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WO2004002939A2 - Aminoalcohol derivatives - Google Patents

Aminoalcohol derivatives Download PDF

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Publication number
WO2004002939A2
WO2004002939A2 PCT/JP2003/008061 JP0308061W WO2004002939A2 WO 2004002939 A2 WO2004002939 A2 WO 2004002939A2 JP 0308061 W JP0308061 W JP 0308061W WO 2004002939 A2 WO2004002939 A2 WO 2004002939A2
Authority
WO
WIPO (PCT)
Prior art keywords
amino
ethyl
biphenyl
hydrogen
compound
Prior art date
Application number
PCT/JP2003/008061
Other languages
French (fr)
Other versions
WO2004002939A3 (en
Inventor
Kouji Hattori
Yasuyo Tomishita
Masashi Imanishi
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from AUPS3241A external-priority patent/AUPS324102A0/en
Priority claimed from AU2002953604A external-priority patent/AU2002953604A0/en
Priority to JP2004517277A priority Critical patent/JP3852708B2/en
Priority to AU2003248247A priority patent/AU2003248247B2/en
Priority to MXPA04012783A priority patent/MXPA04012783A/en
Priority to NZ537206A priority patent/NZ537206A/en
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to BR0311788-0A priority patent/BR0311788A/en
Priority to KR1020047020608A priority patent/KR100693367B1/en
Priority to EP03761807A priority patent/EP1546086A2/en
Priority to CA002492065A priority patent/CA2492065A1/en
Publication of WO2004002939A2 publication Critical patent/WO2004002939A2/en
Priority to NO20050470A priority patent/NO20050470L/en
Publication of WO2004002939A3 publication Critical patent/WO2004002939A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C07C215/30—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C07C215/38—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings with rings other than six-membered aromatic rings being part of the carbon skeleton
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    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C07C215/52—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
    • C07C217/92—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the nitrogen atom of at least one of the amino groups being further bound to a carbon atom of a six-membered aromatic ring
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    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/38—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/32—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
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    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/63—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C2601/14—The ring being saturated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to new aminoalcohol derivatives and salts thereof which are beta-3 ( ⁇ 3) adrenergic receptor agonists and useful as a medicament.
  • This invention relates to new aminoalcohol derivatives which are ⁇ 3 adrenergic receptor agonists and salts thereof.
  • new aminoalcohol derivatives and salts thereof which have gut sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic, anti-urinary incontinence, anti-pollakiuria activities, anti-diabetes and anti-obesity, to processes for the preparation thereof, to a pharmaceutical composition comprising the same and to a method of using the same therapeutically in the treatment and/or prevention of gastro-intestinal disorders caused by smooth muscle contractions in a human being or an animal.
  • a further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said aminoacohol derivatives and salts thereof.
  • Still further object of this invention is to provide a therapeutical method for the treatment and/or prevention of aforesaid diseases in a human being or an animal, using said aminoalcohol derivatives and salts thereof.
  • the object aminoalcohol derivatives of this invention are new and can be represented by compound of the following formula [I] :
  • X is bond, -CH 2 -,
  • R 7 Y is bond, -0-(CH 2 ) n - (in which n is 1, 2, 3 or 4),
  • Z is cyano, tetrazolyl, (benzylsulfonyl) carbamoyl, benzoylsulfamoyl, formyl, carboxy or protected carboxy, is hydrogen, lower alkyl or halogen, is hydrogen or an amino protective group, is hydrogen or lower alkyl, is hydrogen or lower alkyl,
  • R and R° are each independently hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, hydroxy (lower) alkoxy, mono (or di or tri) halo (lower) alkoxy, lower alkoxy (lower) alkoxy, lower alkenyloxy, cyclo (lower) alkyloxy, cyclo (lower) alkyl (lower) alkoxy, benzyloxy, phenoxy, lower alkylthio, cyclo (lower) alkylthio, lower alkylsulfonyl, cyclo (lower) alkylsulfonyl, amino, mono (or di) (lower) alkylamino, mono (or di or tri) halo (lower) alkyl, cyano, piperidinyl or phenyl, R 6 is hydrogen, lower alkyl or halogen, R 9 is hydrogen or lower alkyl, and i is 1 or 2, provided that
  • R ⁇ is not hydrogen
  • the object compounds can be prepared by processes which are illustrated in the following schemes.
  • Process 1
  • R°, R and i are each as defined above, R ⁇ is an amino protective group, R!0 is lower alkyl, and
  • X ] _ and X 2 are each a leaving group.
  • lower is intended to mean a group having 1 to ⁇ , preferably 1 to 4, carbon atom(s), unless otherwise indicated.
  • Suitable "lower alkyl” and “lower alkyl” moiety in the terms of "mono (or di) (lower) alkylamino” and “mono (or di or tri) halo (lower) alkyl” may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-methylpentyl, tert-pentyl, neo-pentyl, hexyl, isohexyl and the like.
  • Suitable "lower alkoxy” may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, tert-butoxy, pentyloxy, tert-pentyloxy, hexyloxy and the like, in which preferable one is methoxy or ethoxy.
  • Suitable "cyclo (lower) alkyl” moiety in the term of "cyclo (lower) alkyloxy" may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, in which preferable one is cyclohexyl.
  • Suitable "halogen” may be fluoro, chloro, bro o and iodo, in which preferable one is chloro.
  • Suitable "mono (or di or tri) halo (lower) alkyl” may include chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 or 2-chloroethyl, 1 or 2- bromoethyl, 1 or 2-fluoroethyl, 1, 1-difluoroethyl, 2,2- difluoroethyl and the like.
  • Suitable “protected carboxy” may include esterified carboxy such as lower alkoxycarbonyl [e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert- butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.], halo (lower) alkoxycarbonyl [e.g.
  • heptyloxycarbonyl octyloxycarbonyl, 2-ethylhexyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, 3, 7-dimethyloctyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl, tridecyloxycarbonyl, tetradecyloxycarbonyl, pentadecyloxycarbonyl, 3-methyl-10- ethyldodecyloxycarbonyl, hexadecyloxycarbonyl, heptadecyloxycarbonyl, octadecyloxycarbonyl, nonadecyloxycarbonyl, icosyloxycarbonyl, etc.], aryloxycarbonyl [e.g.,
  • aryl (lower) alkoxycarbonyl which may have one or more (preferably 1 to 3) suitable substituent (s) such as phenyl (lower) alkoxycarbonyl which may have nitro or lower alkoxy [e.g. benzyloxycarbonyl, phenethyloxycarbonyl, p- nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, etc.], and the like, in which preferable one is lower alkoxycarbonyl and more preferable one is methoxycarbonyl, ethoxycarbonyl or tert- butoxycarbonyl .
  • suitable substituent (s) such as phenyl (lower) alkoxycarbonyl which may have nitro or lower alkoxy [e.g. benzyloxycarbonyl, phenethyloxycarbonyl, p- nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, etc.], and the like,
  • Suitable “leaving group” may include hydroxy, reactive group derived from hydroxy and the like.
  • Suitable "reactive group derived from hydroxy” may include acid residue and the like.
  • Suitable “acid residue” may include halogen (e.g. fluoro, chloro, bro o, iodo) , acyloxy (e.g. acetoxy, tosyloxy, mesyloxy, trifluoromethanesulfonyloxy, etc.) and the like.
  • halogen e.g. fluoro, chloro, bro o, iodo
  • acyloxy e.g. acetoxy, tosyloxy, mesyloxy, trifluoromethanesulfonyloxy, etc.
  • amino protective group may be common amino protective group such as substituted or unsubstituted lower alkanoyl [e.g. formyl, acetyl, propionyl, trifluoroacetyl, etc.], phthaloyl, lower alkoxycarbonyl [e.g. tert-butoxycarbonyl, tert-amyloxycarbonyl, etc.], substituted or unsubstituted aralkyloxycarbonyl [e.g. benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.], substituted or unsubstituted arenesulfonyl [e.g.
  • benzenesulfonyl, tosyl, etc.] nitrophenylsulfenyl, ar (lower) alkyl [e.g. trityl, benzyl, etc.], and the like, in which preferable one is tert-butoxycarbonyl.
  • [I] are pharmaceutically acceptable salts and include conventional non-toxic salts such as an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], an organic acid addition salt [e.g. formate, acetate, trifluoroacetate, oxalate, maleate, fumarate, tartrate, citrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc., an alkali metal salt [e.g. sodium salt, potassium salt, etc.] or the like.
  • an inorganic acid addition salt e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • an organic acid addition salt e.g. formate, acetate, trifluoroacetate, oxalate, maleate, fumarate, tartrate, citrate, methanesulfonate, benzenesulfonate,
  • the object compound [I] or a salt thereof can be prepared by reacting a compound [II] with a compound [III] or a salt thereof.
  • Suitable salt of the compound [III] may be the same as those exemplified for the compound [I].
  • the reaction is preferably carried out in the presence of a base such as an alkali metal carbonate [e.g. sodium carbonate, potassium carbonate, etc.], an alkaline earth metal carbonate [e.g. magnesium carbonate, calcium carbonate, etc.], an alkali metal bicarbonate [e.g. sodium bicarbonate, potassium bicarbonate, etc.], tri (lower) alkylamine [e.g. trimethylamine, triethylamine, etc.], picoline or the like.
  • the reaction is usually carried out in a conventional solvent, such as an alcohol [e.g. methanol, ethanol, propanol, isopropanol, etc.], diethyl ether, tetrahydrofuran, dioxane, or any other organic solvent which does not adversely influence the reaction.
  • the reaction temperature is not critical, and the reaction can be carried out under cooling to heating.
  • the object compound [lb] or a salt thereof can be prepared by subjecting a compound [la] or a salt thereof to elimination reaction of the amino protective group.
  • Suitable salts of the compounds [la] and [lb] may be the same as those exemplified for the compound [I] . This reaction can be carried out in a similar manner to that of Example 11 mentioned below.
  • the object compound [lc] or a salt thereof can be prepared by reacting a compound [IV] or a salt thereof with a compound [V] or a salt thereof.
  • Suitable salts of the compounds [lc], [IV] and [V] may be the same as those exemplified for the compound [I] .
  • This reaction can be carried out in a similar manner to that of Example 15 mentioned below.
  • the object compound [lc] or a salt thereof can be prepared by reacting a compound [IV] or a salt thereof with a compound [VI] or a salt thereof.
  • Suitable salts of the compound [lc], [IV] and [VI] may be the same as those exemplified for the compound [I] .
  • the object compound [Id] or a salt thereof can be prepared by reacting a compound [VII] or a salt thereof with a compound [V] or a salt thereof.
  • Suitable salts of the compounds [Id], [VII] and [V] may be the same as those exemplified for the compound [I] .
  • the object compound [lg] or a salt thereof can be prepared by subjecting a compound [Ie] or a salt thereof to deesterification reaction followed by subjecting a compound [If] or a salt thereof to elimination reaction of the amino protective group.
  • Suitable salts of the compound [lg], [Ie] and [If] may be the same as those exemplified for the compound [I] .
  • the compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, or the like, and converted to the desired salt in conventional manners, if necessary.
  • the compound [I] and the other compounds may include one or more stereoisomers due to asymmetric carbon atoms, and all of such isomers and mixture thereof are included within the scope of this invention. It is further to be noted that isomerization or rearrangement of the object compound [I] may occur due to the effect of the light, acid base or the like, and the compound obtained as the result of said isomerization or rearrangement if also included within the scope of the present invention.
  • the object compound [I] or a salt thereof possesses gut sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic, anti-urinary incontinence and anti-pollakiuria activities, and are useful for the treatment and/or prevention of gastro-intestinal disorders caused by smooth muscle contractions in human beings or animals, and more parcitularly for the treatment and/or prevention of spasm or hyperanakinesia in case of irritable bowel syndrome, gastritis, gastric ulcer, duodenal ulcer, enteritis, cholecystopathy, cholantitis, urinary calculus and the like; for the treatment and/or prevention of ulcer such as gastric ulcer, duodenal ulcer, peptic ulcer, ulcer causes by non steroidal anti-inflammatory drags, or the like; for the treatment and/or prevention of dysuria or overactive bladder disorder such as pollakiuria, urinary incontinence, urge incontinence or the like in case of nervous pollakiuria, neurogenic
  • ⁇ adrenergic receptor agonists are known to lower triglyceride and cholesterol levels and to raise high density lipoprotein levels in mammals (US Patent No. 5,451,677). Accordingly, the object compound [I] in useful in the treatment and/or prevention of conditions such as hyper-triglyceridaemia, hypercholesterolaemia and in lowering high density lipoprotein levels as well as in the treatment of atherosclerotic and cardiovascular diseases and relates conditions.
  • the object compound [I] is useful for inhibiting uterine contractions, preventing premature labor, and treating and preventing dysmenorrhea.
  • Preferred embodiments of the object compound [I] are as follows :
  • X is bond, -0-, -OCH ? -, -S- or -N- (in which R 7 is
  • R7 hydrogen or lower alkyl (more preferably C ⁇ -C4 alkyl, most preferably methyl) )
  • Y is bond, -0-(CH ) n - (in which n is 1, 2, 3 or 4) , -(CH 2 ) m - (in which m is 1, 2, 3 or 4),
  • Z is carboxy or lower alkoxycarbonyl (more preferably C ⁇ -C ⁇ alkoxycarbonyl, most preferably methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl)
  • R l is hydrogen or halogen (more preferably chloro)
  • R 2 is hydrogen
  • R is hydrogen or lower alkyl (more preferably C ⁇ -C alkyl, most preferably methyl)
  • R 4 is hydrogen
  • R is halogen (more preferably chloro) , hydroxy, lower alkyl (more preferably C- ⁇ -Cg, most preferably methyl) , lower alkoxy (more prefefably C ⁇ -Cg alkoxy, most preferably methoxy, ethoxy, propoxy, isopropoxy, butoxy or pentyloxy), hydroxy (lower) alkoxy (more preferably hydroxy (C ⁇ -C ⁇ ) alkyl, most preferably 2-hydroxyethoxy) , mono (or di or tri) halo (lower) alkoxy (more preferably mono (or di or tri) halo (C 1 -C 4 ) alkoxy, most preferably 2- fluoroethoxy, 2, 2-difluoroethoxy, 2, 2, 2-trifluoroethoxy, 3-fluoropropoxy or 3, 3, 3-trifluoropropoxy) , lower alkoxy (lower) alkoxy (more preferably C ⁇ -C ⁇ alkoxy (C-
  • R 8 is hydrgen or lower alkyl (more preferably C ⁇ - - ⁇ alkyl, most preferably methyl)
  • R 9 is hydrogen or lower alkyl (more preferably C- ⁇ - ⁇ alkyl, most preferably methyl)
  • i is 1 or 2.
  • More preferred embodiments of the object compound [I] are as follows:
  • X is bond, -0-, -OCH -, -S- or -N- (in which R 7 is
  • R7 hydrogen or lower alkyl (more preferably C -C alkyl, most preferably methyl) ) ,
  • Y is bond, -0-(CH 2 ) n - (in which n is 1 or 2) or -(CH 2 ) m - (in which m is 1 or 2)
  • Z is carboxy or lower alkoxycarbonyl (more preferably C- ⁇ -C ⁇ alkoxycarbonyl, most preferably methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl),
  • R x is hydrogen or halogen (more preferably chloro)
  • R 2 is hydrogen
  • R 3 is hydrogen or lower alkyl (more preferably C ] _-C 4 alkyl, most preferably methyl)
  • R 4 is hydrogen
  • R 5 is hydrogen, halogen (more preferably chloro) , hydroxy, lower alkyl (more preferably C ⁇ -Cg, most preferably methyl) , or lower alkoxy (more preferaly C- j _-Cg alkoxy, most preferably methoxy) , R° is hydrogen,
  • R° is hydrogen or lower alkyl (more preferably C- ⁇ -C ⁇ alkyl, most preferably methyl) , and i is 1.
  • Z is carboxy or lower alkoxycarbonyl (more preferably C-L-C alkoxycarbonyl, most preferably methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl), R! is hydrogen or halogen (more preferably chloro) , R is hydrogen,
  • R is hydrogen or lower alkyl (more preferably C ⁇ -C4 alkyl, most preferably methyl)
  • R ⁇ is hydrogen
  • R 5 is hydrogen (more preferably chloro) , hydroxy, lower alkyl (more preferably C- ⁇ -C ⁇ alkyl, most preferably methyl) or lower alkoxy (more preferably C ⁇ -C ⁇ alkoxy, most preferably methoxy or ethoxy)
  • R 6 is hydrogen
  • R 8 is hydrogen or lower alkyl (more preferably C- ] _-C alkyl, most preferably methyl) ,
  • R9 is hydrogen or lower alkyl (more preferably C- ⁇ -C ⁇ alkyl, most preferably methyl), and i is 1.
  • the object compound above was protected at the imino group in a conventional manner to give tert-butyl [(2R)-2- (3-chlorophenyl) -2-hydroxyethyl] [2- [4- [ (4-hydroxyphenyl) - thio] phenyl] ethyl] carbamate (200 mg) .
  • Example 2 The following compounds were obtained according to a •similar manner to that of Example 4.
  • Example 3 To a solution of tert-butyl [2- [4- [4- [ [tert- butyl (dimethyl) silyl] oxy] phenoxy] henyl] ethyl] [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] carbamate (370 mg) in tetrahydrofuran (4.0 ml) was added 1M tetrabutylammonium fluoride in tetrahydrofuran (1.2 ml), and the mixture was stirred at room temperature for 1 hour. The mixture was partitioned between ethyl acetate and water.
  • Example 6 To a solution of methyl 4- [4- [2- [ (tert- butoxycarbonyl) [ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] amino] ethyl] henoxy] benzoate (183 mg) in ethanol (1.2 ml) was added IN aqueous sodium hydroxide solution (0.6 ml), and the mixture was stirred at 40°C for 3 hours. The solvent was removed by evaporation, and the aqueous solution was acidified with IN aqueous hydrochloride solution and extracted with ethyl acetate (30 ml x 2) .
  • Example 8 The following compounds were obtained according to a similar manner to that of Example 6.
  • Example 28 The following compounds were obtained according to a similar manner to that of Example 27.
  • Example 31 The following compounds were obtained according to a similar manner to that of Example 30.
  • Example 35 The following compounds were obtained according to a similar manner to that of Example 27.
  • Example 14 The following compounds were obtained according to a similar manner to that of Example 14 followed by a similar manner to that of Example 18.
  • Example 46 The following compound was obtained according to a similar manner to that of Preparation 61.
  • Example 49 The following compound was obtained according to a similar manner to that of Preparation 62.
  • Example 25 The following compound was obtained according to a similar manner to that of Example 1 followed by a similar manner to that of Example 25.
  • Example 25 The following compound was obtained according to a similar manner to that of Example 25 followed by a similar manner to that of Example 18.
  • Example 25 The following compound was obtained according to a similar manner to that of Example 25 followed by a similar manner to that of Example 27.
  • Example 55 The following compound was obtained according to a similar manner to that of Example 7.
  • the mixture was partitioned between ethyl acetate and water.
  • the mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. To a solution of the residue in tetrahydrofuran (10 ml) was added IM tetrabutylammonium fluoride in tetrahydrofuran (3.6 ml) , and the mixture was stirred at room temperature for 8 hours under nitrogen. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure.
  • Example 58 A mixture of 4' - [2- [N-benzyl-N- [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino]ethyl] -1, 1' -biphenyl-4-ol (420 - g) in 4N hydrogen chloride in ethyl acetate (1.0 ml) was stirred for 5 minutes. The solvent was removed by evaporation. A suspension of the residue in ethanol (1.5 ml) and chlorobenzene (3.5 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 10 mg) under hydrogen atmosphere for 1 hour. The catalyst was filtered off, and the filtrate was evaporated.
  • Example 62 The following compound was obtained according to a similar manner to that of Example 6.

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Abstract

The present invention relates to a compound formula [I]: Y is bond, -0-(CH2)n- (in which n is 1, 2, 3 or 4), etc., Z is cyano, tetrazolyl, etc., R1 is hydrogen, lower alkyl, etc., R2 is hydrogen or an amino protective group, R3 is hydrogen or lower alkyl, R4 is hydrogen or lower alkyl,R5 and R8 are each independently hydrogen, halogen, hydroxy,lower alkyl, etc., R6 is hydrogen, lower alkyl, etc., R9 is hydrogen or lower alkyl, and i is 1 or 2,or a salt thereof. The compound [I] of the present invention and pharmaceutically acceptable salts thereof are useful for the prophylactic and/or the therapeutic treatment of pollakiurea or urinary incontinence.

Description

DESCRIPTION
AMINOALCOHOL DERIVATIVES
FIELD OF THE INVENTION
This invention relates to new aminoalcohol derivatives and salts thereof which are beta-3 (β3) adrenergic receptor agonists and useful as a medicament.
BACKGROUND OF THE INVENTION
International Publications No. WO 90/06299, published June 14, 1990, describes derivatives of phenylethanolamines as having an effect on the metabolism, preferably reduction of the blood sugar level and body fat, and International Publication No. WO 02/32897, published April 25, 2002, describes derivatives of alpha-aryl ethanolamines useful as β3 adrenergic receptor agonists.
DISCLOSURE OF THE INVENTION This invention relates to new aminoalcohol derivatives which are β3 adrenergic receptor agonists and salts thereof.
More particularly, it relates to new aminoalcohol derivatives and salts thereof which have gut sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic, anti-urinary incontinence, anti-pollakiuria activities, anti-diabetes and anti-obesity, to processes for the preparation thereof, to a pharmaceutical composition comprising the same and to a method of using the same therapeutically in the treatment and/or prevention of gastro-intestinal disorders caused by smooth muscle contractions in a human being or an animal. One object of this invention is to provide new and useful aminoalcohol derivatives and salts thereof which have gut sympathomimetic, anti-ulcerous, lipolytic, anti-urinary incontinence, anti-pollakiuria activities, anti-diabetes and anti-obesity. Another object of this invention is to provide processes for the preparation of said aminoalcohol derivatives and salts thereof.
A further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said aminoacohol derivatives and salts thereof.
Still further object of this invention is to provide a therapeutical method for the treatment and/or prevention of aforesaid diseases in a human being or an animal, using said aminoalcohol derivatives and salts thereof.
The object aminoalcohol derivatives of this invention are new and can be represented by compound of the following formula [I] :
Figure imgf000004_0001
wherein
Figure imgf000004_0002
X is bond, -CH2-, | , jj , -0-, -OCH2-, -CH20-, -S-
OH 0
-N- η or i (in which R' is hydrogen or lower alkyl),
R7 Y is bond, -0-(CH2)n- (in which n is 1, 2, 3 or 4),
~(CH2)m- (in which m is 1, 2, 3 or 4),
Figure imgf000004_0003
Z is cyano, tetrazolyl, (benzylsulfonyl) carbamoyl, benzoylsulfamoyl, formyl, carboxy or protected carboxy, is hydrogen, lower alkyl or halogen, is hydrogen or an amino protective group, is hydrogen or lower alkyl, is hydrogen or lower alkyl,
R and R° are each independently hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, hydroxy (lower) alkoxy, mono (or di or tri) halo (lower) alkoxy, lower alkoxy (lower) alkoxy, lower alkenyloxy, cyclo (lower) alkyloxy, cyclo (lower) alkyl (lower) alkoxy, benzyloxy, phenoxy, lower alkylthio, cyclo (lower) alkylthio, lower alkylsulfonyl, cyclo (lower) alkylsulfonyl, amino, mono (or di) (lower) alkylamino, mono (or di or tri) halo (lower) alkyl, cyano, piperidinyl or phenyl, R6 is hydrogen, lower alkyl or halogen, R9 is hydrogen or lower alkyl, and i is 1 or 2, provided that
-CH- -C- (1) when X is bond, -CH2- | or II OH o
Figure imgf000005_0001
then R^ is not hydrogen, or
(2) when i is 1,
Figure imgf000005_0002
or a salt thereof.
According to this invention, the object compounds can be prepared by processes which are illustrated in the following schemes. Process 1
Figure imgf000006_0001
[ir [III] or a salt thereof
Figure imgf000006_0002
[1] or a salt thereof
Process 2
Figure imgf000006_0003
[la] or a salt thereof
elimination reaction of the amino protective group
Figure imgf000006_0004
[lb] or a salt thereof Process 3
Figure imgf000007_0001
[IV] [V] or a salt thereof or a salt thereof
Figure imgf000007_0002
[lc] or a salt thereof
Process 4
Figure imgf000007_0003
[IV] [VI] or a salt thereof or a salt thereof
Figure imgf000007_0004
[lc] or a salt thereof Process 5
Figure imgf000008_0001
[VII ] [V] or a salt thereof or a salt thereof
Figure imgf000008_0002
or a salt thereof
Process 6
Figure imgf000008_0003
or a salt thereof
Figure imgf000008_0004
or a salt thereof
elimination reaction of the amino protective group
Figure imgf000008_0005
or a salt thereof wherein ' X' Y' Z' R1' R2' R3' R4' R5' R6'
Figure imgf000009_0001
R°, R and i are each as defined above, R^ is an amino protective group, R!0 is lower alkyl, and
X]_ and X2 are each a leaving group.
As to the starting compounds [II] , [III] , [la] , [IV] , [V], [VI] and [VII], some of them are novel and can be prepared by the procedures described in the Preparations and Examples mentioned below or a conventional manner.
In the above and subsequent description of the present specification, suitable examples of the various definition to be included within the scope of the invention are explained in detail in the following.
The term "lower" is intended to mean a group having 1 to β, preferably 1 to 4, carbon atom(s), unless otherwise indicated.
Suitable "lower alkyl" and "lower alkyl" moiety in the terms of "mono (or di) (lower) alkylamino" and "mono (or di or tri) halo (lower) alkyl" may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-methylpentyl, tert-pentyl, neo-pentyl, hexyl, isohexyl and the like.
Suitable "lower alkoxy" may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, tert-butoxy, pentyloxy, tert-pentyloxy, hexyloxy and the like, in which preferable one is methoxy or ethoxy.
Suitable "cyclo (lower) alkyl" moiety in the term of "cyclo (lower) alkyloxy" may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, in which preferable one is cyclohexyl.
Suitable "halogen" may be fluoro, chloro, bro o and iodo, in which preferable one is chloro.
Suitable "mono (or di or tri) halo (lower) alkyl" may include chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 or 2-chloroethyl, 1 or 2- bromoethyl, 1 or 2-fluoroethyl, 1, 1-difluoroethyl, 2,2- difluoroethyl and the like.
Suitable "protected carboxy" may include esterified carboxy such as lower alkoxycarbonyl [e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert- butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.], halo (lower) alkoxycarbonyl [e.g. (chloro ethoxy) carbonyl, (2, 2, 2-trichloroethoxy) carbonyl, (2, 2, 2-trifluoroethoxy) - carbonyl, (2-chloropropoxy) carbonyl, (l-fluoro-4- bromobutoxy) carbonyl, (4-chloropentyloxy) carbonyl, (6- chlorohexyloxy) carbonyl, etc.], higher alkoxycarbonyl [e.g. heptyloxycarbonyl, octyloxycarbonyl, 2-ethylhexyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, 3, 7-dimethyloctyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl, tridecyloxycarbonyl, tetradecyloxycarbonyl, pentadecyloxycarbonyl, 3-methyl-10- ethyldodecyloxycarbonyl, hexadecyloxycarbonyl, heptadecyloxycarbonyl, octadecyloxycarbonyl, nonadecyloxycarbonyl, icosyloxycarbonyl, etc.], aryloxycarbonyl [e.g. phenoxycarbonyl, naphthyloxycarbonyl, etc. ] , aryl (lower) alkoxycarbonyl which may have one or more (preferably 1 to 3) suitable substituent (s) such as phenyl (lower) alkoxycarbonyl which may have nitro or lower alkoxy [e.g. benzyloxycarbonyl, phenethyloxycarbonyl, p- nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, etc.], and the like, in which preferable one is lower alkoxycarbonyl and more preferable one is methoxycarbonyl, ethoxycarbonyl or tert- butoxycarbonyl .
Suitable "leaving group" may include hydroxy, reactive group derived from hydroxy and the like.
Suitable "reactive group derived from hydroxy" may include acid residue and the like.
Suitable "acid residue" may include halogen (e.g. fluoro, chloro, bro o, iodo) , acyloxy (e.g. acetoxy, tosyloxy, mesyloxy, trifluoromethanesulfonyloxy, etc.) and the like.
