Substituted azole acid derivatives useful as antidiabetic and antiobesity agents and method

Abstract

Compounds are provided which have the structure wherein Q is C or N; R 2a , R 2b , R 2c , X 1 to X 7 , R 1 , R 2 , R 3 , R 3a , R 4 , A, Y, m, and n are as defined herein, which compounds are useful as antidiabetic, hypolipidemic, and antiobesity agents. The present invention further provides a method for treating obesity and dyslipidemia in mammals including humans through simultaneous inhibition of peroxisome proliferator activated receptor-γ (PPARγ) and stimulation of peroxisome proliferator activated receptor-α (PPARα).

1 . A compound which has the structure  
       
         
           
           
               
               
           
         
       
       wherein m is 0, 1 or 2; n=0, 1 or 2; 
 Q is C or N  
 A is (CH 2 ) x  where x is 1 to 5; or A is (CH 2 ) x   1 , where x 1  is 2 to 5, with an alkenyl bond or an alkynyl bond embedded in the chain; or A is —(CH 2 ) x   2 —O—(CH 2 ) x   3 — where x 2  is 0 to 5 and x 3  is 0 to 5, provided that at least one of x 2  and x 3  is other than 0,  
 X 1  is CH or N  
 X 2  is C, N, O or S;  
 X 3  is C, N, O or S;  
 X 4  is C, N, O or S, provided that at least one of X 2 , X 3  and X 4  is N;  
 X 5  is C, N, O or S;  
 X 6  is C or N;  
 X 7  is C, N, O or S, provided that at least one of X 5 , X 6  or X 7  is N; and where in each of X 1  through X 7 , as defined above, C may include CH;  
 R 1  is H or alkyl;  
 R 2  is H, alkyl, alkoxy, halogen, amino or substituted amino;  
 R 2a , R 2b  and R 2c  are the same or different and are selected from H, alkyl, alkoxy, halogen, amino or substituted amino;  
 R 3  and R 3a  are the same or different and are independently selected from H, alkyl, arylalkyl, aryloxycarbonyl, alkyloxycarbonyl, alkynyloxycarbonyl, alkenyloxycarbonyl, arylcarbonyl, alkylcarbonyl, aryl, heteroaryl, alkyl(halo)aryloxycarbonyl, alkyloxy(halo)aryloxycarbonyl cycloalkylaryloxycarbonyl, cycloalkyloxyaryloxycarbonyl, cycloheteroalkyl, heteroarylcarbonyl, heteroaryl-heteroarylalkyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, heteroaryl-heteroarylcarbonyl, alkylsulfonyl, alkenylsulfonyl, heteroaryloxycarbonyl, cycloheteroalkyloxycarbonyl, heteroarylalkyl, aminocarbonyl, substituted aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylalkenyl, cycloheteroalkylheteroarylalkyl, hydroxyalkyl, alkoxy, alkoxyaryloxycarbonyl, arylalkyloxycarbonyl, alkylaryloxycarbonyl, arylheteroarylalkyl, arylalkylarylalkyl, aryloxyarylalkyl, alkynyloxycarbonyl, haloalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycarbonyl, aryloxyaryloxycarbonyl, arylsulfinylarylcarbonyl, arylthioarylcarbonyl, alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl, heteroaryloxyarylalkyl, aryloxyarylcarbonyl, aryloxyarylalkyloxycarbonyl, arylalkenyloxycarbonyl, arylalkylcarbonyl, aryloxyalkyloxycarbonyl arylalkylsulfonyl, arylthiocarbonyl, arylalkenylsulfonyl, hateroarylsulfonyl, arylsulfonyl, alkoxyarylalkyl, heteroarylalkoxycarbonyl, arylheteroarylalkyl, alkoxyarylcarbonyl, aryloxyheteroarylalkyl, heteroarylalkyloxyarylalkyl, arylarylalkyl, arylalkenylarylalkyl, arylalkoxyarylalkyl, arylcarbonylarylalkyl, alkylaryloxyarylalkyl, arylalkoxycarbonylheteroarylalkyl, heteroarylarylalkyl, arylcarbonylheteroarylalkyl, heteroaryloxyarylalkyl, arylalkenylheteroarylalkyl, arylaminoarylalkyl or aminocarbonylarylarylalkyl;  
 Y is CO 2 R 4  (where R 4  is H or alkyl, or a prodrug ester) or Y is a C-linked 1-tetrazole, a phosphinic acid of the structure P(O)(OR 4a )R 5 , (where R 4a  is H or a prodrug ester, R 5  is alkyl or aryl) or a phosphonic acid of the structure P(O) (OR 4a ) 2 ;  
 (CH 2 ) x , (CH 2 ) x   1 , (CH 2 ) x   2 , (CH 2 ) x   3 , (CH 2 ) m , and (CH 2 ) n  may be optionally substituted with 1, 2 or 3 substituents;  
 including all stereoisomers thereof, a prodrug ester thereof, and a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . A compound having the structure  
       
