HMG-CoA reductase inhibitors and method

• US 20050085497A1
• Filed: 09/21/2004
• Published: 04/21/2005
• Est. Priority Date: 09/25/2003
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Ahmad, Saleem, Ngu, Khehyong, Robl, Jeffrey A.
• Granted Patent: US 7,371,759 B2
• Time in Patent Office: Days
• US Class Current: 514/275
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C04B 35/632 Organic additives
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

Compounds are provided having the following structure which 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, dyslipidemia, hormone replacement therapy, hypercholsterolemia, hypertriglyceridemia and atherosclerosis as well as Alzheimer'"'"'s disease and osteoporosis
wherein X is N or CR₅;
and pharmaceutically acceptable salts thereof,
wherein R₁ to R₇ are as defined herein. A method for treating the above diseases employing the above compounds is also provided.

Claims

1. A compound of the formula

2. The compound as defined in claim 1 where X is N.

3. The compound as defined in claim 1 where X is CR₅.

4. The compound as defined in claim 1 wherein the Z group is in form of a free acid, a physiologically acceptable and hydrolyzable ester or δ

lactone thereof, or an alkali metal salt, alkaline earth metal salt, an amine salt or an amino acid salt.

5. The compound as defined in claim 1 wherein

R₁ and R₂ are independently selected from alkyl, cycloalkyl and aryl;

R₃ is aryl, heteroaryl or cycloheteroalkyl; and

R₄ is H, alkyl, lower alkylcarbonyl, lower alkylsulfonyl or lower alkoxycarbonyl.

6. The compounds as defined in claim 1 wherein R₁ is aryl;

and

R₂ is alkyl or cycloalkyl;

R₃ is aryl, heteroaryl, cycloheteroalkyl;

R₄ is H, lower alkyl, lower alkylcarbonyl, lower alkylsulfonyl or lower alkoxycarbonyl;

and

is a double bond.

7. The compound as defined in claim 1 wherein

R₁ is 4-fluorophenyl, 4-fluoro-3-methylphenyl or 3,5-dimethylphenyl;

R₂ is isopropyl, t-butyl or cyclopropyl;

R₃ is aryl which is phenyl, cycloheteroalkyl which is tetrahydrothiophene dioxide, a heteroaryl which is a pyrrazole, a thiadiazole, a pyrazine, pyrimidine, a benzimidazole, a triazole, a tetrazole, a pyridyl, a thiazole, an oxazole or an isoxazole, each of which may be optionally substituted with 1, 2 or 3 substituents which may be the same or different and which can be cycloheteroalkyl, heteroaryl, alkyl, halogen, carboxyl, alkoxycarbonyl, alkylaminocarbonyl, or alkoxy;

R₄ is H, methyl, methylcarbonyl, methoxycarbonylor methanesulfonyl;

is a trans double bond; and

or an alkali or alkaline earth metal salt thereof or an amino acid salt thereof or an amine salt thereof.

8. The compound as defined in claim 7 wherein X is N or CR₅.

9. The compound as defined in claim 1 having the formula I

10. The compound as defined in claim 9 wherein

R₈ and R₉ are the same or different and are independently selected from 4-fluoro, 4-fluoro-3-methyl, or 3,5-dimethyl;

R₂ is isopropyl, t-butyl or cyclopropyl;

R₃ is one of the following groups;

R₄ is H, methyl, methylcarbonyl, methoxycarbonyl or methanesulfonyl.

14. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable carrier therefor.

15. A pharmaceutical combination comprising the HMG CoA reductase inhibitor compound as defined in claim 1 and one or more hypolipidemic agents or lipid-lowering agents, or lipid agents, or lipid modulating agents, and/or one or more other types of therapeutic agents including antidiabetic agents, anti-obesity agents, antihypertensive agents, platelet aggregation inhibitors, anti-dementia agents, anti-Alzheimer'"'"'s agents, anti-osteoporosis agents, and/or hormone replacement therapeutic agents, and/or other cardiovascular agents, anti-anginal agents, anti-arrhythmic agents, anti-atherosclerosis agents, anti-inflammatory agents, anti-arthritis agents, anti-platelet agents, anti-heart failure agents, anti-cancer agents, anti-infective agents, hormone replacement agents, growth hormone secretagogues, selective androgen receptor modulators, and/or immunomodulatory agents.

