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WO1998046599A1 - Nouveaux carboxamides inhibiteurs d'agregation plaquettaire - Google Patents

Nouveaux carboxamides inhibiteurs d'agregation plaquettaire Download PDF

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Publication number
WO1998046599A1
WO1998046599A1 PCT/EP1998/002226 EP9802226W WO9846599A1 WO 1998046599 A1 WO1998046599 A1 WO 1998046599A1 EP 9802226 W EP9802226 W EP 9802226W WO 9846599 A1 WO9846599 A1 WO 9846599A1
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Prior art keywords
alkyl
amino
carbonyl
propionic acid
thiazol
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PCT/EP1998/002226
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English (en)
Inventor
Elena Carceller
Pere J. JIMÉNEZ
Jorge Salas
Original Assignee
J. Uriach & Cia. S.A.
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Publication date
Application filed by J. Uriach & Cia. S.A. filed Critical J. Uriach & Cia. S.A.
Priority to AU75263/98A priority Critical patent/AU7526398A/en
Publication of WO1998046599A1 publication Critical patent/WO1998046599A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • Novel carboxamides as platelet aggregation inhibitors are disclosed.
  • the present invention relates to a new series of carboxamides which are platelet aggregation inhibitors.
  • the invention also relates to processes for preparing such compounds, to pharmaceutical compositions containing them and to their use for the treatment of disorders in which platelet aggregation is involved.
  • Platelet function plays an essential role in the maintenance of blood hemostasis but also in the pathogenesis of a broad range of cardiovascular and cerebrovascular disorders, including unstable angina, myocardial infarction, atherosclerosis, thromboembolism, stroke, restenosis following angioplasty, etc.
  • the hemostatic plug consists essentially of a mass of platelet aggregates and a net of an insoluble protein known as fibrin.
  • fibrin an insoluble protein known as fibrin.
  • platelets In order to be able to aggregate, platelets must be previously activated and this activation process involves, as a last step, the exposure of certain cell adhesion molecules on the external surface of the platelet membrane. These molecules are glycoproteins
  • Fibrinogen the soluble precusor of fibrin
  • GP Ub/IIIa like many other integrins, exhibits high affinity for the tripeptide sequence Arg-Gly-Asp, which is present in many adhesion molecules.
  • Several peptidic compounds based on this sequence have been reported which block the binding of fibrinogen to its receptor, thus inhibiting platelet aggregation.
  • Nonpeptide antagonists of the fibrinogen receptor have also been reported.
  • the present invention discloses new and potent nonpeptide inhibitors of platelet aggregation. It is believed that these compounds act as antagonists of the fibrinogen (GP lib /Ilia) receptor. Description of the invention.
  • the present invention relates to novel compounds of general formula I:
  • one of Yi or Y 2 represents N and the other represents NR5, O or S, or one of Yi or Y 2 represents S and the other represents CR 5 , wherein R 5 represents hydrogen or C 1 - 4 alkyl; m represents 0, 1 or 2;
  • R l represents hydrogen, C 1 - 6 alkyl, C 2 - 6 alkenyl, C 2 -6 alkynyl, C1-6 alkoxy, C 1 -6 haloalkyl, C 3 - 7 cycloalkyl, C 3 .
  • A represents C 0 - 2 alkylene which may be optionally substituted with one or more groups independently selected from C ⁇ - 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C ⁇ - 6 haloalkyl, C 3 - 7 cycloalkyl, C 3 - 7 cycloalkylC ⁇ - 4 alkyl, aryl, arylC ⁇ - 4 alkyl, arylC 3 - 7 cycloalkyl, heteroaryl, heteroarylCi- 4 alkyl, R 6 SO 2 NR 2 C 1 - 4 alkyl, R 6 CONR 2 C ⁇ .
  • R 6 OCONR 2 C ⁇ - 4 alkyl, R 2 R7NCONR 2 C1- 4 alkyl, R 6 S0 2 C ⁇ - alkyl, R 2 R7NSO 2 C 1 - 4 alkyl, R 2 R7NCOC 1 -4 alkyl, R COC1-4 alkyl, R7OOCC 1 -4 alkyl, R 6 OC 1 - 4 alkyl, R 2 R 7 NC 1 - 4 alkyl, R 8 OOC-, or R 2 R7NCO-;
  • R 2 represents independently hydrogen or C 1 - 4 alkyl;
  • R 3 can have any of the meanings disclosed for R and in addition it can represent RsOOC- or R 2 R 7 NCO-, with the proviso that when A represents Co alkylene, then R 3 cannot represent a group that is bonded through a N atom; B represents carboxy or a metabolically labile ester or amide thereof;
  • R 4 represents a group of formula (i) or (ii):
  • R 6 represents C 1 - 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C ⁇ _ 6 haloalkyl, C ⁇ - 4 alkoxyC ⁇ - 4 alkyl, C 3 -7 cycloalkyl, C 3 - 7 cycloalkylC ⁇ - 4 alkyl, aryl, arylC ⁇ - 4 alkyl, arylcarbonylCi- 4 alkyl, heteroaryl or heteroarylC ⁇ - 4 alkyl;
  • R 7 represents hydrogen or any of the meanings disclosed for R&
  • R ⁇ represents hydrogen or C 1 - 4 alkyl
  • p represents 1 or 2;
  • X l represents a group of formula:
  • X 2 represents a group of formula:
  • X 3 represents N or CH, with the proviso that when X 3 is N then X 2 cannot represent a group: / / /
  • Z 2 represents Z and the other represents CH 2 , with the proviso that when X 3 represents N, then Z 2 is CH2;
  • Z represents a group of formula:
  • R 9 represents hydrogen or C 1 - 4 alkyl
  • Rio and Rn independently represent hydrogen or C 1 - 4 alkyl, or they can be bonded together forming a C 2 - 5 polymethylene chain;
  • aryl in the above definitions represents phenyl or naphthyl which can be optionally substituted with one or more groups independently selected from halogen, C 1 - 4 alkyl, C 2 - 4 alkenyl, C 2 - 4 alkynyl, C 1 - 4 alkoxy, hydroxy, C 1 - 4 haloalkyl, C 1 . 4 haloalkoxy, carboxy, cyano, nitro, amino, C . 4 alkylamino, C 1 .
