (IX) wherein R1, R2 and A are described above, and R16 is an es~er protective group, such as t-butyl. A compound of formula (VIII) or (IX) is reacted with a mix~ure of alkali metal alkoxide. such as sodium 6~89 2 0 8 1 ~ 6 2 Pc-r/uss1/02884 "_~
methoxide, and substituted thiol to give, after removal of the ester protective group, products of formula (I).
The propionate precursors of formula (VIII) or (IX) are prepared from the corresponding aldehydes of formulas (VI) and S (VII) by general procedures such as reaction with an alkyl (triphenylphosphoranylidene)aceta~e or by conversion of the aldehyde to a 3-hydroxypropionate derivative, as described above, followed by an elimina2ion reaction to form the double bond.
Additionally, the propenoate precursor is obtained from a 3-me~hane-sulfonyloxypropionate derivative by treatment with triethylamine or from a 3-acetoxypropionate derivative by treatment with 1,8-diazabicyclo-[5,4,0]undec-7-ene at elevated temperature, eg. about 90C.
The compounds of the forrnula tI) wherein Y is CH(OH)(CH2)mCO2H are prepared ~rom an epoxide precursor of ~he following stmctural formulas (X) and (XI) R2~l ~COOR I \N;~, R~ (X) Rl (XI) wherein Rl, R2, A and m are the sarne as described above, and Rl6 is - C1 to C6aLIcoxy. A compound of forrnula (X) or (XI) is reacted in an inert solvent with triethylamine and a substituted thiol selected to give, after removal of ester protecti~e groups, a product of formula (I).
The epoxide precursors of fonnula (X) or (XI) where m is 0 are prepared by reaction of an aldehyde of the formula (VI) or (VII) wi~h a lower alkyl chloroacetare and an alkali metal alkoxide, such as sodium methoxide.
Alternatively, the compounds of the formula (I) wherein Y is CH(OH)COR16 are prepared from a propenoate precursor of formula (VIII) or (IX) wherein R16 is lower all;yl.
The 2-thioimidazole precursors necessary ~o prepare the R-heterocyclic derivatives of formula (I) are known compounds or are wo 9~/16889 P~r/u~ 2l~ fi 2 conveniently prepared employing standard chemical reactions.
Preferably these reactants bearing a carboxyl or carboxymethyl substituent as set forth in R8 and R~ above are employed as the corresponding carboalkoxy derivatives wherein the alkoxy radical contains from one to six carbon atoms. When pr~sent, the alkoxy subs~ituent is subsequently hydrolyzed to give the free carboxyl or carboxymethyl substituted products.
Appropriate modifications of the general processes disclosed, and as further described iD the Examples provided hereinbelow, furnish thc various compounds defined by formula (I).
l~ie leuko~iene antagonist activity of the compounds of this invention is measured by the ability of the compounds to inhibit the leukotriene induced contraction of guinea pig tracheal tissues in vitro.
The following methodology was employed: In vitrQ: Guinea pig (adul~
male albino Hartley strain) tracheal spiral strips of approximate dimensions 2 to 3 mm cross-sectional width and 3.5 cm length were ba~hed in modified Krebs buffer in jacketed 10 ml tissue ba~h and continuously aeratcd with 95% 0~15% C02. The tissues were connected via silk suture to force displacement transducers for 2 0 reeording isometric tension. The tissues were equilibrated for 1 hr, prctreated for 15 minutes with meclofenamic acid (1 mM) to remove intrinsic prostaglandin responses1 and then pretreated for an additional 30 minutes with either the test compound or vehicle control. .9 cumulative concentration-response curve for LTD4 on 2 5 triplicate tissues was generated by successive increases in the bath concentration of.the LTD4. In order to minimize intertissue variabiIity, the contractions elicited by LTD4 were standardized as percentage of the maximum rcsponse obtained to a reference agonist.
carbachol ( I O mM) .
3 0 Calcula~ions: The averages of the ~riplicate LTD4 concentration-response curves both in the presence and absence of the test compound w~,re plotted on log graph paper. The concentration of LTD4 needed to elicit 30% of the contraction elicited by car~achol measured and defined as ~he EC30. The -log KB value for the ~est 3 5 compound was determined by the following equations:
I. ~30 (presence of test compound? = dose ratio = X
EC30 (presence of vehicle control) t;
WO 9l;168~9 2 ~ 8 ~ ~ ~ 2 Pc~rtUS9l/02884 ~
2. KB = concentration of test compound/(X-1) The compounds of this invention possess an~agonist activity against leukotrienes, primarily leukotriene D4. The antagonist 5 aetivity of represen~ative compounds of this invention is ~abula~ed below. The -log KB Yalues were calculated from the above test protocols. Where compounds were tested more than once, the -log KB
~ralues given herein represent the current average da~a. Compound 3-(2-carboxyeth~lthio-3-~3-dodecylthien-2-yl)propionic acid at a molar 10 concentration of 10-5 showed a pKB of 6.5 in comparison lo a pKg of 7.3 for a 10-6 molar concen~ation of 2-hydroxy-3(R)-2-carboxyethylthio)-3-[2-(8-phenyloctyl)phenyl]propionic acid, a known leukotriene antagonist. Likewise, methyl 2-hydroxy-3-(2-carboxyethylthio)-3-(3-dodecylimidazol-2-yl)propionate was tes~ed 15 against the afore men~ioned phenylpropionic acid, the imidazole ha~ing a pKg of 5.9 at a molar concentration of 10-5 and the phenylpropionic acid having a pKg of 8.3 at a molar concentration of The specificity of the antagonist acti~i~y of a number of the 2 0 compounds of this invention is demonstrated by relatively low levels of antagonism toward agonists such as potassium chloride, carbachol.
histamine and PGF2-Pharmaceutical compositions of the present inven~ion comprisea pharmaceutical carrier or diluent and an amount of a compound of 2 5 the formula (I) or a pharmaceutically acceptable salt, such as an alkali me~al salt thereof, sufficient to produce the inhibition of the effects of leukotrienes .