16. The combination as defined in claim 15 wherein the hypolipidemic agent or lipid-lowering agent or other lipid agent or lipid modulating agent or anti-atherosclerotic agent, which is employed comprises 1,2,3 or more MTP inhibitors, squalene synthetase inhibitors, fibric acid derivatives, PPAR α

agonists, PPAR dual α

/γ

agonists, PPAR δ

agonists, ACAT inhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors, ileal Na⁺/bile acid cotransporter inhibitors, upregulators of LDL receptor activity, cholesteryl ester transfer protein inhibitors, bile acid sequestrants, or nicotinic acid and derivatives thereof, ATP citrate lyase inhibitors, phytoestrogen compounds, an HDL upregulators, LDL catabolism promoters, antioxidants, PLA-2 inhibitors, antihomocysteine agents, HMG-CoA synthase inhibitors, lanosterol demethylase inhibitors, or sterol regulating element binding protein-I agents.

17. The pharmaceutical combination as defined in claim 15 comprising said HMG CoA reductase inhibiting compound and an antidiabetic agent which comprises 1,2,3 or more antidiabetic agents or antihyperglycemic agents which is an insulin secretagogue or insulin sensitizer, which is selected from biguanides, sulfonyl ureas, PTP-1B inhibitors, aldose reductase inhibitors, glucosidase inhibitors, PPAR γ

agonists, PPAR α

agonists, PPAR δ

antagonists or agonists, aP2 inhibitors, PPAR α

/γ

dual agonists, dipeptidyl peptidase IV (DP4) inhibitors, SGLT2 inhibitors, glycogen phosphorylase inhibitors, and/or meglitinides, insulin, slow release insulin-Basulin™

, and/or glucagon-like peptide-1 (GLP-1) or a mimetics thereof.

18. The combination as defined in claim 17 wherein the antidiabetic agent is 1, 2, 3 or more of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, Gl-262570, isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD1129, AR-HO39242, GW-409544, KRP297, AC2993, LY315902, P32/98, NVP-DPP-728A, NVP-LAF-237, muraglitazar, BMS 477,188, and/or BMS 538,305.

19. The combination as defined in claim 15 wherein the other type of therapeutic agent which may be optionally employed is 1, 2, 3 or more of an anti-obesity agent which is a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, an aP2 inhibitor, a thyroid receptor beta drug, an anorectic agent, a PTP-1B inhibitor, a CCKA agonist, a neuropeptide Y antagonist, a melanocortin-4-receptor agonist, a PPAR modulator which is a PPAR γ

antagonist, PPAR α

agonist, and/or PPAR δ

antagonist, a leptin inhibitor such as a leptin receptor activator, a fatty acid oxidation upregulator or inducer, a 5HT2c-agonist or an ACC inhibitor.

20. The combination as defined in claim 15 wherein the anti-obesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, and/or mazindol, P57 or CP-644673 (Pfizer);

the lipid modulating agent is an MTP inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of LDL receptor activity, a lipoxygenase inhibitor, or an ACAT inhibitor and the other lipid agent is a cholesteryl ester transfer protein inhibitor; and

the antihypertensive agent employed is an ACE inhibitor, angiotensin II receptor antagonist, NEP inhibitor, a NEP/ACE inhibitor, a calcium channel blocker, a T-channel calcium antagonist, a β

-adrenergic blocker, a diuretic, a α

-adrenergic blocker, a dual action receptor antagonist (DARA), or a heart failure drug, wherein the antihypertensive agent 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 fenofibrate, gemfibrozil, clofibrate, avasimibe, TS-962, MD-700, cholestagel, torcetrapib, JTT-705, niacin, LY295427, muraglitazar, and/or ezetimibe.

21. The combination as defined in claim 15 wherein the HMG CoA reductase inhibitor is in combination with a platelet aggregation inhibitor.

22. The combination as defined in claim 21 wherein the platelet aggregation inhibitor is aspirin, clopidogrel, ticlopidine, dipyridamole, ifetroban, abciximab, tirofiban, eptifibatide, anagrelide, CS-737, melagatran, ximelagatran, razaxaban, or a combination of clopidogrel and aspirin.