Suitable example of "amino protective group" moiety may be common amino protective group such as substituted or unsubstituted lower alkanoyl [e.g. formyl, acetyl, propionyl, trifluoroacetyl, etc.], phthaloyl, lower alkoxycarbonyl [e.g. tert-butoxycarbonyl, tert-amyloxycarbonyl, etc.], substituted or unsubstituted aralkyloxycarbonyl [e.g. benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.], substituted or unsubstituted arenesulfonyl [e.g. benzenesulfonyl, tosyl, etc.], nitrophenylsulfenyl, ar (lower) alkyl [e.g. trityl, benzyl, etc.], and the like, in which preferable one is tert-butoxycarbonyl.
Suitable salts of the object aminoalcohol derivative
[I] are pharmaceutically acceptable salts and include conventional non-toxic salts such as an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], an organic acid addition salt [e.g. formate, acetate, trifluoroacetate, oxalate, maleate, fumarate, tartrate, citrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc., an alkali metal salt [e.g. sodium salt, potassium salt, etc.] or the like.
The Processes 1 to 6 for preparing the object compounds of the present invention are explained in detail in the following.
Process 1 The object compound [I] or a salt thereof can be prepared by reacting a compound [II] with a compound [III] or a salt thereof.
Suitable salt of the compound [III] may be the same as those exemplified for the compound [I]. The reaction is preferably carried out in the presence of a base such as an alkali metal carbonate [e.g. sodium carbonate, potassium carbonate, etc.], an alkaline earth metal carbonate [e.g. magnesium carbonate, calcium carbonate, etc.], an alkali metal bicarbonate [e.g. sodium bicarbonate, potassium bicarbonate, etc.], tri (lower) alkylamine [e.g. trimethylamine, triethylamine, etc.], picoline or the like. The reaction is usually carried out in a conventional solvent, such as an alcohol [e.g. methanol, ethanol, propanol, isopropanol, etc.], diethyl ether, tetrahydrofuran, dioxane, or any other organic solvent which does not adversely influence the reaction.
The reaction temperature is not critical, and the reaction can be carried out under cooling to heating.
Process 2
The object compound [lb] or a salt thereof can be prepared by subjecting a compound [la] or a salt thereof to elimination reaction of the amino protective group.
Suitable salts of the compounds [la] and [lb] may be the same as those exemplified for the compound [I] . This reaction can be carried out in a similar manner to that of Example 11 mentioned below.
Process 3 The object compound [lc] or a salt thereof can be prepared by reacting a compound [IV] or a salt thereof with a compound [V] or a salt thereof.
Suitable salts of the compounds [lc], [IV] and [V] may be the same as those exemplified for the compound [I] . This reaction can be carried out in a similar manner to that of Example 15 mentioned below.
Process 4
The object compound [lc] or a salt thereof can be prepared by reacting a compound [IV] or a salt thereof with a compound [VI] or a salt thereof.
Suitable salts of the compound [lc], [IV] and [VI] may be the same as those exemplified for the compound [I] .
This reaction can be carried out in a similar manner to that of Example 9 mentioned below.
Process 5
The object compound [Id] or a salt thereof can be prepared by reacting a compound [VII] or a salt thereof with a compound [V] or a salt thereof.
Suitable salts of the compounds [Id], [VII] and [V] may be the same as those exemplified for the compound [I] .
This reaction can be carried out in a similar manner to that of Example 7 mentioned below.
Process 6
The object compound [lg] or a salt thereof can be prepared by subjecting a compound [Ie] or a salt thereof to deesterification reaction followed by subjecting a compound [If] or a salt thereof to elimination reaction of the amino protective group.
Suitable salts of the compound [lg], [Ie] and [If] may be the same as those exemplified for the compound [I] .
These reactions can be carried out in a similar manner to that of Example 18 mentioned below.
The compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, or the like, and converted to the desired salt in conventional manners, if necessary.
It is to be noted that the compound [I] and the other compounds may include one or more stereoisomers due to asymmetric carbon atoms, and all of such isomers and mixture thereof are included within the scope of this invention. It is further to be noted that isomerization or rearrangement of the object compound [I] may occur due to the effect of the light, acid base or the like, and the compound obtained as the result of said isomerization or rearrangement if also included within the scope of the present invention.
It is also to be noted that the solvating form of the compound [I] (e.g. hydrate, etc.) and any form of the crystal of the compound [I] are included within the scope of the present invention.
The object compound [I] or a salt thereof possesses gut sympathomimetic, anti-ulcerous, anti-pancreatitis, lipolytic, anti-urinary incontinence and anti-pollakiuria activities, and are useful for the treatment and/or prevention of gastro-intestinal disorders caused by smooth muscle contractions in human beings or animals, and more parcitularly for the treatment and/or prevention of spasm or hyperanakinesia in case of irritable bowel syndrome, gastritis, gastric ulcer, duodenal ulcer, enteritis, cholecystopathy, cholantitis, urinary calculus and the like; for the treatment and/or prevention of ulcer such as gastric ulcer, duodenal ulcer, peptic ulcer, ulcer causes by non steroidal anti-inflammatory drags, or the like; for the treatment and/or prevention of dysuria or overactive bladder disorder such as pollakiuria, urinary incontinence, urge incontinence or the like in case of nervous pollakiuria, neurogenic bladder dysfunction, nocturia, unstable bladder, cystospasm, chronic cystitis, chronic prostatitis, prostatic hypertrophy or the like; for the treatment and/or prevention of pancreatitis, obesity, diabetes, glycosuria, hyperlipidemia, hypertension, atherosclerosis, glaucoma, melancholia, depression or the like; for the treatment and/or prevention of diseases as the result of insulin resistance (e.g. hypertension, hyperinsuline ia, etc.); for the treatment and/or prevention of neurogenetic inflammation; and for reducing a wasting condition, and the like.
Additionally, β adrenergic receptor agonists are known to lower triglyceride and cholesterol levels and to raise high density lipoprotein levels in mammals (US Patent No. 5,451,677). Accordingly, the object compound [I] in useful in the treatment and/or prevention of conditions such as hyper-triglyceridaemia, hypercholesterolaemia and in lowering high density lipoprotein levels as well as in the treatment of atherosclerotic and cardiovascular diseases and relates conditions.
Moreover, the object compound [I] is useful for inhibiting uterine contractions, preventing premature labor, and treating and preventing dysmenorrhea.
In order to show the usefulness of the compound [I] for the prophylactic and therapeutic treatment of above- mentioned disease in human being or animals, a representative compound of the compound [I] was tested on the following pharmaceutical test.
Test Effect on the increase in intravesical pressure induced by carbachol in anesthetized dog
Test compound
(1) 4'-[ (2R)-2-[[ (2R)-2-Phenyl-2-hydroxyethyl] amino] - propyl] -3-methoxy-1, 1' -biphenyl-4-carboxylic acid hydrochloride,
(2) 4 ' - 12- I [ (2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]- ethyl] -2, 3-dimethyl-l, 1' -biphenyl-4-carboxylic acid hydrochloride, (3) 4' - [2- [[ (2R)-2-Hydroxy-2- (3-pyridyl) ethyl] amino] ethyl] - 2-methyl-l, 1' -biphenyl-4-carboxylic acid dihydrochloride, (4) 4'-[ (2R)-2-[ [ (2R)-2-Hydroxy-2- (3-pyridyl) ethyl] amino] - propyl] -3-methoxy-l, 1' -biphenyl-4-carboxylic acid dihydrochloride.
Test Method
Female Beagle dogs weighing 8.0-15.0 kg were fasted for 24 hours and maintained under halothane anesthesia. A 12F Foley catheter was lubricated with water soluble jelly, inserted into the urethral orifice and advanced approximately 10 cm until the balloon tip was placed well inside the bladder. The balloon was then inflated with 5 ml of room air and catheter slowly withdrawn just part the first resistance that is felt at the bladder neck. Urine was completely drained out through the catheter, and 30 ml of biological saline was infused. The catheter was connected to pressure transducer, and intravesical pressure (IVP) was continuously recorded. The test compound was administered intravenously at 30 minutes before the administration of carbachol (1.8 μg/kg). Percent inhibition of IVP increase by test compound was calculated by dividing IVPa (IVP increase induced by carbachol after test compound administration) by IVPb (IVP increase induced by carbachol just before test compound administration) .
Test Results
Treatment Percent inhibition of IVP increase
Test Compound (1) 93
(0.032 mg/kg) Test Compound (2) 91
(0.032 mg/kg) Test Compound (3) 86
(0.032 mg/kg) Test Compound (4) 96
(0.032 mg/kg)
Preferred embodiments of the object compound [I] are as follows :
Figure imgf000017_0001
X is bond, -0-, -OCH?-, -S- or -N- (in which R7 is
R7 hydrogen or lower alkyl (more preferably Cχ-C4 alkyl, most preferably methyl) ) , Y is bond, -0-(CH )n- (in which n is 1, 2, 3 or 4) , -(CH2)m- (in which m is 1, 2, 3 or 4),
Figure imgf000017_0002
Z is carboxy or lower alkoxycarbonyl (more preferably C^-C^ alkoxycarbonyl, most preferably methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl) , Rl is hydrogen or halogen (more preferably chloro) , R2 is hydrogen,
R is hydrogen or lower alkyl (more preferably C^-C alkyl, most preferably methyl) , R4 is hydrogen,
R is halogen (more preferably chloro) , hydroxy, lower alkyl (more preferably C-^-Cg, most preferably methyl) , lower alkoxy (more prefefably Cχ-Cg alkoxy, most preferably methoxy, ethoxy, propoxy, isopropoxy, butoxy or pentyloxy), hydroxy (lower) alkoxy (more preferably hydroxy (C^-C^) alkyl, most preferably 2-hydroxyethoxy) , mono (or di or tri) halo (lower) alkoxy (more preferably mono (or di or tri) halo (C1-C4) alkoxy, most preferably 2- fluoroethoxy, 2, 2-difluoroethoxy, 2, 2, 2-trifluoroethoxy, 3-fluoropropoxy or 3, 3, 3-trifluoropropoxy) , lower alkoxy (lower) alkoxy (more preferably C^-C^ alkoxy (C-|_-C ) alkoxy, most preferably 2-methoxyethoxy) , lower alkenyloxy (mpre preferably C -C4 alkenyl, most preferably allyloxy) , cyclo (lower) alkyloxy (more preferably cyclo (C3-C5) alkyloxy, most preferably cyclohexyloxy) , phenoxy or phenyl, R5 is hydrogen,
R8 is hydrgen or lower alkyl (more preferably C^- - ^ alkyl, most preferably methyl) , R9 is hydrogen or lower alkyl (more preferably C-^- ^ alkyl, most preferably methyl) , and i is 1 or 2.
More preferred embodiments of the object compound [I] are as follows:
Figure imgf000019_0001
X is bond, -0-, -OCH -, -S- or -N- (in which R7 is
R7 hydrogen or lower alkyl (more preferably C -C alkyl, most preferably methyl) ) ,
Y is bond, -0-(CH2)n- (in which n is 1 or 2) or -(CH2)m- (in which m is 1 or 2) , Z is carboxy or lower alkoxycarbonyl (more preferably C-^-C^ alkoxycarbonyl, most preferably methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl),
Rx is hydrogen or halogen (more preferably chloro) , R2 is hydrogen,
R3 is hydrogen or lower alkyl (more preferably C]_-C4 alkyl, most preferably methyl) , R4 is hydrogen,
R5 is hydrogen, halogen (more preferably chloro) , hydroxy, lower alkyl (more preferably C^-Cg, most preferably methyl) , or lower alkoxy (more preferaly C-j_-Cg alkoxy, most preferably methoxy) , R° is hydrogen,
R° is hydrogen or lower alkyl (more preferably C-^-C^ alkyl, most preferably methyl) , and i is 1.
Further more preferred embodiments of the compound [I] are as follows:
Figure imgf000019_0002
Figure imgf000020_0001
X is bond, Y is bond,
Z is carboxy or lower alkoxycarbonyl (more preferably C-L-C alkoxycarbonyl, most preferably methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl), R! is hydrogen or halogen (more preferably chloro) , R is hydrogen,
R is hydrogen or lower alkyl (more preferably Cχ-C4 alkyl, most preferably methyl) , R^ is hydrogen,
R5 is hydrogen (more preferably chloro) , hydroxy, lower alkyl (more preferably C-^-Cή alkyl, most preferably methyl) or lower alkoxy (more preferably C^-C^ alkoxy, most preferably methoxy or ethoxy) , R6 is hydrogen,
R8 is hydrogen or lower alkyl (more preferably C-]_-C alkyl, most preferably methyl) ,
R9 is hydrogen or lower alkyl (more preferably C-^-C^ alkyl, most preferably methyl), and i is 1.
The following Preparations and Examples are given for the purpose of illustrating this invention.
Preparation 1
A solution of N-benzyl-2- (4-bromophenyl) ethanamine (13.5 g) in ethanol (270 ml) was added (2R)-2-(3- chlorophenyl) oxirane (8.63 g) and the solution was refluxed for 48 hours. After cooling to room temperature, the solvent was removed by evaporation and the residue was chromatographed on silica gel (eluent: hexane/ethyl acetate = 9/1) to give (1R) -2- [benzyl [2- (4-bromophenyl) ethyl] amino] - 1- (3-chlorophenyl) ethanol (18.6 g) as a colorless oil.
NMR (CDC13, δ) : 2.58 (IH, dd, J=10, 13Hz) , 2.68-2.89 (5H, m), 3.56 (IH, d, J=13Hz), 3.92 (IH, d, J=13Hz), 4.59 (IH, dd, J=3.4, 10Hz), 6.97 (2H, d, J=8.3Hz), 7.21-7.40 (12H, )
(+)ESI-MS (m/z): 444 and 446 (MH+)
Preparation 2
To a solution of (1R) -2- [benzyl [2- (4- bromophenyl) ethyl] amino] -1- (3-chlorophenyl) ethanol (18.5 g) in N,N-di ethylformamide (40 ml) were successively added imidazole (3.96 g) and tert-butyldimethylsilyl chloride (7.52 g) and the solution was stirred at room temperature for 14 hours. The reaction mixture was quenched by the addition of water (100 ml) and extracted with ethyl acetate (100 ml x 1) . The extract was washed with water (100 ml x 2), brine (100 ml x 1), and dried over magnesium sulfate. Filtration followed by evaporation gave a colorless oil, which was chromatographed on silica gel (eluent: hexane/ethyl acetate) to give (2R) -N-benzyl-N- [2- (4- bro ophenyl) ethyl] -2- [ [tert-butyl (dimethyl) silyl] oxy] -2- (3- chlorophenyl) ethana ine (21.0 g) as a colorless oil.
NMR (CDCI3, δ) : 0.15 (6H, s) , 1.01 (9H, s) , 2.72-2.82 (5H, m) , 2.92 (IH, dd, J=5.9, 13Hz), 3.75 (IH, d, J=13.7Hz), 3.86 (IH, d, J=13.7Hz), 4.71 (IH, t- like, J=6.2Hz), 7.01 (2H, d, J=8.3Hz), 7.26-7.47 (9H, ) , 7.48 (2H, d, J=8.3Hz) (+)ESI-MS (m/z): 558 and 560 (MH+)
Preparation 3
To a solution of tert-butyl [2- (4- bromophenyl) ethyl] [ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] carbamate (500 mg) in 1, 2-dimethoxyethane (6 ml) was added 5-formyl-2-thiopheneboronic acid (206 mg) , tetrakis (triphenylphosphine) alladium (63 mg) and aqueous solution of sodium carbonate (2M, 1.0 ml), and the mixture was stirred at 80°C for 7 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 3/1) to give tert-butyl [(2R)-2-(3- chlorophenyl) -2-hydrxyethyl] [2- [4- (5-formyl-2- thienyl) phenyl] ethyl] carbamate (187 mg) . (+)ESI-MS (m/z): 508 (M+Na)+
Preparation 4
To a suspension of tert-butyl [ (2R) -2- (3-chlorophenyl) - 2-hydroxyethyl] [2- (4-hydroxyphenyl) ethyl] carbamate (710 mg) , 4- [ [tert-butyl (dimethyl) silyl] oxy] phenylboronic acid (457 o mg) , triethylamine (1.26 ml) and powdered 4A molecular sieves (700 mg) in dichloromethane (18 ml) was added copper (II) acetate (330 mg) , and the mixture was stirred at room temperature for 18 hours under ambient atmosphere. The resulting slurry was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give tert-butyl [2- [4- [4- [ [tert-butyl (dimethyl) - silyl] oxy] phenoxy] phenyl] ethyl] [ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] carbamate (600 mg) . (-)ESI-MS (m/z): 569 (M-H) "
Preparation 5
The following compounds were obtained according to a similar manner to that of Preparation 4.
(1) tert-Butyl [2- [4- [ [4- [ [tert-butyl (dimethyl) silyl] oxy] - phenyl] amino] phenyl] ethyl] [ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] carbamate (+) ESI-MS (m/z): 597 (M+H) + (2) tert-Butyl [2- [4- [ [4- [ [tert-butyl (dimethyl) silyl] oxy] - phenyl] (methyl) amino] phenyl] ethyl ] [(2R)-2-(3- chlorophenyl) -2-hydroxyethyl] carbamate (+)ESI-MS (m/z): 611 (M+H)+
Preparation 6
To a solution of tert-butyl [2- (4-aminophenyl) - ethyl] [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] carbamate (1.75 g) and formaldehyde (37% w/w solution in water, 390 μl) in 1, 2-dichloroethane (20 ml) was added sodium triacetoxyborohydride (1.23 g) , and the mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. The resulting mixture was poured into a mixture of IN sodium hydroxide and chloroform, and the mixture was stirred for 20 minutes. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give tert- butyl [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] [2- [4- (methylamino) phenyl] ethyl] carbamate (550 mg) . (+) ESI-MS (m/z): 405 (M+H) +
Preparation 7 To a suspension of 2- [4- [ (4-methoxyphenyl) thio] phenyl] - ethanamine (6.3 g) in methanol (45 ml) and tetrahydrofuran (10 ml) was added ethyl trifluoroacetate (2.89 ml), and the mixture was stirred at room temperature for 1 hour. The mixture was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel
(hexane/ethyl acetate = 2/1) to give 2, 2, 2-trifluoro-N- [2- [4- [ (4-methoxyphenyl) thio] phenyl] ethyl] acetamide (3.95 g) . (+)ESI-MS (m/z): 378 (M+Na)+
Preparation 8 Under nitrogen at 4°C, to a solution of 2,2,2- trifluoro-N- [2- [4- [ (4-methoxyphenyl) thio] phenyl] ethyl] - acetamide (1.5 g) in dichloromethane (15 ml) was added 1M boron tribro ide in dichloromethane (10.5 ml), and the mixture was stirred at room temperature for 15 hours. The mixture was evaporated under reduced pressure. The residue was dissolved in a mixture of dichloromethane and saturated aqueous sodium bicarbonate. After separation, the organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give 2, 2, 2-trifluoro-N- [2- [4- [ (4- hydroxyphenyl) thio] phenyl] ethyl] acetamide (1.42 g) . (+)ESI-MS (m/z): 364 (M+Na) +
Preparation 9 To a solution of 2, 2, 2-trifluoro-N- [2- [4- [ (4- hydroxyphenyl) thio] phenyl] ethyl] acetamide (480 mg) in methanol (5.0 ml) was added IN sodium hydroxide solution (2.8 ml). The mixture was refluxed for 12 hours. The mixture was evaporated under reduced pressure. The residue was dissolved in a mixture of dichloromethane (40 ml) , IN hydrochloric acid solution (2.0 ml) and water (15 ml) .
After separation, the organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give 4-[[4- (2-aminoethyl) phenyl] thio]phenol (300 mg) . (-) ESI-MS (m/z): 244 (M-H) "
Preparation 10
4- [ [4- (2-Aminoethyl) phenyl] thio] phenol (295 mg) and (2R) -2- (3-chlorophenyl) oxirane (186 mg) in ethanol (3.5 ml) was refluxed for 6 hours. The mixture was evaporated. The residue was purified by column chromatography on silica gel (chloroform/methanol = 100/3) to give 4- [ [4- [2- [ [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl]phenyl] thio]phenol (155 mg) . (+) ESI-MS (m/z): 400 (M+H) + The object compound above was protected at the imino group in a conventional manner to give tert-butyl [(2R)-2- (3-chlorophenyl) -2-hydroxyethyl] [2- [4- [ (4-hydroxyphenyl) - thio] phenyl] ethyl] carbamate (200 mg) . (+) ESI-MS (m/z): 500 (M+H) +
Preparation 11
The following compounds were obtained according to a similar manner to that of Preparation 10.
(1) (lR)-2-[ [2- ( -Bromophenyl) ethyl] amino] -l-(3- chlorophenyl) ethanol
(+) ESI-MS (m/z): 354 (M+H)+
(2) tert-Butyl [2- (4-bromophenyl) ethyl] [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] carbamate
(+) ESI-MS (m/z): 454 (M+H)+
Example 1
To a solution of tert-butyl [ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] [2- [4- (5-formyl-2-thienyl) phenyl] ethyl] - carbamate (180 mg) in acetonitrile (2 ml) and pH 4 buffer solution (sodium dihydrogenphosphate) (1 ml) was added 30% hydrogen peroxide solution (30 μl) and 80% sodium chlorite (67 mg) below 10°C. The reaction mixture was stirred at 50°C for 3 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give 5- [4- [2- [ (tert-butoxycarbonyl) [ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] amino] ethyl] phenyl] -2-thiophenecarboxylic acid (160 mg) .
(-) ESI-MS (m/z): 500 (M-H) "
Example 2 The following compounds were obtained according to a •similar manner to that of Example 4.
(1) 5-[4-[2-[ [ (2R)-2- (3-Chlorophenyl) -2-hydroxyethyl] - amino] ethyl] phenyl] -2-thiophenecarboxylic acid hydrochloride
NMR (DMSO-d6, δ) : 3.00-3.25 (6H, ) , 4.95-4.99 (IH, m) , 6.34 (IH, br), 7.33-7.47 (6H, ) , 7.55 (IH, d, J=3.9Hz), 7.70-7.81 (3H, m) , 9.05 (IH, br) (-)ESI-MS (m/z): 400 (M-HC1-H) ~
(2) [4-[ [4-[2-[ [ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] - amino] ethyl] phenyl] amino ]phenoxy] acetic acid hydrochloride NMR (DMS0-d6, δ) : 2.84-3.30 (6H, ) , 4.39 (IH, br) , 4.59 (2H, s) , 4.97-5.03 (IH, ) , 6.37 (IH, br) , 6.80-7.07 (8H, m) , 7.34-7.48 (4H, m) , 8.85' (IH, br), 9.11 (IH, br) (-)ESI-MS (m/z): 439 (M-HCl-H) ~
(3) [4-[ [4-[2-[ [ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] - amino] ethyl] phenyl] (methyl) amino] phenoxy] acetic acid hydrochloride
NMR (DMSO-dβ, δ) : 2.85-3.23 (6H, ) , 3.17 (3H, s), 3.89-4.15 (IH, br) , 4.65 (2H, s) , 4.98-5.02 (IH, ) , 6.68-7.08 (8H, ) , 7.34-7.46 (4H, rα) , 8.86 (IH, br), 9.14 (IH, br) (-)ESI-MS (m/z) : 453 (M-HC1-H) ~
(4) [4- [ [4- [2- [[ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] - amino] ethyl] phenyl] thio] phenoxy] acetic acid hydrochloride
NMR (DMSO-d6, δ) : 2.94-3.33 (6H, m) , 4.70 (2H, s) , 4.97-5.01 (IH, m) , 6.34 (IH, br) , 6.96 (2H, d, J=8.7Hz), 7.02-7.23 (4H, m) , 7.33-7.45 (6H, m) , 8 . 97-9 . 18 ( IH, br) (- ) ESI-MS (m/ z ) : 456 (M-HC1-H) -
Example 3 To a solution of tert-butyl [2- [4- [4- [ [tert- butyl (dimethyl) silyl] oxy] phenoxy] henyl] ethyl] [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] carbamate (370 mg) in tetrahydrofuran (4.0 ml) was added 1M tetrabutylammonium fluoride in tetrahydrofuran (1.2 ml), and the mixture was stirred at room temperature for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give a phenol product. To a solution of the product and potassium carbonate (94 mg) in N,N-dimethylformamide (4.0 ml) was added tert-butyl bromoacetate (133 mg) , and the mixture was stirred at room temperature for 5 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give tert- butyl [4- [4- [2- [ (tert-butoxycarbonyl) [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] phenoxy] phenoxy] - acetate (360 mg) .
(-) ESI-MS (m/z): 597 (M-H) "
Example 4
A solution of tert-butyl [4- [4- [2- [ (tert- butoxycarbonyl) [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] - amino] ethyl] phenoxy] phenoxy] acetate (305 mg) and 4N hydrochloride in 1,4-dioxane (5.0 ml) was stirred at room temperature for 24 hours. The resulting solid was collected by filtration and dried to give [4- [4- [2- [ [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] phenoxy] phenoxy] - acetic acid hydrochloride (220 mg) as a white solid.
NMR (DMSO-d6, δ) : 2.95-3.33 (6H, m) , 4.65 (2H, s),
4.99-5.04 (IH, m) , 6.35 (IH, br) 6.83-7.00 (6H, m) , 7.23 (9H, d, J=8.5Hz), 7.39-7.47 (4H, m) , 8.98-9.12 (IH, br)
(+) ESI-MS (m/z): 442 (M-HC1+H) +
Exa ple 5
To a suspension of tert-butyl [ (2R) -2- (3-chlorophenyl) - 2-hydroxyethyl] [2- (4-hydroxyphenyl) ethyl] carbamate (550 mg) , (4-methoxycarbonylphenyl) boronic acid (300 mg) , o triethylamine (1.0 ml) and powdered 4A molecular sieves (600 mg) in dichloromethane (8 ml) was added copper (II) acetate (255 mg) , and the mixture was stirred at room temperature for 18 hours under ambient atmosphere. The resulting slurry was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give methyl 4- [4- [2- [ (tert-butoxycarbonyl) [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] phenoxy] benzoate (185 mg) .
(+) ESI-MS (m/z): 526 (M+H) +
Example 6 To a solution of methyl 4- [4- [2- [ (tert- butoxycarbonyl) [ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] amino] ethyl] henoxy] benzoate (183 mg) in ethanol (1.2 ml) was added IN aqueous sodium hydroxide solution (0.6 ml), and the mixture was stirred at 40°C for 3 hours. The solvent was removed by evaporation, and the aqueous solution was acidified with IN aqueous hydrochloride solution and extracted with ethyl acetate (30 ml x 2) . The combined organic layers were washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give a benzoic acid product. To a solution of the product in tetrahydrofuran (2.0 ml) was added 4N hydrochloride in 1,4-dioxane (1.0 ml), and the mixture was stirred at room temperature for 12 hours. The resulting solid was collected by filtration and dried to give 4- [4- [2- [ [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] - phenoxy] benzoic acid hydrochloride (127 mg) .
NMR (DMSO-dg, δ) : 3.00-3.28 (6H, ) , 4.99-5.04 (IH, m) , 6.35 (IH, br), 6.97-7.12 (4H, m) , 7.32-7.48 (6H, m) , 7.90-7.98 (2H, ) , 9.03-9.35 (IH, br) (-)ESI-MS (m/z): 410 (M-HC1-H) ~
Example 7
To a solution of tert-butyl [2- (4-bromophenyl) ethyl] - [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] carbamate (400 mg) in 1, 2-dimethoxyethane (6 ml) was added (4-methoxycarbonyl- 2-methylphenyl) boronic acid (171 mg) , tetrakis (triphenylphosphine) palladium (55 mg) and aqueous solution of sodium carbonate (2M, 0.92 ml), and the mixture was stirred at 80°C for 2 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give methyl 4' - [2- [ (tert- butoxycarbonyl) [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] - amino] ethyl] -2-methyl-1, 1 ' -biphenyl-4-carboxylate (320 mg) . (+) ESI-MS (m/z): 524 (M+H) +
Example 8 The following compounds were obtained according to a similar manner to that of Example 6.
(1) 5-Chloro-6- [4- [2- [ [ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] amino] ethyl] phenoxy] nicotinic acid hydrochloride NMR (DMSO-d6, δ) : 3.04-3.32 (6H, m) , 5.03-5.07 (IH, m) , 5.14 (IH, br) , 7.18 (2H, d, J=8.5Hz), 7.33-7.48 (6H, ) , 8.38 (IH, d, J=2.0Hz), 8.54 (IH, d, J=2.0Hz), 9.00 (IH, br) , 9.35 (IH, br) (-) ESI-MS (m/z): 445 (M-HC1-H) "
(2) 4'-[2-[ [ (2R)-2- (3-Chlorophenyl) -2-hydroxyethyl] amino] - ethyl] -2-methyl-l, V -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d6, δ) : 2.28 (IH, s) , 3.01-3.27 (6H, m) ,
5.00-5.04 (IH, m) , 6.36 (IH, br) , 7.28-7.48 (9H, m) , 7.79-7.90 (2H, m) , 9.02 (IH, br) (-) ESI-MS (m/z): 408 (M-HCl-H) ~
Example 9
To a solution of tert-butyl [ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] [2- (4-hydroxyphenyl) ethyl] carbamate (600 mg) and potassium carbonate (254 mg) in dimethylsulfoxide (6.0 ml) was added methyl 5, 6-dichloro-3-pyridinecarboxylate (347 mg) , and the mixture was stirred at room temperature for 12 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give methyl 6- [4- [2- [ (tert-butoxycarbonyl) [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] phenoxy] -5- chloronicotinate (770 mg) .
