Claims for Patent: 7,910,576

Summary for Patent: 7,910,576

Title:	Pyrrole derivatives as P2Y12 antagonists
Abstract:	The present invention relates to compounds of the formula I, ##STR00001## in which R1; R2; R3; R4; R5; R6; R7; R8; R9; R10; R11; R12; R13; A; B, D and E have the meanings indicated in the claims. The compounds of the formula I are valuable pharmacologically active compounds. They exhibit a strong anti-aggregating effect on platelets and thus an anti-thrombotic effect and are suitable e.g. for the therapy and prophylaxis of cardio-vascular disorders like thromboembolic diseases or restenoses. They are reversible antagonists of the platelet ADP receptor P2Y12, and can in general be applied in conditions in which an undesired activation of the platelet ADP receptor P2Y12 is present or for the cure or prevention of which an inhibition of the platelet ADP receptor P2Y12 is intended. The invention furthermore relates to processes for the preparation of compounds of the formula I, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.
Inventor(s):	Klingler; Otmar (Frankfurt, DE), Czech; Joerg (Marburg, DE), Czechtizky; Werngard (Frankfurt, DE), Weiss; Tilo (Frankfurt am Main, DE), Just; Melitta (Langen, DE)
Assignee:	Sanofi-Aventis (Paris, FR)
Application Number:	12/639,500
Patent Claims:	1. A compound of formula I, ##STR00078## wherein R1 is 1) hydrogen atom, 2) --(C.sub.1-C.sub.8)-alkyl, 3) --(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.8)-cycloalkyl, wherein cycloalkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by halogen, 4) --(C.sub.0-C.sub.4)-alkylene-(C.sub.6-C.sub.14)-aryl, and wherein aryl is unsubstituted or mono-, di- or trisubstituted independently of one another by R15, or 5) --(C.sub.0-C.sub.4)-alkylene-heterocyclyl, wherein heterocyclyl is mono or bicyclic and contains 3 to 15 ring carbon atoms and wherein one or more of the ring carbon atoms are replaced by 1, 2, 3 or 4 heteroatoms chosen from nitrogen, sulfur or oxygen, and wherein said heterocyclyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R14; E is 1) a covalent bond, 2) --NH--C(O)-- or 3) --O--C(O)--, R2 is 1) hydrogen atom or 2) --(C.sub.1-C.sub.8)-alkyl, R3 is 1) --(C.sub.1-C.sub.8)-alkyl, 2) --CF.sub.3, or 3) --(C.sub.1-C.sub.8)-alkylene-C(O)--O--R16, R4 is 1) hydrogen atom, 2) --(C.sub.1-C.sub.8)-alkyl, 3) --(C.sub.1-C.sub.8)-alkylene-C(O)--O--R16, 4) --(C.sub.2-C.sub.6)-alkenylene-C(O)--O--R16, 5) --(C.sub.3-C.sub.8)-cycloalkyl-C(O)--O--R16, or 6) halogen, A is selected from oxygen atom or N--OH, B is selected from nitrogen atom or CH, D is 1) a covalent bond, 2) --C(O)-- or 3) --CH.sub.2--, R5, R6, R7, R8 and R9 are independently of one another selected from 1) hydrogen atom, 2) --(C.sub.1-C.sub.8)-alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by halogen, 3) --(C.sub.0-C.sub.4)-alkylene-O--R16, 