When the pharmaceutical composition is employed in the form of a solution or suspension, examples of appropria~e pharmaceutical 3 0 carriers or diluents include: for aqueous systems, water; for non-aqueous systems, ethanol, glycerin, propylene glycol, corn oil, cot~onseed oil, peanut oil, sesame oil, liquid parafins and .nixtures thereof with water; for solid systems, lactose, kaolin and mannitol;
and for aerosol systems, dichlorodifluoromethane, 35 chlorotrifluoroe~hane and compressed carbon dioxide. Also. in addition to the pharmaceutical carrier or diluent, the instant compositions may include other ingredients such as stabilizers.
. i i ~ 08~ ~ 6~
wo 91/16889 ; ~ -~ Pcr/~lssl/o2884 .
- antioxidants, preserva~ives, lubricants, suspending agents, viscosity modifiers and the like, provided that the additional ingredients do no~
have a detrimental effect on the therapeutic action of the instant compositions .
S The nature of the composition and the pharmaceutical carrier or diluent will, of course, depend upon the intended roote of administration, for example parenterally, topically, orally or by inhalation.
In general, particularly for the prophylactic ~reatment of asthma, the compositions will be in a form sui~able for administra~ion by inhalation. Thus the compositions will comprise a suspension or solution of the ac~ive ingredien~ in wa~er for administration by means of a conventionaI nebulizer. Alternatively the compositions will comprise a suspension or solution of the active ingredient in a conventional liquified propellant or compressed gas to be administered from a pressurized aerosol container. The compositions may also comprise the solid active ingredient diluted with a solid diluent for administration from a powder inhalation device. In the above compositions, the amount of carrier or diluent will vary but preferably. ~ill be the major proportion of a suspension or solution of the ac~ive ingredient. When the diluent is a solid it may be presen~ in lesser, equal or greater amounts than the solid active ingredient.
For parenteral administra~ion the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampul or an ? 5 aqueous or nonaqueous liquid suspension.
For topical administration the pharmaceutical composition will be in the form of a cream, ointment, liniment, Ic~ion, pastes, and drops ~uitable for administration to the eye, ear, or nose.
For oral administlation the pharmaceutical composition will be 3 0 in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syrup liquid, or emulsion.
Usually a compoun~l of formula I is administered to a subject in - a composition comprising a nontoxic amount sufficient to produce an inhibition of the symptoms of a dise~se in which leukotrienes are a 3 5 factor. When employed in this manner. the dosage of the composi~ion is selected from the range of from 350 mg to 1000 mo of active ingredient for each administration. For convenience, equ~l doses will wo 91/168X9 2 ~ 8 1 4 ~ 2 Pcr/US91/02884 ~
l 4 be administered l ~o 5 ~imes daily with the daily dosage regimen being selected from about 350 mg to about 5000 mg.
The pharrnaceutical preparations thus described are made following the conventional techniques of the phamaceutical chemist as 5 appropriate to the desired end product.
Included within the scope of this disclosure is the method of treating a disease which comprises administering to a subject a therapeutically effective amount of a compound of formula L
preferably in the form of a pharmaceutical composition. For example, 10 inhibiting the symptoms of an allergic response resulting frorn a mediator release by administration of an effective amount of a compound of formula I is included within the scope of this disclosure.
The administration may be carried out in dosage units at suitable intervals or in single doses as needed. Usually this method will be 15 practiced when relief of symptoms is specifically required. However, the me~hod is also usefully camed out as continuous or prophylactic treatmenl. It is within the skill of the art to determine by routine experimentation the effectiYe dosage to be administered ~rom the dose range set forth above, taking into consideration such factors as 2 0 the degree of severity of the condition or disease being treated, and so forth.
Compounds of this invention, alone and in combination with a histamine Hl-receptor antagonist, inhibi~ antigen-induced conrrac~ion of isolated, sensitized guinea pig ~rachea (a model of respiralory 5 anaphy1axis as described by Weichman, B.M., Wasserman, M.A., Holden, D.A., Osborn, R.R., Woodward, D.F., Ku, T.W., and Gleason, J.G.. J
Ph~macol. Exp. Ther., 227, 700-705, l 983.
Pharmaceutical compositions, as described hereinaoove, of the present invention also comprise a pharmaceutical carrier or diluent 30 and a combina~ion of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, and an histamine Hl-receptor antagonist in amounts sufficient to inhibit antigen- induced respiratory anaphylaxis. The above-defined dosage of a compound of formula I is conveniently employed for this purpose and the kno~ n 3 5 effective dosage for the histamine Hl -receptor antagonist. The methods of administration described above for the single active wo 91/16889 Pcr/ussl2o0 l S
ingredient can similarly be employed for ~he combination with a histamine Hl-receptor anta~onist.
The following examples illustrate the preparation of the compounds of this invention and their incorporation into S pharma~eutical composi~ions and as such are not to be considered as limiting the invention se~ forth in the claims appended hereto.
;E~xam~
>~ ~
2-yl2~rol2ionic acid (i), ~ ~
A mixture of 3-methyl-2-thiophenecarboxylic acid (lO g, 0.07 mole) and thionyl chloride (20 rnL) was hea~ed a~ 50C for 2 hours. IR
analysis indicated l~omplete conversion to ~he acid chloride. Excess l 5 thionyl chloride was evaporated and the residue was azeotroped with dry toluene (3 times). The crude product was dissolved in ether, s~irred with activated charcoal, filtered and concentrated to provide 3-methyl-2-thiophenecarboxylic acid chloride as an oil: which was not purified further.
2 0 (ii) ~
A solution of 3-methyl-2-thiophenecarboxylic acid chloride (9 g.
0.056 mole) in di~hloromethane (50 mL) was treated dropwise below 20C with a solution of 2-amino-2-methyl-l-propanol (9.98 g, O.l l~
mole) in dichloromethane (20 mL). The resulting solution was lhen 2 S stirTed at ambient temperature for 2 hours, extrac~ed with water and the organic phase was dried tMgSO4) and concentrated. This concentrate was suspended in toluene (lO0 mL), and ~hionyl chloride (l35 mL, 0.18 mole) was added dropwise to the st~lTed suspension below 30C. After being sti~red at 25C for l 8 hours, the solvent was 3 0 removed and the residue was partitioned between water and ether.