(+) ESI-MS (m/z): 561 (M+H)+
Example 10
Under nitrogen at 5°C, to a solution of tert-butyl [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] [2- (4- hydroxyphenyl) ethyl] carbamate (1.5 g) , ethyl [3- (hydroxymethyl) henoxy] acetate (885 mg) and triphenyl phosphine (1.1 g) in tetrahydrofuran (30 ml) was added diethyl azodicarboxylate (0.66 ml). The mixture was stirred at room temperature for 12 hours and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give ethyl [3- [ [4- [2- [ (tert-butoxycarbonyl) [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] phenoxy]methyl] - phenoxy] acetate (1.04 g) .
(+)ESI-MS (m/z): 585 (M+H) +
Example 11
To a solution of ethyl [3- [ [4- [2- [ (tert- butoxycarbonyl) [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] - amino] ethyl] phenoxy] methyl] phenoxy] acetate (1.0 g) in tetrahydrofuran (5.0 ml) was added 4N hydrochloride in dioxane (4.3 ml) . The mixture was stirred at room temperature for 8 hours and evaporated under reduced pressure. The residue was diluted with ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (methanol/chloroform = 1/20) to give ethyl [3- [ [4- [2- [ [ (2R) - 2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] phenoxy] - methyl] phenoxy] acetate (632 mg) . (+)ESI-MS (m/z): 484 (M+H) +
The object compound above was hydrolyzed in a conventional manner to give sodium [3- [ [4- [2- [ [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] phenoxy]methyl] - phenoxy] acetate (492 mg) .
NMR (DMSO-d6, δ) : 2.56-2.73 (6H, m) , 4.09 (2H, s) ,
4.58-4.64 (IH, m) , 4.98 (2H, s) , 6.72-6.77 (IH, ) , 6.85-6.91 (4H, m) , 7.08 (2H, d, J=8.5Hz), 7.17- 7.26 (4H, ) , 7.38 (IH, s) (-)ESI-MS (m/z) : 454 (M-Na-H) ~
Example 12
The following compounds were obtained according to a similar manner to that of Example 3.
(1) tert-Butyl [4- [ [4- [2- [ (tert-butoxycarbonyl) [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] phenyl] amino] - phenoxy] acetate (+)ESI-MS (m/z) : 597 (M+H) +
(2) tert-Butyl [4- [ [4- [2- [ (tert-butoxycarbonyl) [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] phenyl] - (methyl) amino] phenoxy] acetate (+)ESI-MS (m/z) : 611 (M+H) +
Example 13
To a solution of tert-butyl [ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] [2-[4- [ (4-hydroxyphenyl) thio]phenyl] ethyl] - carbamate (195 mg) and potassium carbonate (59 mg) in N,N- dimethyl formamide (3 ml) was added tert-butyl bromoacetate (84 mg) , and the mixture was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 3/1) to give tert-butyl [4- [ [4- [2- [ (tert-butoxycarbonyl) [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl]phenyl] thio] - phenoxy] acetate (168 mg) .
(+) ESI-MS (m/z) : 636 (M+Na)+
Preparation 12
To a solution of 4-bromo-2-fluorobenzoate (1.5 g) in N,N-dimethylformamide (30 ml) was added bis (pinacolato) - diboron (1.8 g) , 1, 1' -bis (diphenylphosphino) ferrocene- palladium (II) dichloridedichloromethane complex (1:1) (263 mg) and potassium acetate (1.9 g) , and the mixture was stirred at 100°C for 18 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated., The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 5/1) to give methyl 2-fluoro-4- (4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl)benzoate (350 mg) . (+)ESI-MS (m/z): 303 (M+Na)+
Preparation 13
To a solution of methyl 4-bromo-2-rαethoxybenzoate (2.0 g) in 1,4-dioxane (40 ml) was added bis (pinacolato) diboron (2.07 g) , dichlorobis (triphenylphosphine) palladium (II) (286 mg) and potassium acetate (2.4 g) , and the mixture was stirred at 95°C for 10 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 3/1) to give methyl 2-methoxy-4- (4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl) benzoate (2.0 g) . (+)ESI-MS (m/z): 293 (M+H) +
Preparation 14
To a suspension of methyl 2-methoxy-4- (4, 4, 5, 5- tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (2.0 g) in acetone (70 ml) and water (70 ml) was added ammonium acetate (1.11 g) and sodium periodate (3.08 g) , and the mixture was stirred at room temperature for 15 hours. The solvent was evaporated and the residue was diluted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give [3-methoxy-4- (methoxycarbonyl) phenyl] - boronic acid (1.4 g) .
(+) ESI-MS (m/z): 209 (M-H) _
Preparation 15
The following compounds were obtained according to a similar manner to that of Preparation 14.
(1) [3-Fluoro-4- (methoxycarbonyl) phenyl] boronic acid (+ ) ESI-MS (m/z): 197 (M-H) ~
(2) [2-Chloro-4- (methoxycarbonyl) phenyl] boronic acid (+) ESI-MS (m/z) : 213 (M-H) "
(3) [4- (Ethoxycarbonyl) -2-methoxyphenyl] boronic acid (+) ESI-MS (m/z) : 223 (M-H) ~
Preparation 16
To a solution of ethyl 3-methoxy-4- [ [ (trifluoromethyl) - sulfonyl] oxy] benzoate (1.52 g) in 1,4-dioxane (35 ml) was added bis (pinacolato) diboron (1.18 g) , 1, 1 ' -bis (diphenyl- phosphino) ferrocene-palladium (II ) dichloridedichloromethane complex (1:1) (309 mg) and potassium acetate (1.36 g) , and the mixture was stirred at 100°C for 10 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 5/1) to give ethyl 3-methoxy-4- (4, 4 , 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl) benzoate (700 mg) . (+) ESI-MS (m/z) : 293 (M+H)+
Preparation 17
The following compound was obtained according to a similar manner to that of Preparation 16. Methyl 3-chloro-4- (4,4,5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl) enzoate
(+)ESI-MS (m/z): 297 (M+H) +
Preparation 18
To a solution of tert-butyl [ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] [2- (4-hydroxyphenyl) ethyl] carbamate (5.0 g) and 2, 6-lutidine (2.97 ml) in dichloromethane (75 ml) was added trifluoromethanesulfonic anhydride (2.36 ml) dropwise at -70°C under nitrogen and the mixture was stirred at -70°C for 30 minutes. The mixture was allowed to warm to room temperature and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium biscarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give 4-[2-[(tert- butoxycarbonyl) [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] - amino] ethyl] henyl trifluoromethanesulfonate (6.6 g) . (+ )ESI-MS (m/z): 546 (M+Na) +
Preparation 19 To a solution of methyl 4-bromo-2-methylbenzoate (6.9 g) in 1,4-dioxane (150 ml) was added bis (pinacolato) diboron (8.03 g) , dichlorobis (triphenylphosphine) palladium (II) (1.69 g) and potassium acetate (8.87 g) , and the mixture was stirred at 95°C for 2 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with IN hydrochloric acid and brine, dried over magnesium sulfate and evaporated. To a suspension of the crude product (11 g) in acetone (200 ml) and water (200 ml) was added ammonium acetate (5.1 g) and sodium periodate (14.1 g) , and the mixture was stirred at room temperature for 6 hours. The solvent was evaporated, and the mixture was diluted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The resultant solid was triturated with diisopropyl ether to give [3-methyl-4- (methoxycarbonyl) phenyl] boronic acid (2.65 g) •
(+)ESI-MS (m/z): 193 (M-H) "
Preparation 20
To a solution of 4-hydroxy-2, 3-dimethylbenzaldehyde (1.9 g) and pyridine (5.12 ml) in dichloromethane (40 ml) was added trifluoromethanesulfonic anhydride (2.34 ml) under nitrogen and the mixture was stirred at room temperature for 30 minutes and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure to give 4- formyl-2, 3-dimethylphenyl trifluoromethanesulfonate (2.7 g) . (+)ESI-MS (m/z): 281 (M-H) ~
Preparation 21
To a solution of 4-formyl-2, 3-dimethylphenyl trifluoromethanesulfonate (2.5 g) in 1,4-dioxane (50 ml) was added bis (pinacolato) diboron (2.47 g) , 1, 1 ' -bis (diphenyl- phosphino) ferrocene-palladium (II) dichloridedichloromethane complex (1:1) (1.09 g) and potassium acetate (2.61 g) , and the mixture was stirred at 90°C for 5 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with IN hydrochloric acid and brine, dried over magnesium sulfate and evaporated. To a suspension of the crude product in acetone (80 ml) and water (80 ml) was added ammonium acetate (1.4 g) and sodium periodate (3.95 g) , and the mixture was stirred at room temperature for 6 hours. The solvent was evaporated, and the mixture was diluted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 1/1) to give (4-formyl-2, 3- dimethylphenyl) boronic acid (560 mg) . (+)ESI-MS (m/z): 177 (M-H) "
Preparation 22
To a solution of N-benzyl-N- [2- (4-bromophenyl) ethyl] - carbamate (1.3 g) in 1, 2-dimethoxyethane (20 ml) was added [4- (methoxycarbonyl) -2-methylphenyl] boronic acid (792 mg) , tetrakis (triphenylphosphine) palladium (360 mg) and aqueous solution of sodium carbonate (2M, 4.1 ml), and the mixture was stirred at 80°C for 2 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 3/1) to give methyl 4'-[2- [ [ (benzyloxy) carbonyl] amino] ethyl] -2-methyl-l, 1' -biphenyl-4- carboxylate (660 mg) .
(+ )ESI-MS (m/z): 426 (M+Na) +
Preparation 23
To a solution of 2, 2, 2-trifluoro-N- [3- (4-iodophenyl) - propyl] acetamide (2.5 g) in 1, 2-dimethoxyethane (15 ml) was added [4- (methoxycarbonyl) phenyl] boronic acid (1.51 g) , tetrakis (triphenylphosphine) palladium (809 mg) and aqueous solution of sodium carbonate (2M, 7 ml), and the mixture was stirred at 75°C for 10 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give methyl 4' - [3- [ (trifluoroacetyl) amino]propyl] -1, 1' - biphenyl-4-carboxylate (920 mg) .
MS (m/z) : 366 (M+H)
Preparation 24
The following compound was obtained according to a similar manner to that of Preparation 23.
Ethyl 4 " - [ 2- [[ (benzyloxy) carbonyl] amino] ethyl] -2- methoxy-1 , 1 ' -biphenyl-4-carboxylate MS (m/z) : 434 (M+H)
Preparation 25 A mixture of methyl 4 ' - [3- [ (trifluoroacetyl) amino] - propyl] -1, 1 ' -biphenyl-4-carboxylate (920 mg) , 4N hydrochloride in ethanol (2 ml) and ethanol (2 ml) was refluxed for 18 hours. The mixture was evaporated in vacuo. The residue was diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (chloroform:methanol = 100:1) to give ethyl 4' - (3-aminopropyl) -1, 1' -biphenyl-4-carboxylate (200 mg) as a colorless foam. MS (m/z) : 284 (M+H)
Preparation 26
To a solution of ethyl ( 1R) -1- ( 6-chloro-3-pyridyl) -2- [ [3- (4-iodophenyl) propyl] amino] ethanol (2.0 g) in tetrahydrofuran (3.5 ml) was added di-tert-butyl dicarbonate (53 mg) , and the mixture was stirred at room temperature for 2 hours. The mixture was evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give tert-butyl [(2R)-2-(6- chloro-3-pyridyl) -2-hydroxyethyl] [3- (4-iodophenyl) propyl] - carbamate (2.62 g) .
MS (m/z) : 517 (M+H)
Preparation 27
To a solution of 2, 2, 2-trifluoro-N- [ (IR) -2- (4- iodophenyl) -1-methylethyl] acetamide in dioxane (10 ml) was added IN sodium hydroxide (12 ml) and the mixture was stirred for 1 hour at room temperature. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated to give [ (IR) -2- (4-iodophenyl) -1- methylethyl] amine (2.34 g) as a yellow oil. MS (m/z) : 262 (M+H)
Preparation 28
A solution of [ (IR) -2- (4-iodophenyl) -1-methylethyl] - amine (1.0 g) and 2-chloro-5- [ (2R) -2-oxiranyl] pyridine (298 mg) in ethanol (10 ml) was refluxed for 18 hours. The mixture was evaporated in vacuo . To the residue was added di-tert-butyl dicarbonate (418 mg) and tetrahydrofuran (10 ml) and the mixture was stirred at room temperature for 2 hours and then evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 1/1) to give tert-butyl [ (2R) -2- ( 6-chloro-3-pyridyl) -2- hydroxyethyl] [ (IR) -2- (4-iodophenyl) -1-methylethyl] carbamate (700 mg) .
MS (m/z') : 517 (M+H)
Preparation 29
The following compound was obtained according to a similar manner to that of Preparation 28.
tert-Butyl [ (2R)-2- (6-chloro-3-pyridyl) -2- hydroxyethyl] [2- (4-hydroxyphenyl) ethyl] carbamate MS (m/z ) : 393 (M+H)
Preparation 30
Under nitrogen at -60°C, to a solution of tert-butyl [2- (4-hydroxyphenyl) ethl] [ (2R) -2-hydroxy-2- (3-pyridyl) - ethyl] carbamate (570 mg) and 2,6-lutidine (0.22 ml) in dichloromethane (10 ml) was added trifluoromethanesulfonic anhydride (0.28 ml), and the mixture was stirred at the same temperature for 1 hour. The resulting mixture was poured into aqueous ammonia and the aqueous mixture was extracted with ethyl acetate. The organic layer was washed successively with IN hydrochloric acid, water, saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 1:1) to give 4- [2- [(tert- butoxycarbonyl) [ (2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] - ethyl] phenyl trifluoromethanesulfonate (640 mg) as a colorless foam. MS (m/z) : 491 (M+H)
Preparation 31
The following compound was obtained according to a similar manner to that of Preparation 30.
4- [2- [ (tert-Butoxycarbonyl) [ (2R) -2-hydroxy-2- (3- chlorophenyl ) ethyl ] mino] propyl] phenyl trifluoromethanesulfonate
MS (m/z) : 538 (M+H)
Preparation 32
To a solution of 2, 2, 2-trifluoro-N- [ (IR) -l-methyl-2- phenylethyl] acetamide (3.75 g) in acetic acid (32 ml) - - water (6.5 ml) - sulfuric acid (0.97 ml) were added iodine (1.65 g) and periodic acid dihydrate (740 mg) at room temperature, and the mixture was heated to 60 - 80°C for 5 hours. After being allowed to cool to room temperature, the mixture was partitioned between hexane/ethyl acetate and water. The organic layer was separated, washed successively with water, sodium sulfite solution, water and brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the residue was recrystallized from diisopropyl ether (44 ml) to give 2, 2, 2-trifluoro-N- [ (IR) -2- (4-iodophenyl) -1-methylethyl] acetamide (2.15 g) as a colorless needle.
NMR (CDC13, δ) : 1.21 (3H, d, G=7Hz) , 2.74 (IH, dd, J=14, 7Hz), 2.85 (IH, dd, J=14, 6Hz), 4.26 (IH, m) , 6.04 (IH, br s), 6.92 (2H, d, J=8Hz) 7.65 (2H, d, J=8Hz) (+) ESI-MS (m/z): 380 (M+Na) +
Preparation 33
The following compound was obtained according to a similar manner to that of Preparation 32.
2,2, 2-Trifluoro-N- [3- (4-iodophenyl) propyl] acetamide NMR (CDCI3, δ) : 1.90 (2H, quintet, J=7Hz) , 2.62 (2H, t, J=7Hz), 3.38 (2H, q, J=7Hz) , 6.26 (IH, br s) , 6.93 (2H, d, J=8Hz) , 7.62 (2H, d, J=8Hz) (+) ESI-MS (m/z): 380 (M+Na) +
Preparation 34
To a mixture of 3- (4-hydroxyphenyl) propanoic acid (15.0 g) , (IR) -2-amino-l- (3-chlorophenyl) ethanol hydrochloride (18.8 g) , and 1-hydroxybenzotriazole (14.6 g) in N,N- dimethylformamide (100 ml) was added l-(3- dimethyla inopropyl) -3-ethylcarbodiimide hydrochloride (26.0 g) , and the mixture was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed successively with sodium bicarbonate solution and brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate) to give N- [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] -3- (4- hydroxyphenyl)propanamide (11.61 g) as a white amorphous powder.
MS (m/z) : 320 (M+H)
Preparation 35
To a solution of N- [ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] -3- (4-hydroxyphenyl )propanamide (11.61 g) in tetrahydrofuran (70 ml) was added borane-methyl sulfide complex (10M, 11.9 ml) at 0°C, and the mixture was heated to 80°C for 1 hour. After being allowed to cool to room temperature, the mixture was added 2N hydrochloric acid (20 ml) at 0°C. The mixture was heated to 80°C for 1 hour. After being allowed to cool to room temperature, the mixture was added IN sodium hydroxide ( 40 ml) and di-tert-butyl dicarbonate (8.72 g) and stirred for 1 hour at room temperature. The mixture was partitioned between hexane/ethyl acetate and water. The organic layer was separated, washed successively with water, sodium sulfite solution, water and brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate) to give tert-butyl [ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] [3- (4-hydroxyphenyl) propyl] carbamate (11.36 g) as a white powder. MS (m/z) : 406 (M+H)
Preparation 36
A mixture of methyl 4 ' - [2- [[ (benzyloxy) carbonyl] - amino] ethyl] -2-methyl-l, 1 ' -biphenyl-4-carboxylate (650 mg) , ammonium formate (500 mg) and palladium on carbon powder (400 mg) in methanol (10 ml) and water (1.0 ml) was refluxed for 2 hours. The reaction mixture was filtrated and poured into water and extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to give methyl 4' - (2-aminoethyl) -2-methyl-l, 1' - biphenyl-4-carboxylate (380 mg) . (+) ESI-MS (m/z): 270 (M+H)+
Preparation 37 The following compounds were obtained according to a similar manner to that of Preparation 36.
(1) Ethyl 4 ' - (2-aminoethyl) -2-methoxy-l, 1' -biphenyl-4- carboxylate MS (m/z) : 300 (M+H)
( 2 ) tert-Butyl [ 2- ( 4-hydroxyphenyl ) ethyl ] [ (2R) -2-hydroxy-2- ( 3-pyridyl ) ethyl ] carbamtate
MS (m/z ) : 359 (M+H)
Preparation 38
The following compound was obtained according to a similar manner to that of Example 14.
tert-Butyl [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] [2- [ 4 ' -formyl-2' , 3' -dimethyl-1, 1' -biphenyl-4-yl) ethyl] carbamate (+ )ESI-MS (m/z): 530 (M+Na) +
Example 14 To a solution of tert-butyl [2- (4-bromophenyl) ethyl] -
[ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] carbamate (365 mg) in 1, 2-dimethoxyethane (6 ml) was added [4- (ethoxycarbonyl) -
2-methoxyphenyl] boronic acid (216 mg) , tetrakis (triphenylphosphine) palladium (46 mg) and aqueous solution of sodium carbonate (2M, 0.85 ml), and the mixture was stirred at 80°C for 4 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel
(hexane/ethyl acetate = 2/1) to give ethyl 4' - [2- [ (tert- butoxycarbonyl) [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] - amino] ethyl] -2-methoxy-l, 1' -biphenyl-4-carboxylate (222 mg) . MS (m/z) : 554 (M+H) +
Example 15
The following compounds were obtained according to a similar manner to that of Example 14.
(1) 4'- [ (2R) -2- [[ (2R) -2- (3-Chlorophenyl) -2- hydroxyethyl] amino]propyl] -3-methoxy-l, 1' -biphenyl-4- carboxylic acid hydrochloride
NMR (DMS0-d6, δ) : 1.14 (3H, d, J=6.4Hz), 2.8-3.8 (5H, m) , 3.92 (3H, s) , 5.0-5.3 (IH, m) , 6.3-6.4 (IH, m) , 7.2-7.8 (10H, m) , 8.13 (IH, br s), 8.85 (IH, br s) ,
9.42 (IH, br s) MS (m/z) : 440 (M+H)
(2) 4'-[ (2R)-2-[ [ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] - amino] propyl] -2-methoxy-l, 1' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMS0-d6, δ) : 1.17 (3H, d, J=6.4Hz), 2.8-3.8 (5H, m) , 3.83 (3H, s) , 5.0-5.2 (IH, m) , 6.3-6.4 (IH, ) , 7.2-7.8 (10H, m) , 8.11 (IH, br s), 8.86 (IH, br s) , 9.37 (IH, br s)
MS (m/z) : 440 (M+H)
(3) 4' - [ (2R) -2- [ [ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] - amino] propyl] -2-methyl-l, 1' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d6, δ) : 1.17 (3H, d, J=6.4Hz), 2.28 (3H, s) , 2.8-3.8 (5H, m) , 5.0-5.3 (IH, m) , 6.3-6.4 (IH, m) , 7.2-7.6 (8H, m) , 7.7-7.9 (2H, m) , 8.11 (IH, br s) , 8.86 (IH, br s) , 9.39 (IH, br s) MS (m/z) : 424 (M+H)
(4) 4 ' - [ (2R) -2- [ [ (2S) -2- (3-Chlorophenyl) -2-hydroxyethyl] - amino]propyl] -3-methoxy-l, 1' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d6, δ) : 1.16 (3H, d, J=6.4Hz), 2.8-3.8 (5H, m) , 3.91 (3H, s) , 5.0-5.3 (IH, ) , 6.3-6.4 (IH, ) , 7.2-7.8 (11H, ) , 8.77 (IH, br s) , 9.13 (IH, br s) MS (m/z) : 440 (M+H)
(5) 4'-[ (2R)-2- [ [ (2R) -2-Phenyl-2-hydroxyethyl ] amino] - propyl] -3-methoxy-l, 1' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-d6, δ) : 1.15 (3H, d, J=6.4Hz), 2.8-3.8 (5H, m) , 3.92 (3H, s), 5.0-5.2 (IH, m) , 6.3-6.4 (IH, iti) ,
7.2-7.6 (9H, m) , 7.7-7.9 (3H, ) , 8.81 (IH, br s) ,
9.31 (IH, br s) MS (m/z) : 406 (M+H)
(6) 4'-[ (2R)-2-[ [ (2R) -2-Phenyl-2-hydroxyethyl] amino] - propyl] -2-methyl-l, 1' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-d6, δ) : 1.17 (3H, d, J=6.4Hz), 2.28 (3H, s), 2.8-3.8 (5H, m) , 5.0-5.2 (IH, m) , 6.3-6.4 (IH, m) , 7.2-7.6 (9H, m) , 7.7-7.9 (3H, ) , 8.81 (IH, br s) ,
9.24 (IH, br s) MS (m/z) : 390 (M+H)
( 7 ) 4 ' - [ ( 2R) -2- [ [ ( 2s ) -2-Phenyl-2-hydroxyethyl ] amino] - propyl ] -2-methyl-l , 1 ' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-d6, δ) : 1.19 (3H, d, J=6.4Hz), 2.27 (3H, s), 2.8-3.8 (5H, ) , 5.0-5.2 (IH, m) , 6.2-6.3 (IH, m) , 7.2-7.6 (9H, m) , 7.7-7.9 (3H, ) , 8.80 (IH, br s), 9.35 (IH, br s)
MS (m/z) : 390 (M+H)
(8) 4 ' - [ (2R)-2-[[ (2R)-2- (3-Chlorophenyl) -2-hydroxyethyl] - amino]propyl] -3-isopropyloxy-l, 1' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-d6, δ) : 1.14 (3H, d, J=6.4Hz), 1.30 (6H, d, J=5.8Hz), 2.8-3.8 (5H, ) , 4.6-4.9 (IH, m) , 5.0- 5.3 (IH, ) , 6.2-6.4 (IH, m) , 7.2-7.8 (11H, m) , 8.82 (IH, br s) , 9.24 (IH, br s) MS (m/z) : 468 (M+H)
(9) 4'-[ (2R) -2-[ [ (2R) -2-Phenyl-2-hydroxyethyl ] amino] - propyl] -3-isopropyloxy-l, 1' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d6, δ) : 1.12 (3H, d, J=6.4Hz), 1.30 (6H, d, J=5.8Hz), 2.8-3.8 (5H, m) , 4.6-4.9 (IH, m) , 5.0- 5.3 (IH, m) , 6.2-6.4 (IH, ) , 7.2-7.8 (12H, m) , 8.82 (IH, br s) MS (m/z) : 434 (M+H)
(10) 4'-[ (2R)-2-[ [ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] - amino]propyl] -3-cyclohexyloxy-l, 1' -biphenyl-4- carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.14 (3H, d, J=6.4Hz), 1.2-2.0 (10H, m) , 2.8-3.8 (5H, m) , 4.65 (IH, m) , 5.0-5.2 (IH, ) ,
6.3-6.4 (IH, m) , 7.2-7.9 (11H, m) , 8.79 (IH, br s) ,
9.10 (IH, br s) MS (m/z) : 508 (M+H)
(11) 4'-[ (2R)-2-[ [ (2R) -2-Phenyl-2-hydroxyethyl] amino] - propyl] -3-cyclohexyloxy-l, 1' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-d6, δ) : 1.14 (3H, d, J=6.4Hz), 1.2-2.0 (IOH, m) , 2.8-3.8 (5H, m) , 4.65 (IH, m) , 4.9-5.1 (IH, m) , 6.23 (IH, ) , 7.1-7.9 (12H, m)
MS (m/z) : 474 (M+H)
(12) Methyl 4 ' - [2- [( tert-butoxycarbonyl) [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] -3-methoxy- 1, 1 ' -biphenyl-4-carboxylate (+)ESI-MS (m/z): 562 (M+Na)+
(13) Methyl 4' - [2- [( tert-butoxycarbonyl) [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] -2-chloro- 1, 1' -biphenyl-4-carboxylate (+) ESI-MS (m/z): 544 (M+H) +
Example 16
To a solution of 4- [2- [ (tert-butoxycarbonyl) [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] phenyl trifluoromethanesulfonate (300 mg) in 1, 2-dimethoxyethane (5 ml) was added [3-fluoro-4- (methoxycarbonyl) phenyl] boronic acid (125 mg) , tetrakis (triphenylphosphine) palladium (53 mg) and aqueous solution of sodium carbonate (2M, 0.6 ml), and the mixture was stirred at 80°C for 2 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 3/1) to give methyl 4'-[2- [ (tert-butoxycarbonyl) [ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] amino] ethyl] -3-fluoro-1, 1' -biphenyl-4- carboxylate (230 mg) .
(+)ESI-MS (m/z): 528 (M+H) + Example 17
The following compound was obtained according to a similar manner to that of Example 16.
Methyl 4' - [2- [ (tert-butoxycarbonyl) [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] -3-methyl-l, lf - biphenyl-4-carboxylate
(+JESI-MS (m/z): 546 (M+Na) +
Example 18
To a solution of ethyl 4' - [2- [ (tert-butoxycarbonyl) - [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] -2- methoxy-1, 1' -biphenyl-4-carboxylate (220 mg) in ethanol (2.0 ml) was added IN aqueous sodium hydroxide solution (1.2 ml), and the mixture was stirred at 40°C for 3 hours. The solvent was removed by evaporation, and the aqueous solution was acidified with IN hydrochloric acid and extracted with ethyl acetate (30 ml x 2) . The combined organic layers were washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give a benzoic acid product. To a solution of the product in tetrahydrofuran (1.5 ml) was added 4N hydrochloride in dioxane (1.0 ml), and the mixture was stirred at room temperature for 12 hours. The resultant solid was collected by filtration and dried to give 4' - [2- [[ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] - ethyl ] -2-methoxy-l , 1 ' -biphenyl-4-carboxylic acid hydrochloride (83 mg) .