4) halogen, 5) --(C.sub.0-C.sub.4)-alkylene-O--(C.sub.1-C.sub.8)-alkylene-O--R16, 6) --NO.sub.2, 7) --CN, 8) --(C.sub.0-C.sub.4)-alkylene-N(R16)-R17, 9) --(C.sub.0-C.sub.4)-alkylene-C(O)--R16, 10) --(C.sub.0-C.sub.4)-alkylene-C(O)--O--R16, 11) --(C.sub.0-C.sub.4)-alkylene-C(O)--N(R16)-R17, 12) --O--(C.sub.0-C.sub.4)-alkylene-C(O)--O--R16, 13) --O--(C.sub.0-C.sub.4)-alkylene-C(O)--N(R16)-R17 14) --(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.15)-heterocyclyl, wherein heterocyclyl is un-substituted or mono-, di- or trisubstituted independently of one another by R14, or 15) --O--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.15)-heterocyclyl, wherein heterocyclyl is un-substituted or mono-, di- or trisubstituted independently of one another by R14, or R5 and R6 or R6 and R7 form together with the atoms which they are attached to a 5-, 6- or 7-membered carbon ring, wherein said carbon ring is aromatic, partially unsaturated or saturated, or in which one, two or three of the 5 to 7 ring carbon atoms are replaced by heteroatoms such as nitrogen, oxygen or sulfur, and wherein said carbon ring is unsubstituted or substituted one, two, three or four times by R15, R10, R11, R12 and R13 are independently of one another selected from 1) hydrogen atom, 2) --(C.sub.1-C.sub.8)-alkyl, 3) .dbd.O or 4) --OH, R14 is halogen, --OH, .dbd.O, --(C.sub.1-C.sub.8)-alkyl, --O--(C.sub.1-C.sub.8)-alkyl, --CF.sub.3, --O--CF.sub.3, --NO.sub.2, --CN or --NH.sub.2, R15 is halogen, --OH, --(C.sub.1-C.sub.8)-alkyl, --O--(C.sub.1-C.sub.8)-alkyl, --CF.sub.3, --O--CF.sub.3, --NO.sub.2, --CN, --C(O)OH, --C(O)O--(C.sub.1-C.sub.8)-alkyl, --C(O)NH.sub.2 or --NH.sub.2, R16 is hydrogen atom, --(C.sub.1-C.sub.8)-alkyl or --(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.8)-cycloalkyl, R17 is hydrogen atom or --(C.sub.1-C.sub.8)-alkyl, or R17 and R16 form together with the nitrogen atom to which they are attached a 5-, 6- or 7-membered carbon ring, wherein said carbon ring is unsaturated or saturated, or in which one, two or three of the 5 to 7 ring carbon atoms are replaced by heteroatoms such as nitrogen, oxygen or sulfur, and wherein said carbon ring is unsubstituted or substituted one, two, three or four times by R15, in all its stereoisomeric forms and mixtures thereof in any ratio, and its physiologically tolerable salts. 2. A compound as claimed in claim 1, wherein R1 is 1) --(C.sub.1-C.sub.8)-alkyl, 2) --(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.8)-cycloalkyl, wherein cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyloheptyl or cyclooctyl and is unsubstituted or mono-, di- or trisubstituted independently of one another by halogen, 3) --(C.sub.0-C.sub.4)-alkylene-(C.sub.6-C.sub.14)-aryl, and wherein aryl is selected from phenyl, naphthyl, biphenylyl, indanyl, anthryl or fluorenyl and is