  • heteroaryl in the above definitions represents an aromatic monocyclic 5- or 6- membered heterocycle or an aromatic bicyclic 9- or 10-membered heterocycle containing from one to four heteroatoms selected from N, O and S, and which can be optionally substituted with one or more groups independently selected from halogen, C 1 - 4 alkyl, C 2 - 4 alkenyl, C 2 - 4 alkynyl, C 1 - 4 alkoxy, hydroxy, C 1 - 4 haloalkyl, C
  • prodrug any precursor of a compound of formula I that is capable of releasing a compound of formula I in vivo.
  • Some compounds of formula I may contain one or more chiral centers, which may give rise to different stereoisomers.
  • the present invention covers each of the individual stereoisomers as well as their mixtures.
  • some compounds of the present invention may exhibit cis/trans isomery.
  • the present invention covers each of the geometric isomers as well as their mixtures.
  • the present invention also provides a pharmaceutical composition which comprises an effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof in admixture with a pharmaceutically acceptable excipient.
  • the invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for inhibiting platelet aggregation.
  • the invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for inhibiting the binding of fibrinogen to its receptor.
  • the invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for the treatment or prevention of thromboembolic disorders.
  • the invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for inhibiting platelet aggregation.
  • the invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for inhibiting the binding of fibrinogen to its receptor.
  • the invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof for the treatment or prevention of thromboembolic disorders.
  • the invention further provides a method of inhibiting platelet aggregation in a mammal, which comprises administering to a mammal in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • the invention further provides a method of inhibiting the binding of fibrinogen to its receptor in a mammal, which comprises administering to a mammal in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • the invention further provides a method for the treatment or prevention of thromboembolic disorders in a mammal, which comprises administering to a mammal in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • the invention still further provides a process for preparing a compound of formula I, which comprises: (a) reacting a compound of formula II or a reactive derivative thereof
  • R 4 * represents a group R 4 as defined above or a group convertible thereto, with an amine of formula HI m
  • Ci- n alkyl as a group or part of a group, means a linear or branched alkyl group that contains from one to n carbon atoms. Therefore, when n is 4 it includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. When n is 6 it includes, among others, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, neopentyl and hexyl.
  • a C2-n alkenyl group means a linear or branched alkyl group having from 2 to n carbon atoms and having in addition one or more double bonds. Examples include among others ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3- pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl.
  • a C2-n alkynyl group means a linear or branched alkyl group having from 2 to n carbon atoms and having in addition one or more triple bonds. Examples include among others ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4- hexynyl, 5-hexynyl.
  • halogen or its abbreviation halo means fluoro, chloro, bromo or iodo.
  • C ⁇ - n haloalkyl means a group resulting from the substitution of one or more hydrogen atoms of a C ⁇ - n alkyl group by one or more halogen atoms (i.e. fluorine, chlorine, bromine or iodine), which can be the same or different.
  • halogen atoms i.e. fluorine, chlorine, bromine or iodine
  • Examples include trifluoromethyl, fluoromethyl, chloromethyl, bromomethyl, iodomethyl, 1- and 2-chloroethyl, 1- and 2-fluoroethyl, 1- and 2- bromoethyl, 1- and 2-iodoethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 1-, 2- and 3-fluoropropyl, 1-, 2- and 3-chloropropyl, 3,3,3- trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 1-, 2-, 3- and 4- fluorobutyl, 1-, 2-, 3- and 4-chlorobutyl, nonafluorobutyl, 1-, 2-, 3-, 4- and 5- fluoropentyl, 1-, 2-, 3-, 4- and 5-chloropentyl, 1-, 2-, 3-, 4-, 5-chloropent
  • C3-7 cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • a Co-2 alkylene group means a bond, methylene or ethylene.
  • a C2-5 polymethylene chain means ethylene, propylene, butylene or pentylene.
  • C ⁇ - n alkoxy as a group or part of a group, means a group derived from the union of a C ⁇ - n alkyl group to an oxygen atom of an ether functional group. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, terf-butoxy, pentyloxy and hexyloxy.
  • Ci- 4 alkoxyCi- 4 alkyl group represents a group resulting from the substitution of a hydrogen atom of a C 1 - 4 alkyl group by a C 1 - 4 alkoxy group.
  • Examples include among others methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, butoxymethyl, butoxyethyl, butoxypropyl and butoxybutyl.
  • a C 1 - 4 haloalkoxy group means a group resulting from the substitution of one or more hydrogen atoms of a C 1 - 4 alkoxy group by one or more halogen atoms, which can be the same or different. Examples include trifluoromethoxy, fluoromethoxy, chloroethoxy, fluoroethoxy, iodoethoxy, 2,2,2-trifluoroethoxy pentafluoroethoxy, fluoropropoxy, chloropropoxy, 2,2,3,3,3- pentafluoropropoxy, heptafluoropropoxy, fluorobutoxy, and nonafluorobutoxy.