23. The combination as defined in claim 15 wherein the other therapeutic agent is an anti-Alzheimer'"'"'s agent or anti-dementia agent, which is tacrine HCl (Cognex®

), donepezil (Aricept®

), a Υ

-secretase inhibtor, a β

-secretase inhibitor and/or antihypertensive agent;

an antiosteoporosis agent, which is parathyroid hormone, a bisphosphonate, alendronate, a Ca receptor agonist or a progestin receptor agonist;

a hormone replacement therapeutic agent, which is a selective estrogen receptor modulator (SERM);

a tyrosine kinase inhibitor;

a selective androgen receptor modulator;

an antiarrhythmic agent, which is a β

-blocker, or a calcium channel blocker, or an α

-adrenergic blocker;

coenzyme Q sub. 10;

an agent that upregulates type III endothelial cell nitric acid syntase;

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 Celebrex®

(Searle) or Vioxx®

(Merck) or a glycoprotein IIa/IIIb receptor antagonist;

a 5-HT reuptake inhibitor;

a growth hormone secretagogue;

an anti-atherosclerosis agent;

an anti-infective agent, or an immunosuppressant for use in transplantation, or an antineoplastic agent.

24. A method for treating hypercholesterolemia, dyslipidemia, hyperlipidemia, hyperlipoproteinemia, LDL Pattern B, LDL Pattern A, hypertriglyceridemia or atherosclerosis, or Alzheimer'"'"'s disease or osteoporosis, inhibiting cholesterol biosynthesis or lowering blood serum cholesterol levels and/or modulating blood serum cholesterol levels, lowering LDL cholesterol and/or increasing HDL cholesterol, and/or lowering triglycerides, or treating dyslipidemia, mixed dyslipidemia, LDL Pattern B, LDL Pattern A, hyperlipidemia, hypercholesterolemia, hypo α

-lipoproteinemia, hyperlipoproteinemia or hypertriglyceridemia, and other aberrations of apolipoprotein B metabolism, or reducing levels of Lp(a), or treating or preventing other cholesterol-related diseases, or treating or preventing or reversing progression of atherosclerosis, or preventing or treating Alzheimer'"'"'s disease, or preventing or treating osteoporosis and/or osteopenia, or reducing inflammatory markers, reducing C-reactive protein, or preventing or treating low grade vascular inflammation, or preventing or treating stroke, or preventing or treating dementia, or preventing and treating coronary heart disease, and primary and secondary prevention of myocardial infarction, or preventing or treating stable and unstable angina, or primary prevention of coronary events, or secondary prevention of cardiovascular events, or preventing or treating peripheral vascular disease, preventing or treating peripheral arterial disease, or preventing or treating acute vascular syndromes, or preventing or reducing the risk of undergoing myocardial revascularization procedures, or preventing or treating microvascular diseases such as nephropathy, neuropathy, retinopathy and nephrotic syndrome, or preventing or treating hypertension, preventing or treating diabetes, especially Type 2 diabetes, and related diseases, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, LDL Pattern B, LDL Pattern A, Syndrome X, diabetic complications, dysmetabolic syndrome, and related diseases, and sexual dysfunction, preventing and treating malignant lesions, premalignant lesions, gastrointestinal malignancies, liposarcomas and epithelial tumors, cancer-induced asthenia (fatigue), irritable bowel syndrome, Crohn'"'"'s disease, gastric ulceritis, and gallstones, and HIV infection, drug-induced lipodystrophy, and proliferative diseases, for improving coagulation homeostasis, reducing PAI-I activity, reducing fibrinogen, and/or reducing platelet aggregation, and/or improving endothelial function, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a compound as defined in claim 1.

25. A method for treating cholesterol related diseases, diabetes and related diseases, cardiovascular diseases, cerebrovascular diseases, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a combination of a compound as defined in claim 15 and a hypolipidemic agent, and/or lipid modulating agent and/or antidiabetic agent and/or cardiovascular agent, cerebrovascular agent, and/or other type of therapeutic agent, which comprises administering to a mammalian species in need of treatment a therapeutically efective amount of such combinations.

11. A compound having the structure

12. The compound as defined in claim 11 wherein R₆ is methylamine, ammonium, dicyclohexylamine, t-butyl, Na or Ca.

13. A compound having the structure