NMR (DMS0-d6, δ) : 3.02-3.27 (6H, m) , 3.82 (3H, s),
4.98-5.02 (IH, ) , 6.35 (IH, br) , 7.30-7.64 (11H, m) , 9.05 (IH, br)
(-)ESI-MS (m/z): 424 (M-HCl-H) "
Example 19
The following compounds were obtained according to a similar manner to that of Example 18. (1) 4 ' - [2- [ [ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] amino] - ethyl] -3-methoxy-l, l'-biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d6, δ) : 3.01-3.34 (6H, m) , 3.92 (3H, s) ,
5.02-5.06 (IH, m) , 6.37 (IH, br) , 7.26-7.48 (9H, ) , 7.74 (2H, d, J=7.9Hz), 9.25 (IH, br) (-) ESI-MS (m/z): 424 (M-HCl-H)-
(2) 2-Chloro-4' - [2- [[ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] amino] ethyl] -1,1' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-d6, δ) : 3.01-3.34 (6H, m) , 4.99-5.03 (IH, m) , 6.36 (IH, br) , 7.37-7.55 (9H, m) , 7.93-8.03 (2H, m.) , 9.10 (IH, br)
(-)ESI-MS (m/z): 424 (M-HCl-H) ~
(3) 4 '- - [2- [ [ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] amino] - ethyl] -3-fluoro-l, 1' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-d6, 6) : 3.01-3.33 (6H, ) , 4.98-5.03 (IH, m) , 6.34 (IH, br) , 7.35-7.47 (6H, rα) , 7.61-7.98 (5H, m) , 9.10 (IH, br) (-)ESI-MS (m/z) : 412 (M-HCl-H) "
(4) 4'-[2-[ [ (2R)-2- (3-Chlorophenyl) -2-hydroxyethyl] amino] - ethyl] -3-methyl-l, 1' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-d6, δ) : 2.60 (3H, s), 3.01-3.34 (6H, m) , 4.98-5.02 (IH, m) , 6.34 (IH, br) , 7.36-7.60 (8H, ) , 7.72 (2H, d, J=8.0Hz), 7.91 (IH, d, J=8.0Hz), 9.25 (IH, br) (-)ESI-MS (m/z) : 408 (M-HCl-H) "
Example 20 To a solution of tert-butyl [ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] [2- (4' -formyl-2' , 3' -dimethyl-1, 1' -biphenyl-4- yl) ethyl] carbamate in acetonitrile (2.5 ml) and pH 4 buffer solution (sodium dihydrogenphosphate) (1.3 ml) was added 30% hydrogen peroxide solution (60 μl) • and 80% sodium chlorite (128 mg) below 10°C. The reaction mixture was stirred at 40°C for 1.5 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give a benzoic acid product. To a solution of the product in tetrahydrofuran (1.0 ml) was added 4N hydrochloride in dioxane (1.18 ml), and the mixture was stirred at room temperature for 12 hours. The resultant solid was collected by filtration and dried to give 4' - [2- [ [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] -2, 3-dimethyl-l, 1' - biphenyl-4-carboxylic acid hydrochloride (140 mg) .
NMR (DMSO-dβ, δ) : 2.14 (3H, s), 2.45 (3H, s), 3.00-3.34 (6H, m) , 4.99-5.03 (IH, m) , 6.34 (IH, br) , 7.07 (IH, d, J=8.0Hz), 7.05-7.59 (9H, m) , 9.25 (IH, br) (-) ESI-MS (m/z): 422 (M-HCl-H) -
Example 21
A solution of ethyl 4' - (3-aminopropyl) -1, 1' -biphenyl-4- carboxylate (200 mg) , and 2-chloro-5- [ (2R) -2-oxiranyl] - pyridine (71.5 mg) in ethanol (10 ml) was refluxed for 18 hours. The mixture was evaporated in vacuo . The residue was purified by column chromatography on silica gel (chloroform: ethanol = 100:1) to give ethyl 4' - [3- [ [ (2R) -2- (6-chloro-3-pyridyl) -2-hydroxyethyl] amino] propyl]-!, 1' - biphenyl-4-caroxylate (96 mg) as a colorless foam. MS (m/z) : 439 (M+H)
Example 22
The following compounds were obtained according to a similar manner to that of Example 21. (1) Methyl 4'-[2-[ [ (2R) -2- ( 6-chloro-3-pyridyl) -2- hydroxyethyl] amino] ethyl] -2-methyl-l, 1' -biphenyl-4- carboxylate (+) ESI-MS (m/z): 425 (M+H) +
(2) Ethyl 4'-[2-[ [ (2R)-2- (6-chloro-3-pyridyl)-2- hydroxyethyl] amino] ethyl] -2-methoxy-l, 1' -biphenyl-4- carboxylate MS (m/z) : 454 (M+)
Example 23
To a solution of ethyl 4' - [3- [ [ (2R) -2- (6-chloro-3- pyridyl) -2-hydroxyethyl] amino] propyl] -1,1' -biphenyl-4- carboxylate (96 mg) in tetrahydrofuran (3.5 ml) was added di-tert-butyl dicarbonate (53 mg) , and the mixture was stirred at room temperature for 30 minutes and then evaporated. To the residue were added IN sodium hydroxide solution (0.5 ml) and methanol (0.5 ml), and was stirred for 2 hours at room temperature. The residue was diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 1/1) to give 4' - [3- [ (tert- butoxycarbonyl) [ (2R) -2- (6-chloro-3-pyridyl) -2-hydroxyethyl] - amino]propyl] -1, 1' -biphenyl-4-carboxylic acid (100 mg) as a colorless foam.
MS (m/z) : 512 (M+H)
Example 24
The following compounds were obtained according to a similar manner to that of Example 23.
(1) 4'-[2-[ (tert-Butoxycarbonyl) [ (2R)-2-(6-chloro-3- pyridyl ) -2-hydroxyethyl ] amino ] ethyl ] -2-methyl-l , 1 ' - biphenyl-4-carboxylic acid (+ ) ESI-MS (m/z ) : 509 (M-H) _
(2 ) 4 ' - [2- [ (tert-Butoxycarbonyl ) [ (2R) -2- ( 6~chloro-3- pyridyl ) -2-hydroxyethyl ] amino ] ethyl ] -2-methoxy-l , 1 ' - biphenyl-4-carboxylic acid MS (m/ z ) : 527 (M+H)
Example 25
4'-[3-[ (tert-Butoxycarbonyl) [ (2R) -2- ( 6-chloro-3- pyridyl) -2-hydroxyethyl] amino]propyl] -1, 1' -biphenyl-4- carboxylic acid (100 mg) , ammonium formate (50 mg) and palladium on carbon powder (30 mg) in methanol (5 ml) and water (1.0 ml) was refluxed for 30 minutes. The reaction mixture was filtrated and poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. A mixture of the residue was chromatographed (chloroform- methanol) over silica gel to give 4' - [3- [ (tert- butoxycarbonyl) [ (2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] - propyl] -1, 1' -biphenyl-4-carboxylic acid (90 mg) as a colorless foam.
MS (m/z) : 477 (M+H)
Example 26
The following compounds were obtained according to a similar manner to that of Example 25.
(1) 4' - [2- [ (tert-Butoxycarbonyl) [ (2R)-2-hydroxy-2- (3- pyridyl) ethyl] amino] ethyl] -2-methyl-l, 1' -biphenyl-4- carboxylic acid
(+) ESI-MS (m/z): 475 (M-H) _
(2) 4'-[2-[ (tert-Butoxycarbonyl) [ (2R)-2-hydroxy-2- (3- pyridyl) ethyl] amino] ethyl] -2-methoxy-l, 1' -biphenyl-4- carboxylic acid
MS (m/z) : 493 (M+H)
(3) 4 ' - [3- [ (tert-Butoxycarbonyl) [ (2R) -2-hydroxy-2- (3- pyridyl) ethyl] amino]propyl] -2-methoxy-l, 1' -biphenyl-4- carboxylic acid
MS (m/z) : 507 (M+H)
(4) 4' -[ (2R) -2- [ (tert-Butoxycarbonyl) [ (2R)-2-hydroxy-2- (3- pyridyl) ethyl] amino] propyl] -1,1' -biphenyl-4-carboxylic acid MS (m/z) : 477 (M+H)
Example 27
A solution of tert-butyl 4' - [3- [ (tert-butoxycarbonyl) - [ (2R) -2-hydroxy-2- (3-pyridyl) ethyl] mino] propyl] -1,1'- biphenyl-4-carboxylic acid (90 mg) and 4N hydrochloride in dioxane (5.0 ml) was stirred at room temperature for 24 hours. The resultant solid was collected by filtration and dried to give 4' - [3- [[ (2R) -2-hydroxy-2- (3-pyridyl) ethyl] - amino]propyl] -1, 1' -biphenyl-4-carboxylic acid dihydrochloride (80 mg) as a white solid.
NMR (DMSO-d6, δ) : 2.90-3.90 (8H, m) , 5.10-5.20 (IH, m) , 7.35 (IH, d, J=8Hz), 7.65-7.85 (6H, rα) , 8.05 (IH, d, J=8Hz), 8.25 (IH, d, J=8Hz) , 8.70-8.85 (2H, m) MS (m/z) : 377 (M+H)
Example 28 The following compounds were obtained according to a similar manner to that of Example 27.
(1) 4'-[2-[ [ (2R)-2-Hydroxy-2- (3-pyridyl) ethyl] amino] ethyl] - 2-methyl-l, 1' -biphenyl-4-carboxylic acid dihydrochloride NMR (DMSO-dβ, δ) : 3.10-3.80 (6H, ) , 3.90 (3H, s) ,
5.10-5.20 (IH, m) , 7.40-7.70 (7H, m) , 7.8-7.90 (IH, m) , 8.25 (IH, d, J=8Hz) , 8.70-8.85 (2H, ) (-)ESI-MS (m/z) : 375 (M-2HC1-H) "
(2) 4'- [2-[ [ (2R)-2-Hydroxy-2- ( 3-pyridyl) ethyl] amino] ethyl] - 2-methoxy-l, 1' -biphenyl-4-carboxylic acid dihydrochloride
NMR (DMSO-dg, δ) : 3.10-3.80 (6H, m) , 3.90 (3H, s) , 5.10-5.20 (IH, m) , 7.40-7.70 (7H, m) , 7.80-7.90
(IH, m) , 8.25 (IH, d, J=8Hz) , 8.70-8.85 (2H, ) MS (m/z) : 393 (M+H)
(3) 4'-[3-[ [ (2R) -2-Hydroxy-2- (3-pyridyl) ethyl] amino] - propyl] -2-methoxy-l, 1' -biphenyl-4-carboxylic acid dihydrochloride
NMR (DMSO-dg, δ) : 2.90-3.90 (8H, m) , 3.95 (3H, s) ,
5.10-5.20 (IH, m) , 7.35 (IH, d, J=8Hz) , 7.65-7.85 (6H, ) , 8.05 (IH, d, J=8Hz) , 8.25 (IH, d, J=8Hz) , 8.70-8.85 (2H, m)
MS (m/z) : 407 (M+H)
(4) 2-Chloro-4' - [2- [ [ (2R) -2-hydroxy-2- (3-pyridyl) ethyl] - amino] ethyl] -1, V -biphenyl-4-carboxylic acid dihydrochloride
NMR (DMSO-dg, δ) : 3.10-3.80 (6H, m) , 5.10-5.20 (IH, m) , 7.40-7.70 (7H, m) , 7.90-8.10 (2H, m) , 8.70-8.85 (2H, ) MS (m/z) : 397 (M+H)
(5) 4'-[ (2R)-2-[ [ (2R)-2-Hydroxy-2- (3-pyridyl) ethyl] amino] - propyl] -1, 1' -biphenyl-4-carboxylic acid dihydrochloride NMR (DMSO-dg, δ) : 1.70 (3H, d, J=6Hz) , 3.30-3.90 ( 6H, m) , 5.10-5.20 (IH, ) , 7.40-7.70 (7H, m) , 7.80- 7.90 (IH, m) , 8.25 (IH, d, J=8Hz) , 8.70-8.85 (2H, ) MS (m/ z ) : 377 (M+H)
(6) 4 ' - [3- [ [ (2R)-2- (3-Chlorophenyl) -2-hydroxyethyl] amino] propyl] -2-methyl-l, 1' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 2.00-2.15 (2H, m) , 2.30 (3H, s),
2.60-3.30 (6H, m) , 5.00-5.10 (IH, m) , 7.20-7.60 (9H, m) , 7.75-7.90 (2H, m) MS (m/z) : 424 (M+H)
Example 29
The following compounds were obtained according to a similar manner to that of Example 23.
( 1) Ethyl 4 ' - [ 3- [ (tert-butoxycarbonyl) [ ( 2R) -2- ( 6-chloro-3- pyridyl ) -2-hydroxyethyl ] amino] propyl ] -2-methoxy-l , 1 ' - biphenyl-4-carboxylate
MS (m/z ) : 569 (M+H)
(2) Methyl 4' - [2- [( tert-butoxycarbonyl) [ (2R) -2-hydroxy-2-
( 3-pyridyl) ethyl] amino] ethyl] -2-chloro-1, 1' -biphenyl-4- carboxylate
MS (m/z) : 512 (M+H)
(3) Methy ' ~[ (2R) -2- [( tert-butoxycarbonyl) [ (2R) -2- ( 6- chloro-3-pyridyl) -2-hydroxyethyl] amino] propyl] -1,1'- biphenyl-4-carboxylate
MS (m/z) : 524 (M+H)
(4) Methyl 4' - [3- [ (tert-butoxycarbonyl) [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] propyl] -2-methyl- 1,1' -biphenyl-4-carboxylate
MS (m/z) : 538 (M+H) (5) 4' - [ (2R)-2-[ [ (2R)-2-Hydroxy-2- (3-pyridyl) ethyl] amino] - propyl] -3-methoxy-l, 1' -biphenyl-4-carboxylic acid dihydrochloride
NMR (DMSO-dg, δ) : 1.14 (3H, d, J=6.4Hz), 2.8-3.8 (5H, m) , 3.92 (3H, s) , 5.1-5.3 (IH, ) , 7.2-7.5 (4H, ) ,
7.7-7.9 (4H, m) , 8.2-8.4 (IH, m) , 8.8-9.0 (2H, m) ,
9.36 (IH, br s) MS (m/z) : 407 (M+H)
(6) 4'- [ (2R) -2- [[ (2R) -2-Hydroxy-2- (3-pyridyl) ethyl] amino] - propyl] -2-methoxy-l, 1' -biphenyl-4-carboxylic acid dihydrochloride NMR (DMSO-dg, δ) : 1.14 (3H, d, J=6.4Hz), 2.8-3.8 (5H, m) , 3.83 (3H, s) , 5.1-5.3 (IH, m) , 7.2-7.8 (7H, rα) , 7.8-8.0 (IH, m) , 8.2-8.5 (IH, m) , 8.7-9.0 (2H, m) ,
9.02 (IH, br s), 9.36 (IH, br s) MS (m/z) : 407 (M+H)
(7) 4 ' - [ (2R)-2-[ [ (2R) -2-Hydroxy-2- (3-pyridyl) ethyl] amino] - propyl] -2-methyl-l, 1' -biphenyl-4-carboxylic acid dihydrochloride
NMR (DMSO-dg, δ) : 1.19 (3H, d, J=6.4Hz), 2.48 (3H, s) ,
2.8-3.8 (5H, m) , 5.1-5.3 (IH, m) , 7.2-7.5 (5H, m) ,
7.8-8.0 (3H, ) , 8.37 (IH, d, J=8.2Hz), 8.78 (IH, d, J=4.6Hz), 8.87 (IH, s), 9.04 (IH, br s), 9.35
(IH, br s)
MS (m/z) : 391 (M+H)
(8) 4'- [ (2R)-2-[ [ (2R) -2-Hydroxy-2- (3-pyridyl) ethyl] amino] - propyl] -3-methyl-l, 1' -biphenyl-4-carboxylic acid dihydrochloride
NMR (DMSO-dg, δ) : 1.19 (3H, d, J=6.4Hz), 2.60 (3H, s), 2.8-3.8 (5H, m) , 5.1-5.3 (IH, m) , 7.2-8.0 (8H, m) ,
8.37 (IH, d, J=8.2Hz), 8.79 (IH, d, J=4.6Hz), 8.87 (IH, s), 9.05 (IH, br s), 9.35 (IH, br s) MS (m/ z ) : 391 (M+H)
(9) 4'-[ (2R)-2- [ [ (2R) -2-Hydroxy-2- (3-pyridyl) ethyl] amino] - propyl] -3-isopropyloxy-l, 1' -biphenyl-4-carboxylic acid dihydrochloride
NMR (DMSO-dg, δ) : 1.19 (3H, d, J=6.4Hz), 1.31 (6H, d, J=6.0Hz), 2.8-3.8 (5H, m) , 4.6-4.9 (IH, m) , 5.1- 5.3 (IH, m) , 7.2-7.5 (4H, ) , 7.6-8.0 (4H, m) , 8.37 (IH, d, J=8.2Hz), 8.80 (IH, d, J=4.6Hz), 8.88 (IH, s), 9.02 (IH, br s) , 9.35 (IH, br s)
MS (m/z) : 435 (M+H)
(10) 4'-[ (2R)-2- [ [ (2S)-2-Hydroxy-2- (3-pyridyl) ethyl] amino] - propyl] -1, 1' -biphenyl-4-carboxylic acid dihydrochloride NMR (DMSO-dg, δ) : 1.19 (3H, d, J=6.4Hz), 2.8-3.8 (5H, m) , 5.1-5.3 (IH, ) , 7.2-8.1 (8H, m) , 8.57 (IH, d, J=7.8Hz), 8.81 (IH, d, J=4.6Hz), 8.90 (IH, s), 9.10 (IH, br s), 9.56 (IH, br s) MS (m/z) : 357 (M-H)
(11) 4'-[ (2R)-2-[ [ (2S)-2-Hydroxy-2-(6-chloro-3-pyridyl)- ethyl] amino] propyl] -1,1' -biphenyl-4-carboxylic acid dihydrochloride
NMR (DMSO-dg, δ) : 1.17 (3H, d, J=6.4Hz), 2.8-3.8 (5H, m) , 5.1-5.3 (IH, m) , 7.39 (2H, d, J=8.0Hz), 7.58
(IH, d, J=8.0Hz), 7.6-8.2 (7H, ) , 8.48 (IH, d, J=2.4Hz), 8.86 (IH, br s), 9.22 (IH, br s) MS (m/z) : 409 (M-H)
(12) 4'-[ (2R)-2-[ [ "(2R) -2-Hydroxy-2- (6-chloro-3-pyridyl) - ethyl] amino] propyl] -1, 1' -biphenyl-4-carboxylic acid dihydrochloride
NMR (DMSO-dg, δ) : 1.16 (3H, d, J=6.4Hz), 2.8-3.8 (5H, ) , 5.1-5.3 (IH, ) , 7.38 (2H, d, J=8.0Hz), 7.58 (IH, d, J=8.0Hz), 7.6-8.2 (7H, m) , 8.49 (IH, d, J=2 . 4Hz ) , 8 . 86 ( IH, br s ) , 9 . 45 ( IH, br s ) MS (m/ z ) : 409 (M-H)
(13) 4' - [ (2R) -2- [ [ (2R) -2-Hydroxy-2- (3-pyridyl) ethyl] amino] - propyl] -3-cyclohexyloxy-l, 1' -biphenyl-4-carboxylic acid dihydrochloride
NMR (DMSO-dg, δ) : 1.15 (3H, d, J=6.4Hz), 1.2-2.0 (10H, m) , 2.7-3.8 (5H, ) , 4.65 (IH, m) , 5.31 (IH, ) , 7.2-7.5 (5H, m) , 7.6-7.8 (2H, m) , 7.9-8.0 (IH, ) , 8.45 (IH, ) , 8.82 (IH, d, J=2.6Hz), 8.90 (IH, s),
9.07 (IH, br s), 9.43 (IH, br s) MS (m/z) : 475 (M+H)
Example 30 To a solution of ethyl 4' - [3- [ (tert-butoxycarbonyl) -
[ (2R) -2- (6-chloro-3-pyridyl) -2-hydroxyethyl] amino]propyl] -2- methoxy-1, 1' -biphenyl-4-carboxylate in ethanol (5.0 ml) was added IN sodium hydroxide (1.0 ml) and the mixture was stirred for 2 hours at room temperature. The mixture was diluted with ethyl acetate and IN hydrochloric acid. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 1/1) to give 4' - [3- [ (tert-butoxycarbonyl) [ (2R) -2- ( 6- chloro-3-pyridyl) -2-hydroxyethyl] amino] propyl] -2-methoxy- 1, 1' -biphenyl-4-carboxylic acid (100 mg) . MS (m/z) : 541 (M+H)
Example 31 The following compounds were obtained according to a similar manner to that of Example 30.
(1) 4' - [2- [ (tert-Butoxycarbonyl) [ (2R) -2-hydroxy-2- (3- pyridyl) ethyl] amino] ethyl] -2-chloro-l, 1' -biphenyl-4- carboxylic acid MS (m/ z ) : 497 (M+H)
(2) 4'-[ (2R)-2-[ (tert-Butoxycarbonyl) [ (2R) -2- (6-chloro-3- pyridyl) -2-hydroxyethyl] amino]propyl] -1,1' -biphenyl-4- carboxylic acid
MS (m/z) : 511 (M+H)
(3) 4' - [3- [ (tert-Butoxycarbonyl) [ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] amino] propyl] -1,1' -biphenyl-4-carboxylic acid
MS (m/z) : 524 (M+H)
Preparation 39
The following compound was obtained according to a similar manner to that of Preparation 34.
N- [ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] -3- (3- hydroxyphenyl) propanamide
MS (m/z) : 320 (M+H)
Preparation 40
The following compound was obtained according to a similar manner to that of Preparation 35.
tert-Butyl N- [ (2R) -2- (3-chlorophenyl ) -2-hydroxyethyl] - N- [ 3- ( 3-hydroxyphenyl ) propyl ] carbamate MS (m/z) : 405 (M+H)
Preparation 41 The following compounds were obtained according to a similar manner to that of Preparation 30.
(1) tert-Butyl N- [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] - N- [3- [3- [ [ (trifluoromethyl) sulfonyl] oxy] phenyl] propyl] - carbamate MS (m/ z ) : 537 (M+H)
(2) 4- [2- [N- (tert-Butoxycarbonyl) -N- [ (2R) -2- (5-chloro-3- pyridyl) -2-hydroxyethyl] amino] ethyl] phenyl trifluoromethanesulfonate MS (m/z) : 525 (M+H)
(3) Methyl 4- [[ (trifluoromethyl) sulfonyl] oxy] -1-naphthoate MS (m/z) : 358 (M+Na)
(4) Methyl [4- [[ (trifluoromethyl) sulfonyl] oxy]phenyl] - acetate
NMR (DMSO-dg, δ) : 3.63(3H, s), 3.90(2H, s), 7.46(4H, s)
(5) Methyl [3- [[ (trifluoromethyl) sulfonyl] oxy]phenyl] - acetate
NMR (DMSO-dg, δ) : 3.63(3H, s), 3.83(2H, s), 7.30- 7.60(4H, m)
(6) 5-Hydroxy-l-naphthyl trifluoromethanesulfonate
NMR (DMSO-dg, δ) : 6.80(2H, d, J=8Hz) , 7.20 (2H, t, J=8Hz) , 7.50 (2H, d, J=8Hz)
(7) Ethyl 5- [[ (trifluoromethyl) sulfonyl] oxy] -1-naphthoate
(8) 4- [2- [N- (tert-Butoxycarbonyl) -N- [ (2R) -2-hydroxy-2- phenylethyl] amino] ethyl] phenyl trifluoromethanesulfonate
MS (m/z) : 490 (M+H)
( 9 ) Methyl 4- (benzyloxy) -2- [ [ ( trif luoromethyl ) sul fonyl ] - oxy] benzoate
MS (m/ z ) : 413 (M+Na )
(10) Methyl 5- [[ (trifluoromethyl) sulfonyl] oxy] -1, 1 ' - biphenyl-2-carboxylate MS (m/z) : 383 (M+Na)
Preparation 42 The following compounds were obtained according to a similar manner to that of Preparation 21.
(1) 4- [2- [ [ (2R) -2- (5, 6-Dichloro-3-pyridyl) -2- hydroxyethyl ] amino ] ethyl ] phenol MS (m/z) : 327 (M+H)
(2) 4- [2- [ [ (2R) -2-Hydroxy-2-phenylethyl] amino] ethyl] phenol MS (m/z) : 258 (M+H)
Preparation 43
To a solution of 4- [2- [ [ (2R) -2- (5, 6-dichloro-3- pyridyl) -2-hydroxyethyl] amino] ethyl] phenol (850 mg) in acetic acid (15 ml) and water (1.0 ml) were added tetramethylammonium bromide (5.2 mg) and zinc dust (509 mg) , and the mixture was stirred at 50°C for 10 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give 4- [2- [ [ (2R) -2- (5- chloro-3-pyridyl) -2-hydroxyethyl] amino] ethyl]phenol (500 mg) as a colorless oil.
MS (m/z) : 292 (M+H)
Preparation 44
The following compounds were obtained according to a similar manner to that of Preparation 26.
(1) tert-Butyl N- [ (2R) -2- (5-chloro-3-pyridyl) -2- hydroxyethyl] -N- [2- (4-hydroxyphenyl) ethyl] carbamate MS (m/z) : 393 (M+H)
(2) tert-Butyl N- [ (2R) -2-hydroxy-2-phenylethyl] -N- [2- (4- hydroxyphenyl) ethyl] carbamate MS (m/z) : 358 (M+H)
Preparation 45
To a solution of benzamide (1.42 g) in tetrahydrofuran (50 ml) were added sodium hydride (611 mg) and 4- bromobenzenesulfonyl chloride (3.0 g) , and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give N-benzoyl-4-bromobenzenesulfonamide (2.1 g) as a colorless powder.
NMR (CDC13, δ) : 7.20-8.10 (8H, m)
Preparation 46
The following compounds were obtained according to a similar manner to that of Preparation 12.
(1) 2-Phenoxy-4- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2~ yl) benzaldehyde
MS (m/z) : 325 (M+H)
(2) N-Benzoyl-4- (4,4,5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl) benzenesulfonamide MS (m/z) : 386 (M-H)
(3) Methyl 2-isobutyl-4- (4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl) benzoate
MS (m/z) : 319 (M+H) (4) Methyl 2-isopropyl-4- (4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl ) benzoate MS (m/z) : 327 (M+Na)
(5) Methyl 2-propyl-4- (4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl) benzoate MS (m/z) : 327 (M+Na)
(6) Benzyl (IR) -l-methyl-2- [4- (4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl) phenyl] ethylcarbamate MS (m/z) : 396 (M+H)
Preparation 47
The following compound was obtained according to a similar manner to that of Example 1.
4-Methoxy-l-naphthoic acid
NMR (DMSO-dg, δ) : 7.00 (IH, d, J=6Hz) , 7.50-7.70 (2H, m) , 8.20-8.30(2H, m) , 9.00(1H, d, J=8Hz)
Preparation 48
Under nitrogen, 4-methoxy-l-naphthoic acid (4.33 g) in dichloromethane (45 ml) was added boron tribromide (1M in dichloromethane, 63 ml) dropwise at 0°C, and the mixture was stirred at the same temperature for 2 hours. The resulting mixture was poured into ice-cold water and the precipitate was collected by filtration. The filter cake was added to the mixture of water and ethyl acetate, and then adjusted to pH 9 with IN sodium hydroxide. After separation, the organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to afford 4-hydroxy-l-naphthoic acid (2.19 g) as a colorless powder. MS (m/z) : 187 (M-H)
Preparation 49 To a solution of 4-hydroxy-l-naphthoic acid (2.18 g) in methanol (15 ml) was added sulfuric acid (1.0 ml), and the mixture was stirred at 70°C for 3 hours. The solution was diluted with water and ethyl acetate. The organic layer was separated and washed with brine. The extract was dried over magnesium sulfate, filtrated and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with ethyl acetate and hexane to give methyl 4-hydroxy-l-naphthoate (1.64 g) as a white solid. MS (m/z) : 239 (M+Na)
Preparation 50
The following compounds were obtained according to a similar manner to that of Preparation 16.