  • a C ⁇ - 4 alkylamino or C 1 - 4 dialkylamino group means a group resulting from the substitution of one or two hydrogen atoms respectively of an amino group by one or two C 1 - 4 alkyl groups, which can be the same or different. Examples include methylamino, dimethylamino, ethylamino, diethylamino, ethylmethylamino, propylamino, dipropylamino, isopropylamino and diisopropylamino.
  • a C 1 - 4 alkylcarbonyl group represents a group resulting from the union of a C 1 - 4 alkyl group to a carbonyl group. Examples include acetyl, propionyl, isopropionyl, and butanoyl.
  • a C 1 - 4 alkylcarbonyloxy group represents a group resulting from the union of a C 1 - 4 alkylcarbonyl group to an oxygen atom of an ether functional group. Examples include acetyloxy, propionyloxy, isopropionyloxy, and butanoyloxy.
  • a C ⁇ - 4 alkoxycarbonyl group represents a group resulting from the union of a C - 4 alkoxy group to a carbonyl group. Examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl and terf-butoxycarbonyl.
  • a C ⁇ - 4 alkylsulfonyl group represents a group resulting from the union of a C ⁇ - 4 alkyl group to a sulfonyl group. Examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, and tert-butylsulfonyl.
  • a C ⁇ - 4 alkylsulfinyl group represents a group resulting from the union of a Ci- 4 alkyl group to a sulfinyl group.
  • Examples include methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, and tert-butylsulfinyl.
  • a C ⁇ - 4 alkylthio group represents a group resulting from the union of a C ⁇ - 4 alkyl group to a sulphur atom of a thioether funtional group. Examples include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, and tert-butylt io.
  • a C ⁇ - 4 alkylcarbonylamino group represents a group resulting from the substitution of a hydrogen atom of an amino group by a C ⁇ - 4 alkylcarbonyl group. Examples include acetamido, propanamido and isopropanamido.
  • aryl as a group or part of a group, represents phenyl or naphthyl, or phenyl or naphthyl substituted with one or more, preferably from one to three, groups independently selected from halogen, C 1 -.
  • substituents on an aryl group can form together a methylenedioxy group, thus giving rise to a 1,3-benzodioxole ring.
  • An aryl-C ⁇ - 4 alkyl group represents a group resulting from the substitution of one hydrogen atom of a C 1 - 4 alkyl group by an aryl group as defined above.
  • Examples include among others, benzyl, 1-phenylethyl, 3- phenylpropyl, 2-phenylpropyl, 1-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl, 2-phenylbutyl and 1-phenylbutyl, wherein the phenyl groups can be substituted as described above in the definition of an aryl group.
  • heteroaryl as a group or part of a group, represents any radical from an aromatic monocyclic 5- or 6-membered or bicyclic 9- or 10-membered heterocycle containing from one to four heteroatoms selected from N, O and S and which is stable and obtainable by synthesis.
  • aromatic monocyclic heterocycles include thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole, pyridine, pyrazine, pyrimidine, and pyridazine.
  • bicyclic heteroaryl groups include benzimidazole, benzofuran, indole, isoindole, benzothiophene, benzothiazole, quinoline, isoquinoline, phthalazine, quinazoline, quinoxaline, cinnoline, naphthyridine, indazole, imidazopyridine, imidazopyrimidine, imidazopyrazine, imidazopyridazine, pyrazolopyrazine, pyrazolopyridine and pyrazolopyrimidine. All these groups can be optionally substituted with one or more groups, preferably from one to three groups, as described above.
  • group B represents a carboxy group or a metabolically labile ester or amide thereof.
  • metabolically labile it is understood any group that is capable of being split in vivo, releasing the acid group and which acts as prodrugs thereof.
  • Examples of metabolically labile esters include C ⁇ - 6 alkyl esters, for example methyl, ethyl, propyl, isopropyl ester; C ⁇ - 6 alkoxyC ⁇ - 4 alkyl esters, for example methoxymethyl, 2- methoxyethyl ester; haloC ⁇ - 4 alkyl esters, for example 2-iodoethyl, 2,2,2- trichloroethyl ester; - 6 alkylcarbonyloxyC ⁇ - 4 alkyl esters, for example acetoxymethyl, 1-acetoxyethyl or pivaloyloxymethyl ester; arylCi- 4 alkyl esters, for example benzyl ester; arylcarbonyloxyC - 4 alkyl esters, for example benzoyloxymethyl or 1-benzoyloxy ethyl ester; C 3 - 7 cycloalkylcarbonyloxyCi- 4 alkyl esters; C 1
  • Examples of metabolically labile amides include amides formed with ammonia and amines such as C ⁇ -6 alkylamines, for example methyl- or ethylamine; diC ⁇ -6 alkylamines, for example dimethylamine or ethylmethylamine; C ⁇ -6 alkoxyC ⁇ -6 alkylamines, for example methoxyethylamine; arylCi-4 alkylamines, for example benzylamine; and amino acids, for example glycine, or esters thereof.
  • C ⁇ -6 alkylamines for example methyl- or ethylamine
  • diC ⁇ -6 alkylamines for example dimethylamine or ethylmethylamine
  • C ⁇ -6 alkoxyC ⁇ -6 alkylamines for example methoxyethylamine
  • arylCi-4 alkylamines for example benzylamine
  • amino acids for example glycine, or esters thereof.
