Heterocyclic modulators of the glucocorticoid receptor, AP-1, and/or NF-kB activity and use thereof

• US 20050182083A1
• Filed: 01/13/2005
• Published: 08/18/2005
• Est. Priority Date: 01/16/2004
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Weinstein, David S., Gilmore, John L., Sheppeck, James
• Granted Patent: US 7,605,264 B2
• Time in Patent Office: Days
• US Class Current: 514/286
• CPC Class Codes: C07D 471/18 Bridged systems

Abstract

Novel non-steroidal compounds are provided which are useful in treating diseases associated with modulation of the glucocorticoid receptor, AP-1, and/or NF-κB activity including obesity, diabetes, inflammatory and immune diseases, and have the structure of formula (I)
or stereoisomers or prodrugs or solvates or pharmaceutically acceptable salts thereof, wherein A, B, J, K, Z, R, R^a, R^b, R^c, and R^d, are defined herein. Also provided are pharmaceutical compositions and methods of treating obesity, diabetes and inflammatory or immune associated diseases comprising said compounds.

Claims

1. A compound of formula I:

2. The compound as defined in claim 1, including all stereoisomers thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein one of A and B is an optionally substituted 5-membered heterocyclic ring.

3. The compound as defined in claim 1, including all stereoisomers thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein

one of J and K is N and the other is C or N;

R is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, arylalkyl, aryloxy, heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, cyanoalkyl, aminoalkyl, hydroxyalkyl, aryloxyalkyl, hydroxyaryl or NR¹R², wherein R¹ and R² are the same or different and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amino, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloalkenyl, monoalkylaminoalkyl, dialkylaminoalkyl, cycloheteroalkylalkyl, hydroxyaryl, aryloxyalkyl, alkoxyalkyl, hydroxyalkyl, or a heterocyclic ring;

Z is independently selected from the group consisting of CONR¹R², CH₂NR¹R² or SO₂NR¹R², wherein R¹ and R² are the same or different and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amino, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloalkenyl, monoalkylatninoalkyl, dialkylaminoalkyl, cycloheteroalkylalkyl, hydroxyaryl, aryloxyalkyl, alkoxyalkyl, hydroxyalkyl, or a heterocyclic ring; and

one of A and B is an optionally substituted 5-membered heterocyclic ring and the other is an optionally substituted 6-membered carbocyclic ring.

4. The compound as defined in claim 1, including all stereoisomers thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein the A ring has the structure

5. The compound as defined in claim 4 having the structure

6. The compound as defined in claim 5 having the structure

7. The compound as defined in any one of claim 6, including all stereoisomers thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, where R is hydrogen, alkyl or hydroxyalkyl;

R^a is selected from hydrogen, halo, alkyl, CN, NO₂, NH₂, CHO, CO₂ alkyl, CONR^eR^f, NR^gR^h or CH₂NR^gR^h;

R^b is selected from hydrogen, halo, alkyl, CN, NO₂, NH₂, CHO, CO₂ alkyl, CONRⁱR^j, NR^kR^l or CH₂NR^kR^l;

R^c and R^d are the same or different and are independently selected from hydrogen, alkyl, or hydroxy; and

R¹⁶ is the same or different and is independently selected from hydrogen, hydroxy, or alkyl.

8. The compound as defined in claim 6 having the structure

9. The compound as defined in any one of claim 8, including all stereoisomers thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein

R is hydrogen or alkyl;

R^b is selected from hydrogen, halo, alkyl, CN, NO₂, NH₂, CHO, CO₂ alkyl, CONRⁱR^j, NR^kR^l or CH₂NR^kR^l;

one of R¹ and R² is

R^m at each occurrence is independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, alkoxy, —

CO₂(alkyl), —

C(O)N(alkyl)₂, alkyl, heteroarylalkyl, arylalkyl, aryl and heteroaryl;

R^o is hydrogen or alkyl;

q is 1 or2;

and

R¹⁶ is the same or different and is independently selected from hydrogen, hydroxy, or alkyl.

10. The compound as defined in any one of claim 9, including all stereoisomers thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein

R is alkyl;

R^b is hydrogen or alkyl;

one of R¹ and R² is

R¹⁶ is the same or different and is independently hydroxy or alkyl.

12. The compound as defined in claim 1 having the structure:

16. A method of treating a disease or disorder which is associated with the expression product of a gene whose transcription is stimulated or repressed by glucocorticoid receptors, or a method of treating a disease or disorder associated with AP-1- and/or NFκ

B-induced transcription, or a method for treating a disease or disorder associated with AP-1 and/or NFκ

B dependent gene expression, wherein the disease is associated with the expression of a gene under the regulatory control of AP-1 and/or NF-κ

β

, the method comprises administering to a patient in need of treatment a therapeutically effective amount of a compound as defined in claim 1.