unsubstituted or mono-, di- or trisubstituted independently of one another by R15, or 4) --(C.sub.0-C.sub.4)-alkylene-heterocyclyl, wherein heterocyclyl is selected from acridinyl, 8-aza-bicyclo[3.2.1]oct-3-yl, azaindole (1H-pyrrolopyridinyl), azabenzimidazolyl, azaspirodecanyl, azepinyl, azetidinyl, aziridinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydrochinolinyl, 4,5-dihydrooxazolinyl, dioxazolyl, dioxazinyl, 1,3-dioxolanyl, 1,3-dioxolenyl, 3,3-dioxo[1,3,4]oxathiazinyl, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]-tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isothiazolidinyl, isothiazolinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, 2-isoxazolinyl, ketopiperazinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2-oxa-thiepanyl, 1,2-oxathiolanyl, 1,4-oxazepanyl, 1,2-oxazinyl, 1,3-oxazinyl, 1,4-oxazinyl, oxazolidinyl, oxazolinyl, oxazolyl, oxetanyl, oxocanyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinonyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothiophenyl, tetrazinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, 1,2-thiazinyl, 1,3-thiazinyl, 1,4-thiazinyl, 1,3-thiazolyl, thiazolyl, thiazolidinyl, thiazolinyl, thienyl, thietanyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thietanyl, thiomorpholinyl, thiophenolyl, thiophenyl, thiopyranyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl, and is unsubstituted or mono-, di- or trisubstituted independently of one another by R14; E is 1) a covalent bond, 2) --NH--C(O)-- or 3) --O--C(O)--, R2 is 1) hydrogen atom or 2) --(C.sub.1-C.sub.8)-alkyl, R3 is 1) --(C.sub.1-C.sub.8)-alkyl, or 2) --(C.sub.1-C.sub.8)-alkylene-C(O)--O--R16, R4 is 1) hydrogen atom, 2) --(C.sub.2-C.sub.6)-alkenylene-C(O)--O--R16, 3) --(C.sub.1-C.sub.8)-alkyl or 4) halogen, A is selected from oxygen atom or N--OH, B is selected from nitrogen atom or CH, D is 1) a covalent bond, 2) --C(O)-- or 3) --CH.sub.2--, R5, R6, R7, R8 and R9 are independently of one another selected from 1) hydrogen atom, 2) --(C.sub.1-C.sub.8)-alkyl, 3) --(C.sub.0-C.sub.4)-alkylene-O--R16, 4) halogen, 5) --(C.sub.0-C.sub.4)-alkylene-O--(C.sub.1-C.sub.8)-alkylene-O--R16, 6) --NO.sub.2, 7) --CN, 8) --(C.sub.0-C.sub.4)-alkylene-N(R16)-R17, 9) --(C.sub.0-C.sub.4)-alkylene-C(O)--R16, 10) --(C.sub.0-C.sub.4)-alkylene-C(O)--O--R16, 11) --(C.sub.0-C.sub.4)-alkylene-C(O)--N(R16)-R17, 12) --O--(C.sub.0-C.sub.4)-alkylene-C(O)--O--R16, 13) --O--(C.sub.0-C.sub.4)-alkylene-C(O)--N(R16)-R17 14) --(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.15)-heterocyclyl, wherein heterocyclyl is as defined above and is un-substituted or mono-, di- or trisubstituted independently of one another by R14, or 15) --O--(C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.15)-heterocyclyl, wherein heterocyclyl is as defined above and is un-substituted or mono-, di- or