Claims for Patent: 8,022,064

Summary for Patent: 8,022,064

Title:	Phenylpentadienoyl derivatives and their use as PAR 1 antagonists
Abstract:	The present invention relates to compounds of general formula (I): wherein: R.sub.1 and R.sub.2, identical or different, represent: an atom of hydrogen or halogen, CN or NO.sub.2, with R.sub.1 and R.sub.2 not representing hydrogen simultaneously, m represents: 1 or 2 n represents: 0, 1 or 2 R.sub.3 represents: phenyl substituted or not by one or more residues chosen among halogen, hydroxyl or C.sub.1-C.sub.6 alkyl; C.sub.2-C.sub.6 alkyl substituted or not by one or more residues chosen among halogen or hydroxyl; cycloalkyl; pyridine; thiophene; pyrrole substituted or not by C.sub.1-C.sub.6 alkyl; thiazole or furan; or the therapeutically-acceptable salts or solvates thereof. ##STR00001##
Inventor(s):	Perez; Michel (Castres, FR), Lamothe; Marie (Castres, FR), Le Grand; Bruno (Lautrec, FR), Letienne; Robert (Castres, FR)
Assignee:	Pierre Fabre Medicament (Boulogne-Billancourt, FR)
Application Number:	12/305,447
Patent Claims:	1. Compounds of general formula (I): ##STR00015## wherein: R.sub.1 and R.sub.2, identical or different, represent: an atom of hydrogen or halogen, CN or NO.sub.2, with R.sub.1 and R.sub.2 not representing hydrogen simultaneously, m represents: 1 or 2 n represents: 0, 1 or 2 R.sub.3 represents: phenyl substituted or not by one or more residues chosen among halogen, hydroxyl or C.sub.1-C.sub.6 alkyl; C.sub.2-C.sub.6 alkyl substituted or not by one or more residues chosen among halogen or hydroxyl; cycloalkyl; pyridine; thiophene; pyrrole substituted or not by C.sub.1-C.sub.6 alkyl; thiazole or furan; or the therapeutically-acceptable salts thereof. 2. Compounds according to claim 1, wherein R.sub.1 is nitro, R.sub.2 is hydrogen, m equals 1, n equals 0 and R.sub.3 is phenyl substituted by one or more halogens or C.sub.1-C.sub.6 alkyls, cycloalkyl or pyridine. 3. Compounds according to claim 1, wherein R.sub.1 is cyano, R.sub.2 is hydrogen, m equals 1, n equals 0 and R.sub.3 is phenyl substituted by one or more halogens or C.sub.1-C.sub.6 alkyls, cycloalkyl or pyridine. 4. A compound according to claim 1 selected among: 2-[5-Oxo-5-(4-pyridin-2-yl-piperazin-1-yl)-penta-1,3-dienyl]-benzonitrile- ; 2-[5-(4-Cyclopentyl-piperazin-1-yl)-5-oxo-penta-1,3-dienyl]-benzonitrile- ; 2-[5-(4-Cyclohexyl-piperazin-1-yl)-5-oxo-penta-1,3-dienyl]-benzonitrile; 2-{5-[4-(3-Chloro-propyl)-piperazin-1-yl]-5-oxo-penta-1,3-dienyl}-benzoni- trile; 2-{5-[4-(3-Chloro-phenyl)-piperazin-1-yl]-5-oxo-penta-1,3-dienyl}-b- enzonitrile; 2-{5-[4-(2-Hydroxy-phenyl)-piperazin-1-yl]-5-oxo-penta-1,3-dienyl}-benzon- itrile; 2-{5-[4-(2,4-Dimethyl-benzyl)-[1,4]diazepan-1-y1]-5-oxo-penta-1,3-- dienyl}-benzonitrile; 2-{5-[4-(2-Methyl-benzyl)-[1,4]diazepan-1-yl]-5-oxo-penta-1,3-dienyl}-ben- zonitrile; 5-(2-Chloro-phenyl)-1-(4-cyclopentyl-piperazin-1-yl)-penta-2,4-- dien-1-one; 5-(2-Chloro-phenyl)-1-(4-cyclohexyl-piperazin-1-yl)-penta-2,4-dien-1-one; 5-(2-Chloro-phenyl)-1-(4-cycloheptyl-piperazin-1-yl)-penta-2,4-dien-1-one- ; 5-(2-Chloro-phenyl)-1-[4-(3-chloro-propyl)-piperazin-1-yl]-penta-2,4-die- n-1-one; 5-(2-Chloro-phenyl)-1-(4-pyridin-2-yl-piperazin-1-yl)-penta-2,4-d- ien-1-one; 5-(2-Chloro-phenyl)-1-[4-(2-methyl-benzyl)-[1,4]diazepan-1-yl]-- penta-2,4-dien-1-one; 5-(2-Chloro-phenyl)-1-[4-(2-fluoro-benzyl)-[1,4]diazepan-1-yl]-penta-2,4-- dien-1-one; 5-(2-Nitro-phenyl)-1-(4-phenyl-piperazin-1-yl)-penta-2,4-dien-1-one; 1-(4-Cyclohexyl-piperazin-1-yl)-5-(2-nitro-phenyl)-penta-2,4-dien-1-one; 1-(4-Cyclopentyl-piperazin-1-yl)-5-(2-nitro-phenyl)-penta-2,4 dien-1-one; 1-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-5-(2-nitro-phenyl)-penta-2,4 dien-1-one; 1-[4-(3-Chloro-propyl)-piperazin-1-yl]-5-(2-nitro-phenyl)-penta-2,4 dien-1-one; 