Modulators of the glucocorticoid receptor and method

• US 7,459,474 B2
• Filed: 06/10/2004
• Issued: 12/02/2008
• Est. Priority Date: 06/11/2003
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Moree, Wilna J., Rueter, Jaimie K., Robinson, Leslie A.
• Primary Examiner(s): Marschel; Ardin
• Assistant Examiner(s): Lewis; Amy A
• Application Number:
  US10/865,443
• Publication Number:
  US 20040266831A1
• Time in Patent Office: 1,636 Days
• Field of Search: None
• US Class Current: 514/383
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: C07D 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Abstract

Novel non-steroidal compounds are provided which are glucocorticoid receptor modulators which are useful in treating diseases requiring glucocorticoid receptor agonist or antagonist therapy such as obesity, diabetes, inflammatory and immune disorders, and have the structure

where A, B, and R¹-R⁶ are defined herein.

Claims

1. A compound having formula (I),

2. A compound of claim 1, including all stereoisomers thereof, or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted phenyl.

3. A compound of claim 2, including all stereoisomers wherein R², R³ and R⁴ are independently hydrogen, C_1-6alkyl, C_1-6heteroalkyl, C_1-6arylalkyl, C_1-6heteroarylalkyl, C_2-6alkenyl, or C_2-6alkynyl, wherein the heteroaryl or aryl component of the C_1-6arylalkyl and C_1-6heteroarylalkyl groups is optionally substituted.

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

14. A pharmaceutical combination comprising a compound as defined in claim 1 and an immunosuppressant, an anticancer agent, an anti-viral agent, an anti-inflammatory agent, an anti-fungal agent, an anti-biotic, an anti-vascular hyperproliferation agent, an anti-depressant agent, a lipid-lowering agent, a lipid modulating agent, an antidiabetic agent, an anti-obesity agent, an antihypertensive agent, a platelet aggregation inhibitor and/or an antiosteoporosis agent, wherein

the antidiabetic agent is 1, 2, 3 or more of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR γ

agonist, a PPAR α

/γ

dual agonist, an SGLT2 inhibitor, a DP4 inhibitor, an aP2 inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin and/or a meglitinide;

the anti-obesity agent is a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor agonist, an aP2 inhibitor or an anorectic agent;

the lipid lowering agent is an MTP inhibitor, an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of LDL receptor activity, a lipoxygenase inhibitor or an ACAT inhibitor; and

the antihypertensive agent is an ACE inhibitor, angiotensin II receptor antagonist, NEP/ACE inhibitor, calcium channel blocker or β

-adrenergic blocker.

15. The combination as defined in claim 14 wherein

the antidiabetic agent is 1, 2, 3 or more of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, G1-262570, isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD1129, AR-HO39242, GW-409544, KRP297, AC2993, LY315902, P32/98 and/or NVP-DPP-728A;

the anti-obesity agent is selected from orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, and/or mazindol;

the lipid lowering agent is pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, itavastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe, TS-962, MD-700, cholestagel, niacin and/or LY295427;

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, [S [(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino[-2,2-dimethyl-7-oxo-1H-azepine-1-acetic acid (gemopatrilat) or CGS 30440 or an angiotensin II receptor antagonist which is irbesartan, losartan or valsartan;

amlodipine besylate, prazosin HCl, verapamil, nifedipine, nadolol, propranolol, carvedilol or clonidine HCl ; and

the platelet aggregation inhibitor is aspirin, clopidogrel, ticlopidine, dipyridamole or ifetroban.

16. The combination as defined in claim 15 wherein

the immunosuppressant is a cyclosporin, mycophenolate, interferon-beta, deoxyspergolin, FK-506 or Ant.-IL-2;

the anti-cancer agent is azathiprine, 5-fluorouracel, cyclophosphamide, cisplatin, methotrexate, thiotepa, or carboplatin;

the anti-viral agent is abacavir, aciclovir, ganciclovir, zidanocin, or vidarabine; and

the antiinflammatory drug is ibuprofen, celecoxib, rofecoxib, aspirin, naproxen, ketoprofen, diclofenac sodium, indomethacin, piroxicam, prednisone, dexamethasone, hydrocortisone, or triamcinolone diacetate.

4. A compound having formula (II),

5. A compound of claim 4, including all stereoisomers thereof, wherein B is an optionally substituted phenyl ring.

6. A compound of claim 5, including all stereoisomers thereof, wherein R¹ is hydrogen or C_1-6alkyl.

7. A compound of claim 5, including all stereoisomers thereof, wherein T¹ through T⁵ is independently selected from H, F, Cl, Br, I, and —

OC_1-6alkyl.

8. A compound having formula (III),

9. A compound of claim 8, including all stereoisomers thereof, wherein T¹ through T¹⁰ are selected independently from hydrogen, F, Cl, Br I, and —

OC_1-6alkyl.

10. A compound of claim 9, including all stereoisomers, thereof, wherein R³ and R⁴ are selected independently from hydrogen and C_1-6alkyl.

11. A compound of claim 10, including all stereoisomers thereof, wherein R⁴ is hydrogen and R³ is C_1-6alkyl.

12. A compound selected from:

(i)