trisubstituted independently of one another by R14, or R5 and R6 or R6 and R7 form together with the atoms which they are attached to a 5-, 6- or 7-membered carbon ring selected from cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclopenta-1,3-dienyl, cyclohexenyl, cyclohexa-1,3-dienyl, cyclohexa-1,4-dienyl, cycloheptenyl, cyclohepta-1,3-dienyl, cyclohepta-1,4-dienyl, cyclohepta-1,3,5-trienyl, phenyl, 1,4 diazepane, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, diaziridine, diazirine, dihydroimidazolone, dioxazole, dioxazine, 1,4-dioxine, dioxole, 1,3-dioxolene, 1,3-dioxolane, furan, imidazole, imidazoline, imidazolidine, imidazolidinone, isothiazole, isothiazolidine, isothiazoline, isoxazole, isoxazoline, isoxazolidine, morpholine, 1,2-oxa-thiepane, 1,2-oxathiolane, 1,4-oxazepane, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazolone, oxazole, [1,3,4]oxathiazinane 3,3-dioxide, oxaziridine, oxazolidinone, oxetan, oxirane, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyridinone, pyrimidine, pyrimidine-2,4-dione, pyrrole, pyrrolidine, pyrrolidinone, pyrroline, tetrahydrofuran, tetrahydropyran, tetrahydropyridine, thiadiazine thiadiazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,3-thiazole, thiazole, thiazolidine, thiazoline, thienyl, thietan, thiomorpholine, thiomorpholine 1,1-dioxide thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1,2,4-triazole, and wherein said carbon ring is unsubstituted or substituted one, two, three or four times by R15, R10, R11, R12 and R13 are independently of one another selected from 1) hydrogen atom, 2) --(C.sub.1-C.sub.8)-alkyl or 3) --OH, R14 is halogen, --OH, .dbd.O, --(C.sub.1-C.sub.8)-alkyl, --O--(C.sub.1-C.sub.8)-alkyl, --CF.sub.3, --O--CF.sub.3, --NO.sub.2, --CN or --NH.sub.2, R15 is halogen, --OH, --(C.sub.1-C.sub.8)-alkyl, --O--(C.sub.1-C.sub.8)-alkyl, --CF.sub.3, --O--CF.sub.3, --NO.sub.2, --CN or --NH.sub.2, R16 is hydrogen atom or --(C.sub.1-C.sub.8)-alkyl, R17 is hydrogen atom or --(C.sub.1-C.sub.8)-alkyl, in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically tolerable salts. 3. A compound as claimed in claim 1, wherein R1 is 1) --(C.sub.1-C.sub.4)-alkyl, 2) --(C.sub.0-C.sub.2)-alkylene-(C.sub.3-C.sub.6)-cycloalkyl, wherein cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, 3) --(C.sub.0-C.sub.2)-alkylene-phenyl, or 4) --(C.sub.0-C.sub.2)-alkylene-heterocyclyl, wherein heterocyclyl is selected from furanyl, pyridyl or tetrahydropyranyl, E is 1) a covalent bond, 2) --NH--C(O)-- or 3) --O--C(O)--, R2 is hydrogen atom, R3 is 1) --(C.sub.1-C.sub.4)-alkyl, or 2) --(C.sub.1-C.sub.4)-alkylene-C(O)--O--R16, R4 is 1) hydrogen atom, 2)-ethenylene-C(O)--O--R16, or 3) --(C.sub.1-C.sub.4)-alkyl, A is selected from oxygen atom or N--OH, B is selected from nitrogen atom or CH, D is 1) a covalent bond, 2) --C(O)-- or 3) --CH.sub.2--, R5, R6, R7, R8 