(1) Methyl 4- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) -
1-naphthoate
MS (m/z) : 313 (M+H)
(2) Methyl [4- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)phenyl] acetate
NMR (DMSO-d6, δ) : 1.66(12H, s), 3.60(3H, s) , 3.70(2H, s), 7.20(2H, d, J=8Hz), 7.60 (2H, d, J=8Hz)
(3) Methyl [3- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl) phenyl] acetate
NMR (DMSO-dg, δ) : 3.60(3H, s), 3.82(2H, s) , 7.20-7.60 ( 6H, m)
(4) Methyl 5- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) - 1,1' -biphenyl-2-carboxylate MS (m/z) : 361 (M+Na)
Preparation 51 To a solution of 4-bromo-2-fluorobenzaldehyde (5.0 g) in dimethylsulfoxide (40 ml) were added phenol (2.78 g) and potassium carbonate (4.08 g) , and the mixture was stirred at 10θ"C for 3 hours. The solution was diluted with water and ethyl acetate. The organic layer was separated and washed with brine. The extract was dried over magnesium sulfate, filtrated and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with ethyl acetate and hexane to give 4-bromo-2-phenoxy-l- benzaldehyde (7.3 g) as a white solid. NMR (CDC13, δ) : 6.90-7.60(7H, m) , 7.80(1H, d,J=8Hz), 10.48(1H, s)
Preparation 52
The following compounds were obtained according to a similar manner to that of Preparation 14.
(1) 4- (2-Methoxy-2-oxoethyl) henylboronic acid MS (m/z) : 193 (M-H)
(2) 3- (2-Methoxy-2-oxoethyl) phenylboronic acid MS (m/z) : 194 (M+H)
(3) 4- [ (2R) -2- [ [ (Benzyloxy) carbonyl] amino]propyl] - phenylboronic acid MS (m/z) : 312 (M-H)
(4) 4 - [ 2 - [N-Benzyl-N- (tert-butoxycarbonyl) amino] ethyl] - phenylboronic acid
(-) ESI-MS m/z: 354 (M-H) ~
Preparation 53
The following compounds were obtained according to a similar manner to. that of Preparation 23.
(1) Methyl [4 '-[ (2R) -2- [[ (benzyloxy) carbonyl] mino]propyl] - 1,1' -biphenyl-4-yl] acetate MS (m/z) : 418 (M+H)
(2) Ethyl 5- [4- [ (2R) -2- [[ (benzyloxy) carbonyl] amino]propyl] - phenyl] -1-naphthoate
MS (m/z) : 490 (M+Na)
( 3 ) Methyl 5- (benzyloxy) -1 , 1 ' -biphenyl-2-carboxylate MS (m/ z ) : 341 (M+Na)
Preparation 54
The following compounds were obtained according to a similar manner to that of Preparation 36.
(1) Methyl [4 ' - [ (2R) -2-aminopropyl] -1, 1 ' -biphenyl-4- yl] acetate MS (m/z) : 284 (M+H)
(2) Ethyl 5- [4- [ (2R) -2-aminopropyl] phenyl] -1-naphthoate MS (m/z) : 356 (M+Na)
(3) Methyl 5-hydroxy-l, 1 ' -biphenyl-2-carboxylate MS (m/z) : 251 (M+Na)
Preparation 55
To a mixture of 5-hydroxy-l-naphthyl trifluoromethanesulfonate (8.0 g) in N,N-dimethyl formamide (35 ml) and ethanol (5.0 ml) were added 1, 3-bis (diphenylphosphino) - propane (621 mg) , palladium acetate (II) (3.7 mg) and triethylamine (1.35 g) , and the mixture was stirred at 100°C for 1 hour under carbon-monoxide. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 5/1) to give ethyl 5-hydroxy-l-naphthoate (1.7 g) as a colorless oil. MS (m/z) : 239 (M+Na)
Preparation 56 To a solution of 4-bromo-2-fluorobenzoic acid (2.0 g) in tetrahydrofran (15 ml) was added 2M isobutylmagnesium bromide in diethyl ether (13.5 ml) dropwise on ice-cooling, and the mixture was stirred at 0°C for 1 hour. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. To the solution of the residue in N,N-dimethylformamide (20 ml) was added methyliodide (1.14 g) and potassium carbonate (1.89 g) , and the mixture was stirred at 20°C for 3 hours. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give methyl 4-bromo-2-isobutylbenzoate (1.5 g) as a colorless oil.
NMR (DMSO-dg, δ) : 0.80(6H, d, J=8Hz), 1.80-2.00 (IH, ) , 2.80(2H, d, J=8Hz), 3.80(3H, s), 7.40-7.80 (3H, m)
Preparation 57 The following compounds were obtained according to a similar manner to that of Preparation 56.
(1) Methyl 4-bromo-2-isopropylbenzoate
NMR (DMSO-dg, δ) : 1.20(6H, d, J=7Hz) , 3.50-3.60 (IH, m) , 3.83(1H, s), 7.50-7.70(3H, )
MS (m/z) : 516 (M+H)
(2) Methyl 4-bromo-2-propylbenzoate
NMR (DMSO-dg, δ) : 0.85(3H, t, J=7Hz) , 1.40-1. 0 (2H, m) , 2.80-3.00(2H, ) , 3.82(3H, s) , 7.60-7. 0 (3H, m) Preparation 58
The following compound was obtained according to a similar manner to that of Preparation 28.
tert-Butyl N- ( (2R) -2-hydroxy-2-phenylethyl) -N- [ (IR) -2- ( 4-iodophenyl) -1-methylethyl] carbamate MS (m/z) : 482 (M+H)
Preparation 59
The following compounds were obtained according to a similar manner to that of Preparation 13.
(1) tert-Butyl N-benzyl-N- [2- [4- (4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl)phenyl] ethyl] carbamate
(+) ESI-MS m/z: 460 (M+Na)+
(2) 2- (1-Piperidinyl) -4- (4,4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl) benzaldehyde (+) ESI-MS m/z: 581 (M+Na)+
Preparation 60
To a solution of 2- (3-methoxyphenyl) ethana ine (5.6 g) in dichloromethane (50 ml) was added IM boron tribromide in dichloromethane (75 ml) . The mixture was stirred at 20°C for 16 hours and evaporated in vacuo . To the residue, saturated sodium bicarbonate (50 ml) and tetrahydrofuran (150 ml) were added. The pH value of the mixture was kept between 7 to 8 with IN aqueous sodium hydroxide solution. To the mixture, a solution of di-tert-butyl dicarbonate
(8.08 g) in tetrahydrofuran (10 ml) was added, stirred at 20°C for 1 hour. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated to give tert-butyl 2- (3-hydroxyphenyl) ethylcarbamate (8.2 g) . ( + ) ESI-MS m/ z : 260 (M+Na ) +
Preparation 61
To a solution of tert-butyl 2- (3-hydroxyphenyl) - ethylcarbamate (730 mg) and potassium carbonate (893 mg) in N,N-dimethylformamide (10 ml) was added methyl 4-bromo-(3- bromomethyl) benzoate (1.52 g) , and the mixture was stirred at room temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give methyl 4-bromo-3- [ [3- [2- [ (tert-butoxycarbonyl) amino] ethyl] phenoxy] methyl] - benzoate (970 mg) .
(+) ESI-MS m/z: 464 (M+H)+
Preparation 62
To a solution of methyl 4-bromo-3- [ [3- [2- [ (tert- butoxycarbonyl) amino] ethyl] phenoxy]methyl] benzoate (410 mg) in N,N-dimethylacetamide (4.0 ml) was added dichlorobis (triphenylphosphine) palladium (II) (124 mg) and sodium acetate (362 mg) , and the mixture was stirred at 130°C for 1.5 hours under nitrogen. The mixture was cooled to room temperature, diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 3/1) to give methyl 3-[2-[(tert- butoxycarbonyl) amino] ethyl] -6H-benzo [c] chromene-8- carboxylate (190 mg) .
(+) ESI-MS m/z: 406 (M+Na) +
Preparation 63 The following compounds were obtained according to a similar manner to that of Example 7.
(1) Ethyl 6- [4- [2- [N-benzyl-N- (tert-butoxycarbonyl) amino] ethyl ] phenyl ] nicotinate (+)ESI-MS m/z: 461 (M+H) +
(2) Methyl 4 '- [2- [N-benzyl-N- (tert-butoxycarbonyl) amino] - ethyl] -2, 6-dimethyl-l, 1 ' -biphenyl-4-carboxylate
(+) ESI-MS m/z: 474 (M+H) +
Preparation 64
The following compounds were obtained according to a similar manner to that of Example 27.
(1) Methyl 3- (2-aminoethyl) -6H-benzo [c] chromene-8- carboxylate (+)ESI-MS m/z: 284 (M+H)+
(2) Ethyl 6- [ 4 - [ 2- (benzylamino) ethyl] henyl] nicotinate hydrochloride
(+) ESI-MS m/z: 361 (M+H) +
Preparation 65
The following compounds were obtained according to a similar manner to that of Preparation 16.
(1) 3- [2- [N- (tert-Butoxycarbonyl) -N- [ (2R) -2- (3- chlorophenyl ) -2-hydroxyethyl ] amino ] ethyl ] phenyl trifluoromethanesulfonate (+) ESI-MS m/z: 546 (M+Na)+
(2) 4- [2- [N- (tert-Butoxycarbonyl) -N-[ (2R)-2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] -2- methoxyphenyl trifluoromethanesulfonate ' (+)ESI-MS m/z: 576 (M+Na)+ (3) 4- [2- [N- (tert-Butoxycarbonyl) -N- [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] -2- chlorophenyl trifluoromethanesulfonate (+)ESI-MS m/z: 581 (M+Na)+
Preparation 66
The following compound was obtained according to a similar manner to that of Example 5.
Methyl 4 '- [2- (benzylamino) ethyl] -2, 6-dimethyl-l, 1'- biphenyl- -carboxylate
(+)ESI-MS m/z: 374 (M+H) +
Preparation 67
To a mixture of 3-chloro-4-hydroxyphenylacetic acid (2.96 g) , (IR) -2-amino-l- (3-chlorophenyl) ethanol hydrochloride (3.0 g) , and 1-hydroxybenzotriazole (2.14 g) in N,N-diιnethylformamide (20 ml) was added l-(3- dimethylaminopropyl) -3-ethylcarbodiimide (2.46 g) , and the mixture was stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed successively with sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure to give an amide product. To a tetrahydrofuran (30 ml) solution of the product, 2M borane-dimethyl sulfide complex in tetrahydrofuran (23 ml) was added at room temperature, and the mixture was refluxed for 30 minutes. To the mixture, 6N hydrochloride acid (29.5 ml) was added dropwise below 10°C, and the mixture was stirred at room temperature for 3 hours . To the reaction mixture, 3N aqueous sodium hydroxide solution (58 ml) below 10°C was added and di-tert-butyl dicarbonate (3.46 g) was added portionally at room temperature. The pH value was kept between 7 to 8 by using IN aqueous sodium hydroxide solution. The mixture was stirred at room temperature for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give tert-butyl N-[2-(3- chloro-4-hydroxyphenyl) ethyl] -N- [ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] carbamate (7.0 g) . (+) ESI-MS m/z: 448 (M+Na)+
Preparation 68
The following compound was obtained according to a similar manner to that of Preparation 67.
tert-Butyl N- [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] - N- [2- (4-hydroxy-3-methoxyphenyl) ethyl] carbamate (+) ESI-MS m/z: 444 (M+Na)+
Preparation 69
A mixture of 4-bromo-2-fluorobenzaldehyde (3.0 g) , piperidine (2.93 ml) and potassium carbonate (5.11 g) in N, N-dimethylformamide (30 ml) was stirred at 100°C for 12 hours. The mixture was cooled to room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, saturated aqueous ammonium chloride solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 9/1) to give 4-bromo- 2- (1-piperidinyl) benzaldehyde (3.5 g) . (+) ESI-MS m/z: 268 (M+H) +
Preparation 70 The following compound was obtained according to a similar manner to that of Example 23.
tert-Butyl N-benzyl-N- [2- (4-bromophenyl ) ethyl ] carbamate (+)ESI-MS m/z: 390 (M+H)+
Example 32
The following compounds were obtained according to a similar manner to that of Example 7.
(1) 4 '-[ (2R) -2- [[ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] - amino] propyl] -3-propoxy-l, 1 ' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.05(3H, t, J=7.4Hz), 1.35 (3H, d,
J=6.2Hz), 1.6-1.9(2H, m) , 2.8-3.8(5H, m) , 4.11(2H, t, J=7.4Hz), 5.0-5.3(lH, m) , 6.3-6.4(lH, m) , 7.2-
7.8(11H, ) , 8.55(1H, br s), 9.19(1H, br s) MS m/z: 468 (M+H)
(2) 4 '-[2- [ [ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] amino] - ethyl] -3-hydroxy-l, 1 ' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 2.8-3.0(6H, m) , 4.8-5.0(lH, ) ,
6.33 (IH, m) , 7.0-7.9(llH, m) MS m/z: 411 (M+H)
(3) 3-Hydroxy-4'-[ (2R)-2-[ [ (2R) -2-hydroxy-2-phenylethyl] - amino] propyl] -1,1' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.12(3H, d, J=6.4Hz), 2.6-3.2(5H, ) , 4.9-5.K1H, m) , 6.23(1H, ) , 7.2-7.9(llH, m) ,
8.77(1H, br s), 9.03(1H, br s) MS m/z: 392 (M+H)
(4) 3-Ethoxy-4'-[ (2R)-2-[ [ (2R) -2-hydroxy-2-phenylethyl] - amino] propyl] -1, 1 ' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.15 (3H, d, J=6.4Hz), 1.36(3H, t, J=7.0Hz), 2.6-3.2(5H, m) , 4.21(2H, q, J=7.0Hz), 4.9-5.K1H, m) , 6.23(1H, m) , 7.2-7.7(llH, m) MS m/z: 418 (M-H)
(5) 4'- [ (2R)-2-[ [ (2R)-2-Hydroxy-2-phenylethyl] amino] - propyl] -3-propoxy-l, 1 ' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 1.03 (3H, t, J=7.4Hz), 1.12 (3H, d,
J=6.4Hz), 1.74(2H, m) , 2.6-3.2(5H, m) , 4.11(2H, q, J=7.0Hz), 4.9-5.K1H, m) , 6.23(1H, m) , 7.2-7.7(llH, ) MS m/z: 434 (M+H)
(6) 3-Butoxy-4'-[ (2R) -2- [ [ (2R) -2-hydroxy-2-phenylethyl] - amino] propyl] -1,1' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 0.9 (3H, t, J=7.4Hz), 1.12 (3H, d, J=6.4Hz), 1.3-1.8(4H, m) , 2.6-3.2(5H, ) , 4.15(2H, q, J=7.0Hz), 4.9-5.1(lH, m) , 6.23(1H, m) , 7.2- 7.7(11H, ) MS m/z: 448 (M+H)
(7) 4'-[ (2R)-2-[ [ (2R) -2-Hydroxy-2-phenylethyl] amino] - propyl] -3- (pentyloxy) -1,1' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 0.89(3H, t, J=7.4Hz), 1.13(3H, d,
J=6.4Hz), 1.2-1.8(6H, m) , 2.6-3.2(5H, ) , 4.14(2H, q, J=7.0Hz), 4.9-5.1(lH, m) , 6.23(1H, ) , 7.2-
7.7(11H, m) MS m/z: 462 (M+H)
(8) 3-(Heptyloxy)-4'-[ (2R)-2-[ [ (2R) -2-hydroxy-2- phenylethyl] amino]propyl] -1, 1 ' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 0.86(3H, t, J=7.4Hz), 1.16(3H, d,
J=6.4Hz), 1.1-1.8(10H, m) , 2.6-3.2 (5H, m) , 4.14(2H, q, J=7.0Hz), 4.9-5.1(lH, m) , 6.23(1H, m) , 7.2- 7.7(11H, )
MS m/z: 490 (M+H)
(9) 4'- [ (2R)-2-[ [ (2R)-2-Hydroxy-2-phenylethyl] amino] - propyl] -3-isobutoxy-l, 1 ' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.03(6H, t, J=6.2Hz), 1.16(3H, d,
J=6.4Hz), 1.8-2.2(1H, m) , 2.6-3.2(5H, m) , 3.93(2H, d, J=6.2Hz), 4.9-5.1(lH, m) , 6.23(1H, ) , 7.2- 7.7(11H, m) MS m/z: 448 (M+H)
(10) 3- (Allyloxy) -4'- [ (2R) -2- [ [ (2R) -2-hydroxy-2- phenylethyl] amino]propyl] -1,1' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 1.16(3H, d, J=6.4Hz), 2.6-3.2(5H, m) , 4.77(2H, ) , 4.9-5.1(lH, m) , 5.27(1H, dd, J=1.8, 10.6Hz), 5.40(1H, dd, J=1.8, 17.2Hz), 5.9-6.2(lH, m) , 6.23(1H, ) , 7.2-7.7(llH, m) MS m/z: 432 (M+H)
(11) 4'-[ (2R)-2-[ [ (2R)-2-Hydroxy-2-phenylethyl] amino] - propyl] -3- [ (2-methyl-2-propenyl) oxy] -1,1' -biphenyl-4- carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.16(3H, d, J=6.4Hz), 1.69(3H, s), 2.6-3.2(5H, m) , 4.77(2H, m) , 4.65(2H, s), 4.9-
5.1(1H, m) , 4.9-5.2(2H, m) , 6.23(1H, m) , 7.2- 7.7(11H, ) MS m/z: 446 (M+H)
(12) 3- (2-Fluoroethoxy)-4'-[ (2R)-2-[[ (2R)-2-hydroxy-2- phenylethyl] amino]propyl] -1,1' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.16(3H, d, J=6.4Hz), 2.6-3.2 (5H, m) , 4.3-4.8(4H, ) , 4.9-5.1(lH, ) , 6.23(1H, m) , 7.2- 7.7(11H, m)
MS m/z: 438 (M+H)
(13) 3- (2,2-Difluoroethoxy)-4'-[ (2R)-2-[ [ (2R) -2-hydroxy-2- phenylethyl] amino]propyl] -1,1' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.13(3H, d, J=6.4Hz), 2.6-3.2 (5H, m) , 4.3-4.7(2H, m) , 4.9-5.1(lH, ) , 6.0-6.5(2H, m) , 7.2-7.7(llH, m) MS m/z: 456 (M+H)
(14) 4 '- [ (2R) -2- [ [ (2R) -2-Hydroxy-2-phenylethyl] amino] - propyl] -3- (2, 2, 2-trifluoroethoxy) -1, 1 ' -biphenyl-4- carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.13 (3H, d, J=6.4Hz), 2.6-3.2 (5H, m) , 4.7-5.M3H, m) , 6.24(1H, m) , 7.2-7.7(llH, m)
MS m/z: 472 (M-H)
(15) 3- (2-Hydroxyethoxy) -4'- [ (2R) -2- [ [ (2R) -2-hydroxy-2- phenylethyl] amino] propyl] -1,1' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.13 (3H, d, J=6.4Hz), 2.6-3.2 (5H, ) , 3.8(2H, m) , 4.15(2H, ) , 4.9-5.1(lH, m) , 6.24(1H, m) , 7.2-7.7(llH, m) MS m/z: 434 (M-H)
(16) 4'-[ (2R)-2-[ [ (2R)-2-Hydroxy-2-phenylethyl] amino] - propyl] -3- (2-methoxyethoxy) -1,1' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.12 (3H, d, J=6.4Hz), 2.6-3.2 (5H, m) , 3.33(3H, s) , 3.70(2H, ) , 4.29(2H, m) , 4.9-5.1(lH, ) , 6.22(1H, m) , 7.2-7.7(llH, ) MS m/z: 450 (M+H)
(17) 3-(3-Fluoropropoxy)-4'-[ (2R)-2-[ [ (2R) -2-hydroxy-2- phenylethyl] amino]propyl] -1,1' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.13(3H, d, J=6.4Hz), 2.0-2.4(2H, m) , 2.6-3.2(5H, m) , 4.25(2H, t, J=6.0Hz), 4.56(1H, t, J=5.8Hz), 4.83(1H, t, J=6.0Hz), 4.9-5.1(lH, m) , 6.24(1H, m) , 7.2-7.7(llH, m)
MS m/z: 452 (M+H)
(18) 4 '- [ (2R) -2- [ [ (2R) -2-Hydroxy-2-phenylethyl] amino] - propyl] -3- (3, 3, 3-trifluoropropoxy) -1,1 ' -biphenyl-4- carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.13(3H, d, J=6.4Hz), 2.6-3.2(7H, m) , 4.39(2H, t, J=6.0Hz), 4.9-5.1(lH, ) , 6.24(1H, m) , 7.2-7.7(llH, m) MS m/z: 488 (M+H)
(19) 3- (Cyclopropyloxy) -4 '- [ (2R) -2- [ [ (2R) -2-hydroxy-2- phenylethyl] amino] propyl] -1,1' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.13 (3H, d, J=6.4Hz), 2.6-3.2 (5H, ) , 4.9-5.K2H, m) , 6.24(1H, m) , 7.2-7.7(llH, m)
MS m/z: 432 (M+H)
(20) 3- (Cyclobutyloxy) - ' - [ (2R) -2- [ [ (2R) -2-hydroxy-2- phenylethyl] amino]propyl] -1,1' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.13 (3H, d, J=6.4Hz), 1.2-2.4 (6H, m) , 2.6-3.2(5H, m) , 4.9-5.1(2H, m) , 6.24(1H, m) , 7.2- 7.7(11H, ) MS m/z: 446 (M+H) (21) 3-(Cyclopentyloxy)-4'-[ (2R)-2-[ [ (2R) -2-hydroxy-2- phenylethyl] amino]propyl] -1, 1 ' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.13(3H, d, J=6.4Hz), 1.2-2.0(8H, m) , 2.6-3.2(5H, m) , 4.9-5.K2H, ) , 6.24(1H, m) , 7.2-
7.7(11H, m) MS m/z: 460 (M+H)
(22) 3-(Cyclopropylmethoxy)-4'-[ (2R)-2-[ [ (2R) -2-hydroxy-2- phenylethyl] amino]propyl] -1,1' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 0.2-0.7(2H, m) , 0.9-1.3(6H, m) , 2.6- 3.2(5H, ) , 4.03(2H, d, J=6.6Hz), 4.9-5.K1H, m) , 6.24 (IH, m) , 7.2-7.7 (11H, m) MS m/z: 446 (M+H)
(23) 3- (Cyclohexylmethoxy)-4'-[ (2R)-2-[ [ (2R) -2-hydroxy-2- phenylethyl] amino]propyl] -1, 1 ' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 1.0-1.9(14H, m) , 2.6-3.2(5H, m) ,
3.93(2H, d, J=6.6Hz), 4.9-5.1(lH, ) , 6.24(1H, m) , 7.2-7.7(llH, ) MS m/z: 488 (M+H)
(24) 4'-[2-[ [ (2R) -2-Phenyl-2-hydroxyethyl] amino] ethyl] -1, 1'- biphenyl-4-nitrile MS m/z: 457 (M+H)
(25) 4'-[ (2R) -2- [ [ (2R) -2-Hydroxy-2-phenylethyl] amino] - propyl] -3-phenoxy-l, 1 ' -biphenyl-4-carboxylic acid hydrochloride • NMR (DMSO-dg, δ) : 1.13 (3H, d, J=6.4Hz), 2.6-3.2 (5H, m) ,
4.9-5.1(lH, ) , 6.24(1H, m) , 6.8-7.9(16H, m) MS m/z: 468 (M+H) (26) 4'-[2-[ [ (2R) -2-Hydroxy-2-phenylethyl] amino] ethyl] -3- methoxy-1, 1 ' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 2.8-3.3 (6H, m) , 4.9-5.1 (IH, ) ,
6.22(1H, m) , 7.2-7.8(12H, ) MS m/z: 392 (M+H)
(27) 3-Ethoxy-4'-[2-[ [ (2R) -2-hydroxy-2-phenylethyl] amino] - ethyl] -1, 1 ' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 1.35(3H, t, J=6.8Hz), 2.8-3.3(6H, m) , 4.20(2H, q, J=6.8Hz), 4.9-5.1(lH, m) , 6.22(1H, ) ,
7.2-7.8(12H, m) MS m/z: 406 (M+H)
(28) 4'- [2- [ [ (2R) -2-Hydroxy-2-phenylethyl] amino] ethyl] -3- propoxy-1, 1 ' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.01 (3H, t, J=6.8Hz), 1.6-1.9 (2H, m) , 2.9-3.4(6H, m) , 4.11(2H, q, J=6.8Hz), 4.9-5.1(lH, m) , 6.22(1H, m) , 7.2-7.8(12H, m)
MS m/z: 420 (M+H)
(29) 4 ' - [2- [ [ (2R) -2-Hydroxy-2-phenylethyl] amino] ethyl] -3- isopropoxy-1, 1 ' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ): 1.31 (6H, t, J=6.8Hz), 2.9-3.4 (6H, ) , 4.7-4.9(lH, m) , 4.9-5.1(lH, m) , 6.22(1H, m) , 7.2-
7.8(12H, m) MS m/z: 420 (M+H)
(30) 4 ' - [2- [ [ (2R) -2-Hydroxy-2-phenylethyl] amino] ethyl] -3- isobutoxy-1, 1 ' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 1.02 (6H, t, J=6.8Hz), 1.9-2.1 (IH, m) , 2.9-3.4(6H, m) , 3.92(2H, d, J=6.8Hz) , -4.9-5.1 (IH, m) , 6.22(1H, m) , 7.2-7.8(12H, m) MS m/z: 434 (M+H) (31) 3- (Allyloxy)-4'-[2-[ [ (2R) -2-hydroxy-2-phenylethyl] - amino] ethyl] -1,1' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 2.9-3.4 (6H, m) , 3.92 (2H, d, J=6.8Hz), 4.72(2H, m) , 5.2-5.7(2H, m) , 4.9-5.K1H, m) , 6.0-
6.2(1H, m) , 6.22(1H, m) , 7.2-7.8(12H, m) MS m/z: 418 (M+H)
(32) 3- (2-Fluoroethoxy) -4 ' - [2- [ [ (2R) -2-hydroxy-2- phenylethyl] amino] ethyl] -1, 1 ' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 2.9-3.4(6H, m) , 4.3-4.7(3H, ) , 4.8- 4.9(1H, m) , 4.9-5.1(lH, ) , 6.22(1H, m) , 7.2- 7.8(12H, m) MS m/z: 424 (M+H)
(33) 3- (3-Fluoropropoxy) -4 '- [2- [ [ (2R) -2-hydroxy-2- phenylethyl] amino] ethyl] -1,1' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 1.9-2.3(2H, m) , 2.9-3.4(6H, m) ,
4.25(2H, t, J=6.0Hz), 4.56(1H, t, J=5.9Hz), 4.80(1H, t, J=5.8Hz), 4.9-5.1(lH, m) , 6.22(1H, m) , 7.2-7.8U2H, m) MS m/z: 438 (M+H)
(34) 3- (Cyclopropyloxy) -4 '- [2- [ [ (2R) -2-hydroxy-2- phenylethyl] amino] ethyl] -1,1' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 2.9-3.4 (6H, m) , 4.9-5.1 (IH, ) , 6.22(1H, ) , 7.2-7.8(12H, m)
MS m/z: 392 (M+H)
(35) 3-(Cyclohexyloxy)-4'-[2-[ [ (2R) -2-hydroxy-2- phenylethyl] amino] ethyl] -1,1' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d6, δ) : 1.2-2.0(10H, ) , 2.9-3.4(6H, m) , 4.64(1H, m) , 4.9-5.1(lH, m) , 6.22(1H, m) , 7.2- 7.8 (12H, m)
MS m/z: 460 (M+H)
(36) 4'-[2-[ [ (2R) -2-Hydroxy-2-phenylethyl] amino] ethyl] -3- phenoxy-1, 1 ' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d6, δ) : 2.9-3.4 (6H, m) , 4.9-5.1 (IH, ) ,
6.22(1H, m) , 6.9-8.0(17H, ) MS m/z: 454 (M+H)
(37) 3- (Benzyloxy) -4'- [2- [ [ (2R) -2-hydroxy-2- phenylethyl] amino] ethyl] -1, 1 ' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 2.9-3.4(6H, ) , 4.9-5.K1H, m) , 5.33(2H, ) , 6.22(1H, m) , 7.2-7.8(17H, ) MS m/z: 468 (M+H)