The aqueous layer was extracted with additional ether, and the combined organic layer was washed ~ h brine, dried tMgSO4) and concen~rated to 11.9 g of crude ma~erial. This was purified by Qash chromatography over silica gel with 9: l petroleum ether/ether to 3 5 provide 4,4-dimethyl-2-[2-(3-methylthienvl)]oxazoline as an oil; 90 MHz lH NMR (CDC13): 1.3 ppm (s, 6H), 2.55 (s, 3H), 4.05 ~s. 2H?, 6.~5 (d, lH), 7.25 (d, lH).
?wo ~ s889 pcr/us~l/o2884 ,_ 2081~62 (iii) 4~ ~2 ~ Qdecvl th ie~Lox azoline ~, To a solution of 4,4-dimethyl-2-E2-(3-methylthienyl)]oxazoline (2 g, 10.2 mmole) in ethyl ether (15 mL) cooled to -78C was added dropwise n.-butyl lithiurn (8.8 mL of 2.5 M in hexanes). The resulting solution was stirred an additional 20 minutes at -78C, and then stirred for 30 to 40 minutes at 0C. The reaction mixture was recooled to -78C, and a solution of l-bromodecane (2.58 g, 11 mmole) in ether (10 rnL) was added slowly. l~e coolant was removed, and the mixture was stirred at ambient temperature for 18 hours. The reaction was quenched with saturated NH4Cl solution. The product was extracted with additional ether, and the organic phase was then washed with brine, dried and was concentrated. Chromatography over silica gel with 5% e~hyl ether in petroleum ether afforded the 4,4-dimethyl~2-~2-(3-dodecylthienyl)]oxazoline as an oil; 90 MHz I H
NMR tCDC13): 9.4-1.8 ppm (m, 23H), 1.32 (s, 6H), 2.95 (broad t. 2H), 4.1 (s, 2H), 6.9 (d, lH), 7.3 (d, lH).
(iv) ~ ~-dQdecvlthis~ ~ethYlo~Yazolinium iodide.
A mixture of 4,4-dimethyl-2-[2-(3-dodecylthienyl)]oxazoline (6.2 g, 31.7 mmole) and methyl iodide (70 rnl,) was refluxed for 24 2 ~ hours under an argon atmosphere. Excess methyl iodide was evaporated, the semi-solid residue was suspended in petroleum ether and filtered. The solid was stirred in diethyl ether and filtered to obtain solid 2-[2-~3-dodecylthienyl)]-3,4,4-trimethyloxazolinium iodide; mp 148-154C; 90 MHz lH NMR (CDC13): 0.65-1.75 ppm (m~
23H), 1.75 (s, 6H), 2.95 ~broad t, 2H), 3.65 (s, 3H), 5.1 (broad s, ~H), 7.2 (d, lH), 8.1 (d, lH).
(v) 3-dodecy~ ~ thiophenecarboxa~ehvde.
A solution of sodium bis-(2-methoxyethoxy)aluminum hydride ~ in toluene (15 rnL of 0.34 M solution, 5.1 mmole) was cooled to -70C3 0 under an argon atmosphere, and was treated dropwise with a solution of 7-~2-(3-dodecylthienyl)]-3,4,4-trimethyloxazolinium iodide (4 g, 8.1 mmole) in THF (20 mL) while maintaining the temperature belo~
-~C. ~hen the mixture was stirred at -SC to 10C for 4 hours. E.Yces hydride reagent was quenched by the slow addition of dilute HCI. and the mixture was then stirred at 25C fo}- 18 hours. The separated organic layer was washed wi~h sodium sulfite solution and wa~er, and the co.~.centrated, dried product was flash chromatographed over silica wo 91/16889 . , pcr/us91/o2884 . .
gel with 5 % ether in petroleum ether to afford 3-dodecyl-2-thiophenecarboxaldehyde as an oil; 90 MHz lH NMR (CDC13): 0.75-1.9 ppm (m, 23H), 3.0 (broad t, 2~), 7.0 (d, lH), 7.65 (d, lH), 10.1 (s, lH).
(vi) ~DL~-Lithium diisopropyl amide was prepared by ~he ad~ition of n-butyl lithium (1.1 mL of 2.5 M in hexanes) to a solution of diisopropylamine (288 mg, 2.85 mmole) in THl: (5 rnL) held at -78C
under an argon atmosphere. After being stirred for S minutes, t-butyl acetate (330 mg, 2.85 mmole) in TX~ (5 rnL) was then added dropwise, and the resulting solution was stirred at -78C for 15 minutes. Then a solution of 3-dodecyl-2-thiophenecarboxaldehyde (799 mg, 2.85 mmole) in THF (5 m7 ) was added slowly, and the resulting mixture was stirred an additional hour at -78C. The mixture was allowed to slowly warm to ambient tempera~ure, and stirring was ~hen continued for another hour. Saturated NH4C 1 solution and ether were added, and the organic phase was washed wi~h brine, dried, concentrated and flash chromatographed over silic~
gel with an elu~on system of 15% of ethyl ether and 85% of petroleum ether to afford t-butyl 3-[2-(3-dodecylthienyl)]-3-hydroxypropionate as an oil;
270 MHz lH NMR (CDC13): 0.89 ppm (t,3H), 1.5 (broad s, 18H), 1.49-1.65 (m and s~ llH), 2.55-2.85 (m,4H); 3.44 (s,lH), 5.4 (dd, lH), 6.88 (d,lH), 7.19 (d,lH).
(Yii) ~L2-carboxvethvlthio)~ -dodecvlthien-2-vl~propioniç acid.
2 5 A solution of t-butyl 3-[2-(3-dodecylthienyl)]-3-hydroxypropionate (400 mg, 1 mmole) in dichloromethane (6 mL) was cooled to -10C and 3-mercaptopropionic acid (634 mg, 6 mmole was added. Then tri~uoroacetic acid (8 mL) was added dropwise a~
-10C. After being stirred at -10C for 45 minutes and a~ 0C for 5 3 0 hours, the mixture was partitioned between dichloromethane and water. The organic extract was washed with water, dried, concentrated and chromatographed over silica gel with a solution of 80:20 hexaneslethyl ~cetate containing 0.25% of formic acid to provide 3-(2-carboxyethylthio)-3-(3-dodecylthien-2-yl)propionic ~cid (oily); 270 MHz lH NMR (CDC13): 0.86 ppm (t.3H), 1.25 (broad s~ 18H~.