and R9 are independently of one another selected from 1) hydrogen atom, 2) --(C.sub.1-C.sub.4)-alkyl, 3) --O--R16, 4) chlorine, 5) fluorine, 6) --O--(C.sub.1-C.sub.4)-alkylene-O--R16, 7) --NO.sub.2, 8) --CN, 9) --NH.sub.2, 10) --C(O)--R16, 11) --C(O)--O--R16, 12) --(C.sub.0-C.sub.4)-alkylene-C(O)--N(R16)-R17, 13) --O--(C.sub.1-C.sub.4)-alkylene-C(O)--O--R16, 14) --O--(C.sub.1-C.sub.4)-alkylene-C(O)--N(R16)-R17, or 15) --O--(C.sub.1-C.sub.4)-alkylene-piperidinyl, or R5 and R6 or R6 and R7 form together with the atoms which they are attached to a ring selected from 1,4-dioxine or pyrrole, R10, R11, R12 and R13 are independently of one another selected from 1) hydrogen atom or 2) --(C.sub.1-C.sub.4)-alkyl, R16 is hydrogen atom or --(C.sub.1-C.sub.4)-alkyl, and R17 is hydrogen atom or --(C.sub.1-C.sub.4)-alkyl, in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically tolerable salts. 4. A compound as claimed in claim 1, wherein R1 is -phenyl, E is a covalent bond, R2 is hydrogen atom, R3 is 1) --(C.sub.1-C.sub.4)-alkyl, or 2) --(C.sub.1-C.sub.4)-alkylene-C(O)--O--R16, R4 is 1) hydrogen atom or 2) -ethenylene-C(O)--O--R16, 3) --(C.sub.1-C.sub.4)-alkyl, A is oxygen atom, B is nitrogen atom, D is a covalent bond, R5, R6, R7, R8 and R9 are independently of one another selected from 1) hydrogen atom, 2) --(C.sub.1-C.sub.4)-alkyl, 3) --O--R16, 4) chlorine, 5) fluorine, 6) --O--(C.sub.1-C.sub.4)-alkylene-O--R16, 7) --NO.sub.2, 8) --CN, 9) --NH.sub.2, 10) --C(O)--R16, 11) --C(O)--O--R16, 12) --(C.sub.0-C.sub.4)-alkylene-C(O)--N(R16)-R17, 13) --O--(C.sub.1-C.sub.4)-alkylene-C(O)--O--R16, 14) --O--(C.sub.1-C.sub.4)-alkylene-C(O)--N(R16)-R17 or 15) --O--(C.sub.1-C.sub.4)-alkylene-piperidinyl, or R5 and R6 or R6 and R7 form together with the atoms which they are attached to a ring selected from 1,4-dioxine or pyrrole, R10, R11, R12 and R13 are each a hydrogen atom, R16 is hydrogen atom or --(C.sub.1-C.sub.4)-alkyl, and R17 is hydrogen atom or --(C.sub.1-C.sub.4)-alkyl, in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically tolerable salts. 5. A compound as claimed in claim 1, wherein the compound is 1-(2-Methyl-5-phenyl-1H-pyrrol-3-yl)-2-[4-(3-trifluoromethyl-phenyl)-pipe- razin-1-yl]-ethane-1,2-dione, 1-(2-Methyl-5-phenyl-1H-pyrrol-3-yl)-2-(4-phenyl-piperazin-1-yl)-ethane-1- ,2-dione, 1-[4-(3-Methoxy-phenyl)-piperazin-1-yl]-2-(2-methyl-5-phenyl-1H-- pyrrol-3-yl)-ethane-1,2-dione, 1-[4-(3-Chloro-phenyl)-piperazin-1-yl]-2-(2-methyl-5-phenyl-1H-pyrrol-3-y- l)-ethane-1,2-dione, 1-[4-(4-Chloro-phenyl)-piperazin-1-yl]-2-(2-methyl-5-phenyl-1H-pyrrol-3-y- l)-ethane-1,2-dione, 1-[4-(3-Methyl-phenyl)-piperazin-1-yl]-2-(2-methyl-5-phenyl-1H-pyrrol-3-y- l)-ethane-1,2-dione, 1-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-2-(2-methyl-5-phenyl-1H-p- yrrol-3-yl)-ethane-1,2-dione, 