(38) 4'-[2-[ [ (2R) -2-Hydroxy-2-phenylethyl] amino] ethyl] -3- (2, 2,2-trifluoroethoxy) -1, 1 ' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 2.9-3.4 (6H, m) , 4.3-5.1 (2H, ) , 6.22(1H, m) , 7.2-7.8(12H, m)
MS m/z: 460 (M+H)
(39) 4'-[2-[ [ (2R) -2-Hydroxy-2-phenylethyl] amino] ethyl] -2- methyl-1, 1 ' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 2.28 (3H, s) , 2.9-3.4 (6H, m) , 4.9-
5.K1H, m) , 5.33(2H, ) , 6.22(1H, m) , 7.2-7.8(12H, m)
MS m/z: 476 (M+H)
(40) 4 '-[2- [ [ (2R)-2- (3-Fluorophenyl) -2-hydroxyethyl] - amino] ethyl] -3-propoxy-l, 1 ' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 1.01(3H, t, J=7.4Hz), 1.5-1.9(2H, ) , 2.9-3.4(6H, m) , 4.11(2H, q, J=7.4Hz), 4.9-5.1(lH, m) , 6.22(1H, m) , 7.1-7.8(11H, m) MS m/z: 438 (M+H)
(41) 4'- [ (2R) -2-[ [ (2R) -2- (3-Fluorophenyl) -2-hydroxyethyl] - amino]propyl] -3-propoxy-l, 1 ' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 0.99(3H, t, J=7.4Hz), 1.10(3H, d, J=6.8Hz), 1.5-1.9(2H, m) , 2.7-3.4(5H, ) , 4.03(2H, q, J=7.4Hz), 4.9-5.K1H, m) , 6.22(1H, m) , 7.1- 7.8(11H, ) MS m/z: 450 (M-H)
(42) 4'- [2- [[ (2R) -2- (3-Fluorophenyl) -2-hydroxyethyl] amino] - ethyl] -3-isopropoxy-l, 1 ' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.31 (6H, d, J=6.0Hz), 2.9-3.4 (6H, m) , 4.81(1H, ) , 4.9-5.1(lH, ) , 6.22(1H, m) , 7.1- 7.8(11H, m)
MS m/z: 438 (M+H)
(43) 4'-[ (2R)-2-[ [ (2R) -2- (3-fluorophenyl) -2-hydroxyethyl] - amino] propyl] -3-isopropoxy-l, 1 ' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.10 (3H, d, J=6.8Hz), 1.31 (6H, d,
J=6.0Hz), 2.7-3.4(5H, m) , 4.82(1H, ) , 4.9-5.1(lH, m) , 6.22(1H, m) , 7.1-7.8(11H, m) MS m/z: 450 (M-H)
(44) 3- (Cyclohexyloxy)-4'-[ (2R)-2-[ [ (2R)-2- (3-fluorophenyl) - 2-hydroxyethyl] amino] propyl] -1, 1 ' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.13(3H, d, J=6.8Hz), 1.2-2.0(10H, m) , 2.7-3.4(5H, ) , 4.65(1H, ) , 4.9-5.1(lH, m) , 6. 22 ( IH, m) , 7 . 1- 7 . 8 ( 11H, m) MS m/ z : 490 (M-H)
(45) 4'-[2-[[ (2R)-2- ( 4-Chlorophenyl) -2-hydroxyethyl] amino] - ethyl] -3-propoxy-l, 1 ' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.01 (3H, t, J=7.4Hz), 1.5-1.9 (2H, m) ,
2.9-3.4(6H, m), 4.10(2H, q, J=7.4Hz), 4.9-5.1(lH, m) , 6.28(1H, m) , 7.1-7.8(11H, ) MS m/z: 438 (M+H)
(46) 4'- [2-[ [ (2R) -2- (4-Chlorophenyl) -2-hydroxyethyl] amino] - ethyl] -3-isopropoxy-l, 1 ' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 1.29(6H, d, J=6.0Hz), 2.9-3.4 (6H, m) , 4.84(1H, m) , 4.9-5.1(lH, ) , 6.30(1H, m) , 7.1- 7.8(11H, ) MS m/z: 454 (M+H)
(47) 4'- [ (2R) -2- [[ (2R) -2- (4-Chlorophenyl) -2-hydroxyethyl] - amino]propyl] -3-propoxy-l, 1 ' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.00 (3H, t, J=7.4Hz), 1.12 (3H, d,
J=6.8Hz), 1.5-1.9(2H, ) , 2.7-3.4(5H, m) , 4.03(2H, q, J=7.4Hz), 4.9-5.1(lH, m) , 6.32(1H, ) , 7.1-
7.8(11H, ) MS m/z: 468 (M-H)
(48) 4'- [ (2R)-2-[ [ (2R)-2- (4-Chlorophenyl) -2-hydroxyethyl] - amino] propyl] -3-isopropoxy-l, 1 ' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 1.09(3H, d, J=6.8Hz), 1.29(6H, d,
J=6.0Hz), 2.7-3.4(5H, m) , 4.82(1H, ) , 4.9-5.1(lH, m) , 6.32(1H, m) , 7.1-7.8(11H, ) MS m/z: 468 (M-H) (49) 3-Ethoxy-4'-[ (2R)-2-[ [ (2R) -2-hydroxy-2- (3-pyridyl) - ethyl] amino] propyl] -1, 1 ' -biphenyl-4-carboxylic acid dihydrochloride NMR (DMSO-dg, δ) : 1.19(3H, d, J=6.8Hz), 1.36(3H, t, J=7.0Hz), 2.7-3.4(5H, m) , ,4.23(2H, q, J=7.0Hz), 5.1-5.3(1H, ) , 6.32(1H, m) , 7.2-7.9(8H, m) , 8.25(1H, d, J=8Hz), 8.7-8.9(2H, m) , 8.94(1H, m) , 9.20(1H, ) MS m/z: 421 (M+H)
(50) 4'-[ (2R)-2-[ [ (2R)-2-Hydroxy-2- (3-pyridyl) ethyl] - amino] propyl] -3-propoxy-l, 1 ' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 1.01 (3H, t, J=7.4Hz), 1.19 (3H, d,
J=6.8Hz), 1.5-1.9(2H, m) , 2.7-3.4(5H, m) , 4.04(2H, q, J=7.4Hz), 5.1-5.3(1H, ) , 6.32(1H, ) , 7.2- 7.9(8H, ) , 8.25(1H, d, J=8Hz) , 8.7-8.9(2H, ) , 8.94(1H, m) , 9.20(1H, m) MS m/z: 435 (M+H)
(51) 4'-[ (2R)-2-[ [ (2R)-2-Hydroxy-2- (3-pyridyl) ethyl] - amino] propyl] -3-isobutoxy-l, 1 ' -biphenyl-4-carboxylic acid dihydrochloride NMR (DMSO-dg, δ) : 1.01 (6H, t, J=6.8Hz), 1.17 (3H, d,
J=6.8Hz), 1.9-2.K1H, m) , 2.7-3.4(5H, m) , 3.93(2H, d, J=6.4Hz), 5.2-5.4(lH, m) , 7.2-7.9(8H, ) , 8.4(1H, d, J=8Hz), 8.7-8.9(2H, m) , 9.09(1H, m) , 9.42(1H, m) MS m/z: 449 (M+H)
(52) N-[ [4'-[ (2R)-2-[ [ (2R) -2-Hydroxy-2- (3-pyridyl) ethyl] - amino] propyl] -1,1 ' -biphenyl-4-yl] carbonyl] -1- phenylmethanesulfonamide dihydrochloride MS m/z: 528 (M-H) (53) 4'-[ (2R)-2-[ [ (2R)-2- ( 6-Chloro~3-pyridyl) -2- hydroxyethyl] amino]propyl] -3-propoxy-l, 1 ' -biphenyl-4- carboxylic acid dihydrochloride
NMR (DMSO-dg, δ) : 1.01 (3H, t, J=7.4Hz), 1.12 (3H, d,
J=6.8Hz), 1.7-1.9(2H, m) , 2.7-3.4(5H, m) , 4.11(2H, q, J=7.4Hz), 4.9-5.3(lH, ) , 7.2-7.8(10H, m) , 8.56(1H, s)
MS m/z: 469 (M+H)
(54) 4'-[2-[ [ (2R)-2-Hydroxy-2- (3-pyridyl) ethyl] amino] - ethyl] -3-isopropoxy-l, 1 ' -biphenyl-4-carboxylic acid dihydrochloride
NMR (DMSO-dg, δ) : 1.29(6H, d, J=6.0Hz), 2.9-3.4 (6H, ) , 4.84(1H, ) , 4.9-5.1(lH, m) , 7.2-7.5(4H, ) , 7.6-
7.9(4H, m) , 8.2-8.5(lH, m) , 8.7-8.9(2H, ) , 9.0- 9. (2H, m) MS m/z: 421 (M+H)
(55) 4 '- [2- [[ (2R)-2-Hydroxy-2- (3-pyridyl) ethyl] amino] - ethyl] -3-propoxy-l , 1 ' -biphenyl-4-carboxylic acid dihydrochloride
NMR (DMSO-dg, δ): 1.01 (3H, t, J=7.4Hz), 1.5-1.9 (2H, m) , 3.0-3.4(6H, m) , 4.11(2H, q, J=7.4Hz), 5.0-5.3(lH, m) , 7.2-7.5(4H, m) , 7.6-7.9(4H, m) , 8.3-8.5(lH, m) ,
8.7-8.9(2H, m) , 9.0-9.4(2H, m) MS m/z: 421 (M+H)
(56) 3- (Cyclohexyloxy)-4'-[2-[ [ (2R) -2-hydroxy-2- (3- pyridyl) ethyl] amino] ethyl] -1,1' -biphenyl-4-carboxylic acid dihydrochloride NMR (DMSO-dg, δ) : 1.0-2.0 (10H, m) , 2.9-3.4 (6H, m) ,
4.65(1H, m) , 5.0-5.3(lH, ) , 7.2-7.5(4H, m) , 7.6- 8.0(4H, ) , 8.4-8.6(lH, m) , 8.7-8.9(2H, ) , 9.0- 9.4(2H, ) MS m/ z : 461 (M-H)
(57) 4'-[2-[ [ (2R)-2- ( 6-Chloro-3-pyridyl) -2-hydroxyethyl] - amino] ethyl] -3-propoxy-l, 1 ' -biphenyl-4-carboxylic acid dihydrochloride
NMR (DMSO-dg, δ) : 1.01 (3H, t, J=7.4Hz), 1.6-1.9 (2H, m) , 3.0-3.4(6H, m) , 4.11(2H, q, J=7.4Hz), 5.0-5.3(lH, m) , 7.1-7.9(9H, m) , 8.46(1H, s) MS m/z: 453 (M-H)
(58) 3-Butyl-4'-[ (2R)-2-[ [ (2R) -2-hydroxy-2-phenylethyl] - amino] propyl] -1, 1 ' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 0.90 (3H, t, J=7.4Hz), 1.0-1.8 (9H, m) , 2.8-3.8(5H, m) , 5.0-5.3(lH, ) , 6.3-6.4(lH, m) ,
7.2-7.8(llH, ) MS m/z: 432 (M+H)
(59) 3-(3-Butenyl)-4»-[ (2R)-2-[ [ (2R) -2-hydroxy-2- phenylethyl] amino] propyl] -1, 1 ' -biphenyl-4-carboxylic acid hydrochloride MS m/z: 430 (M+H)
(60) 4 ' - [2- [ [ (2R) -2-hydroxy-2-phenylethyl] amino] -2- rαethylpropyl] -3-isopropoxy-l , 1 ' -biphenyl-4-carboxylic acid hydrochloride MS m/z: 482 (M+H)
(61) 4'- [3-[ [ (2R)-2-Hydroxy-2-phenylethyl]amino]propyl]-3- isopropoxy-1, 1 ' -biphenyl-4-carboxylic acid hydrochloride
MS m/z: 434 (M+H)
(62) 4 '- [2- [ [ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] amino] - ethyl] -3-isopropoxy-l, 1 ' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.31 (6H, d, J=6.0Hz), 2.8-3.0 (6H, m) , 4.79 (IH, q, J=6.0Hz), 4.8-5.0 (IH, m) , 6.33 (IH, ) , 7.0-7.9 (11H, ) MS m/z: 454 (M+H)
(63) Ethyl '- [2- [N- (tert-butoxycarbonyl) -N- [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] -1, 1 ' - biphenyl-3-carboxylate (+) ESI-MS m/z: 524 (M+H)+
(64) Methyl 3 '- [2- [N- (tert-butoxycarbonyl) -N- [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] -1,1'- biphenyl-4-carboxylate (+) ESI-MS m/z: 510 (M+H) +
(65) Methyl 4 '- [2- [N- (tert-butoxycarbonyl) -N- [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] -2-fluoro- 1,1' -biphenyl-4-carboxylate (+) ESI-MS m/z: 550 (M+Na)+
(66) Methyl 4 '- [2- [N- (tert-butoxycarbonyl) -N- [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] -3-chloro- 1,1' -biphenyl-4-carboxylate (+) ESI-MS m/z: 566 (M+Na)+
(67) Methyl 4 '- [2- [N- (tert-butoxycarbonyl) -N- [ (2R) -2- (3- chlorophenyl ) -2-hydroxyethyl] amino] ethyl] -2 ' -methoxy- 1,1' -biphenyl-4-carboxylate (+) ESI-MS m/z: 540 (M+H) +
(68) Methyl 4 '- [2- [N- (tert-butoxycarbonyl) -N- [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] -2 ' -chloro- 1,1' -biphenyl-4-carboxylate (+) ESI-MS m/z: 544 (M+H) + (69) tert-Butyl N- [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] N- [2- [4 ' -formyl-3 ' - (1-piperidinyl) -1,1' -biphenyl-4- yl] ethyl] carbamate (+)ESI-MS m/z: 563 (M+H) +
(70) Methyl 4 '- [3- [N- (tert-butoxycarbonyl) -N- [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] propyl] -1,1'- biphenyl-4-carboxylate MS (m/z) : 524 (M+H)
(71) Ethyl 4'- [3- [N- (tert-butoxycarbonyl) -N-[ (2R)-2- (3- chlorophenyl) -2-hydroxyethyl] amino]propyl] -1,1'- biphenyl-3-carboxylate MS (m/z) : 538 (M+H)
(72) Methyl 4 '- [3- [N- ( tert-butoxycarbonyl) -N- [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] propyl] -3-fluoro- 1,1' -biphenyl-4-carboxylate MS (m/z) : 542 (M+H)
(73) Methyl 4 '- [3- [N- (tert-butoxycarbonyl) -N- [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] propyl] -3-methoxy- 1,1' -biphenyl-4-carboxylate MS (m/z) : 554 (M+H)
(74) Methyl 4 '- [3- [N- (tert-butoxycarbonyl) -N- [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino]propyl] -3-chloro- 1,1' -biphenyl-4-carboxylate MS (m/z) : 558 (M+H)
(75) Methyl 4 '- [3- [N- (tert-butoxycarbonyl) -N- [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino]propyl] -3-methyl- 1,1' -biphenyl-4-carboxylate MS (m/z) : 538 (M+H) ( 76 ) Methyl 3 ' - [ 3- [N- (tert-butoxycarbonyl ) -N- [ (2R) -2- ( 3- chlorophenyl ) -2-hydroxyethyl ] amino ] propyl ] -1 , 1 ' - biphenyl-4-carboxylate MS (m/ z ) : 523 (M+H)
(77) Ethyl 3 '- [3- [N- ( tert-butoxycarbonyl) -N- [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] propyl] -1,1'- bipheny1-3-carboxylate MS (m/z) : 538 (M+H)
(78) Methyl 4 '- [2- [N- (tert-butoxycarbonyl) -N- [ (2R) -2- (5- chloro-3-pyridyl) -2-hydroxyethyl] amino] ethyl] -1,1'- biphenyl-4-carboxylate MS (m/z) : 511 (M+H)
(79) tert-Butyl N- [ (2R) -2- ( 6-chloro-3-pyridyl) -2- hydroxyethyl]-N- [ (lR)-2- (4 ' -formyl-3 ' -phenoxy-1, 1 ' - biphenyl-4-yl) -1-methylethyl] carbamate MS (m/z) : 587 (M+H)
(80) tert-Butyl N- [2- (4 ' -formyl-3' -phenoxy-1, 1 ' -biphenyl-4- yl) ethyl] -N- [ (2R) -2-hydroxy-2- (3-pyridyl) ethyl] - carbamate MS (m/z) : 539 (M+H)
(81) Methyl [4 '- [2- [N- (tert-butoxycarbonyl) -N- [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] -1,1'- biphenyl-4-yl] acetate MS (m/z) : 524 (M+H)
(82) Methyl [4 '- [2- [N- (tert-butoxycarbonyl) -N- [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] -1,1'- biphenyl-3-yl] acetate MS (m/z) : 524 (M+H) (83) Methyl 4- [4- [ (2R) -2- [N- (tert-butoxycarbonyl) -N- [ (2R) -2-
(6-chloro-3-pyridyl) -2-hydroxyethyl] amino] propyl] - phenyl] -1-naphthoate MS (m/z) : 575 (M+H)
(84) tert-Butyl N- [ (IR) -2- [4 '-[ (benzoylamino) sulfonyl] -1, 1 ' - biphenyl-4-yl] -1-methylethyl] -N- [ (2R) -2- ( 6-chloro-3- pyridyl) -2-hydroxyethyl] carbamate MS (m/z) : 650 (M+H)
(85) tert-Butyl N- [2- [4 ' -formyl-3 '- (1-piperidinyl) -1, 1 ' - biphenyl-4-yl] ethyl] -N- [ (2R) -2-hydroxy-2-phenylethyl] - carbamate MS (m/z) : 529 (M+H)
(86) 4'-[2-[ [ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] amino] - ethyl] -3- (2-methoxyethoxy) -1,1' -biphenyl-4-carboxylic acid hydrochloride MS (m/z) : 470 (M+H)
(87) 3- (2-Ethoxyethoxy) -4'- [2- [ [ (2R) - (3-chlorophenyl) -2- hydroxyethyl] amino] ethyl] -1,1' -biphenyl-4-carboxylic acid hydrochloride MS (m/z) : 484 (M+H)
(88) 4 ' - [2- [ [ (2R) -2- (3-Chlorophenyl ) -2-hydroxyethyl] amino] - ethyl] -3-propyl-l, 1' -biphenyl-4-carboxylic acid hydrochloride MS (m/z) : 438 (M+H)
(89) 4' - [2- [ [ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] amino] - ethyl] -3-propoxy-l, 1' -biphenyl-4-carboxylic acid hydrochloride MS (m/z) : 454 (M+H) (90) 4'- [2-[ [ (2R)-2-Hydroxy-2-phenylethyl] amino] ethyl] -3- (2- methoxyethoxy) -1,1' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 2.8-3.0 (6H, m) , 3.32 (3H, s) , 3.70 (2H, m), 4.29 (2H, m) , 4.8-5.0 (IH, m) , 6.33 (IH, m) , 7.0-7.9 (12H, m) MS m/z: 436 (M+H)
(91) 3-(2-Ethoxyethoxy)-4'-[2-[ [ (2R)-2-hydroxy-2- phenylethyl] amino] ethyl] -1,1' -biphenyl-4-carboxylic acid hydrochloride MS m/z: 450 (M+H)
(92) 3-[2-(Dimethylamino)ethoxy]~4'-[2-[ [ (2R)-2-hydroxy-2- phenylethyl] amino] ethyl] -1,1' -biphenyl-4-carboxylic acid dihydrochloride
NMR (DMSO-dg, δ) : 1.12 (3H, d, J=6.5Hz), 2.8-3.6 (7H, m) , 2.88 (6H, s) , 4.58 (2H, m) , 4.8-5.0 (IH, m) , 6.33 (IH, ) , 7.0-7.9 (12H, m)
MS m/z: 462 (M+H)
(93) 4'- [2-[ [ (1S,2R) -2-Hydroxy-2- (4-hydroxyphenyl) -1- ethylethyl] amino] ethyl] -3-isopropoxy-l, 1' -biphenyl-4- carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 0.98 (3H, d, J=6.6Hz), 1.31 (6H, d, J=6.0Hz), 2.8-3.5 (5H, m) , 4.79 (IH, q, J=6.0Hz), 5.0-5.2 (IH, m) , 6.0 (IH, m) , 6.7-7.9 (11H, m) MS m/z: 450 (M+H)
Example 33
To the mixture of 4 ' - [2- [ [ (2R) -2-phenyl-2- hydroxyethyl] amino] ethyl] -1, 1 ' -biphenyl-4-nitrile (100 mg) in DMF (N,N-dimethylformamide) (10 ml) were added sodium azide (30 mg) and ammonium chloride (30 mg) , and stirred at 120°C for 12 hours. The resulting mixture was poured into a mixture of ethyl acetate and water, and the organic layer was washed with brine. After the solvent was evaporated under pressure, the residue was purified by column chromatography on silica gel to give the corresponding tetrazole. The obtained tetrazole was diluted with 6N hydrogen chloride in 1,4-dioxane (10 ml) and the mixture was allowed to keep at the room temperature for 4 hours. The mixture was evaporated under reduced pressure and the obtained solid was washed with ether to give
(lR)-2-[ [ (lR)-l-methyl-2-[4'- (lH-tetrazol-5-yl) -1, 1 ' - biphenyl-4-yl] ethyl] amino] -1-phenylethanol hydrochloride (25 mg) .
NMR (DMSO-dg, δ) : 1.14 (3H, d, J=6.4Hz), 2.6-3.2 (5H, m) , 3.93(2H, d, J=6.6Hz), 4.9-5.1(lH, ) , 6.24(1H, m) ,
7.2-7.5(7H, m) , 7.77(2H, d, J=8.0Hz), 7.94(2H, d, J=8.0Hz), 8.15(2H, d, J=8.0Hz) MS m/z: 400 (M+H)
Example 34
The following compounds were obtained according to a similar manner to that of Example 30.
(1) 4'- [3- [N- (tert-Butoxycarbonyl) -N-[ (2R)-2- (3- chlorophenyl) -2-hydroxyethyl] amino] propyl] -1,1'- biphenyl-4-carboxylic acid MS (m/z) : 510 (M+H)
(2) 4'- [3- [N- (tert-Butoxycarbonyl) -N-[ (2R)-2- (3- chlorophenyl) -2-hydroxyethyl] amino] propyl] -1, 1' - biphenyl-3-carboxylic acid MS (m/z) : 510 (M+H)
(3) 4'- [3- [N- (tert-Butoxycarbonyl) -N-[ (2R)-2- (3- chlorophenyl) -2-hydroxyethyl] amino]propyl] -3-fluoro- 1, 1 '-biphenyl-4-carboxylic acid MS (m/z) : 528 (M+H)
(4) 4'- [3- [N- (tert-Butoxycarbonyl) -N-[ (2R)-2- (3- chlorophenyl) -2-hydroxyethyl] amino] propyl] -3-methoxy- 1, 1 ' -biphenyl-4-carboxylic acid MS (m/z) : 540 (M+H)
(5) 4'-[3-[N- (tert-Butoxycarbonyl) -N-[ (2R)-2- (3- chlorophenyl) -2-hydroxyethyl] amino] propyl] -3-chloro- 1, 1 ' -biphenyl-4-carboxylic acid MS (m/z) : 544 (M+H)
(6) 4'- [3-[N- (tert-Butoxycarbonyl) -N-[ (2R)-2- (3- chlorophenyl) -2-hydroxyethyl] amino]propyl] -3-methyl- 1, 1 ' -biphenyl-4-carboxylic acid MS (m/z) : 524 (M+H)
(7) 3'- [3- [N- (tert-Butoxycarbonyl) -N-[ (2R)-2- (3- chlorophenyl) -2-hydroxyethyl] amino] propyl] -1,1'- biphenyl-4-carboxylic acid MS (m/z) : 523 (M+H)
(8) 3'-[3-[N- (tert-Butoxycarbonyl) -N-[ (2R)-2- (3- chlorophenyl) -2-hydroxyethyl] amino] propyl] -1,1'- biphenyl-3-carboxylic acid MS (m/z) : 510 (M+H)
(9) [4'-[ (2R) -2- [N- (tert-Butoxycarbonyl) -N-[ (2R)-2-(3- chlorophenyl) -2-hydroxyethyl] amino] propyl] -1,1'- biphenyl-4-yl] acetic acid MS (m/z) : 524 (M+H)
(10) 4'-[2-[N- (tert-Butoxycarbonyl) -N-[ (2R)-2- (5-chloro-3- pyridyl) -2-hydroxyethyl] mino] ethyl] -1,1' -biphenyl-4- carboxylic acid
MS (m/z) : 497 (M+H)
(11) [4'-[2-[N- (tert-Butoxycarbonyl) -N-[ (2R)-2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] -1,1'- biphenyl-4-yl] acetic acid MS (m/z) : 510 (M+H)
(12) 4-[4-[N-(2R)-2-[N- (tert-Butoxycarbonyl) -N- [ (2R)-2- (6- chloro-3-pyridyl) -2-hydroxyethyl] amino] propyl] phenyl ] -
1-naphthoic acid MS (m/z) : 561 (M+H)
Example 35 The following compounds were obtained according to a similar manner to that of Example 27.
(1) 4'-[3-[ [ (2R)-2- (3-Chlorophenyl) -2-hydroxyethyl] amino] - propyl] -1, 1 ' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 1.70-2.10 (2H, m) , 2.60-3.40 ( 6H, m) , 4.90-5.10 (IH, ) , 7.40-7.60 ( 6H, m) , 7.70-7.90 (4H, m) , 8.10 (IH, d, J=8Hz) MS (m/z) : 410 (M+H)
(2) 4'- [3- [[ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] - amino] propyl] -1,1' -biphenyl-3-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.80-2.10 (2H, m) , 2.60-3.40 ( 6H, m) , 4.90-5.10(lH, ) , 7.30-7.60 (9H, m) , 7.80-7.90 (IH, m) , 8.10(1H, s)
MS (m/z) : 410 (M+H)
(3) 4'-[3-[ [ (2R)-2- (3-Chlorophenyl) -2-hydroxyethyl] amino] - propyl] -3-fluoro-1, 1 ' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 1.80-2.10 (2H, ) , 2.60-3.40 (6H, m) , 4.90-5.10(lH, m) , 7.30-7.80 (IOH, m) , 8.00(1H, t, J=8Hz)
MS (m/z) : 428 (M+H)
(4) 4' - [3- [ [ (2R)-2- (3-Chlorophenyl) -2-hydroxyethyl] amino] - propyl] -3-methoxy-l, 1 ' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.80-2.10 (2H, ) , 2.60-3.40 ( 6H, m) , 4.00(3H, s), 4.90-5.10 (IH, ) , 7.30-7.50 ( 8H, m) ,
7.70-7.80(3H, m) MS (m/z) : 440 (M+H)
(5) 3-Chloro-4'-[3-[ [ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] amino]propyl] -1,1' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.80-2.10 (2H, ) , 2.60-3.40 ( 6H, m) , 4.90-5.10 (IH, ) , 7.30-7.60 ( 6H, ) , 7.70-7.90 (5H, m) MS (m/z) : 444 (M+H)
(6) 4'-[3-[ [ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] amino] - propyl] -3-methyl-l, 1 ' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 1.80-2.10 (2H, m) , 2.60(3H, s) , 2.60- 3.40(6H, m) , 4.90-5.10 (IH, ) , 7.30-7.60 (10H, m) , 7.90(1H, s) MS (m/z) : 424 (M+H)
(7) 3' - [3- [[ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] amino] - propyl] -1, 1 ' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 1.80-2.10 (2H, m) , 2.60-3.40 ( 6H, m) , 4.90-5.10(lH, m) , 7.30-7.60 (8H, m) , 7.80(2H, d, J=8Hz), 8.10 (2H, d, J=8Hz) MS (m/z) : 410 (M+H) (8) 3'-[3-[ [ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] amino] - propyl] -1, 1 ' -biphenyl-3-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 1.80-2.10 (2H, m) , 2.60-3.40 ( 6H, m) , 4.90-5.10(lH, m) , 7.30-7.60 (9H, ) , 7.80-7.90 (2H, m) , 8.20(1H, s) MS (m/z) : 410 (M+H)
(9) [4'-[ (2R)-2- [ [ (2R)-2- (3-Chlorophenyl) -2-hydroxyethyl] - amino ] propyl ]-l, 1 ' -biphenyl-4-yl] acetic acid hydrochloride
NMR (DMSO-dg, δ) : 1.05(3H, d, J=6Hz) , 2.80-3.60 (7H, m) ,
5.00-5.15(lH, m) , 7.20-7.70 ( 12H, m) MS (m/z) : 424 (M+H)
(10) 4'-[2-[ [ (2R)-2- (5-Chloro-3-pyridyl) -2-hydroxyethyl] - amino] ethyl] -1,1' -biphenyl-4-carboxylic acid dihydrochloride
NMR (DMSO-dg, δ) : 3.10-3.40 ( 6H, m) , 5.00-5.10 (IH, ) , 7.40-8.10 (9H, m) , 7.70-7.80 (2H, m)
MS (m/z) : 397 (M+H)
(11) 4'-[ (2R)-2-[ [ (2R)-2-Hydroxy-2- (3-pyridyl) ethyl] - amino] propyl] -3-phenoxy-l, 1 ' -biphenyl-4-carboxylic acid dihydrochloride
NMR (DMSO-dg, δ) : 1.13 (3H, d, J=6Hz) , 2.70-2.80 (IH, m) , 2.80-3.60(4H, m) , 5.30-5.40 (IH, m) , 6.90-7.60 (7H, ) , 7.90-8.00(2H, m) , 8.50-8.60 (IH, ) , 8.80- 8.90(2H, m) MS (m/z) : 469 (M+H)
(12) 4 •- [2- [ [ (2R)-2-Hydroxy-2- (3-pyridyl) ethyl] amino] - ethyl] -3-phenoxy-l, 1 ' -biphenyl-4-carboxylic acid dihydrochloride NMR (DMSO-dg, δ) : 3.00-3.50 ( 6H, m) , 5.20-5.30 (IH, m) , 7 . 00-7 . 70 ( 7H, m) , 7 . 90-8 . 00 ( 2H, m) , 8 . 40- 8 . 50 ( IH, ) , 8 . 80-8 . 90 ( 2H, m) MS (m/ z ) : 455 (M+H)
(13) [4'- [2- [[ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] amino] - ethyl] -1, 1 ' -biphenyl-4-yl] acetic acid hydrochloride NMR (DMSO-dg, δ) : 2.90-3.40 ( 6H, m) , 3.62 (2H, s), 4.90-
5.10(1H, ) , 7.30-7.70(12H, m) MS (m/z) : 410 (M+H)
(14) N-Benzoyl-4'- [ (2R)-2- [ [ (2R) -2-hydroxy-2- (3-pyridyl) - ethyl] amino] propyl] -1,1 '-biphenyl-4-sulfonamide dihydrochloride
NMR (DMSO-dg, δ) : 1.01 (3H, d, J=6Hz) , 2.60-3.60 (5H, m) , 5.00-5.15(lH, m) , 7.20-8.10 (13H, m) , 8.30-8. 0 (IH, m) , 8.70-8.80 (2H, ) MS (m/z) : 516 (M+H)
(15) 4'- [2-[ [ (2R) -2-Hydroxy-2-phenylethyl] amino] ethyl] -3- (1- piperidinyl) -1, 1 ' -biphenyl-4-carboxylic acid dihydrochloride
NMR (DMSO-dg, δ) : 1.50-1.80 ( 6H, d, m) , 3.00-3.40 (10H, m) , 5.00-5.10 (IH, ) , 7.20-7.50 (7H, ) , 7.70- 7.80(3H, m) , 8.10-8.20(2H, ) MS (m/z) : 445 (M+H)
Example 36
The following compounds were obtained according to a similar manner to that of Example 21.