         
           
           
               
               
           
         
       
       wherein m is 0, 1 or 2; n=0, 1 or 2; 
 Q is C or N  
 x 2  is 0 to 5 and x 3  is 0 to 5, provided that at least one of x 2  and x 3  is other than 0,  
 X 2  is C, N, O or S;  
 X 3  is C, N, O or S;  
 X 4  is C, N, O or S, provided that at least one of X 2 , X 3  and X 4  is N;  
 and where in each of X 2  through X 4 , as defined above, C may include CH;  
 R 1  is H or alkyl;  
 R 2  is H, alkyl, alkoxy, halogen, amino or substituted amino;  
 R 2a , R 2b  and R 2c  are the same or different and are selected from H, alkyl, alkoxy, halogen, amino or substituted amino;  
 R 3  and R 3a  are the same or different and are independently selected from H, alkyl, arylalkyl, aryloxycarbonyl, alkyloxycarbonyl, alkynyloxycarbonyl, alkenyloxycarbonyl, arylcarbonyl, alkylcarbonyl, aryl, heteroaryl, alkyl(halo)aryloxycarbonyl, alkyloxy(halo)aryloxycarbonyl cycloalkylaryloxycarbonyl, cycloalkyloxyaryloxycarbonyl, cycloheteroalkyl, heteroarylcarbonyl, heteroaryl-heteroarylalkyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, heteroaryl-heteroarylcarbonyl, alkylsulfonyl, alkenylsulfonyl, heteroaryloxycarbonyl, cycloheteroalkyloxycarbonyl, heteroarylalkyl, aminocarbonyl, substituted aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylalkenyl, cycloheteroalkylheteroarylalkyl, hydroxyalkyl, alkoxy, alkoxyaryloxycarbonyl, arylalkyloxycarbonyl, alkylaryloxycarbonyl, arylheteroarylalkyl, arylalkylarylalkyl, aryloxyarylalkyl, alkynyloxycarbonyl, haloalkoxyaryloxycarbonyl, alkoxycarbonylaryloxycarbonyl, aryloxyaryloxycarbonyl, arylsulfinylarylcarbonyl, arylthioarylcarbonyl, alkoxycarbonylaryloxycarbonyl, arylalkenyloxycarbonyl, heteroaryloxyarylalkyl, aryloxyarylcarbonyl, aryloxyarylalkyloxycarbonyl, arylalkenyloxycarbonyl, arylalkylcarbonyl, aryloxyalkyloxycarbonyl arylalkylsulfonyl, arylthiocarbonyl, arylalkenylsulfonyl, hateroarylsulfonyl, arylsulfonyl, alkoxyarylalkyl, heteroarylalkoxycarbonyl, arylheteroarylalkyl, alkoxyarylcarbonyl, aryloxyheteroarylalkyl, heteroarylalkyloxyarylalkyl, arylarylalkyl, arylalkenylarylalkyl, arylalkoxyarylalkyl, arylcarbonylarylalkyl, alkylaryloxyarylalkyl, arylalkoxycarbonylheteroarylalkyl, heteroarylarylalkyl, arylcarbonylheteroarylalkyl, heteroaryloxyarylalkyl, arylalkenylheteroarylalkyl, arylaminoarylalkyl or aminocarbonylarylarylalkyl;  
 (CH 2 ) x   2 , (CH 2 ) x   3 , (CH 2 ) m , and (CH 2 ) n  may be optionally substituted with 1, 2 or 3 substituents;  
 including all stereoisomers thereof, a prodrug ester thereof, and a pharmaceutically acceptable salt thereof.  
 