1.54 (m,2H), 2.42 (t,2H), 2.46-2.65 (m,4H), 2.68 (dd, 1 H), ~.8~ (dd, I H`).
:! - ` 2 0 81 a~ 6 2 pcr/us9l/o2884 3.34 (s,2H), 4.61 (t,lH), 6,82 (d,lH), 7.32 (d,lH). Anal. Calcd. for C22H36O4S2:C, 61.64; H, 8.47. ~ound: C, 62.03; H, 8.14.
, ~mJ~1~2 ~ ~rbQxvethvl~hio)-(i) ~
A mixture of 1 8-crown-6 (0.8 g) and potassium t-butoxide (3.9 g, 0.035 mmole) in benzene (50 mL) was stirred for 15 minutes. Then 10 imidazole (2.04 g, 0.03 mole) was added, and, after 30 minutes at 2~C, the mixture was heated to 60C and dodecyl bromide (8.71 g~
0.035 mole) in benzene (20 mL) was added over 15 minutes. This mixture was heated at 60C for one hour, then cooled, diluted with water, and the layers were separated. The wa~er-washed, dried 15 organic layer was concentra~ed and the residue was flash chromatographed over silica gel with 4:1 ethyl acetate/methanol to provide 1-dodecylimidazole.
lH NMR tCDC13): 0.82-1.02 ppm (m,3H), 1.16-1.54 (m,18H), 1.7 (t,2H), 3.96 (t,2H), 6.92 (s,lH), 7.06 (s,1H), 7.46 (s,lH).
2 0 (ii) ~Q~c~limida~le-2-carboxaldehvde.
A solution of l-dodecylimidazole (~.77 g, 11.7 mmole) in ethyl ether (100 mL) was cooled to -50C and n-butyl lithium (5 mL of 2.6 M in hexanes) was addPd. After one hour of stirrin" at -50C, dimethylformamide (2 mT ) was then added and the mixture .was 2 5 allowed to warm to ambient temperature over 30 minutes. The reaction was diluted wi~h satura~ed NH4CI solution, the ether layer was separaled and washed with brine, dried and concentrated. This crude product was chromatographed over silica gel with 50% ethyl acetate in hcxanes to afford l-dodecylimida~ole-2-carboxaldehyde as 30 an oil; lH NMR (CDC13): 0.78-0.96 ppm (m,3H), 1.15-1.50 (m,18H), 1.58-2.02 (m,2H), 440 (t,2H), 7.16 (s,lH), 7.26 (s,lH), 9.85 (s,lH).
(iii) ~
A solution of l-dodecylimidazole-2-carboxaldehyde (1.4 g, 5 3 mmole) in dichloromethane (25 mL) was cooled to -~0C and tre~ted 3 5 with methyl chloroacetate (763 mg, 7.03 mmole) followed by sodium methoxide in methanol (1.27 mL of 25% I` aOMe). The temperature 20~62 WO 91/1688g PCr/uSslto2884 .. .. ..
was raised to 0C, stirred for 2.5 hours at 0C, and then poured into cold O.SN HCI. The layers were se:parated, and the organic phase was dried, concentrated and the residuc was flash chromatographed over silica gel with ethyl acetate to yield of the oily ~rans-2-carbomethoxv 3-(1-dodecylimidazol-2-yl)-oxirane; lH NMR (CDC13): 0.72-0.90 ppm (m,3H), 1.05-1.40 (m,l 8H), 1.54-1.94 (m,2H), 3.67 (s,lH), 3,82 (s.3H), 3.92 (s,1H), 4.10 (t72H), 6.88 (s,lH), 6.92 (s,lH).
~odeçvlimida~ Y~S~a~e~
A~ ~olution of trans 2-carbomethoxy-3-( 1 -dodecylimidazol-2-yl)oxirane (1.06 g, 3.16 mmole), methyl 3-mercaptopropionate (4.16 mg, 3.47 mmole), triethylamine (0.47 mL, 3.47 mmole) in methanol (10 mL) was stirred at ambient temperature for 16 hours. The sol~cnt was evaporated and the residue was chromatographed over silica gel with 7:3 hexanes/ethyl aeetate to give methyl 2-hydroxy-3-(2-carbomethoxyethylthio-3-(1-dodecylimidazol-2-yl)propionate (oil).
lH NMR (CDC13): 0.80-0.94 ppm (t,3H), 1.10-1.50 (m,14H), 1.60-1.92 (m.2H), 2.22-2.50 (m,2H), 2.72-2.96 (m,2H), 3.67 ~s,6H), 3.88-4.20 (m,2H), 4.40 (d,lH), 4.75 (d,lH), 6.57 (broad s, lH), 6.88 (s,2H).
2 0 ~v! ~f~.S~-hvdrQxy-3~$.R)-(~-c~r~QxYethYlthioi-3-(1-A solution of methyl 2-hydroxy-3-(2-carbomethoxyethyl~hio)-3-(1-dodecylimidazol-2-yl)propionate (400 mg, 0.88 mmole) in methanol (12 mL) was ~eated with a solution of sodium hydroxide (96 mg, 2.4 mmole) in water (4 mL). This mixture was stirred at ambient temperature for 28 hours. The solvents were evaporated, the residue was dissolved in water (20 mL) and the aqueous solution was acidified with 3.0 N HCl (0.8 mL). The product was extracted into 1:1 methyl ethyl ketone and ethyl acetate. The washed extrac~s were 3 0 dried, and the solvent was evaporated to afford homogeneous, oily 2(R,S)-hydroxy-3(S ,R)-(2-carboxymethylthio)-3 -(1 -dodecylimidazol -2-yl)propionic acid;
lH NMR (Me2CO-D6): 0.70-1.01 ppm (m,3H), 1.06-1.60 (m,l~H).
1.67-2.13 (m,2H), 2.36-3.06 (m,4H), 4.20 (t,2H), 4.68 (d,lH), 4.78 3 5 (d,IH), 7.21 (s,1H), 7.36 (s,lH), 10.18 (broad, 3H).
WO`91/16889 2 0 8 ~ ~ 6 2 PCI`/US91/02884 ~
~ .
~ .' The title compound is prepared by the method described in Example 1 (i-vii) by using 2-methyl-3-~hiophenecarboxylic acid in 5 place of 3-methyl-2-thiophenecarboxylic acid.
