Claims for Patent: 7,659,281

Summary for Patent: 7,659,281

Title:	HMG-CoA reductase inhibitors
Abstract:	Compounds are provided of the following structure are HMG CoA reductase inhibitors and thus are active in inhibiting cholesterol biosynthesis, modulating blood serum lipids, for example, lowering LDL cholesterol and/or increasing HDL cholesterol, and treating hyperlipidemia and dyslipidemia, hypercholesterolemia, hypertriglyceridemia and atherosclerosis ##STR00001## wherein variables A and B are defined herein.
Inventor(s):	Stein; Philip D. (Pennington, NJ), Seitz; Steven P. (Swarthmore, PA), Carini; David J. (Wallingford, CT), Shi; Yan (Flourtown, PA), Robl; Jeffrey A. (Newtown, PA), Markwalder; Jay A. (New London, PA), He; Chunhong (Boothwyn, PA)
Assignee:	Bristol-Myers Squibb Company (Princeton, NJ)
Application Number:	11/789,335
Patent Claims:	1. A compound having the structure ##STR00647## wherein A is selected from ##STR00648## wherein R.sub.1 and R.sub.2 are the same or different and are independently selected from H or lower alkyl; B is ##STR00649## wherein n is 1 or 2; R.sub.6 (a substituent in the benzo ring) is, when n=1, nitro, --N(H)C(O)NR.sub.8R.sub.9, --N(H)C(O)CH.sub.2NMe.sub.2, --N(H)C(O)NH.sub.2 tetrazole linked through its carbon atom and which is optionally substituted by methyl, methyl substituted with N(H)SO.sub.2Me or N(H)C(O)NHMe, SO.sub.2N(H)R.sub.10, C(O)N(H)R.sub.11, --N.dbd.C(NH.sub.2)NH.sub.2 or ##STR00650## ##STR00651## or R.sub.6 is identical at each occurrence and is, when n=2, CN, CO.sub.2H, COOMe; or R.sub.6 is, when R.sub.3 is 3-carboxy-4-fluorophenyl and n=1 or 2, H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclo, or an alkyl substituent; wherein each of the above R.sub.6 groups may be independently substituted with a member selected from the group consisting of halogen, nitro, cyano, OR.sub.22, alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heterocyclo; wherein R.sub.22 is selected from the group consisting of H, C.sub.1-C.sub.8alkyl, C.sub.2-C.sub.8alkenyl, C.sub.2-C.sub.8alkynyl, C.sub.3-C.sub.8cycloalkyl, C.sub.6-C.sub.10aryl or C.sub.3-C.sub.9heterocyclo; R.sub.3 and R.sub.4 are the same or different and are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heterocyclo (wherein the attachment atom in the heterocyclo group is a carbon); wherein each of the above R.sub.3 and R.sub.4 groups may be independently substituted with a member selected from the group consisting of halogen, nitro, cyano, OR.sub.22, alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heterocyclo; wherein R.sub.22 is selected from the group consisting of H, C.sub.1-C.sub.8alkyl, C.sub.2-C.sub.8alkenyl, C.sub.2-C.sub.8alkynyl, C.sub.3-C.sub.8cycloalkyl, C.sub.8-C.sub.10aryl or C.sub.3-C.sub.9heterocyclo; R.sub.8 is H, or methyl; R.sub.9 is a) alkyl which is optionally substituted by one or more groups independently selected from carboxy, methylamino, dimethylamino, aminoalkyl, and/or hydroxyl, b) alkyl substituted by carboxy and amino, or c) heterocyclo; wherein each of the above R.sub.9 groups may be independently substituted with a member selected from the group consisting of halogen, nitro, cyano, OR.sub.22, alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heterocyclo; wherein R.sub.22 is selected from the group consisting of H, C.sub.1-C.sub.8alkyl, C.sub.2-C.sub.8alkenyl, C.sub.2-C.sub.8alkynyl, C.sub.3-C.sub.8cycloalkyl, C.sub.8-C.sub.10aryl or C.sub.3-C.sub.9heterocyclo; R.sub.10 is H, or alkyl which is optionally substituted with one or more groups independently selected from hydroxy, dimethylamino and/or 4-morpholino, SO.sub.2Me, C(O)Me, or C(O)NHMe; R.sub.11 is alkyl (which is optionally substituted with dimethylamino), MeO, SO.sub.2Me, or heterocyclo; or a pharmaceutically acceptable salt thereof, or an ester thereof, a prodrug ester thereof, and all stereoisomers thereof. 