  • Yl represents N and Y2 represents S; and /or m represents 0; and /or
  • A represents methylene which can be optionally substituted, as described above; and /or
  • R3 represents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, Ci-6 haloalkyl, C3-7 cycloalkyl, C3-7 cycloalkylC ⁇ -4 alkyl, aryl, arylCi-4 alkyl, arylCi-4 alkoxy, arylC3-7 cycloalkyl, heteroaryl, heteroarylC ⁇ -4 alkyl, R6SO2NR2-,
  • R 6 CONR 2 C ⁇ -4 alkyl, R6 ⁇ CONR 2 C ⁇ - 4 alkyl, R2R7NCONR2C1-4 alkyl, R 6 S ⁇ 2C ⁇ - 4 alkyl, R2R7NSO2C1- 4 alkyl, R2R7NCOC1-4 alkyl, R6COC1-4 alkyl, R7OOCC 1 -4 alkyl, R6OC1.4 alkyl, R2R7NC 1 - 4 alkyl, R 8 OOC or R2R7NCO-; and /or R 4 represents a group selected from:
  • a preferred class of compounds of the present invention are those compounds of formula I wherein: m represents 0; and Ri, R 2 , R 3 , R 4 , Yi, Y 2 , A and B are as defined above in connection with formula I.
  • a more preferred class of compounds of the present invention are those compounds of formula I wherein m represents 0 and A represents methylene (which can be optionally substituted as described above), that is those compounds of formula la:
  • RA represents independently hydrogen, C 1 -6 alkyl, C 2 -6 alkenyl, C 2 - 6 alkynyl, C 1 - 6 haloalkyl, C 3 - 7 cycloalkyl, C 3 - 7 cycloalkylCi- 4 alkyl, aryl, arylC ⁇ - 4 alkyl, arylC 3 _ 7 cycloalkyl, heteroaryl, heteroarylC ⁇ - 4 alkyl, R 6 SO 2 NR 2 C 1 - 4 alkyl, R 6 CONR 2 C ⁇ - 4 alkyl, R 6 OCONR 2 Ci- alkyl, R2R7NCONR2C1-4 alkyl, R 6 S0 C ⁇ - 4 alkyl, R 2 R 7 NS0 2 C 1 - 4 alkyl, R 2 R7NCOC 1 -4 alkyl, R6COC ⁇ .
  • R ⁇ , ⁇ l . ⁇ 2 and B are as defined above.
  • a still more preferred class of compounds of the present invention are those compounds of formula la wherein: R 4 represents a group selected from:
  • R 2/ R 3 , RA, YI, Y 2 and B are as defined above.
  • An even more preferred class of compounds of the present invention are those compounds of formula la wherein:
  • a particularly preferred class of compounds of the present invention are those compounds of formula la wherein: R 4 represents a group selected from (a)-(f);
  • Yl represents N and Y2 represents S
  • RA represents hydrogen
  • R3 represents C1-6 alkyl, C2-6 alkenyl, C 2 -6 alkynyl, Ci-6 alkoxy, -6 haloalkyl, C3-7 cycloalkyl, C3-7 cycloalkylC ⁇ -4 alkyl, aryl, arylC ⁇ -4 alkyl, arylC ⁇ - 4 alkoxy, arylC3-7 cycloalkyl, heteroaryl, heteroarylC ⁇ -4 alkyl, R6SO2NR2-, R 6 CONR 2 -, R 6 OCONR 2 -, R2R7NCONR2-, R2R7N-, R6SO2NR2C1-4 alkyl, R 6 CONR 2 C ⁇ -4 alkyl, R 6 OCONR 2 Ci-4 alkyl, R2R7NCONR2C1-4 alkyl, R 6 S0 2 C ⁇ - 4 alkyl, R2R7NSO2C1-4 alkyl, R2R7NCOC1-4 alkyl, R COC1-4 alkyl
  • Another particularly preferred class of compounds of the present invention are those compounds of formula la wherein:
  • R4 represents a group selected from (a)-(f); Yi represents N and Y2 represents S;
  • RA independently represents hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkylC ⁇ -4 alkyl, aryl, arylC ⁇ -4 alkyl, heteroaryl, or heteroarylCi- 4 alkyl, with the proviso that at least one of the RA groups is different from hydrogen;
  • R3 represents hydrogen;
  • Ri, R2 and B are as defined above.
  • the compounds of formula I contain one or more basic nitrogen atoms and may contain one or more acid protons and, consequently, they can form salts with acids and bases both organic and inorganic, which salts are also included in the present invention. There is no limitation on the nature of these salts, provided that, when used for therapeutic purposes, they are pharmaceutically acceptable.
  • salts with inorganic cations such as sodium, potassium, calcium, magnesium, lithium, aluminium, zinc, etc; and salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, N-methylglucamine, procaine and the like; salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid; and salts with organic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid, maleic acid, citric acid, succinic acid, tartaric acid; as well as other mineral and carboxylic acids well known to those skilled in the art.
  • inorganic acids such as sodium,
  • the salts are prepared by reacting the compound of formula I with a sufficient amount of the desired acid or base to produce a salt in the conventional manner.
  • Free compounds and their salts differ in certain physicochemical properties, such as solubility, but they are equivalent for the purposes of the invention.
  • the compounds of the present invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like, are equivalent to the unsolvated forms for the purposes of the invention.
  • Some compounds of the present invention can exist as different diastereoisomers and/or optical isomers. Diastereoisomers can be separated by conventional techniques such as chromatography or fractional crystallization.
  • optical isomers can be resolved using any of the conventional techniques of optical resolution to give optically pure isomers. Such a resolution can be performed in any chiral synthetic intermediate as well as in the products of general formula I. Optical resolution techniques include separation by chromatography on a chiral phase or formation of a diastereoisomeric pair, resolution and subsequent recovery of the two enantiomers. The optically pure isomers can also be individually obtained using enantiospecific synthesis. The present invention covers each of the individual isomers and their mixtures (e.g. racemic mixtures), whether as obtained by synthesis or by physically mixing them up.