~lç ~
The title compound is prepared by the method described in 10 Exarnple l(i-vii) by using 2-me~hyl-3-furancarboxylic acid in place of 3-methyl-2-thiophenecarboxylic acid.
~mple 5 3-('~-Carbo~xvethYl~hio!-3-~3-~8-pheny!Qctyl)thien-2-vllpropionic acid 1~ The title compound is synthesized from 3-(8-phenyloctyl)-2-thiophenecarboxaldehyde, prepared from 4,4-dimethyl-2-[2-(3-methoxythienyl]oxazoline and 8-phenyloctyl bromide following ~he procedure given in EPO application No. 0 202 759 published 26 November, 1 986.
Examp~_6 ~-(2-C.arboxYeth~ ~ L~dodecvl-lH-~imidazol-2-vl~propionic ~cid The title compound is prepared by using 1-dodecylimidazol-~-carboxaldehyde [Example 2(ii)] in the method outlined in Example 2 5 1 (vi-vii) for 3-dodecyl-2-thiophenecarboxaldehyde.
xamp~
3-(2-carboxvethvlthio-~-rl -f 8-~henvl~ctYI~- I H-imidazol-~-3 0 The title compound is prepared by the method described in Example 1 (vi-vii) by using I -(8-phen.yloctyl)- 1 H-imidazole-2-~,arboxaldehyde ~whieh is Frepared by the methods outlined in Example 2(i-ii) using 8-phenyloctyl bromide] in place of dodecyl bromide in place of 3-dodecyl-2-thiophenecarboxaldehyde.
Examp!e 8 3-(2-Carhoxvethvlthio)-3-(3 -dodecvlthien-~ -vl-~0~1~62 wo 91/16889 ~ Pcr/uss1/o2884 .
~-hvdr~x~r~ionic acid The title compound is prepared by the method described in Example 2(iii-Y) by using 3-dodecyl-2-thiophenecarboxaldehyde in place of 1-dodecylimidazole-2-carboxaldehyde.
~2!Q2 ~-(2-~boxYethylthio~ dQ
~hvdroxv~Q~
l~e ~tle compound is prepared by the method described in 10 Ex~mple 2(iii-v) by using 3-dodecyl-2-furancarboxaldehyde in place of l-dodecylimidazole-2-carboxaldehyde.
E~am~2~
l 5 ¢tetrazol-5-vl~hexanQlc acid The title compound is prepared from 3-dodecyl-2-thiophenecarboxaldehyde by condensation with ethyl 2-(tetrazol-5-yl) acetate (as per EPO application No. 0 2Q2 759 published 26 November, 1986) after which the condensation product is oxidized to 2 0 méthyl 3-(3-dodecylthien-2-yl-3-keto-2-(~etrazol-5-yl)propionate by manganese dioxide in refluxing toluene. This B-keto acid is decarboxylated in hot acetic acid/hydrochloric acid as described in the above reference, the resulting (3-dodecylthien-2-yl)-5-methyltetrazolketone is reduced with sodium borohydride in 2 5 methanol to provide the 3-hydroxy derivative, and the ti~le compound is obtained on treatment with 3-mercaptopropionic acid in trifluoroacetic acid as described in Example 1 ~vii).
~ample 1, 1 30 4-Thia-5-(1-dodecvl-1~-imidazol-2-yl)-6-(tetrazol-5-vl~hexanoic acid The title compound is prepared by tke method described in Example 10 by using 1-dodecylimidazole-2-carboxaldehyde in place of 3-dodecyl-2-~hiophenecarboxaldehyde.
3 5 Example 12 2-(4-Carbosvphenoxv)-2-(3-dodecvlthien-2-vl)acetic acid (i) methyl 2-chloro-2-(3-dodecylthien-2-yl)acetate.
WO 9~/16X89 2 0 8 1 ~L 6 2 PCr/US91/02884 ~
i The title compound is prepared from 3-dodecyl-2-thio-phenecarboxaldehyde 1 (v) following the procedure given in U.S .
Patent No. 4,820,719 for the preparation of methyl 2-chloro-2-(2-dodecyl-phenyl)acetate frorn 2-dodecylbenzaldehyde.
5 (ii) 2-~4-Carboxyphenoxy)-2-(3-doclecylthien-2-yl)acetic acid The title compound is prepared from methyl 2-chloro-2-(3-dodecylthien-2-yl)acetate by reaction with methyl 4-hydroxy-benzoate and potassium carbonate in dimethylformamide followed by saponi~lcation of the diester.
ExamR~
Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forrns and with numerous exeipients. Examples of such formularions are given below.
n~redients Per Tabiet Per 10,000 I~ets:
1. Ac~ive ingrediont 2 0 (Cpd of Forrn. I) 40 mg 400 g 2. Corn Starch 20 mg 200 g 3. Alginic acid 20 mg 200 g 4. Sodium alginate 20 mg 200 g 5. Mg stearate 1.3_rng~
101.3 mg 1013 g Procedure for tablets:
Step 1 Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitabl~ mixer/blender.
3 0 Step 2 Add sufficient water portion-wise to the blend from Step 1 with careful mixing after each addition. Such addirions of water and mixing until the mass is of a consistency to permit its conversion to wet granules.
Step 3 The we~ mass is converted tO granules by passing it 3 5 through an oscillating granulator using a ~o. 8 mesh (.3S
mm) screen.
9 . `: `, ` . i ~ PCr/US91~02884 Step 4 The wet granules are the~n dried in an oven at 410F
(60C) unlil dry.
Step 5 The dry granules are lubricated with ingredient No. S.
Step 6 The lubricated granules are compressed on a suitable tablet press.
Tn~ nts Pçr ~u~ P~r lQ00 Su~p.
1. Formula I compound40.0 mg 40 g Active ingredient 2. Polyethylelle Glycol 1350.0 mg 1,350 g 3. polyethylene glycol ~
4000 1 840.0 mg 1 ,840 g Procedure:
Step 1. Melt ingredient No. 2 and No. 3 cogether and s~ir until uniform .
20 Step 2. Dissolve ingredient No. 1 in the molten mass from Step 1 and stir until uniform.
Step 3. Pour the molten mass from Step 2 into supository moulds and chill.