2. The compound as defined in claim 1 where the A group is in the form of a free acid, a physiologically acceptable and hydrolyzable ester or .delta. lactone thereof, or an alkali metal salt, alkaline earth metal salt or an amino acid salt. 3. The compound as defined in claim 1 wherein R.sub.1 is H; the A group is a free acid, a physiologically acceptable and hydrolyzable ester or .delta. lactone thereof, or an alkali metal salt, alkaline earth metal salt or an amine salt or an amino acid salt; C.dbd.C is trans; R.sub.3 is aryl; and R.sub.4 is alkyl or cycloalkyl, wherein each of the above R.sub.3 and R.sub.4 groups may be independently substituted with a member selected from the group consisting of halogen, nitro, cyano, OR.sub.22, alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heterocyclo; wherein R.sub.22 is selected from the group consisting of H, C.sub.1-C.sub.8alkyl, C.sub.2-C.sub.8alkenyl, C.sub.2-C.sub.8alkynyl, C.sub.3-C.sub.8cycloalkyl, C.sub.8-C.sub.10aryl or C.sub.3-C.sub.9heterocyclo. 4. The compound as defined in claim 1 having the structure ##STR00652## ##STR00653## ##STR00654## 5. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable carrier therefor. 6. A pharmaceutical combination comprising the HMG CoA reductase inhibitor compound as defined in claim 1 and an antidiabetic agent which is 1, 2, 3 or more of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, muraglitazar, insulin, Gl-262570, isaglitazone, JTT-501, N,N-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD1129, GW-409544, KRP297, AC2993, LY315902, P32/98 and/or NVP-DPP-728A, or an anti-obesity agent which is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, human Ciliary neurotrophic factor with a 15 amino acid truncation of the C-terminus and 2 amino acid substitutions, dexamphetamine, phentermine, phenylpropanolamine, and/or mazindol, P57 or CP-644673 (Pfizer); or an antihypertensive agent which is an ACE inhibitor which is captopril, fosinopril, enalapril, lisinopril, quinapril, benazepril, fentiapril, ramipril or moexipril; an NEP/ACE inhibitor which is omapatrilat, gemopatrilat, or CGS 30440; an angiotensin II receptor antagonist which is irbesartan, losartan or valsartan; amlodipine besylate, prazosin HCl, verapamil, nifedipine, nadolol, propranolol, or clonidine HCl, carvediol; atenolol, hydrochlorothiazide, torasemide, furosemide, spironolactone or indapamide; and the lipid modulating agent is pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, pitavastatin, rosuvastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe, TS-962, MD-700, cholestagel, niacin, and/or LY295427; or which is an anti-Alzheimer's agent which is tacrine HCl, donepezil; an antiosteoporosis agent, which is parathyroid hormone, alendronate, coenzyme Q.sub.10; a chondroprotective compound which is polysulfated glycosaminoglycan (PSGAG), glucosamine, chondroitin sulfate (CS), hyaluronic acid (HA), pentosan polysulfate (PPS), doxycycline or minocycline; a cyclooxygenase (COX)-2 inhibitor, which is celecoxib or rofecoxib. 7. The combination as defined in claim 6 wherein the HMG CoA reductase inhibitor is in combination with a platelet aggregation inhibitor which is aspirin, clopidogrel, ticlopidine, dipyridamole, ifetroban, abciximab, tirofiban, eptifibatide, or anagrelide. 8. The combination as defined in claim 7 wherein the platelet inhibitor is clopidogrel, aspirin or a combination of clopidogrel and aspirin.

Details for Patent 7,659,281

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Janssen Biotech, Inc.	REOPRO	abciximab	Injection	103575	12/22/1994		2026-04-25
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2026-04-25