  • mixtures e.g. racemic mixtures
  • some of the compounds of the present invention may exhibit cis/trans isomery.
  • the present invention covers each of the geometric isomers and the mixtures thereof.
  • Some compounds of the present invention may also exhibit tautomery for example those compounds containing an amidino group. All the possible tautomer forms as well as their mixtures are encompassed by the present invention.
  • the present invention also provides processes for preparing a compound of formula I.
  • the compounds of formula I may be prepared using the methods described below. It will be apparent to those skilled in the art that the precise method used for the preparation of a given compound may vary depending on its chemical structure. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being effected. Moreover, in the majority of the processes described below it will be desirable or necessary to protect reactive or labile groups using conventional protecting groups, for example the groups described below. Both the nature of these protecting groups and the procedures for their introduction and removal are well known in the art.
  • the compounds of formula I can be prepared by reaction between an acid of formula II and an amine of formula III, as shown in the following scheme:
  • R 4 * represents a group R 4 or a group convertible thereto.
  • any known method for preparing amide bonds can be used.
  • an acid of formula II can be reacted with an amine of formula HI in the presence of a suitable condensing agent, such as a diimide (e.g. dicyclohexylcarbodiimide), alone or associated with 1- hydroxybenzotriazole, in a suitable solvent; as examples of suitable solvents we can mention substituted amides such as dimethylformamide, and ethers such as dioxane and tetrahydrofuran.
  • a suitable condensing agent such as a diimide (e.g. dicyclohexylcarbodiimide), alone or associated with 1- hydroxybenzotriazole, in a suitable solvent; as examples of suitable solvents we can mention substituted amides such as dimethylformamide, and ethers such as dioxane and tetrahydrofuran.
  • a suitable condensing agent such as a diimide (e.g. dicyclohe
  • the amide bond can be prepared by reacting amine HI with a reactive derivative of acid II, such as the acid chloride, anhydride or mixed anhydride.
  • a reactive derivative of acid II such as the acid chloride, anhydride or mixed anhydride.
  • the reaction is carried out in the presence of a proton scavenger base, for example pyridine or triethylamine, in a suitable solvent, for example dichloromethane or chloroform, or the proton scavenger amine itself can be used as the solvent.
  • protecting groups can be employed any conventional protecting group known in the art, for example those described in Greene T.W., "Protective Groups in Organic Synthesis", John Wiley & Sons, New York, 1981.
  • protecting groups of an amino or amidino function the groups tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) and fluorenylmethoxycarbonyl (Fmoc) can be used.
  • Carboxy groups can be protected for example as C 1 - 4 alkyl esters, such as methyl, ethyl or tert-butyl esters, or arylC ⁇ - 4 alkyl esters, such as benzyl ester.
  • C 1 - 4 alkyl esters such as methyl, ethyl or tert-butyl esters
  • arylC ⁇ - 4 alkyl esters such as benzyl ester.
  • compounds II or III contain protecting groups, it will be necessary a subsequent deprotection step, which is carried out under usual conditions, for example those disclosed in the above-mentioned reference.
  • the group R 4 can be present as such or can be present as a precursor group, i.e. a group easily convertible thereto.
  • R 4 * represents a group convertible into R 4
  • This conversion is carried out in one or more steps using widely known reactions in organic synthesis, such as those mentioned below and those disclosed in the examples. As examples, thus not being intended to be a limiting list, some of these conversions are listed in the following table:
  • Conversions A, B and D can be carried out in dimethylsulfoxide as solvent in the presence of diisopropylethylamine and heating, or in pyridine at reflux.
  • Conversion C is carried out under standard alkylation conditions, for example in chloroform in the presence of triethylamine.
  • Conversion E is carried out under standard reductive amination conditions, for example by treatment with sodium triacetoxyborohydride in tetrahydrofuran/ acetic acid.
  • some compounds of formula I can also be obtained by interconversion from another compound of formula I in one or more steps using widely employed procedures of organic synthesis.
  • conversions include alkylations, preparation of esters, amides, sulfonamides, carbamates and ureas, and hydrolysis of esters and amides.
  • a compound of the present invention can also be converted to a metabolically labile ester or amide thereof using standard methods, for example by esterification of a compound of formula I under usual experimental conditions or by reaction of an acid, or a reactive derivative thereof, with the desired amine as described above for the reaction of II with III.
  • the salts of the compounds of formula I can be prepared by conventional methods for example by treatment with an acid such as hydrochloric acid, sulfuric acid, nitric acid, oxalic acid or methanesulfonic acid, or by treatment with a base such as sodium hydroxide or potassium hydroxide.
  • Starting acids of formula II or derivatives thereof are commercially available, widely described in the literature or can be prepared by methods analogous to those known in the art. In general, these methods involve the construction of the 5-membered heterocycle following the procedures widely described in the literature for preparing this type of heterocycles and subsequent deprotection of the carboxy group, usually obtained in protected form as its C 1 - 4 alkyl ester.
  • the substituent R4 * represents a group R4, this can already be present as such in the starting product used for preparing the heterocyle or alternatively, the heterocyclic nucleus can be prepared first and then the precursor of R4 is converted into R4 using methods analogous to those described above.
  • the compounds of formula III are commercially available, widely described in the literature or can be prepared by methods analogous to those described starting from commercially available products.
  • the compounds of the present invention act by inhibiting the binding of fibrinogen to its receptor. Therefore, they are useful as preventive and therapeutic agents for the treatment of disorders requiring the inhibition of platelet aggregation.