17. A method as defined in claim 16 wherein the disease or disorder is selected from an endocrine disorder, rheumatic disorder, collagen disease, dermatologic disease, allergic disease, ophthalmic disease, respiratory disease, hematologic disease, gastrointestinal disease, inflammatory disease, immune disease, neoplastic disease and metabolic disease.

18. A method as defined in claim 17 wherein the disease or disorder is an inflammatory or autoimmune disease.

19. The method as defined in claim 18 wherein the disease or disorder is selected from transplant rejection of kidney, liver, heart, lung, pancreas, bone marrow, cornea, small bowel, skin allografts, skin homografts, heart valve xenograft, serum sickness, and graft vs. host disease, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Type I and Type II diabetes, juvenile diabetes, obesity, asthma, inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, pyoderma gangrenum, systemic lupus erythematosis, myasthenia gravis, psoriasis, dermatitis, dermatomyositis;

eczema, seborrhoea, pulmonary inflammation, eye uveitis, hepatitis, Grave'"'"'s disease, Hashimoto'"'"'s thyroiditis, autoimmune thyroiditis, Behcet'"'"'s or Sjorgen'"'"'s syndrome, pernicious or immunohaemolytic anaemia, atherosclerosis, Addison'"'"'s disease, idiopathic adrenal insufficiency, autoimmune polyglandular disease, glomerulonephritis, scleroderma, morphea, lichen planus, viteligo, alopecia areata, autoimmune alopecia, autoimmune hypopituatarism, Guillain-Barre syndrome, and alveolitis;

contact hypersensitivity, delayed-type hypersensitivity, contact dermatitis, uticaria, -skin allergies, respiratory allergies, hayfever, allergic rhinitis arid gluten-sensitive enteropathy, osteoarthritis, acute pancreatis, chronic pancreatitis, acute respiratory distress syndrome, Sezary'"'"'s syndrome, restenosis, stenosis and artherosclerosis, congenital adrenal hyperplasia, nonsuppurative thyroiditis, hypercalcemia associated with cancer, juvenile rheumatoid arthritis, Ankylosing spondylitis, acute and subacute bursitis, acute nonspecific tenosynovitis, acute gouty arthritis, post-traumatic osteroarthritis, synovitis of osteoarthritis, epicondylitis, acute rheumatic carditis, pemphigus, bullous dermatitis herpetitformis, severe erythema multiforme, exfoliative dermatitis, psoriasis, seborrheic dermatitis, seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, drug hypersensitivity reactions, allergic conjuncivitis, keratitis, herpes zoster ophthalmicus, iritis and iridocyclitis, chorioretinitis, optic neuritis, symptomatic sarcoidosis, fulminating or disseminated pulmonary tuberculosis chemotherapy, idiopathic thrombocytopenic purpura in adults, secondary thrombocytopenia in adults, acquired (autoimmune) hemolytic anemia, leukemias and lymphomas in adults, acute leukemia of childhood, ulcerative colitis, regional enteritis, Crohn'"'"'s disease, Sjogren'"'"'s syndrome, autoimmune vasculitis, multiple sclerosis, myasthenia gravis, sepsis, and chronic obstructive pulmonary disease.

20. The method as defined in claim 19 wherein the disease or disorder is selected from transplant rejection, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Type I diabetes, asthma, inflammatory bowel disease, systemic lupus erythematosis, psoriasis and chronic pulmonary disease.

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

22. 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, wherein 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 and/or an anorectic agent, wherein 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, wherein the antihypertensive agent is an ACE inhibitor, angiotensin II receptor antagonist, NEP/ACE inhibitor, calcium channel blocker and/or β

-adrenergic blocker.

23. The combination as defined in claim 22 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, wherein the anti-obesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, and/or mazindol, wherein 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, 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, [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;

an angiotensin II receptor antagonist which is irbesartan, losartan or valsartan;

amlodipine besylate, prazosin HCl, verapamil, nifedipine, nadolol, propranolol, carvedilol, or clonidine HCl, wherein the platelet aggregation inhibitor is aspirin, clopidogrel, ticlopidine, dipyridamole or ifetroban;

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.

24. A pharmaceutical composition comprising a combination as defined in claim 22 and a pharmaceutically acceptable carrier therefor.

11. A compound having the structure