5-(2-Nitro-phenyl)-1-(4-pyridin-2-yl-piperazin-1-yl)-penta-2,4-dien-1-one- ; 1-(4-Cyclopentylmethyl-piperazin-1-yl)-5-(2-nitro-phenyl)-penta-2,4-dien- -1-one; 5-(2-Nitro-phenyl)-1-(4-thiophen-3-ylmethyl-piperazin-1-yl)-penta-- 2,4 dien-1-one; 1-[4-(4-Fluoro-benzyl)-piperazin-1-yl]-5-(2-nitro-phenyl)-penta-2,4-dien-- 1-one; 1-(4-Butyl-piperazin-1-yl)-5-(2-nitro-phenyl)-penta-2,4-dien-1-one; 1-[4-(3-Chloro-phenyl)-piperazin-1-yl]-5-(2-nitro-phenyl)-penta-2,4-dien-- 1-one; 5-(2,6-Difluoro-phenyl)-1-(4-phenyl-piperazin-1-yl)-penta-2,4-dien-- 1-one; 1-(4-Cyclohexyl-piperazin-1-yl)-5-(2,6-difluoro-phenyl)-penta-2,4-d- ien-1-one; 1-[4-(3-Chloro-propyl)-piperazin-1-y1]-5-(2,6-difluoro-phenyl)-- penta-2,4-dien-1-one; 1-(4-Cyclopentyl-piperazin-1-yl)-5-(2,6-difluoro-phenyl)-penta-2,4-dien-1- -one; 5-(2,6-Difluoro-phenyl)-1-[4-(4-fluoro-benzyl)-piperazin-1-yl]-penta- -2,4-dien-1-one; 1-(4-Cyclopentyl-piperazin-1-yl)-5-(2-fluoro-phenyl)-penta-2,4-dien-1-one- ; 1-(4-Cyclohexyl-piperazin-1-yl)-5-(2-fluoro-phenyl)-penta-2,4-dien-1-one- ; 5-(2-Fluoro-phenyl)-1-(4-pyridin-2-yl-piperazin-1-yl)-penta-2,4-dien-1-o- ne; 5-(2-Fluoro-phenyl)-1-(4-phenyl-pip erazin-1 -yl)-penta-2 4-dien-1 -one; 1-[4-(3-Chloro-propyl)-piperazin-1-yl]-5-(2-fluoro-phenyl)-penta-2,- 4-dien-1-one; as well as therapeutically-acceptable salts thereof. 5. A method of preparation of compounds of general formula (I) according to claim 1, which comprises condensation of an intermediate of general formula (II) ##STR00016## wherein R.sub.1 and R.sub.2 are defined as in the description of general formula (I) of claim 1, wherein X represents a leaving group or X represents hydroxyl, with an amine of general formula (III) ##STR00017## wherein P.sub.1 represents a protective group, to yield an intermediate of general formula (IV), ##STR00018## wherein R.sub.1, R.sub.2 and P.sub.1 are defined as previously; and deprotection and reaction of the deprotected intermediate of general formula (IV) with a reagent of general formula R.sub.3(CH.sub.2).sub.nY, wherein R.sub.3 and n are defined as in the description of general formula (I) of claim 1 and Y represents a leaving group, or with an aldehyde of formula R.sub.3--(CH.sub.2).sub.n-1--CHO wherein R.sub.3 and n are defined as previously. 6. A method of preparation of compounds of general formula (I) according to claim 1, which comprises condensation of an intermediate of general formula (II) ##STR00019## wherein R.sub.1 and R.sub.2 are defined as in the description of general formula (I) of claim 1 and X is a leaving group or hydroxyl, with an amine of general formula (V) ##STR00020## wherein m, n and R.sub.3 are defined as in the description of general formula (I) of claim 1, yielding compounds of general formula (I). 7. The method according to claim 5, wherein X is chlorine. 8. The method according to claim 5, wherein Y is Cl, Br, I, OSO.sub.2CH.sub.3, OSO.sub.2CF.sub.3 or O-tosyl. 9. The method according to claim 6, wherein X is chlorine. 10. Pharmaceutical compositions containing as an active product at least one compound according to claim 1, in combination with a pharmaceutically-acceptable vehicle. 11. A composition comprising at least one compound according to claim 1 and another cardiovascular agent as a combination product, which is in the form of a simultaneous, separate or time-release formulation suitable for cardiovascular therapy. 12. The composition according to claim 11, wherein the other cardiovascular agent is an antiplatelet aggregation agent. 13. The composition according to claim 12 wherein the antiplatelet aggregation agent is aspirin, clopidogrel, ticlopidine, abciximab, tirofiban or eptifibatide.

Details for Patent 8,022,064

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Janssen Biotech, Inc.	REOPRO	abciximab	Injection	103575	12/22/1994		2026-06-19