Step 4. Remove ~he suppositories from rnoulds and wrap.
(60C) unlil dry.
Step 5 The dry granules are lubricated with ingredient No. S.
Step 6 The lubricated granules are compressed on a suitable tablet press.
Tn~ nts Pçr ~u~ P~r lQ00 Su~p.
1. Formula I compound40.0 mg 40 g Active ingredient 2. Polyethylelle Glycol 1350.0 mg 1,350 g 3. polyethylene glycol ~
4000 1 840.0 mg 1 ,840 g Procedure:
Step 1. Melt ingredient No. 2 and No. 3 cogether and s~ir until uniform .
20 Step 2. Dissolve ingredient No. 1 in the molten mass from Step 1 and stir until uniform.
Step 3. Pour the molten mass from Step 2 into supository moulds and chill.
Step 4. Remove ~he suppositories from rnoulds and wrap.
Claims (29)
1. The compounds of formula (I) (I) wherein R1 is not substituted on A or B;
X is O or S(O)q where q is 0, 1 or 2 with the proviso that R1 is not alkylthio or phenylthioalkyl when q is 1 or 2;
R1 is C8 to C13 alkyl, C7 to C12 alkoxy, C7 to C12 alkylthio, C10 to C12 I-alkynyl, 10-undecynyloxy, 11-dodecynyl, phenyl-C4 to C10 alkyl, phenyl-C3 to C9 alkoxy, phenylthio-C3 to C9 alkyl with each phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, C1 to C4 alkoxy, methylthio or trifluoromethylthio, furyl-C4 to C10 alkyl, trifluoromethyl-C7 to C12 alkyl or cyclohexyl-C4 to C10 alkyl;
A is O, or N;
B is CH or NR2;
R2 is H, C1 to C13 alkyl, C10 to C12-I-alkynyl, 11-docedynyl, phenyl-C4 to C10 alkyl with phenyl optionally monosubstituted or ;
the dotted line between A and B indicates a single bond in one position and a double bond in the other;
Y is R3, CH(R4)(CH2)mR3, CH(R4)-tetrazol-5-yl, or tetrazol-5-yl;
R3 is -COR5 where R5 is -OH or OE where E is a pharmaceutically acceptable cation or a pharmaceutically acceptable ester-forming group, -CN, -SO3H, -SO2NH2, -NHSO2R7, -CH(NH2)COR5, or -CONHCH2COR5, or R3 is -CON(R6)2 where R6 is H, C1 to C6 alkyl.
phenylC1-C6alkyl, or the two R6 groups are combined to form a cyclic group having 3 to 5 carbons;
R4 is hydrogen, methyl, C1 to C4 alkoxy, fluoro or hydroxy;
R7 is C1 to C10-alkyl, phenyl or substituted phenyl;
m is 0, 1, or 2;
R is -(CH2)nD, -(CH2)nArD or ArD where n is 0-6, Ar is phenyl or substituted phenyl, thienyl, pyridyl, imidazolyl, tetrazol-5-yl or thiazolyl and D is -(CH2)nR3, -COR3, tetrazol-5-yl, -CH(NH2)R3, -CONHCH2COR5, -NHSO2R7, -SO3H, -CN, or-SO2NH2; or a pharmaceutically acceptable salt thereof.
X is O or S(O)q where q is 0, 1 or 2 with the proviso that R1 is not alkylthio or phenylthioalkyl when q is 1 or 2;
R1 is C8 to C13 alkyl, C7 to C12 alkoxy, C7 to C12 alkylthio, C10 to C12 I-alkynyl, 10-undecynyloxy, 11-dodecynyl, phenyl-C4 to C10 alkyl, phenyl-C3 to C9 alkoxy, phenylthio-C3 to C9 alkyl with each phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, C1 to C4 alkoxy, methylthio or trifluoromethylthio, furyl-C4 to C10 alkyl, trifluoromethyl-C7 to C12 alkyl or cyclohexyl-C4 to C10 alkyl;
A is O, or N;
B is CH or NR2;
R2 is H, C1 to C13 alkyl, C10 to C12-I-alkynyl, 11-docedynyl, phenyl-C4 to C10 alkyl with phenyl optionally monosubstituted or ;
the dotted line between A and B indicates a single bond in one position and a double bond in the other;
Y is R3, CH(R4)(CH2)mR3, CH(R4)-tetrazol-5-yl, or tetrazol-5-yl;
R3 is -COR5 where R5 is -OH or OE where E is a pharmaceutically acceptable cation or a pharmaceutically acceptable ester-forming group, -CN, -SO3H, -SO2NH2, -NHSO2R7, -CH(NH2)COR5, or -CONHCH2COR5, or R3 is -CON(R6)2 where R6 is H, C1 to C6 alkyl.
phenylC1-C6alkyl, or the two R6 groups are combined to form a cyclic group having 3 to 5 carbons;
R4 is hydrogen, methyl, C1 to C4 alkoxy, fluoro or hydroxy;
R7 is C1 to C10-alkyl, phenyl or substituted phenyl;
m is 0, 1, or 2;
R is -(CH2)nD, -(CH2)nArD or ArD where n is 0-6, Ar is phenyl or substituted phenyl, thienyl, pyridyl, imidazolyl, tetrazol-5-yl or thiazolyl and D is -(CH2)nR3, -COR3, tetrazol-5-yl, -CH(NH2)R3, -CONHCH2COR5, -NHSO2R7, -SO3H, -CN, or-SO2NH2; or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 where X is S(O)q where q is 0 and Y is -(CH2)0-3COR5 represented by formula (II) (II) where R and R1 are the same as described in claim 1, A is O or N and B is CH or NR2.
3. A compound of claim 2 where X is S, R is -(CH2)nD, -(CH2)nArD or ArD, Y is -CH2COR5, A is O, or N, and B is CH or -NR2 where the group is not R2, and R1 is C8 to C13-alkyl or phenyl-C4 to C10-alkyl.
4. A compound of claim 3 where X is S, A is N, B is NR2 and Y
is -CH2COR5 represented by the formula:
with the proviso that R2 is not , or a pharmaceutically acceptable salt thereof.
is -CH2COR5 represented by the formula:
with the proviso that R2 is not , or a pharmaceutically acceptable salt thereof.