1-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-2-(2-methyl-5-phenyl-1H-pyrrol-3-- yl)-ethane-1,2-dione, 1-[4-(4-Acetyl-phenyl)-piperazin-1-yl]-2-(2-methyl-5-phenyl-1H-pyrrol-3-y- l)-ethane-1,2-dione, 1-[4-(4-Chloro-3-trifluoromethyl-phenyl)-piperazin-1-yl]-2-(2-methyl-5-ph- enyl-1H-pyrrol-3-yl)-ethane-1,2-dione, 1-[4-(3,4-Dichloro-phenyl)-piperazin-1-yl]-2-(2-methyl-5-phenyl-1H-pyrrol- -3-yl)-ethane-1,2-dione, 1-[4-(3,5-Dichloro-phenyl)-piperazin-1-yl]-2-(2-methyl-5-phenyl-1H-pyrrol- -3-yl)-ethane-1,2-dione, 1-[4-(3-Hydroxy-phenyl)-piperazin-1-yl]-2-(2-methyl-5-phenyl-1H-pyrrol-3-- yl)-ethane-1,2-dione, 1-(2-Methyl-5-phenyl-1H-pyrrol-3-yl)-2-(3-methyl-4-m-tolyl-piperazin-1-yl- )-ethane-1,2-dione, 1-[4-(1H-Indol-4-yl)-piperazin-1-yl]-2-(2-methyl-5-phenyl-1H-pyrrol-3-yl)- -ethane-1,2-dione, 4-{4-[2-(2-Methyl-5-phenyl-1H-pyrrol-3-yl)-2-oxo-acetyl]-piperazin-1-yl}-- benzonitrile, 1-[4-(3,5-Dimethyl-phenyl)-piperazin-1-yl]-2-(2-methyl-5-phenyl-1H-pyrrol- -3-yl)-ethane-1,2-dione, 1-[4-(3-Fluoro-phenyl)-piperazin-1-yl]-2-(2-methyl-5-phenyl-1H-pyrrol-3-y- l)-ethane-1,2-dione, 1-[4-(3-Bromo-phenyl)-piperazin-1-yl]-2-(2-methyl-5-phenyl-1H-pyrrol-3-yl- )-ethane-1,2-dione, 1-[4-(3,5-Bis-trifluoromethyl-phenyl)-piperazin-1-yl]-2-(2-methyl-5-pheny- l-1H-pyrrol-3-yl)-ethane-1,2-dione, 1-[4-(3,4-Difluoro-phenyl)-piperazin-1-yl]-2-(2-methyl-5-phenyl-1H-pyrrol- -3-yl)-ethane-1,2-dione, 1-(2,5-Dimethyl-1H-pyrrol-3-yl)-2-[4-(3-trifluoromethyl-phenyl)-piperazin- -1-yl]-ethane-1,2-dione, 1-(2-Methyl-5-phenyl-1H-pyrrol-3-yl)-2-[4-(3-trifluoromethyl-phenyl)-pipe- razin-1-yl]-ethane-1,2-dione 1-oxime, 1-(2-Methyl-5-phenyl-1H-pyrrol-3-yl)-2-[4-(4-nitro-3-trifluoromethyl-phen- yl)-piperazin-1-yl]-ethane-1,2-dione, 1-[4-(3-Chloro-4-fluoro-phenyl)-piperazin-1-yl]-2-(2-methyl-5-phenyl-1H-p- yrrol-3-yl)-ethane-1,2-dione, 1-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-piperazin-1-yl]-2-(2-methyl-5-ph- enyl-1H-pyrrol-3-yl)-ethane-1,2-dione, 3-(3-{2-oxo-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-acetyl}-5-phe- nyl-1H-pyrrol-2-yl)-propionic acid, 2-(3-{4-[2-(2-Methyl-5-phenyl-1H-pyrrol-3-yl)-2-oxo-acetyl]-piperazin-1-y- l}-phenoxy)-acetamide, (3-{4-[2-(2-Methyl-5-phenyl-1H-pyrrol-3-yl)-2-oxo-acetyl]-piperazin-1-yl}- -phenoxy)-acetic acid ethyl ester, 1-(2-Methyl-5-phenyl-1H-pyrrol-3-yl)-2-{4-[3-(2-piperidin-1-yl-ethoxy)-ph- enyl]-piperazin-1-yl}-ethane-1,2-dione, 1-{4-[3-(2-Methoxy-ethoxy)-phenyl]-piperazin-1-yl}-2-(2-methyl-5-phenyl-1- H-pyrrol-3-yl)-ethane-1,2-dione, 1-[2-Methyl-5-(tetrahydro-pyran-4-yl)-1H-pyrrol-3-yl]-2-[4-(3-trifluorome- thyl-phenyl)-piperazin-1-yl]-ethane-1,2-dione, 3-{4-[2-(2-Methyl-5-phenyl-1H-pyrrol-3-yl)-2-oxo-acetyl]-piperazin-1-yl}-- benzoic acid ethyl ester, 1-(2-Methyl-5-phenyl-1H-pyrrol-3-yl)-2-(4-m-tolyl-piperidin-1-yl)-ethane-- 1,2-dione, 1-(2-Methyl-5-phenyl-1H-pyrrol-3-yl)-2-[4-(3-trifluoromethyl-ph- enyl)-piperidin-1-yl]-ethane-1,2-dione, 