HMG-CoA reductase inhibitors and method

• US 20050171140A1
• Filed: 11/15/2004
• Published: 08/04/2005
• Est. Priority Date: 11/20/2003
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Murugesan, Natesan, Kolla, Laxma R., Bisaha, Sharon, Quinlan, Sandra L., Sausker, Justin, Petsch, Dejah, Natalie, Kenneth J. Jr., Ahmad, Saleem, Stein, Philip D., Shi, Yan, Ngu, Khehyong, Guo, Zhenrong, Soundararajan, Nachimuthu, O'Connor, Stephen P., Robl, Jeffrey, Fan, Junying
• Granted Patent: US 7,420,059 B2
• Time in Patent Office: Days
• US Class Current: 514/300
• CPC Class Codes: C07D 211/76 attached in position 2 or 6
• CPC Class Codes: C07D 213/80 in position 3
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/04 Ortho-condensed systems
• CPC Class Codes: C07D 498/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

Compounds are provided having the following structure
and pharmaceutically acceptable salts thereof,
wherein R₁, R₂, R₃, R₄, U, V, W, Y, and n are as defined above, which compounds 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, hypercholesterolemia, hypertriglyceridemia and atherosclerosis as well as Alzheimer'"'"'s disease and osteoporosis and may be employed as hormone replacement therapy. A method for treating the above diseases employing the above compounds is also provided.

Claims

1. A compound having the structure

5. The compound as defined in claim 1 wherein R₁ and R₂ are independently selected from alkyl, cycloalkyl and aryl;

R₄ is H;

n is 0.

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

2. A compound having the structure

3. The compound as defined in claim 2 wherein U, V, W and Y are as defined below.

4. The compound as defined in claim 2 where the A group is in the form of a free acid, a physiologically acceptable and hydrolyzable ester or 6 lactone thereof, or an alkali metal salt, alkaline earth metal salt or an amino acid salt.

6. The compound as defined in claim 4 wherein R₁ is phenyl which contains 1 or 2 substituents,

R₂ is alkyl or cycloalkyl;

R₄ is H; and

is a trans double bond, in the form of a free acid, an alkali metal salt, or an alkaline earth metal salt or an amino acid salt.

7. The compound as defined in claim 6 wherein R₁ is 4-fluorophenyl, 4-fluoro-3-methylphenyl, or 3,5-dimethylphenyl;

and

R₂ is isopropyl, t-butyl or cyclopropyl.

8. The compound as defined in claim 2 wherein A has the structure

9. The compound as defined in claim 2 in the form of its calcium salt, sodium salt or arginine salt.

10. The compound as defined in claim 2 where

R₁ and R₂ are the same or different and are independently selected from alkyl, cycloalkyl and aryl,

R₃ is selected from alkyl, SO₂R_8a, or C(O)R₈,

R₄ is H,

U is selected from C═

O, a bond, or —

CH₂—

, wherein one or both of the hydrogen atoms may be optionally replaced by an ‘

alkyl substituent’

,

V is selected from a bond, —

NR₃—

, —

O—

, —

CH₂—

wherein one or both of the hydrogen atoms may be optionally replaced by an ‘

alkyl substituent’

,

W is selected from —

O—

, —

NR₃C—

or —

CH₂—

wherein one or both of the hydrogen atoms may be optionally replaced by an ‘

alkyl substituent’

,

Y is selected from —

SO₂—

, C═

O, or —

CH₂—

wherein one or both of the hydrogen atoms may be optionally replaced by an ‘

alkyl substituent’

, and

n is 0.

11. The compound as defined in claim 2 wherein

12. The compound as defined in claim 2 wherein

R₁ is 4-fluorophenyl,

R₂ is isopropyl,

R₃ is selected from SO₂CH₃, SO₂CH₂CH₃, SO₂(1-methylimidazol-4-yl), SO₂CH(CH₃)₂, SO₂Ph, C(O)CH₃, or CH₃,

R₄ is H,

U is selected from C═

O, a bond or —

CH₂—

wherein one or both of the hydrogen atoms may be optionally replaced by an ‘

alkyl substituent’

,

V is selected from a bond, —

NR_3b—

, —

O—

, or —

CH₂—

wherein one or both of the hydrogen atoms may be optionally replaced by an ‘

alkyl substituent’

,

W is selected from —

O—

or —

CH₂—

wherein one or both of the hydrogen atoms may be optionally replaced by an ‘

alkyl substituent’