(1) Methyl 4 ' - [2- [ [ (2R) -2- ( 6-chloro-3-pyridyl) -2- hydroxyethyl] amino] ethyl] -1,1' -biphenyl-4-carboxylate MS (m/z) : 410 (M+H)
(2) Methyl [4 '-[ (2R) -2- [[ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] amino]propyl] -1,1' -biphenyl-4-yl] acetate MS (m/z) : 438 (M+H)
(3) Ethyl 5-[4-[ (2R)-2-[ [ (2R)-2- (6-chloro-3-pyridyl)-2- hydroxyethyl] amino] propyl] phenyl] -1-naphthoate
MS (m/z) : 489 (M+H)
(4) Methyl 4 '- [2- [ [ (2R) -2- (4-chlorophenyl) -2- hydroxyethyl] amino] ethyl] -1, 1 ' -biphenyl-4-carboxylate MS (m/z) : 410 (M+H)
(5) Ethyl 6- [4- [2- [N-benzyl-N- [ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl ] amino ] ethyl ] phenyl ] nicotinate
(+ ) ESI-MS m/ z : 515 (M+H) +
( 6 ) Methyl 4 ' - [ 2- [N-benzyl-N- [ (2R) -2- ( 3-chlorophenyl ) -2- hydroxyethyl ] amino ] ethyl ] -2 , 6-dimethyl-l , 1 ' -biphenyl-4- carboxylate
( + ) ESI-MS m/ z : 528 (M+H) +
Example 37
Under nitrogen to a solution of methyl 4 ' - [2- [ [ (2R) -2- ( 6-chloro-3-pyridyl) -2-hydroxyethyl] amino] ethyl] -1,1'- biphenyl-4-carboxylate (110 mg) in tetrahydrofran (10 ml) was added IM methylzinc chloride in tetrahydrofran (0.8 ml) and tetrakis (triphenylphosphine) palladium (15.5 mg) at room temperature. The mixture was stirred at 80°C for 24 hours, and then poured into an aqueous solution (60 ml) of ethylenediaminetetraacetic acid (1 g) . The resulting mixture was neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform-.methanol = 100:1) to give methyl 4 '- [2- [ [ (2R) ~2- hydroxy-2- (6-methyl-3-pyridyl) ethyl] amino] ethyl] -1,1'- biphenyl-4-carboxylate (41 mg) as a colorless oil. MS (m/z) : 391 (M+H)
Example 38
The following compounds were obtained by alkaline hydrolysis of each ester thereof in a conventional manner.
(1) Sodium 4'-[2-[ [ (2R) -2-hydroxy-2- (6-methyl-3- pyridyl) ethyl] amino] ethyl] -1, 1 ' -biphenyl-4-carboxylate NMR (DMSO-d6, δ) : 2.50(3H, s) , 2.60-2.90 ( 6H, m) , 4.60- 4.70(1H, ) , 7.10-7.40(3H, m) , 7.50-7.70 (5H, m) , 7.90(1H, d, J=8Hz), 8.40(1H, s)
(2) Sodium 4'-[2-[ [ (2R) -2- ( 6-chloro-3-pyridyl) -2- hydroxyethyl] amino] ethyl] -1,1' -biphenyl-4-carboxylate NMR (DMSO-dg, δ) : 2.80-3.80 (6H, m) , 4.90(1H, t, J=6Hz), 7.10-7.90(8H, ) , 7.98(2H, d, J=8Hz) , 8.30(1H, d, J=2Hz) MS (m/z) : 397 (M+H)
(3) Sodium 4 ' - [2- [ [ (2R) -2- (4-chlorophenyl) -2- hydroxyethyl] amino] ethyl] -1,1' -biphenyl-4-carboxylate NMR (DMSO-dg, δ) : 2.70-3.50 ( 6H, m) , 4.50-4.60 ( IH, m) , 7.10-7.60 (8H, m) , 7.94(2H, d, J=8Hz)
MS (m/z) : 396 (M+H)
Example 39
The following compounds were obtained according to a similar manner to that of Preparation 29.
(1) Methyl [4'- [ (2R) -2- [N- (tert-butoxycarbonyl) -N-[ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] propyl] -1,1'- biphenyl-4-yl] acetate MS (m/z) : 538 (M+H) (2) Ethyl 5- [4- [ (2R) -2- [N- (tert-butoxycarbonyl) -N-[ (2R) -2- ( 6-chloro-3-pyridyl) -2-hydroxyethyl] amino] propyl] - phenyl] -1-naphthoate MS (m/z) : 589 (M+H)
Example 40
The following compounds were obtained according to a similar manner to that of Example 18.
(1) [4'-[2-[ [ (2R)-2- (3-Chlorophenyl) -2-hydroxyethyl] amino] - ethyl] -1, 1 ' -biphenyl-3-yl] acetic acid hydrochloride NMR (DMS0-d6, δ) : 2.80-3.40 ( 6H, m) , 3.65(2H, s), 4.90-
5.10(1H, m) , 7.20-7.70(12H, m) MS (m/z) : 408 (M-H)
(2) 4'- [2-[ [ (2R)-2- (3-Chlorophenyl) -2-hydroxyethyl] amino] - ethyl] -1, 1 ' -biphenyl-3-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 3.01-3.29 ( 6H, ) , 4.97-5.02 (IH, m) , 6.34(1H, br), 6.90(1H, m) , 7.71-7.48 (9H, ) , 7.89-
7.95(2H, m),8.18(lH, d, J=1.5Hz), 8.96(lH,br) (-) ESI-MS m/z: 394 (M-HCl-H)"
(3) 3- [2- [ [ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] amino] - ethyl] -6H-benzo [c] chromene-8-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 3.00-3.28 ( 6H, ) , 4.96-5.01 (IH, m) ,
5.20(2H, s), 6.34(1H, br) , 6.94-7.03 (2H, ) , 7.34- 7.47(4H, m) , 7.86-7.94 (4H, m) , 8.94(1H, br) (-) ESI-MS m/z: 422 (M-HCl-H)"
(4) 2- [2- [ [ (2R)-2- (3-Chlorophenyl) -2-hydroxyethyl] amino] - ethyl] -6H-benzo [c] chromene-8-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 3.00-3.26 ( 6H, m) , 5.03-5.07 (IH, m) , 5.19(2H, s), 6.38(1H, br) , 6.99(1H, d, J=8.2Hz), 7.20-7.25(2H, ) , 7.35-7.48 (4H, m) , 7.85-7.98 (4H, m) , 9.10(1H, br) (-) ESI-MS m/z: 422 (M-HCl-H)"
(5) 6- [4- [2-[ [ (2R)-2- (3-Chlorophenyl) -2-hydroxyethyl] - amino] ethyl] phenyl] nicotinic acid hydrochloride
NMR (DMSO-dg, δ) : 3.08-3.24 (6H, m) , 5.00-5.07 (IH, br) , 7.34-7.47 (6H, ) , 8.09-8.17 (3H, m) , 8.31-8.38 (IH, ) , 8.98(1H, br) , 9.12-9.16 (IH, m) , 9.30(1H, br)
(-) ESI-MS m/z: 395 (M-HCl-H)"
(6) 3'-[2-[ [ (2R)-2- (3-Chlorophenyl) -2-hydroxyethyl] amino] - ethyl] -1, 1 ' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 3.01-3.28 ( 6H, m) , 4.97-5.02 (IH, m) , 6.34(1H, br) , 7.34-7.48 ( 6H, ) , 7.62-7.65 (2H, m) , 7.78-7.83(2H, m) , .8.01-8.05 (2H, m) , 8.96(1H, br) (-) ESI-MS m/z: 394 (M-HCl-H)"
(7) 4'- [2- [[ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] amino] - ethyl] -2-fluoro-1, 1 ' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 3.01-3.28 (6H, m) , 5.02-5.05 (IH, ) , 6.38(1H, br) , 7.37-7.87 (11H, m) , 9.10(1H, br) (-) ESI-MS m/z: 412 (M-HCl-H)"
(8) 4'- [2-[ [ (2R)-2- (3-Chlorophenyl) -2-hydroxyethyl] amino] - ethyl] -2, 6-dimethyl-l, 1 ' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 2.00(6H, ) , 3.06-3.11 ( 6H, in), 4.98- 5.04(1H, m) , 6.36-6.85(lH, br) , 7.11-7.15 (2H, m) ,7.35-7.49(6H, ) , 7.70-7.72 (2H, m) , 9.06(1H, br) (-) ESI-MS m/z: 422 (M-HCl-H)" (9) 3-Chloro-4'- [2-[ [ (2R)-2- (3-chlorophenyl) -2- hydroxyethyl] amino] ethyl] -1,1' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 3.01-3.28 (6H, m) , 5.00-5.04 (IH, ) , 6.36(1H, br), 7.35-7.47 ( 6H, m) , 7.70-7.91 (5H, ) ,
9.07{1H, br) (-)ESI-MS m/z: 428 (M-HCl-H)"
(10) 4 '-[2-[ [ (2R)-2- (3-Chlorophenyl) -2-hydroxyethyl] amino] - ethyl] -2 ' -methoxy-1, 1' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 3.03-3.27 ( 6H, m) , 3.80 (3H, s), 5.03- 5.07(1H, m) , 6.38(1H, br) , 6.96(1H, d, J=7.9Hz), 7.06(1H, s), 7.29-7.48 (5H, ) , 7.58(1H, d, J=8.3Hz), 7.96(1H, d, J=8.3Hz), 9.13-9.18 ( IH, br)
(-)ESI-MS m/z: 424 (M-HCl-H)"
(11) 2'-Chloro-4'-[2-[ [ (2R)-2- (3-chlorophenyl) -2- hydroxyethyl] amino] ethyl] -1,1' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 3.00-3.27 ( 6H, m) , 5.01-5.07 ( IH, m) , 6.37-6.39(lH, br) , 6.96(1H, d, J=7.9Hz), 7.34- 7.57(9H, m) , 8.04(2H, d, J=8.3Hz), 9.04- 9.30(lH,br) (-) ESI-MS m/z: 428 (M-HCl-H)"
(12) 4' -[2- [ [ (2R) -2-Hydroxy-2-phenylethyl] amino] ethyl] -3- (isopropylthio) -1,1' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 1.31 (6H, d, J=6.5Hz), 2.99-3.33 (6H, m) , 3.69-3.82 (IH, m) , 4.96-5.00 (IH, ) , 6.22 (IH, m) , 7.30-7.92 (12H, m) (-)ESI-MS m/z: 434 (M-HCl-H)"
(13) 4' -[2- [ [ (2R)-2-Hydroxy-2-phenylethyl] amino] ethyl] -3- (isopropylsulfonyl) -1, l'-biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.25 (6H, d, J=6.8Hz), 2.99-3.33 (6H, m) , 3.94-4.08 (IH, m) , 4.96-5.00 (IH, m) , 6.22 (IH, ) , 7.27-8.12 (12H, m)
(-) ESI-MS m/z: 466 (M-HCl-H)"
Example 41
The following compounds were obtained according to a similar manner to that of Example 14 followed by a similar manner to that of Example 18.
(1) 4 '- [2- [ [ (2R) -2-Hydroxy-2-phenylethyl] amino] ethyl] -3- isobutyl-1, 1 ' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 0.89 (6H, d, J=8Hz) , 1.80-2.00 (IH, m) , 2.90-3.40(8H, m) , 4.90-5.10 (IH, ) , 7.30-7.80 (12H, m) MS (m/z) : 418 (M+H)
(2) 4'- [ (2R)-2- [ [ (2R)-2-Hydroxy-2-phenylethyl] amino] - propyl] -3-isobutyl-l, 1 ' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 0.89 (7H, d, J=6Hz) , 1.21 (3H, d,
J=6Hz), 1.80-1.90 (IH, m) , 2.70-3.60 (7H, m) , 5.00- 5.10(1H, m) , 7.20-7.80 (12H, )
MS (m/z) : 432 (M+H)
(3) 4'-[2-[ [ (2R) -2-Hydroxy-2-phenylethyl] amino] ethyl] -3- isopropyl-1, 1 ' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 1.20 (3H, d, J=7Hz), 2.90-3.40 (6H, m) , 3.80-3.90(lH, m) , 4.90-5.00 ( IH, m) , 7.20-7.80 (12H, ) MS (m/z) : 404 (M+H)
(4) 4'-[2-[ [ (2R)-2-Hydroxy-2-phenylethyl] amino] ethyl] -3- phenyl-1, 1' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 2.90-3.40 ( 6H, m) , 4.95-5.10 (IH, ) ,
7.30-7.80(17H, ) MS (m/z) : 438 (M+H)
(5) 4'-[2-[ [ (2R) -2-Hydroxy-2-phenylethyl] amino] ethyl] -3- propyl-1, 1 ' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 0.90-1.05 (3H, m) , 1.50-1.70 (2H, m) ,
• 2.80-3.40(8H, m) , 4.90-5.05 (IH, m) , 7.20-7.80 (12H, m)
MS (m/z) : 404 (M+H)
(6) 4'-[ (2R)-2-[ [ (2R) -2-Hydroxy-2-phenylethyl] amino] - propyl] -3-propyl-l , 1 ' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 0.80-1.70 ( 8H, m) , 2.70-3.20 (7H, m) ,
5.00-5.15(lH, m) , 7.10-7.90 (12H, m) MS (m/z) : 418 (M+H)
(7) 4'-[ (2R)-2-[ [ (2R) -2-Hydroxy-2-phenylethyl] amino] - propyl] -3-isopropyl-l, 1 ' -biphenyl-4-carboxylic acid hydrochloride
NMR (DMSO-dg, δ) : 1.05-1.10 ( 9H, m) , 2.05-2.15 (IH, m) ,
2.80-3.60(5H, m) , 5.00-5.15 (IH, m) , 7.20-7.80 (12H, m)
MS (m/z) : 418 (M+H)
(8) 4' - [ (2R) -2- [ [ (2R) -2-Hydroxy-2- (3-pyridyl) ethyl] - amino]propyl] -3-phenyl-l, 1' -biphenyl-4-carboxylic acid dihydrochloride
NMR (DMSO-dg, δ) : 1.15 (3H, d, J=6Hz) , 2.80-2.90 (IH, m) , 3.20-3.60(4H, m) , 5.10-5.20 (IH, m) , 7.30-7.90 (13H, m) , 8.30-8.40(lH, m) , 8.70-8.90 (2H, m) MS (m/z) : 453 (M+H) (9) 4'-[2-[ [ (2R) -2-Hydroxy-2-phenylethyl] amino] ethyl] -3- phenyl-1, 1' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-dg, δ) : 3.00-3.60 ( 6H, ) , 5.20-5.30 (IH, m) ,
7.20-7.90(13H, m) , 8.30-8.40 (IH, ) , 8.70-8.80 (2H, m)
MS (m/z) : 439 (M+H)
Example 42
The following compounds were obtained by conversion of an amino protective group from each corresponding amino protective group of benzyl in a conventional manner.
(1) Ethyl 6- [4- [2- [N- (tert-butoxycarbonyl) -N-[ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl]phenyl] - nicotinate
(+) ESI-MS m/z: 547 (M+Na)+
(2) Methyl 4 '- [2- [N- ( tert-butoxycarbonyl) -N- [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] -2, 6-dimethyl- 1, 1 ' -biphenyl-4-carboxylate (+) ESI-MS m/z: 560 (M+Na)+
Example 43
The following compound was obtained according to a similar manner to that of Example 55.
tert-Butyl N- [ (2R)-2- (3-chlorophenyl) -2-hydroxyethyl] - N- [2- (3 ' -hydroxy-1, 1 ' -biphenyl-4-yl) ethyl] carbamate (+)ESI-MS m/z: 468 (M+H)+
Example 44
The following compound was obtained by a replacement reaction of the object compound of Example 43 with tert- butyl 2-bromoacetate in a conventional manner. tert-Butyl [ [4 r - [2- [N- (tert-butoxycarbonyl) -N- [ (2R)-2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] -1, 1 ' -biphenyl- 3-yl] oxy] acetate
(+)ESI-MS m/z: 582 (M+H) +
Example 45
The following compound was obtained by elimination of two amino protective groups of the object compound of Example 44 in a conventional manner.
[ [4'- [2- [ [ (2R)-2- (3-Chlorophenyl) -2-hydroxyethyl] - amino] ethyl] -1,1' -biphenyl-3-yl] oxy] acetic acid hydrochloride
NMR (DMSO-dg, δ) : 3.00-3.27 ( 6H,m) , 4.76(2H,s), 5.01- 5.05(lH,m), 6.36(lH,br), 6.90(lH,m), 7.15-
7.48(9H,m), 7.64 (2H, d, J=8.0Hz) , 9.09-9.21 (lH,br) (-)ESI-MS m/z: 424 (M-HCl-H)"
Example 46 The following compound was obtained according to a similar manner to that of Preparation 61.
Methyl 4-bromo-3- [ [4- [2- [N- (tert-butoxycarbonyl) -N- [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] - phenoxy] ethyl] benzoate
(+) ESI-MS m/z: 617, 619 (M+H) +
Example 47
The following compound was obtained according to a similar manner to that of Example 20.
tert-Butyl N- [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] ■ N- [2- [ '-formyl-3'- (1-piperidinyl) -1,1 ' -biphenyl-4- yl] ethyl] carbamate NMR (DMSO-dg, δ) : 1.71-2.00 (6H, m) , 3.09-3.20 ( 6H,m) , 3.47-3.59(4H, br) , 5.06-5.10 (IH, m) , 7.28-7.48 ( 6H, ) , 7.82-7.89(3H, m) , 8.12-8.21 (2H, m) (-) ESI-MS m/z: 474 (M-HCl-H)"
Example 48
The following compound was obtained according to a similar manner to that of Preparation 28.
Methyl 3- [2- [N- ( tert-butoxycarbonyl) -N- [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] -6H- benzo [c] chromene-8-carboxylate (+) ESI-MS m/z: 538 (M+H) +
Example 49 The following compound was obtained according to a similar manner to that of Preparation 62.
Methyl 2- [2- [N- (tert-butoxycarbonyl) -N- [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] -6H- benzo [c] chromene-8-carboxylate (+) ESI-MS m/z: 560 (M+Na)+
Example 50
The following compounds were obtained according to a similar manner to that of Example 1.
(1) 4'-[2-[N- (tert-Butoxycarbonyl) -N- [ (2R) -2-hydroxy-2- (3- pyridyl) ethyl] amino] ethyl] -3-phenoxy-l, 1 ' -biphenyl-4- carboxylic acid MS (m/z) : 555 (M+H)
( 2 ) 4 ' - [ 2- [N- ( tert-Butoxycarbonyl ) -N- [ ( 2R) -2-hydroxy-2- phenylethyl ] amino ] ethyl ] -3- ( 1-piperidinyl ) -1 , 1 ' - biphenyl-4-carboxylic acid MS (m/ z ) : 545 (M+H) Example 51
The following compound was obtained according to a similar manner to that of Example 1 followed by a similar manner to that of Example 25.
4'- [ (2R)-2-[N- (tert-Butoxycarbonyl) -N-[ (2R) -2-hydroxy- 2- (3-pyridyl) ethyl] amino] propyl] -3-phenoxy-l, 1 ' -biphenyl-4- carboxylic acid MS (m/z) : 569 (M+H)
Example 52
The following compound was obtained according to a similar manner to that of Example 25 followed by a similar manner to that of Example 18.
5- [4- [ (2R)-2-[ [ (2R)-2-Hydroxy-2- (3-pyridyl) ethyl] - amino] propyl] phenyl] -1-naphthoic acid dihydrochloride MS (m/z) : 426 (M+H)
Example 53
The following compound was obtained according to a similar manner to that of Example 25 followed by a similar manner to that of Example 27.
4-[4-[ (2R)-2-[ [ (2R)-2-Hydroxy-2- (3-pyridyl) ethyl] - amino] propyl] phenyl] -1-naphthoic acid dihydrochloride MS (m/z) : 427 (M+H)
Example 54
The following compound was obtained according to a similar manner to that of Example 25.
tert-Butyl N- [ (lR)-2- [4'- [ (benzoylamino) sulfonyl] -1 , 1 ' biphenyl-4-yl] -1-methylethyl] -N- [ (2R) -2-hydroxy-2- (3- pyridyl) ethyl] carbamate MS (m/z) : 616 (M+H)
Example 55 The following compound was obtained according to a similar manner to that of Example 7.
Methyl 4 ' - [2- [N- (tert-butoxycarbonyl) -N- [ (2R) -2- hydroxy-2-pyenylethyl] amino] ethyl] -3- (isopropylthio) -1, 1' - biphenyl-4-carboxylate
(+)ESI-MS (m/z) : '572 (M+Na)+
Example 56
To a solution of methyl 4' - [2- [N- (tert-butoxycarbonyl) - N- [ (2R) -2-hydroxy-2-phenylethyl] amino] ethyl] -3-
(isopropylthio) -1, 1' -biphenyl-4-carboxylate (338 mg) in chloroform (8 ml) and N,N-dimethylformamide (4 ml) was added m-chloroperbenzoic acid (594 mg) at room temperature and the mixture was stirred at the same temperature for 1 hour. To the mixture was added water and extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give methyl 4 ' - [2- [N- (tert- butoxycarbonyl) -N- [ (2R) -2-hydroxy-2-phenylethyl] amino] - ethyl] -3- (isopropylsulfonyl) -1, 1' -biphenyl-4-carboxylate (340 mg) .
(+) ESI-MS m/z: 604 (M+Na)+
Preparation 71
To a solution of (2R) -N-benzyl-N- [2- (4-bromophenyl) - ethyl] -2- [ [tert-butyl (dimethyl) silyl] oxy] -2- (3- chlorophenyl) ethana ine (2.1 g) in tetrahydrofuran (25 ml) was added a solution of butyllithium in hexane (1.59M, 2.83 ml) dropwise at -70°C under nitrogen and the mixture was stirred at -70°C for 30 minutes. To the reaction mixture was added 4- [ [tert-butyl (dimethyl) silyl] oxy] benzaldehyde (977 mg) at -70°C, and the mixture was stirred at -70°C for 1 hour. The mixture was allowed to warm to room temperature and partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium biscarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 10/1) to give [4- [2- [N-benzyl-N-
[ (2R) -2- [ [tert-butyl (dimethyl) silyl] oxy] -2- (3-chlorophenyl) - ethyl] amino] ethyl]ρhenyl] [4- [ [tert-butyl (dimethyl) silyl] - oxy] henyl] methanol (1.1 g) .
(+)ESI-MS m/z: 716 (M+H) +
Preparation 72
To a solution of (IR) -2- [ [2- (4-bromophenyl) ethyl] - amino] -1- (3-chlorophenyl) ethanol (5.1 g) and imidazole (2.9 g) in N,N-dimethylformamide (30 ml) was added tert- butyl (dimethyl) silyl chloride (5.85 g) and the mixture was stirred at 40°C for 24 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, 5% acetic acid solution, saturated sodium biscarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure to give a crude product. To a solution of the product in tetrahydrofuran (80 ml) and triethylamine (2.0 ml) was added di-tert-butyl dicarbonate (3.14 g) , and the mixture was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 20/1) to give tert-butyl N-[2- (4-bromophenyl) ethyl] -N- [ (2R) -2- [ [tert-butyl (dimethyl) - silyl] oxy] -2- (3-chlorophenyl) ethyl] carbamate (5.0 g) . (+)ESI-MS m/z: 568 (M+H)+
Preparation 73 To a solution of tert-butyl N- [2- (4-bromophenyl) - ethyl] -N- [ (2R) -2- [ [tert-butyl (dimethyl) silyl] oxy] -2- (3- chlorophenyl) ethyl] carbamate (880 mg) in tetrahydrofuran (13 ml) was added a solution of butyllithium in hexane (1.59M, 1.07 ml) dropwise at -70°C under nitrogen and the mixture was stirred at -70°C for 30 minutes. To the reaction mixture was added 4- [ [tert-butyl (dimethyl) silyl] oxy] -N- methoxy-N-methylbenzamide (480 mg) at -70°C, and the mixture was stirred at -70°C for 1 hour. The mixture was allowed to warm to room temperature and partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 10/1) to give tert-butyl N-[2- [4- [4- [ [tert-butyl (dimethyl) silyl] oxy] benzoyl] phenyl] ethyl] - N-[ (2R)-2-[ [tert-butyl (dimethyl) silyl] oxy] -2- (3- chlorophenyl) ethyl] carbamate (710 mg) . (+) ESI-MS m/z: 746 (M+Na)+
Preparation 74
Di-tert-butyl dicarbonate (2.18 g) was added to a solution of 2- (4-bromophenyl) ethanamine (2.0 g) in tetrahydrofuran (5 ml) under ice water cooling over 10 minutes and the mixture was stirred at room temperature for further 1 hour. The reaction mixture was evaporated in vacuo to give tert-butyl 2- (4-bromophenyl) ethylcarbamate (2.98 g) as a colorless foam.
NMR (CDC13, δ) : 1.43 (9H, s), 2.75 (2H, t, J=8Hz) , 3.36 (2H, t, J=8Hz) , 7.00-7.10 (2H, m) , 7.30-7.50 (2H, m) Preparation 75
The following compound was obtained according to a similar manner to that of Preparation 3.
Methyl 4' - [2- [ (tert-butoxycarbonyl) amino] ethyl] -1,1'- biphenyl-4-carboxylate MS m/z: 356 (M+H)
Preparation 76
The following compound was obtained according to a similar manner to that of Example 4.