     
     
         3 . The compound as defined in  claim 1  having the structure  
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound as defined in  claim 1  having structure  
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound as defined in  claim 1  wherein (CH 2 ) x , (CH 2 ) x   1 , (CH 2 ) x   2 , (CH 2 ) x   3  are alkylene, alkenylene, allenyl, or alkynylene.  
     
     
         6 . The compound as defined in  claim 1  wherein X 1  is CH.  
     
     
         7 . The compound as defined in  claim 1  wherein X is N.  
     
     
         8 . The compound as defined in  claim 1  having the structure  
       
         
           
           
               
               
           
         
       
       wherein R 1  is alkyl, x 2  is 1, 2 or 3, m is 0 or 1, or (CH 2 ) m  is CHOH or CH-alkyl, n is 1, (CH 2 ) n  is a bond or CH 2 , X 2 , X 3 , and X 4  represent a total of 1, 2 or 3 nitrogens, R 3  is aryl, arylalkyl or heteroaryl and R 3a  is H or alkyl.  
     
     
         9 . The compound as defined in  claim 8  wherein R 1  is CH 3 , and R 3  is phenyl or phenyl substituted with alkyl, polyhaloalkyl, halo or alkoxy.  
     
     
         10 . The compound as defined in  claim 1  having the structure  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         11 . A pharmaceutical composition comprising a compound as defined in  claim 1  and a pharmaceutically acceptable carrier therefor.  
     
     
         12 . A method for lowering blood glucose levels, or for treating diabetes which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound as defined in  claim 1 .  
     
     
         13 . A method for treating a premalignant disease, an early malignant disease, a malignant disease, or a dysplastic disease, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound as defined in  claim 1 .  
     
     
         14 . A pharmaceutical combination comprising a compound as defined in  claim 1  and 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 PPARγ 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.  
     
     
         15 . The combination as defined in  claim 12  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.    
     
     
         16 . A method for treating insulin resistance, hyperglycemia, hyperinsulinemia, or elevated blood levels of free fatty acids or glycerol, hyperlipidemia, obesity, Syndrome X, dysmetabolic syndrome, inflammation, diabetic complications, impaired glucose homeostasis, impaired glucose tolerance, hypertriglyceridemia or atherosclerosis which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a pharmaceutical combination as defined in  claim 14 .  
     
     
         17 . The method as defined in  claim 13  wherein the disease is a liposarcoma or an epithelial tumor.  
     
     
         18 . The method as defined in  claim 17  wherein the epithelial tumor is a tumor of the breast, prostate, colon, ovaries, stomach or lung.  
     
     
         19 . A method for treating irritable bowel syndrome, Crohn's disease, gastric ulceritis or osteroporosis, or psoriasis, or for treating obesity, insulin resistance, dyslipidemia, cardiovascular diseases and liver abnormalities, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a compound as defined in  claim 1 .  
     
     
         20 . A method for treating obesity and cardiovascular disease through altering the expression of a gene selected from the following: HMGic, glycerol-PO 4  dehydrogenase, fatty acid transport protein, G-protein coupled receptor 26, adipophilin, keratinocyte, fatty acid binding protein, angiotensinogen, PAI-1, and renin, through administration of a dual PPARgamma antagonist/PPARalpha agonist.