,

Y is selected from —

SO₂—

, C═

O, or —

CH₂—

wherein one or both of the hydrogen atoms may be optionally replaced by an ‘

alkyl substituent’

,

n is 0 and

A is

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

13. The compound as defined in claim 2 wherein

R₁ is 4-fluorophenyl;

R₂ is isopropyl;

R₃ is selected from SO₂CH₃, SO₂CH₃CH₃, SO₂(1-methylimidazol-4-yl), SO₂CH(CH₃), SO₂Ph, C(O)CH₃ or CH₃;

R₄ is H; and

U, V, W and Y are —

CH₂CH₂—

, —

CH₂CH₂ CH₂—

, —

CH₂OCH₂—

, —

CH₂CH₂CH₂CH₂—

,

or —

CH₂—

O—

CH₂CH₂— and

n is 0.

14. The compound as defined in claim 2 having the structure

17. A pharmaceutical combination comprising the HMG CoA reductase inhibitor compound as defined in claim 2 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 (including 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.

18. The combination as defined in claim 17 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, antihomocysteine agents, HMG-CoA synthase inhibitors, lanosterol demethylase inhibitors, or sterol regulating element binding protein-I agents.

19. The pharmaceutical combination as defined in claim 18 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 secretagogues or insulin sensitizers, 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, and/or glucagon-like peptide-1 (GLP-1) or a mimetics thereof.

20. The combination as defined in claim 19 wherein the antidiabetic agent is 1, 2, 3 or more of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, muraglitizar, insulin, GI-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, MK-431, BMS-477118, and BMS-538305.

21. The combination as defined in claim 17 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/or a dopamine reuptake inhibitor, an aP2 inhibitor, a thyroid receptor beta drug, an anorectic agent, a PTP-1B inhibitor, a CCKA agonist, a CB1 antagonist, 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

agonist, a leptin inhibitor such as a leptin receptor activator, a fatty acid oxidation upregulator or inducer.

22. The combination as defined in claim 19 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, rimonabant, 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.

23. The combination as defined in claim 17 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

fenofibrate, gemfibrozil, clofibrate, avasimibe, torcetrapib, JTT-705, TS-962, MD-700, cholestagel, niacin, and/or LY295427.

24. The combination as defined in claim 17 wherein the HMG CoA reductase inhibitor is in combination with a platelet aggregation inhibitor.

25. The combination as defined in claim 24 wherein the platelet inhibitor is clopidogrel, aspirin or a combination of clopidogrel and aspirin.

26. The combination as defined in claim 24 wherein the platelet aggregation inhibitor is aspirin, clopidogrel, ticlopidine, dipyridamole, ifetroban, abciximab, tirofiban, eptifibatide, or anagrelide.

27. The combination as defined in claim 17 wherein the other therapeutic agent is an anti-Alzheimer'"'"'s agent which is tacrine HCl (Cognex®

), donepezil (Aricept®

), a -secretase inhibitor, 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.

28. A method for treating hypercholesterolemia, dyslipidemia, hyperlipidemia, hyperlipoproteinemia, LDL Pattern B, LDL Pattern A, hypertriglyceridemia or atherosclerosis, or Alzheimer'"'"'s disease or osteoporosis, for inhibiting cholesterol biosynthesis or lowering blood serum cholesterol levels and/or modulating blood serum cholesterol levels, lowering LDL cholesterol and/or increasing HDL cholesterol, 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 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, improving coagulation homeostasis, reducing PAI-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 2.

29. 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 2 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 effective amount of such combinations.

15. A compound having the structure

30. An intermediate compound of the structure

31. A process for preparing an intermediate of the structure

32. The process as defined in claim 31 where in intermediate 3

R₁ is 4-fluorophenyl

R₂ is isopropyl

R is methyl

and in intermediate 50, R₈ is methyl, and in step 1) compound 47 is added to a solution of sec-butyllithium in cyclohexane-THF at about 60°

C. or below, and compound 3 is reacted with the above mixture.

33. A process for preparing aldehyde intermediate of the structure 53

34. A process for preparing an intermediate of the structure 58

35. A process for preparing an intermediate of the structure 58

36. A process for preparing an intermediate of the structure 68

37. A process for preparing an intermediate of the structure 57

38. A process for preparing aldehyde intermediate of the structure 10