1-(2-Methyl-5-phenyl-1H-pyrrol-3-yl)-2-[4-(3-methoxy-phenyl)-piperidin-1-- yl]-ethane-1,2-dione, 1-[4-(3-Amino-phenyl)-piperidin-1-yl]-2-(2-methyl-5-phenyl-1H-pyrrol-3-yl- )-ethane-1,2-dione, 3-{1-[2-(2-Methyl-5-phenyl-1H-pyrrol-3-yl)-2-oxo-acetyl]-piperidin-4-yl}-- benzonitrile, 3-{1-[2-(2-Methyl-5-phenyl-1H-pyrrol-3-yl)-2-oxo-acetyl]-piperidin-4-yl}-- benzoic acid methyl ester, 1-[4-(3-Bromo-phenyl)-piperidin-1-yl]-2-(2-methyl-5-phenyl-1H-pyrrol-3-yl- )-ethane-1,2-dione, 1-[4-(4-Fluoro-3-nitro-phenyl)-piperidin-1-yl]-2-(2-methyl-5-phenyl-1H-py- rrol-3-yl)-ethane-1,2-dione, 3-{1-[2-(2-Methyl-5-phenyl-1H-pyrrol-3-yl)-2-oxo-acetyl]-piperidin-4-yl}-- benzoic acid, 1-[4-(4-Methoxy-benzoyl)-piperidin-1-yl]-2-(2-methyl-5-phenyl-1H-pyrrol-3- -yl)-ethane-1,2-dione, 1-[4-(4-Fluoro-benzoyl)-piperidin-1-yl]-2-(2-methyl-5-phenyl-1H-pyrrol-3-- yl)-ethane-1,2-dione, 1-[4-(2,4-Dichloro-benzyl)-piperazin-1-yl]-2-(2-methyl-5-phenyl-1H-pyrrol- -3-yl)-ethane-1,2-dione, 1-[4-(4-Chloro-benzoyl)-piperidin-1-yl]-2-(2-methyl-5-phenyl-1H-pyrrol-3-- yl)-ethane-1,2-dione, 1-[4-(4-Methyl-benzoyl)-piperidin-1-yl]-2-(2-methyl-5-phenyl-1H-pyrrol-3-- yl)-ethane-1,2-dione, 1-[4-(3-Methyl-benzoyl)-piperazin-1-yl]-2-(2-methyl-5-phenyl-1H-pyrrol-3-- yl)-ethane-1,2-dione, 1-(2-Methyl-5-phenyl-1H-pyrrol-3-yl)-2-[4-(4-trifluoromethyl-benzoyl)-pip- eridin-1-yl]-ethane-1,2-dione, 1-[4-(3-Methyl-benzoyl)-piperidin-1-yl]-2-(2-methyl-5-phenyl-1H-pyrrol-3-- yl)-ethane-1,2-dione, 1-[4-(4-Bromo-benzoyl)-piperidin-1-yl]-2-(2-methyl-5-phenyl-1H-pyrrol-3-y- l)-ethane-1,2-dione, 1-[4-(3-Chloro-benzoyl)-piperidin-1-yl]-2-(2-methyl-5-phenyl-1H-pyrrol-3-- yl)-ethane-1,2-dione, 1-(2-Methyl-5-pyridin-2-yl-1H-pyrrol-3-yl)-2-[4-(3-trifluoromethyl-phenyl- )-piperazin-1-yl]-ethane-1,2-dione, 1-(2-Methyl-5-pyridin-3-yl-1H-pyrrol-3-yl)-2-[4-(3-trifluoromethyl-phenyl- )-piperazin-1-yl]-ethane-1,2-dione, 3,5-Dimethyl-4-{2-oxo-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ace- tyl}-1H-pyrrole-2-carboxylic acid ethyl ester, 3,5-Dimethyl-4-{2-oxo-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ace- tyl}-1H-pyrrole-2-carboxylic acid, [(3,5-Dimethyl-4-{2-oxo-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-a- cetyl}-1H-pyrrole-2-carbonyl)-amino]-acetic acid ethyl ester, 4-{2-[4-(3-Chloro-4-fluoro-phenyl)-piperazin-1-yl]-2-oxo-acetyl}-3,5-dime- thyl-1H-pyrrole-2-carboxylic acid (furan-2-ylmethyl)-amide, 4-{2-[4-(4-Chloro-3-trifluoromethyl-phenyl)-piperazin-1-yl]-2-oxo-acetyl}- -3,5-dimethyl-1H-pyrrole-2-carboxylic acid (furan-2-ylmethyl)-amide, 4-{2-[4-(4-Chloro-3-trifluoromethyl-phenyl)-piperazin-1-yl]-2-oxo-acetyl}- -3,5-dimethyl-1H-pyrrole-2-carboxylic acid cyclopropylmethyl-amide, 4-{2-[4-(4-Chloro-3-trifluoromethyl-phenyl)-piperazin-1-yl]-2-oxo-acetyl}- -3,5-dimethyl-1H-pyrrole-2-carboxylic acid propylamide, 