Methyl 4' - (2-aminoethyl) -1, 1' -biphenyl-4-carboxylate hydrochloride
NMR (DMSO-dg, δ) : 2.80-3.10 (4H, m) , 3.88 (3H, s), 7.40 (2H, d, J=8Hz), 7.60-8.10 (6H, m)
Preparation 77 To a solution of. methyl 4' - (2-aminoethyl) -1, 1' - biphenyl-4-carboxylate hydrochloride (420 mg) and benzaldehyde (153 mg) in dichloromethane (5 ml) was stirred for 3 hours, and the mixture was evaporated in vacuo . To the residue in methanol (10 ml) was added sodium borohydride (65 mg) on ice cooling, and stirred at the same temperature for 1 hour. The resulting mixture was poured into saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (hexane - ethyl acetate) over silica gel to afford methyl 4' - [2- (benzylamino) ethyl] -1, 1' - biphenyl-4-carboxylate (460 mg) as a colorless powder. MS m/z: 346 (M+H)
Preparation 78 Under nitrogen at 4°C, to a solution of 2,2,2- trifluoro-N- [2- [4- [ (4-methoxyphenyl) thio] phenyl] ethyl] - acetamide (1.5 g) in dichloromethane (15 ml) was added IM boron tribromide in dichloromethane (10.5 ml), and the mixture was stirred at room temperature for 15 hours. The mixture was evaporated under reduced pressure. The residue was dissolved in a mixture of dichloromethane and saturated aqueous sodium bicarbonate. After separation, the organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give 2, 2, 2-trifluoro-N- [2- [4- [ (4- hydroxyphenyl) thio] phenyl] ethyl] acetamide (1.42 g) . (+)ESI-MS m/z: 364 (M+Na)+
Preparation 79 To a solution of 2, 2, 2-trifluoro-N- [2- [4- [ (4- hydroxyphenyl) hio] phenyl] ethyl] acetamide (480 mg) in methanol (5.0 ml) was added IN sodium hydroxide solution (2.8 ml) . The mixture was refluxed for 12 hours. The mixture was evaporated under reduced pressure. The residue was dissolved in a mixture of dichloromethane (40 ml) , IN hydrochloric acid solution (2.0 ml) and water (15 ml) . After separation, the organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give 4-[[4- (2-aminoethyl) phenyl] thio]phenol (300 mg) . (-)ESI-MS m/z: 244 (M-H) ~
Preparation 80
To a solution of (αS, βR) -4-hydroxynorephedrine (500 mg) and 4-bromophenylethyl bromide (500 mg) in N,N- dimethylformamide (5 ml) was added N,N-diiospropylethylamine
(0.5 ml), and the mixture was stirred for 6 hours at 80°C.
The mixture was partitioned between ethyl acetate and water.
The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residual oil was diluted in tetrahydrofuran (10 ml) . To the solution was added di-tert-butyl dicarbonate (1 g) at room temperature, and the mixture was stirred at the same temperature for 12 hours. The resulting mixture was evaporated under pressure and the residue was purified by column chromatography on silica gel to give 4-[2-[N-
[ (1S,2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] -N- (tert-butyloxycarbonyl) amino] ethyl] phenyl bromide (520 mg) . MS m/z: 550 (M+H)
Example 57
To a solution of (2R) -N-benzyl-N- [2- (4-bromophenyl) - ethyl] -2- [ [tert-butyl (dimethyl) silyl] oxy] -2- (3- chlorophenyl) ethanamine (850 mg) in 1, 2-dimethoxyethane (9 ml) was added 4- [ [tert-butyl (dimethyl) silyl] oxy] - phenylboronic acid (498 mg) , tetrakis (triphenylphosphine) - palladium (88 mg) and aqueous solution of sodium carbonate (2M, 1.6 ml), and the mixture was stirred at 75°C for 10 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. To a solution of the residue in tetrahydrofuran (10 ml) was added IM tetrabutylammonium fluoride in tetrahydrofuran (3.6 ml) , and the mixture was stirred at room temperature for 8 hours under nitrogen. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give 4' - [2- [N-benzyl-N- [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] -1, 1' - biphenyl-4-ol (540 mg) .
(+) ESI-MS m/z: 458 (M+H)+
Example 58 A mixture of 4' - [2- [N-benzyl-N- [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino]ethyl] -1, 1' -biphenyl-4-ol (420 - g) in 4N hydrogen chloride in ethyl acetate (1.0 ml) was stirred for 5 minutes. The solvent was removed by evaporation. A suspension of the residue in ethanol (1.5 ml) and chlorobenzene (3.5 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 10 mg) under hydrogen atmosphere for 1 hour. The catalyst was filtered off, and the filtrate was evaporated. The residue was diluted with chloroform (40 ml) and methanol (5 ml) . The organic layer was washed with saturated sodium biscarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. To the residue was added tetrahydrofuran (3 ml) and di-tert-butyl dicarbonate (220 mg) , and the mixture was stirred at room temperature for 12 hours. The mixture was partitioned between ethyl acetate and water.
The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give tert- butyl (2R) -N- [2- (3-chlorophenyl) -2-hydroxyethyl] -N- [ 2- (4' - hydroxy-1, 1' -biphenyl-4-yl) ethyl] carbamate (245 mg) . (+) ESI-MS m/z: 490 (M+Na)+
Example 59 To a solution of tert-butyl (2R) -N- [2- (3-chlorophenyl) - 2-hydroxyethyl] -N- [2- (4' -hydroxy-1, 1' -biphenyl-4- yl) ethyl] carbamate (240 mg) and potassium carbonate (78 mg) in N,N-dimethylformamide (4 ml) was added tert-butyl bromoacetate (110 mg) , and the mixture was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 3/1) to give tert-butyl [[4'-[2-[N- (tert-butoxycarbonyl) -N- [ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] amino] ethyl] -1, 1' -biphenyl-4-yl] oxy] acetate (245 mg) .
(+) ESI-MS m/z: 582 (M+H) +
Example 60
The following compounds were obtained according to a similar manner to that of Example 4.
(1) [ [4'- [2- [[ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] - amino] ethyl] -1, 1' -biphenyl-4-yl] oxy] acetic acid hydrochloride
NMR (DMSO-dg, δ) : 3.02-3.35 (6H, m) , 4.72 (2H, s) , 5.00-5.05 (IH, m) , 6.37 (IH, br) , 6.99 (2H, d, J=8.7Hz), 7.30-7.61 (10H, m) , 9.04 (IH, br) , 13.03
(IH, br) (-) ESI-MS m/z: 424 (M-HCl-H)"
(2) [4-[4-[2-[ [ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] - amino] ethyl] benzoyl] phenoxy] acetic acid hydrochloride NMR (DMSO-dg, δ) : 3.01-3.32 (6H, m) , 4.81 (2H, s), 4.96-5.00 (IH, ) , 6.35 (IH, br) , 7.07 (2H, d, J=8.8Hz), 7.35-7.47 (6H, m) , 7.66-7.75 (4H, ) , 8.99 (IH, br) (-)ESI-MS m/z: 452 (M-HCl-H)"
Example 6]
To a solution of tert-butyl N- [2- (4-bromophenyl) ethyl] - N- [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] carbamate (435 mg) in 1, 2-dimethoxyethane (6 ml) were added 4-methoxycarbonyl- phenyl boronic acid (224 mg) , tetrakis (triphenylphosphine) - palladium (55 mg) and aqueous solution of sodium carbonate (2M, 1.0 ml), and the mixture was stirred at 80°C for 2 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 3/1) to give methyl 4' - [2- [N- (tert-butoxycarbonyl) -N- [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] -1,1' -biphenyl-4- carboxylate (400 mg) .
(+) ESI-MS m/z: 510 (M+H) +
Example 62 The following compound was obtained according to a similar manner to that of Example 6.
4'- [2-[ [ (2R)-2- (3-Chlorophenyl) -2-hydroxyethyl] amino] - ethyl] -1, 1' -biphenyl-4-carboxylic acid hydrochloride NMR (DMSO-d6, δ) : 3.01-3.27 (6H, m) , 5.01-5.06 (IH, m) , 6.36 (IH, br) , 7.34-7.48 (6H, m) , 7.70-7.81 (6H, ) , 8.02 (2H, d, J=8.4Hz), 9.11 (IH, br) (-) ESI-MS m/z: 394 (M-HCl-H)"
Example 63
To a solution of [4- [2- [N-benzyl-N- [ (2R) -2- [ [tert- butyl (dimethyl) silyl] oxy] -2- (3-chlorophenyl) ethyl] amino] - ethyl]phenyl] [4- [ [tert-butyl (dimethyl) silyl] oxy]phenyl] - methanol (1.1 g) in tetrahydrofuran (15 ml) was added IM tetrabutylammonium fluoride in tetrahydrofuran (5.0 ml) at 0°C, and the mixture was stirred at room temperature for 24 hours under nitrogen. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 2/1) to give 4- [ [4- [2- [N-benzyl-N- [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] - phenyl] (hydroxy) methyl] phenol (550 mg) . (+) ESI-MS m/z: 486 (M-H)" Example 64
A mixture of 4- [ [4- [2- [N-benzyl-N- [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl]phenyl] (hydroxy) - methyl]phenol (545 mg) in 4N hydrogen chloride in 1,4- dioxane (1.0 ml) was stirred for 5 minutes. The solvent was removed by evaporation. A suspension of the residue in ethanol (2.2 ml) and chlorobenzene (5.2 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 55 mg) under hydrogen atmosphere for 2 hours. The catalyst was filtered off, and the filtrate was evaporated. The residue was diluted with ethyl acetate and saturated sodium biscarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 4- [4- [2- [[ (2R) -2- (3-chlorophenyl) - 2-hydroxyethyl] amino] ethyl]benzyl]phenol (395 mg) . (+) ESI-MS m/z: 382 (M+H) +
Example 65 To a solution of 4- [4- [2- [[ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] amino] ethyl] benzyl] phenol (390 mg) in tetrahydrofuran (3.5 ml) and water (3.5 ml) was added di- tert-butyl dicarbonate (223 mg) , and the mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give tert- butyl (2R)-N-[2- (3-chlorophenyl) -2-hydroxyethyl] -N- [2- [4- (4- hydroxybenzyl) phenyl] ethyl] carbamate (480 mg) . (+) ESI-MS m/z: 482 (M+H) +
Example 66
The following compounds were obtained according to a similar manner to that of Example 57. (1) tert-Butyl [4- [4- [2- [N- (tert-butoxycarbonyl) -N- [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl]benzyl] - phenoxy] acetate (+) ESI-MS m/z: 598 (M+H) +
(2) tert-Butyl [4- [4- [2- [N- (tert-butoxycarbonyl) -N- [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl]benzoyl] - phenoxy] acetate (+)ESI-MS m/z: 610 (M+H)+
Example 67
A solution of tert-butyl [4- [4- [2- [N- (tert- butoxycarbonyl) -N- [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] - amino] ethyl] benzyl] phenoxy] acetate (240 mg) and 4N hydrochloride in 1,4-dioxane (3.0 ml) was stirred at room temperature for 24 hours. The mixture was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (methanol/acetic acid/chloroform = 10/1/100) to give a product. To a tetrahydrofuran (2.0 ml) solution of the product, 4N hydrogen chloride in 1,4-dioxane (1.0 ml) was added. The mixture was stirred for 5 minutes and evaporated under reduced pressure to give [4- [4- [2- [[ (2R) -2- (3-chlorophenyl) - 2-hydroxyethyl] amino] ethyl] benzyl] phenoxy] acetic acid hydrochloride (72 mg) .
NMR (DMSO-dg, δ) : 2.91-3.24 (6H, m) , 3.84 (2H, s), 4.61 (2H, s), 4.94-4.99 (IH, ) , 6.32 (IH, br) , 6.80 (2H, d, J=8.7Hz), 7.10-7.21 (6H, m) , 7.29-7.46 (4H, m) , 8.89 (IH, br) (-) ESI-MS m/z: 438 (M-HCl-H)"
Example 68
The following compound was obtained according to a similar manner to that of Example 61. tert-Butyl N- [ (2R) -2- (3-chlorophenyl) -2-hydroxyethyl] - N- [2- [4- (4-hydroxybenzoyl) phenyl] ethyl] carbamate (+) ESI-MS m/z: 496 (M+H) +
Example 69
A solution of methyl 4' - [2- (benzylamino) ethyl] -1, 1' - biphenyl-4-carboxylate (460 mg) , and 2-chloro-5- [ (2R) -2- oxiranyl] pyridine (207 mg) in ethanol (10 ml) was refluxed for 18 hours. The mixture was evaporated in vacuo. The residue was purified by column chromatography on silica gel (chlorofor:methanol = 100:1) to give methyl 4' - [2- [N-benzyl- N- [ (2R) -2- ( 6-chloro-3-pyridyl) -2-hydroxyethyl] amino] ethyl] - 1, 1' -biphenyl-4-carboxylate (470 mg) as a colorless foam. MS m/z: 501 (M+H)
Example 70
Methyl 4' -[2- [N-benzyl-N- [ (2RJ-2- (6-chloro-3-pyridyl) - 2-hydroxyethyl] amino] ethyl] -1, 1' -biphenyl-4-carboxylate (470 mg) , ammonium formate (296 mg) and palladium on carbon powder (100 mg) in methanol (10 ml) and water (1.0 ml) was refluxed for 30 minutes. The reaction mixture was filtrated and poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. A mixture of the residue was chromatographed (chloroform-methanol) over silica gel to give methyl 4' - [2- [[ (2R) -2-hydroxy-2- (3-pyridyl) ethyl] - amino] ethyl] -1, 1' -biphenyl-4-carboxylate (326 mg) as a colorless foam.
MS m/z: 377 (M+H)
Example 71
At room temperature, to a solution of methyl 4'-[2- [ [ (2R)-2-hydroxy-2- (3-pyridyl) ethyl] amino] ethyl] -1, V - biphenyl-4-carboxylate (326 mg) in methanol was added IN sodium hydride (0.87 ml), and the mixture was stirred at the same temperature for 3 hours. The resulting mixture was evaporated under reduced pressure and dried to give sodium 4- [4- [2- [ [ (2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] - ethyl] ]-l, 1' -biphenyl-4-carboxylate (220 mg) as a colorless powder.
NMR (DMSO-dg, δ) : 2.50-2.80 (6H, m) , 4.70 (IH, t, J=6Hz) , 7.10-7.40 (3H, m) , 7.50-7.70 (5H, m) , 7.90-8.00 (IH, m) , 8.40-8.50 (2H, m) MS m/z: 361 (M-H)
Example 72
4- [ [4- (2-Aminoethyl) phenyl] thio] phenol (295 mg) and
(2R) -2- (3-chlorophenyl) oxirane (186 mg) in ethanol (3.5 ml) was refluxed for 6 hours. The mixture was evaporated. The residue was purified by column chromatography on silica gel
(chloroform/methanol = 100/3) to give 4- [ [4- [2- [ [ (2R) -2- (3- chlorophenyl) -2-hydroxyethyl] amino] ethyl] phenyl] thio] phenol
(155 mg) .
(+) ESI-MS m/z: 400 (M+H) +
Example 73
To a solution of tert-butyl N- [ (2R) -2- (3-chlorophenyl) - 2-hydroxyethyl] -N- [2- [4- [ (4-hydroxyphenyl) thio] phenyl] - ethyl] carbamate (195 mg) and potassium carbonate (59 mg) in N,N-dimethylformamide (3 ml) was added tert-butyl bromoacetate (84 mg) , and the mixture was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 3/1) to give tert-butyl [4- [[4- [2- [N- (tert-butoxycarbonyl) -N- [ (2R) -2- (3-chlorophenyl) -2- hydroxyethyl] amino] ethyl] phenyl] thio] phenoxy] cetate (168 mg) . (+) ESI-MS m/z: 636 (M+Na)

Claims

C L A I M S A compound of the formula [I] w ere n X is bond, -CH -, | , n -0-, -OCH2-, -CH20-, OH 0 -N- or I-, (in which R' is hydrogen or lower alkyl), Y is bond, -0-(CH2)n- (in which n is 1, 2, 3 or 4), -(CH )m- (in which is 1, 2, 3 or 4), Z is cyano, tetrazolyl, (benzylsulfonyl) carbamoyl, benzoylsulfamoyl, formyl, carboxy or protected carboxy, ι Rx is hydrogen, lower alkyl or halogen, R2 is hydrogen or an amino protective group, R is hydrogen or lower alkyl, R4 is hydrogen or lower alkyl, R^ and R° are each independently hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy, hydroxy (lower) alkoxy, mono (or di or tri) halo (lower) alkoxy, lower alkoxy (lower) alkoxy, lower alkenyloxy, cyclo (lower) alkyloxy, cyclo (lower) alkyl (lower) alkoxy, benzyloxy, phenoxy, lower alkylthio, cyclo (lower) alkylthio, lower alkylsulfonyl, cyclo (lower) alkylsulfonyl, amino, mono (or di) (lower) alkylamino, mono (or di or tri) halo (lower) alkyl, cyano, piperidinyl or phenyl, R° is hydrogen, lower alkyl or halogen, R9 is hydrogen or lower alkyl, and i is 1 or 2, provided that — CH- — C— ( 1 ) when X is bond, -CH2- , | or || , OH 0 then R5 is not hydrogen, or (2 ) when i is 1 , or a salt thereof. A compound of claim 1, wherein X is bond, -0-, -OCH2-, -S- or -N- (in which R' is R7 hydrogen or lower alkyl) , Y is bond, -0-(CH2)n- (in which n is 1, 2, 3 or 4) , -(CH2)m- (in which m is 1, 2, 3 or 4), Z is carboxy or lower alkoxycarbonyl, R! is hydrogen or halogen, R2 is hydrogen, R3 is hydrogen or lower alkyl, R^ is hydrogen, R~ is halogen, hydroxy, lower alkyl, lower alkoxy, hydroxy (lower) lkoxy, mono (or di or tri) halo (lower) alkoxy, lower alkoxy (lower) alkoxy, lower alkenyloxy, cyclo (lower) alkyloxy, phenoxy or phenyl, R° is hydrogen, R° is hydrogen or lower alkyl, R9 is hydrogen or lower alkyl, and i is 1 or 2. A compound of claim 2, wherein -N- , X is bond, -0-, -OCH2-, -S- or | (in which R' is R^ hydrogen or lower alkyl) , Y is bond, _0-(CH2)n- (in which n is 1 or 2) or -(CH )m- (in which is 1 or 2) , Z is carboxy or lower alkoxycarbonyl, R! is hydrogen or halogen, R2 is hydrogen, R is hydrogen or lower alkyl, R^ is hydrogen, R^ is halogen, hydroxy, lower alkyl or lower alkoxy, R° is hydrogen, R^ is hydrogen or lower alkyl, R9 is hydrogen or lower alkyl, and i is 1. A compound of claim 3, wherein X is bond, Y is bond, Z is carboxy or lower alkoxycarbonyl, R! is hydrogen or halogen, R^ is hydrogen, R3 is hydrogen or lower alkyl, R4 is hydrogen, R5 is halogen, hydroxy, lower alkyl or lower alkoxy, R6 is hydrogen, R8 is hydrogen or lower alkyl, R9 is hydrogen or lower alkyl, and i is 1. A compound of claim 4, which selected from the group consisting of
(1) 4'-[2-[ [ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] - amino] ethyl] -2-methyl-l, 1' -biphenyl-4-carboxylic acid,
(2) 4' - [ (2R) -2- [ [ (2R) -2-Phenyl-2-hydroxyethyl] amino] - propyl] -3-methoxy-l, 1' -biphenyl-4-carboxylic acid,
(3) 4' - [ (2R) -2- [ [ (2R) -2- (3-Chlorophenyl) -2- hydroxyethyl] amino]propyl] -3-isopropyloxy-l, 1' - biphenyl-4-carboxylic acid,
(4) 4'-[2-[ [ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] - amino] ethyl] -3-methoxy-l, 1' -biphenyl-4-carboxylic acid, •
(5) 4'- [2- [[ (2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] - amino] ethyl] -2, 3-dimethyl-l, 1' -biphenyl-4- carboxylic acid, (6) 4' - [2- [[ (2R)-2-Hydroxy-2- (3-pyridyl) ethyl] amino] - ethyl] -2-methyl-l, 1' -biphenyl-4-carboxylic acid, (7) 4' - [ (2R) -2- [ [ (2R) -2-Hydroxy-2- (3-pyridyl) ethyl] - amino]propyl] -3-methoxy-l, 1' -biphenyl-4-carboxylic acid, (8) 4 '- [2- [[ (2R) -2- (3-Fluorophenyl) -2-hydroxyethyl] - amino] ethyl] -3-propoxy-l, 1 ' -biphenyl-4-carboxylic acid,
(9) 4'-[ (2R)-2-[ [ (2R)-2- (3-Fluorophenyl) -2- hydroxyethyl] amino] propyl] -3-propoxy-l, 1 ' - biphenyl-4-carboxylic acid,
(10) 4'- [2-[ [ (lS,2R)-2-Hydroxy-2- (4-hydroxyphenyl) -1- methylethyl] amino] ethyl] -3-isopropoxy-l, 1' - biphenyl-4-carboxylic acid, and
(11) 4'-[2-[ [ (2R)-2-Hydroxy-2-phenylethyl] amino] ethyl] - 3-isobutyl-l, 1 ' -biphenyl-4-carboxylic acid, or a pharmaceutically acceptable salt thereof.
6. A process for preparing a compound of claim 1, or a salt thereof, which comprises,
(i) reacting a compound [II] of the formula:
0
/ \ Ri. — .CH-CH [II] $ A* wherein R , R9 and Q^- are each as defined in claim 1, with a compound [III] of the formula:
Figure imgf000128_0001
wherein J@ ' X' Y' Z' R2' R3' R4' R5' R6' R8 and I i are each as defined in claim 1, or a salt thereof, to give a compound [I] of the formula:
Figure imgf000128_0002
wherei
Figure imgf000128_0003
X' Y' Z' R1' R2' R3, R< R5, R
R , R and i are each as defined in claim 1, or a salt thereof,
(ii) subjecting a compound [la] of the formula:
Figure imgf000128_0004
R9 and i are each as defined in claim 1, and R is an amino protective group, or a salt thereof, to elimination reaction of the amino protective group, to give a compound [lb] of the
Figure imgf000129_0001
where m A" X , Y, Z , R1 , R- R' R* R< Rc
Figure imgf000129_0002
Ry and i are each as defined in claim 1, or a salt thereof,
!iii) reacting a compound [IV] of the formula:
Figure imgf000129_0003
wherein ("^ , R , R , R , R , R , R and i are each as defined in claim 1, or a salt thereof, with a compound [V] of the formula:
Figure imgf000129_0004
wherein Έ> " , Y, Z, R5 and R8 are each as defined in
' claim 1, or a salt thereof, to give a compound [lc] of the formula :
Figure imgf000129_0005
, Y, Z, R1, R2, R3, R4, R5, Rβ, R°,
Figure imgf000129_0006
R9 and i are each as defined in claim 1, or a salt thereof,
(iv) reacting a compound [IV] of the formula:
Figure imgf000130_0001
wherein PA" , R , R R , R , R , R and i are each as defined in claim 1, or a salt thereof, with a compound [VI] of the formula:
Figure imgf000130_0002
wherein B , Y, Z, R^ and R8 are each as defined in 1 claim 1, and X _ is a leaving group, or a salt thereof, to give a compound [lc] of the formula:
Figure imgf000130_0003
wherein , Y, z, R1, R2, R3, R4, R5, Rβ,
Figure imgf000130_0004
R , R9 and i are each as defined in claim 1, or a salt thereof, [v) reacting a compound [VII] of the formula:
Figure imgf000131_0001
R9 and j_ are eacγl as
Figure imgf000131_0002
defined in claim 1, X is a leaving group, or a salt thereof, with a compound [V] of the formula:
Figure imgf000131_0003
wherein B , Y, Z, R° and R° are each as defined in claim 1, or a salt thereof, to give a compound [Id] of the formula:
Figure imgf000131_0004
, Y, Z, R1, R2, R3, RL- R5, Rβ, Rε
Figure imgf000131_0005
Ry and i are each as defined in claim 1, or a salt thereof, and
(vi) subjecting a compound [le] of the formula:
Figure imgf000132_0001
whereln^' . X, Y, R1, R3, R< R5, Rβ, Rc
Ry and i are each as defined in claim 1,
R!° is lower alkyl, and
Ra is an amino protective group, or a salt thereof, to deesterification reaction, to give a compound [If] of the formula:
Figure imgf000132_0002
wherein
Figure imgf000132_0003
R^ and i are each as defined in claim 1, and R is defined above, or a salt thereof, and then subjecting the compound [If] above to elimination reaction of amino protective group, to give a compound [lg] of the formula:
Figure imgf000132_0004
, X, Y, R1, R3, R4, R5, R6, RJ
Figure imgf000132_0005
or a salt thereof.
7. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers or excipients
8. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament.
9. A compound of claim 1 or a pharmaceutically acceptable salt thereof for use as a medicament.
10. A compound of claim 1 or a pharmaceutically acceptable salt thereof for use as selective β3 adrenergic receptor agonists.
11. A method for the prophylactic and/or the therapeutic treatment of pollakiuria or urinary incontinence which comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to a human being or an animal.
PCT/JP2003/008061 2002-06-27 2003-06-25 Aminoalcohol derivatives WO2004002939A2 (en)

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CA002492065A CA2492065A1 (en) 2002-06-27 2003-06-25 Aminoalcohol derivatives_as b3 adrenergic receptor agonist
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AU2003248247A AU2003248247B2 (en) 2002-06-27 2003-06-25 Aminoalcohol derivatives
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NZ537206A NZ537206A (en) 2002-06-27 2003-06-25 Aminoalcohol derivatives
JP2004517277A JP3852708B2 (en) 2002-06-27 2003-06-25 Amino alcohol derivative
BR0311788-0A BR0311788A (en) 2002-06-27 2003-06-25 Aminoalcoholic derivative compound, process for its preparation, pharmaceutical composition, comprising, its use and method of treatment
KR1020047020608A KR100693367B1 (en) 2002-06-27 2003-06-25 Aminoalcohol derivatives
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WO2005070872A1 (en) 2004-01-12 2005-08-04 Theravance, Inc. Aryl aniline derivatives as beta2 adrenergic receptor agonists
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US7317023B2 (en) 2004-07-21 2008-01-08 Theravance, Inc. Diaryl ether β2 adrenergic receptor agonists
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JP2008526903A (en) * 2005-01-14 2008-07-24 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング Phenylbenzoic acid derivative, process for its preparation, pharmaceutical composition containing this derivative, and therapeutic use thereof
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WO2005061433A3 (en) * 2003-12-23 2005-10-27 Astellas Pharma Inc Aminoalcohol derivatives
WO2005061433A2 (en) * 2003-12-23 2005-07-07 Astellas Pharma Inc. Aminoalcohol derivatives
US7417060B2 (en) 2003-12-23 2008-08-26 Astellas Pharma Inc. Aminoalcohol derivatives
US7622467B2 (en) 2004-01-12 2009-11-24 Theravance, Inc. Aryl aniline derivatives as β2 adrenergic receptor agonists
WO2005070872A1 (en) 2004-01-12 2005-08-04 Theravance, Inc. Aryl aniline derivatives as beta2 adrenergic receptor agonists
US7994165B2 (en) 2004-01-12 2011-08-09 Theravance, Inc. Aryl aniline derivatives as β2 adrenergic receptor agonists
US7317023B2 (en) 2004-07-21 2008-01-08 Theravance, Inc. Diaryl ether β2 adrenergic receptor agonists
US7662815B2 (en) 2004-07-21 2010-02-16 Theravance, Inc. Diaryl ether β2 adrenergic receptor agonists
WO2006033446A1 (en) * 2004-09-21 2006-03-30 Astellas Pharma Inc. Aminoalcohol derivatives
AU2005285812B2 (en) * 2004-09-21 2011-02-24 Astellas Pharma Inc. Aminoalcohol derivatives
US7928264B2 (en) 2004-09-21 2011-04-19 Astellas Pharma Inc. Aminoalcohol derivatives
JP4893620B2 (en) * 2004-09-21 2012-03-07 アステラス製薬株式会社 Amino alcohol derivative
JP2008526903A (en) * 2005-01-14 2008-07-24 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング Phenylbenzoic acid derivative, process for its preparation, pharmaceutical composition containing this derivative, and therapeutic use thereof
WO2008005338A1 (en) * 2006-06-29 2008-01-10 Arena Pharmaceuticals, Inc. Modulators of the histamine h3-receptor useful for the treatment of disorders related thereto

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KR20050013582A (en) 2005-02-04
TWI331137B (en) 2010-10-01
CA2492065A1 (en) 2004-01-08
JP4587127B2 (en) 2010-11-24
RU2319698C2 (en) 2008-03-20
KR100693367B1 (en) 2007-03-12
WO2004002939A3 (en) 2005-05-06
EP1546086A2 (en) 2005-06-29
NZ537206A (en) 2007-06-29
TW200401761A (en) 2004-02-01
MXPA04012783A (en) 2005-02-24
JP3852708B2 (en) 2006-12-06
NO20050470L (en) 2005-02-28
US7037938B2 (en) 2006-05-02
JP2006321809A (en) 2006-11-30
BR0311788A (en) 2005-03-15
US7629366B2 (en) 2009-12-08
US20060100252A1 (en) 2006-05-11
PL375195A1 (en) 2005-11-28
JP2005530852A (en) 2005-10-13
RU2005101876A (en) 2005-08-27
US20040006143A1 (en) 2004-01-08

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