5. A compound of claim 4 wherein is at the 2-position, and R2 is C8 to C13 alkyl or a phenyl-C4 to C10-alkyl radical.
6. A compound of claim 5 which is 3-(2-carboxyethylthio)-3-(1-dodecyl-1H-imidazol-2-yl-)propionic acid or a pharmaceutically acceptable salt thereof.
7. A compound of claim 6 which is 2-(2-carboxyethylthio)-3-[1-(8-phenyloctyl)-1H-imidazol-2-yl]propionic acid or a pharmaceutically acceptable salt thereof.
8. A compound of claim 2 where X is S, A is O and B is CH.
9. A compound of claim 1 where Y is -C(OH)HCOR5, R is -(CH2)nD, -(CH2)nArD or ArD, R1 is C8 to C13-alkyl or phenyl-C4 to C10-alkyl, A is O, or N and B is CH or -NR2 where the group is not R2.
10. A compound of claim 9 where A is N, B is NR2 where R2 is 8-phenyloctyl or dodecyl, and R is -CH2CH2COOH or a pharmaceutically acceptable salt hereof.
11. A compound of claim 11 which is 3-(2-carboxyethylthio)-3-(1-dodecyl-1H-imidazol-2-yl)-2-hydroxypropionic acid or 3-(2-carboxyethylthio)-3-(1-(8-phenyloctyl)-1H-imidazol-2-yl)-2-hydroxypropionic acid or a pharmaceutically acceptable salt thereof.
12. a compound of claim 9 where A is O, B is CH, is at the 2-position, R is CH2CH2COOH and R1 is 3-(8-phenyloctyl) or 3-dodecyl, or a pharmaceutically acceptable salt thereof.
13. A compound of claim 1 where Y is (CH2)0-1-tetrazol-5-yl or -CH(OH)-tetrazol-5-yl, X is S, R is -(CH2)nD, -(CH2)nArD or ArD, A is O, S or N, B is -CH- or NR2 where the group is not R2.
14. A compound of claim 13 where A is N, B is NR2 where R2 is 8-phenyloctyl or dodecyl, and R is -CH2CH2COOH or a pharmaceutically acceptable salt hereof.
15. A compound of claim 13 where A is O, B is CH, is at the 2-position, R is CH2CH2COOH and R1 is 3-(8-phenyloctyl) or 3-dodecyl or a pharmaceutically acceptable salt thereof.
16. A compound of claim 1 where X is O.
17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula 1 according to claim 1.
18. A pharmaceutical composition according to claim 17 in which the active ingredient is 2(S)-hydroxy-3(R)-(2-carboxyethyl-thio)-3-(1-dodecyl-1H-imidazol-2-yl)propionoic acid or 2(S)-hydroxy-3(R)-(2-carboxyethylthio)-3-(1-(8-phenyloctyl)-1H-imidazol-2-yl)propionoic acid or a pharmaceutically acceptable salt thereof.
19. A method of treating a pulmonary disease in which leukotrienes are a factor in a subject in need thereof comprising administering to such subject an effective amount of a compound of claim 1 either alone or in combination with a pharmaceutically acceptable carrier.
20. A method of treating a non-pulmonary disease in which leukotrienes are a factor in a subject in need thereof comprising administratering to such subject an effective amount of a compound of claim 1 either alone or in combinatin with a pharmaceutically acceptable carrier.
21. The compounds of formula (I) (I) wherein R1 is not substituted on A or B;
X is O or S(O)q where q is 0, 1 or 2 with the proviso that R1 is not alkylthio or phenylthioalkyl when q is 1 or 2;
R1 is C8 to C13 alkyl, C7 to C12 alkoxy, C7 to C12 alkylthio, C10 to C12 I-alkynyl, 10-undecynyloxy, 11-dodecynyl, phenyl-C4 to C10 alkyl, phenyl-C3 to C9 alkoxy, phenylthio-C3 to C9 alkyl with each phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, C1 to C4 alkoxy, methylthio or trifluoromethylthio, furyl-C4 to C10 alkyl, trifluoromethyl-C7 to C12 alkyl or cyclohexyl-C4 to C10 alkyl;
A is S;
B is CH or NR2;
R2 is H, C1 to C13 alkyl, C10 to C12-1-alkynyl, 11-docedynyl, phenyl-C4 to C10 alkyl with phenyl optionally monosubstituted or ;
the dotted line between A and B indicates a single bond in one position and a double bond in the other;
Y is R3, CH(R4)(CH2)mR3, CH(R4)-tetrazol-5-yl, or tetrazol-5-yl;
R3 is -COR5 where R5 is -OH or OE where E is a pharmaceutically acceptable cation or a pharmaceutically acceptable ester-forming group, -CN, -SO3H, -SO2NH2, -NHSO2R7, -CH(NH2)COR5, or -CONHCH2COR5, or R3 is -CON(R6)2 where R6 is H, C1 to C6 alkyl, phenylC1-C6alkyl, or the two R6 groups are combined to form a cyclic group having 3 to 5 carbons;
R4 is hydrogen, methyl, C1 to C4 alkoxy, fluoro or hydroxy;
R7 is C1 to C10-alkyl, phenyl or substituted phenyl;
m is 0, 1, or 2;
R is -(CH2)nD, -(CH2)nArD or ArD where n is 0-6, Ar is phenyl or substituted phenyl, thienyl, pyridyl, imidazolyl, tetrazol-5-yl or thiazolyl and D is -(CH2)nR3, -COR3, tetrazol-5-yl, -CH(NH2)R3, -CONHCH2COR5, -NHSO2R7, -SO3H, -CN, or -SO2NH2; or a pharmaceutically acceptable salt.