  • thromboembolic disorders such as arterial or venous cardiovascular or cerebrovascular thromboembolic disorders including, but not limited to, venous thrombosis, deep vein thrombosis, thrombophlebitis, pulmonary embolism, arterial embolism, renal embolism, transient ischemic attack, stroke, myocardial infarction, unstable and stable angina and atherosclerosis.
  • Other applications of the compounds of the present invention include the prevention of thromboembolism and reocclusion during and after thrombolytic therapy, and the prevention of thromboembolism and reocclusion after angioplasty of the coronary and other arteries.
  • integrins structurally related to the fibrinogen receptor (fibronectin, vitronectin, osteopontin, collagen, thrombospondin) that are able to recognize the sequence Arg-Gly-Asp, for which reason the compounds of the present invention might also inhibit the adhesion processes where these other integrins are involved and could thus find additional utility as suppressors of the metastasis of cancerous cells and as inhibitors of bone resorption in osteoporosis.
  • fibrinogen receptor fibronectin, vitronectin, osteopontin, collagen, thrombospondin
  • the present invention further provides compositions that comprise a compound of the invention together with an excipient and optionally other auxiliary agents, if necessary.
  • the compounds of the present invention can be administered in different pharmaceutical preparations, the precise nature of which will depend, as it is well known, upon the chosen route of administration and the nature of the pathology to be treated.
  • solid compositions, according to the present invention, for oral administration include compressed tablets, dispersible powders, granules and capsules.
  • the active component is admixed with at least one inert diluent such as lactose, starch, mannitol, microcrystalline cellulose or calcium phosphate; granulating and disintegrating agents, for example corn starch, gelatine, microcrystalline cellulose or polyvinylpyrrolidone; and lubricating agents for example magnesium stearate, stearic acid or talc.
  • the tablets may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and, thereby, provide a sustained action over a longer period.
  • Gastric film-coated or enteric film-coated tablets can be made with sugar, gelatin, hydroxypropylcellulose, or acrylic resins.
  • Tablets with a sustained action may also be obtained using an excipient which provides regressive osmosis, such as the galacturonic acid polymers.
  • Formulations for oral use may also be presented as hard capsules of absorbable material, such as gelatin, wherein the active ingredient is mixed with an inert solid diluent and lubricating agents, or pasty materials, such as ethoxylated saturated glycerides.
  • Soft gelatin capsules are also possible, wherein the active ingredient is mixed with water or an oily medium, for example peanut oil, liquid paraffin or olive oil.
  • Dispersible powders and granules suitable for the preparation of a suspension by the addition of water provide the active ingredient in admixture with dispersing or wetting agents; suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl- cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, xantham gum, gum acacia; and one or more preservatives, such as methyl or ⁇ -propyl- p-hydroxybenzoate. Additional excipients, for example sweetening, flavoring and coloring agents may also be present.
  • suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl- cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, xantham gum, gum acacia
  • preservatives such as methyl or ⁇ -propyl- p-hydroxybenzoate.
  • Additional excipients for example sweetening, flavoring
  • Liquid compositions for oral administration include emulsions, solutions, suspensions, syrups and elixirs containing commonly used inert diluents, such as distilled water, ethanol, sorbitol, glycerol, or propylene glycol. Such compositions may also comprise adjuvants such as wetting agents, suspending agents, sweetening, flavoring, perfuming, preserving agents and buffers.
  • Preparations for injection, according to the present invention, for parenteral administration by bolus injection or continuous infusion include sterile aqueous or non-aqueous solutions, suspensions or emulsions, in a non-toxic parentally-acceptable diluent or solvent.
  • aqueous solvents or suspending media examples are distilled water for injection, Ringer's solution, and isotonic sodium chloride solution.
  • non-aqueous solvents or suspending media examples include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, or alcohols such as ethanol.
  • These compositions may also include adjuvants such as wetting, preserving, emulsifying and dispersing agents. They may be sterilized by any known method or manufactured in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use. When all of the components are sterile, the injectables will maintain the sterility if they are manufactured in sterile environment.
  • the compounds of the present invention can be administered in combination with one or more additional therapeutic agents commonly used for the treatment of the above-mentioned disorders, for example other platelet antiaggregants (such as aspirin, triflusal, ticlopidine, thromboxane inhibitors, thromboxan synthase inhibitors), thrombolytic agents (such as tPA and its derivatives, anistreplase, streptokinase, urokinase, prourokinase), or anticoagulant agents (such as warfarin and heparin).
  • the therapeutic agents may be formulated together in the same dosage unit or may be administered separately, either at the same time or sequentially, in which case it is not necessary that all components be administered by the same route.
  • the activity of the compounds of the present invention as platelet aggregation inhibitors may be tested as follows:
  • Test 1 inhibition of ADP-induced platelet aggregation in human blood
  • Platelet-rich plasma was obtained by centrifugation of whole blood at 200 g for 10 min at 4°C. PRP was collected and the remaining blood was subjected to further centrifugation at 700 g for 10 min to obtain platelet-poor plasma (PPP). PRP was adjusted to 2xl0 8 platelets /sample by diluting with PPP. Platelet aggregation was measured at
  • step a) To a solution of the compound obtained in step a) (2 g, 9 mmol) and triethylamine (2.55 mL) in CHCI3 (40 mL), cooled to 0 °C, was added in portions 4-methoxybenzenesulfonyl chloride (2 g, 10 mmol) and the reaction mixture was stirred at room temperature for 18 h. The resulting solution was washed with water, dried and concentrated, to afford 5 g of a crude product.