4-{2-[4-(3-Chloro-4-fluoro-phenyl)-piperazin-1-yl]-2-oxo-acetyl}-3,5-dime- thyl-1H-pyrrole-2-carboxylic acid cyclopropylmethyl-amide, 4-{2-[4-(3-Chloro-phenyl)-piperazin-1-yl]-2-oxo-acetyl}-3,5-dimethyl-1H-p- yrrole-2-carboxylic acid cyclopropylamide, 4-{2-[4-(4-Chloro-3-trifluoromethyl-phenyl)-piperazin-1-yl]-2-oxo-acetyl}- -3,5-dimethyl-1H-pyrrole-2-carboxylic acid (pyridin-3-ylmethyl)-amide, 3,5-Dimethyl-4-{2-oxo-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ace- tyl}-1H-pyrrole-2-carboxylic acid propylamide, 3,5-Dimethyl-4-{2-oxo-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-ace- tyl}-1H-pyrrole-2-carboxylic acid (furan-2-ylmethyl)-amide, 4-{2-[4-(3-Chloro-phenyl)-piperazin-1-yl]-2-oxo-acetyl}-3,5-dimethyl-1H-p- yrrole-2-carboxylic acid (furan-2-ylmethyl)-amide, 4-{2-[4-(3-Chloro-phenyl)-piperazin-1-yl]-2-oxo-acetyl}-3,5-dimethyl-1H-p- yrrole-2-carboxylic acid cyclopropylmethyl-amide, 1-(4-Bromo-2-methyl-5-phenyl-1H-pyrrol-3-yl)-2-[4-(3-trifluoromethyl-phen- yl)-piperazin-1-yl]-ethane-1,2-dione, (E)-3-(5-Methyl-4-{2-oxo-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-- acetyl}-2-phenyl-1H-pyrrol-3-yl)-acrylic acid methyl ester, or (E)-3-(5-Methyl-4-{2-oxo-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-- acetyl}-2-phenyl-1H-pyrrol-3-yl)-acrylic acid. 6. A process for the preparation of a compound of formula I as claimed in claim 1, which comprises reacting a compound of formula II with a compound of formula III ##STR00079## in which the residues R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, A, B, D and E have the meanings indicated in claim 1, to give a compound of formula I, or reacting a compound of formula IV with a compound of formula V ##STR00080## in which the residues R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, A, B and D have the meanings indicated in claim 1, G1 is a carboxylic acid group, and G2 is an amino or hydroxyl group, to give a compound of formula I. 7. A pharmaceutical composition comprising at least one compound as claimed in claim 1, a pharmaceutically acceptable carrier and a fibrinogen-receptor antagonist, a thrombin inhibitor, a factor Xa inhibitor, a heparin, a low-molecular-weight heparin, or aspirin. 8. The pharmaceutical composition of claim 7 wherein the fibrinogen-receptor antagonist is a GP IIb/IIIa monoclonal antibody abciximab (ReoPro), eptifibatide (Integrelin), tirofiban (Aggrastat), roxifiban, lotrafiban, orbofiban, sibrafiban or xemilofiban; the thrombin inhibitor is ximelagatran, dabigatran or etexilate; the factor Xa inhibitor is otamixaban, rivaroxaban, apixaban, idraparinux or fondaparinux; and the low-molecular-weight heparin is enoxaparin or dalteparin.

Details for Patent 7,910,576

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Janssen Biotech, Inc.	REOPRO	abciximab	Injection	103575	12/22/1994		2027-06-18