X is O or S(O)q where q is 0, 1 or 2 with the proviso that R1 is not alkylthio or phenylthioalkyl when q is 1 or 2;
R1 is C8 to C13 alkyl, C7 to C12 alkoxy, C7 to C12 alkylthio, C10 to C12 I-alkynyl, 10-undecynyloxy, 11-dodecynyl, phenyl-C4 to C10 alkyl, phenyl-C3 to C9 alkoxy, phenylthio-C3 to C9 alkyl with each phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, C1 to C4 alkoxy, methylthio or trifluoromethylthio, furyl-C4 to C10 alkyl, trifluoromethyl-C7 to C12 alkyl or cyclohexyl-C4 to C10 alkyl;
A is S;
B is CH or NR2;
R2 is H, C1 to C13 alkyl, C10 to C12-1-alkynyl, 11-docedynyl, phenyl-C4 to C10 alkyl with phenyl optionally monosubstituted or ;
the dotted line between A and B indicates a single bond in one position and a double bond in the other;
Y is R3, CH(R4)(CH2)mR3, CH(R4)-tetrazol-5-yl, or tetrazol-5-yl;
R3 is -COR5 where R5 is -OH or OE where E is a pharmaceutically acceptable cation or a pharmaceutically acceptable ester-forming group, -CN, -SO3H, -SO2NH2, -NHSO2R7, -CH(NH2)COR5, or -CONHCH2COR5, or R3 is -CON(R6)2 where R6 is H, C1 to C6 alkyl, phenylC1-C6alkyl, or the two R6 groups are combined to form a cyclic group having 3 to 5 carbons;
R4 is hydrogen, methyl, C1 to C4 alkoxy, fluoro or hydroxy;
R7 is C1 to C10-alkyl, phenyl or substituted phenyl;
m is 0, 1, or 2;
R is -(CH2)nD, -(CH2)nArD or ArD where n is 0-6, Ar is phenyl or substituted phenyl, thienyl, pyridyl, imidazolyl, tetrazol-5-yl or thiazolyl and D is -(CH2)nR3, -COR3, tetrazol-5-yl, -CH(NH2)R3, -CONHCH2COR5, -NHSO2R7, -SO3H, -CN, or -SO2NH2; or a pharmaceutically acceptable salt.
22. A compound of claim 21 where X is S(O)q where q is 0 and Y is -(CH2)0-3COR5 represented by formula (II) (II) where R and R1 are the same as described in claim 24, A is S and B is CH or NR2.
23. A compound of claim 22 where X is S, R is -(CH2)nD, -(CH2)nArD or ArD, Y is -CH2COR5, A is S, O, or N, and B is CH or -NR2 where the group is not R2, and R1 is C8 to C13-alkyl or phenyl-C4 to C10-alkyl.
24. A compound of claim 23 where R is -CH2CH2COR5, A is S
and B is -CH-, represented by the formula:
or a pharmaceutically acceptable salt thereof.
and B is -CH-, represented by the formula:
or a pharmaceutically acceptable salt thereof.
25. A compound of claim 24 wherein R1 is C8 to C13 alkyl or phenyl-C4 to C10 alkyl.
26. A compound of claim 25 which is 3-(2-carboxyethylthio)-3-(3-dodecylthien-2-yl)propanoic acid or a pharmaceutically acceptable salt thereof.
27. A compound of claim 26 which is 3-(2-carboxyethylthio)-3-[3-(8-phenyloctyl)thien-2-yl]propanoic acid or a pharmaceutically acceptable salt thereof.
28. A compound of claim 23 where is at the 2-position, X
is S(O)q, Y is C(OH)COR5, and R is -CH2CH2COR3.
is S(O)q, Y is C(OH)COR5, and R is -CH2CH2COR3.
29. A compound of claim 28 where R1 is 3-(8-phenyloctyl) or 3-dodecyl or a pharmaceutically acceptable salt thereof.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US51712090A | 1990-05-01 | 1990-05-01 | |
| US517,120 | 1990-05-01 | ||
| PCT/US1991/002884 WO1991016889A1 (en) | 1990-05-01 | 1991-04-26 | Five-membered ring alkanoic acid leukotriene antagonists |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2081462A1 true CA2081462A1 (en) | 1991-11-02 |
Family
ID=24058448
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002081462A Abandoned CA2081462A1 (en) | 1990-05-01 | 1991-04-26 | Five-membered ring alkanoic acid leukotriene antagonists |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0528957A4 (en) |
| JP (1) | JPH05507082A (en) |
| AU (1) | AU7902991A (en) |
| CA (1) | CA2081462A1 (en) |
| WO (1) | WO1991016889A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003078418A1 (en) * | 2002-03-19 | 2003-09-25 | Mitsubishi Chemical Corporation | 3-hydroxy-3-(2-thienyl)propionamide compound, process for producing the same, and process for producing 3-amino-1-(2-thienyl)-1-propanol compound therefrom |
| US7659409B2 (en) | 2002-03-19 | 2010-02-09 | Mitsubishi Chemical Corporation | 3-Hydroxy-3-(2-thienyl) propionamides and production method thereof, and production method of 3-amino-1-(2-thienyl)-1-propanols using the same |
| DE10212301A1 (en) * | 2002-03-20 | 2003-10-02 | Bayer Ag | Process for the preparation of aryl aminopropanols |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4609744A (en) * | 1983-04-21 | 1986-09-02 | Merck Frosst Canada Inc. | 4-oxo-benzopyran carboxylic acids |
| US4730005A (en) * | 1984-01-19 | 1988-03-08 | Smithkline Beckman Corporation | Leukotriene antagonist |
| CA1276937C (en) * | 1985-04-19 | 1990-11-27 | Smith Kline & French Canada Ltd. | Leukotriene antagonists |
| ZA896260B (en) * | 1988-08-22 | 1990-05-30 | Merrell Dow Pharma | Phenylalkylthiophenes and related compounds |
| US4954513A (en) * | 1988-12-23 | 1990-09-04 | Smithkline Beecham Corporation | Leukotriene antagonists |
-
1991
- 1991-04-26 CA CA002081462A patent/CA2081462A1/en not_active Abandoned
- 1991-04-26 AU AU79029/91A patent/AU7902991A/en not_active Abandoned
- 1991-04-26 EP EP19910910099 patent/EP0528957A4/en not_active Withdrawn
- 1991-04-26 JP JP91509375A patent/JPH05507082A/en active Pending
- 1991-04-26 WO PCT/US1991/002884 patent/WO1991016889A1/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AU7902991A (en) | 1991-11-27 |
| JPH05507082A (en) | 1993-10-14 |
| EP0528957A4 (en) | 1993-05-05 |
| EP0528957A1 (en) | 1993-03-03 |
| WO1991016889A1 (en) | 1991-11-14 |
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