  • step d) To a solution of the product obtained in step d) (0.67 g, 2.1 mmol) and 1- hydroxybenzotriazole (0.3 g) in anhydrous DMF (15 mL) was added dicyclohexylcarbodiimide (0.45 g) and the reaction mixture was stirred for 1 h at room temperature. The resulting solution was cooled in an ice bath and NEt 3
  • Example 3 3-[N-[[4-tert-Butyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]propionic acid Following the procedure described in example 1, but using methyl 2- chloro-4,4-dimethyl-3-oxopentanoate instead of ethyl 2-chloro-2- isobutyrylacetate, the title compound was obtained.
  • Example 6 3-[N-[[2-[4-(4-Pyridyl)piperazin-l-yl]-4-trifluoromethylthiazol-5- yl]carbonyl]amino]propionic acid Following the procedure described in example 1, but using ethyl 2- chloro-4,4,4-trifluoro-3-oxobutanoate instead of ethyl 2-chloro-2- isobutyrylacetate, the title compound was obtained.
  • Example 7 3-[N-[[2-[4-(4-Pyridyl)piperazin-l-yl]-4-trifluoromethylthiazol-5- yl]carbonyl]amino]propionic acid Following the procedure described in example 1, but using ethyl 2- chloro-4,4,4-trifluoro-3-oxobutanoate instead of ethyl 2-chloro-2- isobutyrylacetate, the title compound was obtained.
  • Example 7
  • Example 8 3-[N-[[4-Propyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]propionic acid Following the procedure described in example 1, but using ethyl 2- chloro-2-butyrylacetate instead of ethyl 2-chloro-2-isobutyrylacetate, the title compound was obtained.
  • Example 13 3-[N-[[4-(2-Phenylethyl)-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]propionic acid Following the procedure described in example 1, but using ethyl 2- chloro-5-phenyl-3-oxopentanoate instead of ethyl 2-chloro-2-isobutyrylacetate, the title compound was obtained.
  • Example 15 3-[N-[[4-Isopropyl-2-[l-(4-pyridyl)piperidin-4-yl]thiazol-5- yl]carbonyl]amino]propionic acid a) Ethyl 4-isopropyl-2-(4-piperidinyl)thiazol-5-carboxylate Following a similar procedure to that described in example lc, but using l-(tert-butoxycarbonyl)piperidin-4-carbothioamide (prepared from isonipecotamide by treatment with Lawesson's reagent and subsequent protection with BOC 2 0) instead of [4-(4-pyridylpiperazin-l-yl]carbothioamide, the desired compound was obtained. b) Ethyl 4-isopropyl-2-[l-(4-pyridyl)piperidin-4-yl]thiazol-5-carboxylate
  • step d and e Following a similar procedure to that described in example 1 (steps d and e), but starting from the compound obtained in step a) above, and carrying out the final hydrolysis with 6N HCl, the title compound was obtained.
  • step a) To a solution of the product obtained in step a) (1.35 g, 4.6 mmol) in CHCI3 (25 mL) and NEt (0.64 mL) was added ethyl 4-isopropyl-2-(4- piperidinyl)thiazol-5-carboxylate (1.30 g, 4.6 mmol, obtained in example 15a) and Nal (0.68 g, 4.6 mmol) and the mixture was refluxed overnight. H 2 0 and IN NaOH were added and it was extracted with CHCI3 (3x). The combined organic extracts were dried and concentrated to give 1.8 g of a crude product. This was purified by chromatography on silica gel (CH 2 Cl2-MeOH, 5%), to give 1.05 g of the desired product. c) Title compound
  • the title compound was obtained by hydrolysis of the compound obtained in step b) with IN NaOH in EtOH, subsequent reaction of the resulting carboxylic acid with ⁇ -alanine tert-butyl ester as described in example le and finally deprotection of the resulting compound with 6N HCl at room temperature.
  • Example 20 3-[N-[[2-(4,4'-Bipiperidin-l-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]propionic acid a) [l'-(terf-Butoxycarbonyl)-4 / 4'-bipiperidin-l-yl]carbothioamide A mixture of l'-(tert-butoxycarbonyl)-4,4'-bipiperidine (11 g, 42 mmol) and ethoxycarbonyl isothiocyanate (5 mL, 42 mmol) was heated at reflux for 4 h. The mixture was allowed to cool and the solvent was removed.
  • Example 21 3-[N-[[2-(4,4'-Bipiperidin-l-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]- 2- methylpropionic acid
  • methyl 3-amino-2-methylpropionate instead of ⁇ -alanine tert-butyl ester and hydrolyzing the resulting methyl ester with 6N HCl at room temperature overnight, the title compound was obtained.
  • step c) The compound obtained in step c) was allowed to react with ⁇ -alanine tert-butyl ester as described in example le, and was finally hydrolyzed with trifluoroacetic acid, as described in example If, to give the title compound.
  • Example 25 3-[N-[[4-Isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]- 2(S)-(4-methoxybenzenesulfonylamino)propionic acid Following a similar procedure to that described in example le, but using the compound obtained in reference example 3 instead of ⁇ -alanine tert-butyl ester and hydrolyzing the resulting methyl ester with 6N HCl, the title compound was obtained.
  • Example 26 2(S)-(Benzyloxycarbonylamino)-3-[N-[[4-isopropyl-2-[4-(4-pyridyl)piperazin-l- yl]thiazol-5-yl]carbonyl]amino]propionic acid a) Methyl 2(S)-(benzyloxycarbonylamino)-3-[N-[[4-isopropyl-2-[4-(4- pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]propionate Following a similar procedure to that described in example le, but using the compound obtained in reference example 2 instead of ⁇ -alanine tert-butyl ester, the desired compound was obtained. b) Title compound The methyl ester obtained in step a) was hydrolyzed by treatment with
  • Example 27 3-[N-[[4-Isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]- 2(S)-(2-thienylcarbonylamino)propionic acid Following a similar procedure to that described in example le, but using the compound obtained in reference example 4 instead of ⁇ -alanine tert-butyl ester and hydrolyzing the resulting methyl ester with 5N HCl in EtOH, the title compound was obtained.
