Claims for Patent: 9,808,473

Summary for Patent: 9,808,473

Title:	Preparation and use of 3-pyridyl substituted-6,6-difluoro bicyclic himbacine derivatives as par-1 receptor antagonists
Abstract:	The present invention relates to bicyclic himbacine derivatives of the formula ##STR00001## or a pharmaceutically acceptable salt thereof wherein: R.sup.1 is halo; --CN; alkyl; cycloalkyl; alkoxy; phenyl, which is optionally substituted one or twice independently by alkyl, halo, or --CN; or a thiophene ring, which is optionally substituted once or twice independently by alkyl. The compounds of the invention are effective inhibitors of the PAR-1 receptor. The inventive compounds may be used for the treatment or prophylaxis of disease states such as ASC, secondary prevention of myocardial infarction or stroke, or PAD.
Inventor(s):	Dropinski; James Francis (Freehold, NJ), Maletic; Milana (Summit, NJ), Kim; Jae-Hun (Scotch Plains, NJ), Sha; Deyou (Yardley, PA)
Assignee:	Merck Sharp & Dohme Corp. (Rahway, NJ)
Application Number:	14/912,315
Patent Claims:	1. A compound of the formula ##STR00030## or a pharmaceutically acceptable salt thereof wherein: R.sup.1 is halo; --CN; alkyl; cycloalkyl; alkoxy; phenyl, which is optionally substituted one or twice independently by alkyl, halo, or --CN; or a thiophene ring, which is optionally substituted once or twice independently by alkyl. 2. The compound as defined in claim 1 or a pharmaceutically acceptable salt thereof wherein R.sup.1 is methoxy, --CN, --F, --Cl, or cyclopropyl. 3. A compound as defined in claim 1, which is: 6'-((E)-2-((3R,3aR,4R,5S,7aS)-6,6-difluoro-7a-hydroxy-3,5-dimethyl-1-oxoo- ctahydro isobenzofuran-4-yl)vinyl)-[3,3'-bipyridine]-2-carbonitrile; (3R,3aR,4R,5S,7aS)-6,6-difluoro-7a-hydroxy-3,5-dimethyl-4-((E)-2-(2'-phen- yl-[3,3'-bipyridin]-6-yl)vinyl)hexahydroisobenzofuran-1(3H)-one; (3R,3aR,4R,5S,7aS)-6,6-difluoro-7a-hydroxy-4-((E)-2-(2'-methoxy-[3,3'-bip- yridin]-6-yl)vinyl)-3,5-dimethylhexahydroisobenzofuran-1(3H)-one; (3R,3aR,4R,5S,7aS)-4-((E)-2-(2'-chloro-[3,3'-bipyridin]-6-yl)vinyl)-6,6-d- ifluoro-7a-hydroxy-3,5-dimethylhexahydroisobenzofuran-1(3H)-one; (3R,3aR,4R,5S,7aS)-4-((E)-2-(2'-fluoro-[3,3'-bipyridin]-6-yl)vinyl)-7a-hy- droxy-3,5-dimethylhexahydroisobenzofuran-1(3H)-one; (3R,3aR,4R,5S,7aS)-4-((E)-2-(2'-cyclopropyl-[3,3'-bipyridin]-6-yl)vinyl)-- 6,6-difluoro-7a-hydroxy-3,5-dimethylhexahydroisobenzofuran-1(3H)-one; 3R,3aR,4R,5S,7aS)-6,6-difluoro-7a-hydroxy-3,5-dimethyl-4-((E)-2-(2'-(5-me- thylthiophen-2-yl)-[3,3'-bipyridin]-6-yl)vinyl)hexahydroisobenzofuran-1(3H- )-one; or a pharmaceutically acceptable salt thereof. 4. A pharmaceutical composition comprising an effective amount of a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 5. The pharmaceutical composition as defined in claim 4, which further comprises a therapeutically effective amount of at least one additional cardiovascular agent selected from the group consisting of: aspirin, seratrodast, picotamide, ramatroban, clopidogrel, meloxicam, rofecoxib, celecoxib, valsartan, telmisartan, candesartran, irbesartran, losartan, eprosartan, tezosentan, milrinoone, enoximone, captopril, enalapril, enaliprilat, spirapril, quinapril, perindopril, ramipril, fosinopril, trandolapril, lisinopril, moexipril, benazepril, candoxatril, ecadotril, ximelagatran, fondaparin, enoxaparin, chlorothiazide, hydrochlorothiazide, ethacrynic acid, furosemide, amiloride, abciximab and eptifibatide. 6. The pharmaceutical composition as defined in claim 5, wherein the at least one additional cardiovascular agent is aspirin or clopidogrel, wherein clopidogrel is a free base or pharmaceutically acceptable salt. 7. A pharmaceutical composition comprising an effective amount of a compound as defined in claim 3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 8. The pharmaceutical composition as defined in claim 7, which further comprises a therapeutically effective amount of at least one additional cardiovascular agent selected from the group consisting of: aspirin, seratrodast, picotamide, ramatroban, clopidogrel, meloxicam, rofecoxib, celecoxib, valsartan, telmisartan, candesartran, irbesartran, losartan, eprosartan, tezosentan, milrinoone, enoximone, captopril, enalapril, enaliprilat, spirapril, quinapril, perindopril, ramipril, fosinopril, trandolapril, lisinopril, moexipril, benazepril, candoxatril, ecadotril, ximelagatran, fondaparin, enoxaparin, chlorothiazide, hydrochlorothiazide, ethacrynic acid, furosemide, amiloride, abciximab and eptifibatide. 9. The pharmaceutical composition as defined in claim 8, wherein the at least one additional cardiovascular agent is aspirin or clopidogrel, wherein clopidogrel is a free base or pharmaceutically acceptable salt. 10. A method for treating acute coronary syndrome or peripheral artery disease by administering a compound as defined in claim 1 to a mammal in need of such treatment. 11. A method of inhibiting platelet aggregation comprising administering to a mammal an effective amount of a compound as defined in claim 1. 12. A method for treating acute coronary syndrome or peripheral artery disease by administering a compound as defined in claim 3 or a pharmaceutically acceptable salt thereof to a mammal in need of such treatment. 13. A method of inhibiting platelet aggregation comprising administering to a mammal an effective amount of compound as defined in claim 3 or a pharmaceutically acceptable salt thereof.

Details for Patent 9,808,473

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Janssen Biotech, Inc.	REOPRO	abciximab	Injection	103575	12/22/1994		2033-08-22