  • Example 28 2(S)-(Ethanesulfonylamino)-3-[N-[[4-isopropyl-2-[4-(4-pyridyl)piperazin-l- yl]thiazol-5-yl]carbonyl]amino]propionic acid a) Methyl 2(S)-amino-3-[N-[[4-isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]propionate
  • step a) To a solution of the compound obtained in step a) (0.7 g, 1.62 mmol) and NEt 3 (0.45 mL) in CHCI3 (20 mL) was added ethanesulfonyl chloride (0.23 mL) and the mixture was stirred at room temperature overnight. IN NaOH was added and it was extracted with CHCI3. The organic phase was dried and concentrated to a crude product that was purified by chromatography on silica gel (CHCI3 : MeOH : NH3 60:4:0.2), to yield the desired compound (130 mg). c) Title compound
  • step b) The compound obtained in step b) was hydrolyzed by treatment with 5N HCl at room temperature overnight and then at 60 °C for 1 h, to give the title compound.
  • Mp 262-263°C (C21H30N6O5S2.2H2O.O.5NH4CI).
  • Example 29 3-[N-[[4-Isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]- 2(S)-(phenylacetylamino)propionic acid a) 2(S)-Amino-3-[N-[[4-isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]propionic acid
  • step b) The compound obtained in step b) was hydrolyzed by treatment with 6N
  • Example 34 3-[N-[[2-(l,4'-Bipiperidin-4-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]-2(S)-(4- methoxybenzenesulfonylamino)propionic acid Following a similar procedure to that described in example 33, but using the compound obtained in reference example 3 instead of the compound obtained in reference example 1, the title compound was obtained.
  • Example 37 3-[N-[[2-(l,4'-Bipiperidin-4-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]-2(S)-(n- butoxycarbonylamino)propionic acid Following a similar procedure to that described in example 33, but using the compound obtained in reference example 6 instead of the compound obtained in reference example 1, the title compound was obtained.
  • Example 46 3-[N-[[4-Isopropyl-2-[4-(piperidin-4-yl)piperazin-l-yl]thiazol-5- yl]carbonyl]amino]-2(S)-(4-methoxybenzenesulfonylamino)propionic acid
  • the title compound was obtained.
  • Example 52 3-[N-[[4-Isopropyl-2-[4-(4-pyridyl)piperazin-l-yl]thiazol-5-yl]carbonyl]amino]- 2(S)-(2-phenyl-2-oxoethylamino)propionic acid Following a similar procedure to that described in example 29, but using phenacyl chloride instead of phenylacetic acid chloride, the title compound was obtained.
  • Example 57 3-[N-[[2-(l,4'-Bipiperidin-4-yl)-4-isopropylthiazol-5-yl]carbonyl]amino]-2-(2- phenylethyDpropionic acid
  • the compound obtained in example 33a instead of the compound obtained in example Id and ethyl 2-(aminomethyl)-4-phenylbutanoate instead of ⁇ -alanine tert-butyl ester, and hydrolyzing the resulting ethyl ester with 6N HCl at room temperature overnight and then at 50 °C for 1 h, the title compound was obtained.
  • iH NMR 300MHz, CDC1 3 + CD 3 OD) ⁇ (TMS): 7.25 (m, 2H), 7.16 (m, 3H), 4.47 (s,

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Abstract

L'invention concerne des composés de formule (I) et leurs sels et solvates, formule dans laquelle l'un des éléments Y1 ou Y2 représente N et l'autre représente NR5, O ou S ou bien l'un des éléments Y1 ou Y2 représente S et l'autre représente CR5, R5 représentant hydrogène ou alkyle C1-4; m vaut 0, 1 ou 2; A représente alcylène C0-2 éventuellement substitué par un ou plusieurs groupes sélectionnés indépendamment parmi alkyle C1-6, alcényle C2-6, alcynyle C2-6, haloalkyle C1-6, cycloalkyle C3-7, cycloalkyle C3-7 alkyle C1-4, aryle, arylalkyle C1-4, arylcycloalkyle C3-7, hétéroaryle, hétéroarylalkyle C1-4, R6SO2NR2 alkyle C1-4, R6CONR2 alkyle C1-4, R6OCONR2 alkyle C1-4, R2R7NCONR2 alkyle C1-4, R6SO2 alkyle C1-4, R2R7NSO2 alkyle C1-4, R2R7NCO alkyle C1-4, R6CO alkyle C1-4, R7OOC alkyle C1-4, R6O alkyle C1-4, R2R7N alkyle C1-4, R8OOC- ou R2R7NCO-; R2 représente indépendamment hydrogène ou alkyle C1-4; B représente carboxy ou un de ses esters ou amides instable métaboliquement; R4 représente un groupe de formule (i) ou (ii), le cycle terminal dans ces deux groupes pouvant être facultativement susbtitué par un ou plusieurs groupes halogène ou alkyle C1-4. R1 et R3, tels qu'ils sont définis dans la description, sont des inhibiteurs d'agrégation plaquettaire et sont utiles pour le traitement ou la prévention de désordres thromboemboliques. L'invention concerne également les compositions pharmaceutiques contenant ces composés et les procédés pour leur préparation.
PCT/EP1998/002226 1997-04-16 1998-04-16 Nouveaux carboxamides inhibiteurs d'agregation plaquettaire WO1998046599A1 (fr)

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