Substituted Heteroaryl- and Phenylsulfamoyl Compounds

Abstract

The present invention is directed at substituted heteroaryl and phenylsulfamoyl compounds, pharmaceutical compositions containing such compounds and the use of such compounds as peroxisome proliferator actuator receptor (PPAR) agonists. PPAR alpha activators, pharmaceutical compositions containing such compounds and the use of such compounds to elevate certain plasma lipid levels, including high density lipoprotein-cholesterol and to lower certain other plasma lipid levels, such as LDL-cholesterol and triglycerides and accordingly to treat diseases which are exacerbated by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases, in mammals, including humans. The compounds are also useful for the treatment of negative energy balance (NEB) and associated diseases in ruminants.

1 - 16 . (canceled)  
   
   
       17 . A compound selected from the group consisting of: 
 2-Methyl-5-[4-(5-methyl-benzooxazol-2-yl)-phenylsulfamoyl]-benzoic acid;    5-[4-(5-Chloro-benzooxazol-2-yl)-phenylsulfamoyl]-2-methyl-benzoic acid;    2-Methyl-5-[4-(4-trifluoromethyl-benzylsulfanyl)-phenylsulfamoyl]-benzoic acid;    5-[4-(4-tert-Butyl-benzylsulfanyl)-phenylsulfamoyl]-2-methyl-benzoic acid;    2-Ethyl-5-[4-(5-methyl-benzooxazol-2-yl)-phenylsulfamoyl]-benzoic acid;    5-[4-(3,4-Difluoro-benzylsulfanyl)-phenylsulfamoyl]-2-methyl-benzoic acid;    5-[4-(3,4-Dimethyl-benzylsulfanyl)-phenylsulfamoyl]-2-methyl-benzoic acid;    5-[4-(5,7-Difluoro-benzothiazol-2-ylmethylsulfanyl)-phenylsulfamoyl]-2-methyl-benzoic acid;    2,3-Dimethyl-5-(4′-trifluoromethoxy-biphenyl-4-ylsulfamoyl)-benzoic acid;    2-Ethyl-5-[4-(4-trifluoromethoxy-benzylsulfanyl)-phenylsulfamoyl]-benzoic acid;    2-Ethyl-5-(4′-trifluoromethoxy-biphenyl-4-ylsulfamoyl)-benzoic acid;    2-Isopropyl-5-[2-(4-trifluoromethoxy-phenyl)-benzooxazol-5-ylsulfamoyl]-benzoic acid; and    2-Methyl-5-(4′-trifluoromethoxy-biphenyl-4-ylsulfamoyl)-benzoic acid;    or a pharmaceutically acceptable salt of said compound.    
   
   
       18 . (canceled)  
   
   
       19 . A method for treating dyslipidemia, obesity, overweight condition, hypertriglyceridemia, hyperlipidemia, hypoalphalipoproteinemia, metabolic syndrome, diabetes mellitus (Type I and/or Type II), hyperinsulinemia, impaired glucose tolerance, insulin resistance, diabetic complications, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, inflammation, osteoporosis, thrombosis, peripheral vascular disease, cognitive dysfunction, or congestive heart failure in a mammal by administering to a mammal in need of such treatment a therapeutically effective amount of a compound of  claim 33 , or a pharmaceutically acceptable salt of said compound.  
   
   
       20 . A pharmaceutical composition which comprises a therapeutically effective amount of a compound of  claim 33  or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.  
   
   
       21 . A pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising 
 a first compound, said first compound being a compound of  claim 33 , or a pharmaceutically acceptable salt of said compound;    a second compound, said second compound being a lipase inhibitor, an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, an HMG-CoA reductase gene expression inhibitor, an HMG-CoA synthase gene expression inhibitor, an MTP/Apo B secretion inhibitor, a CETP inhibitor, a bile acid absorption inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a squalene synthetase inhibitor, a squalene epoxidase inhibitor, a squalene cyclase inhibitor, a combined squalene epoxidase/squalene cyclase inhibitor, a fibrate, niacin, a combination of niacin and tovastatin, an ion-exchange resin, an antioxidant, an ACAT inhibitor, a bile acid sequestrant, or a prodrug of said compound or a pharmaceutically acceptable salt of said compound or prodrug; and    a pharmaceutically acceptable carrier, vehicle or diluent.    
   
   
       22 . A pharmaceutical combination composition of  claim 21  wherein the second compound is an HMG-CoA reductase inhibitor or a CETP inhibitor.  
   
   
       23 . A pharmaceutical combination composition of  claim 22  wherein the second compound is rosuvastatin, rivastatin, pitavastatin, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, or [2R, 4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester or a prodrug of said compound or a pharmaceutically acceptable salt of said compound or prodrug.  
   
   
       24 . A method for treating atherosclerosis in a mammal comprising administering to a mammal in need of treatment thereof, 
 a first compound, said first compound being a compound of  claim 33 , or a pharmaceutically acceptable salt of said compound, and    a second compound, said second compound being a lipase inhibitor, an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, an HMG-CoA reductase gene expression inhibitor, an HMG-CoA synthase gene expression inhibitor, an MTP/Apo B secretion inhibitor, a CETP inhibitor, a bile acid absorption inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a squalene synthetase inhibitor, a squalene epoxidase inhibitor, a squalene cyclase inhibitor, a combined squalene epoxidase/squalene cyclase inhibitor, a fibrate, niacin, a combination of niacin and lovastatin, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant.    wherein the amounts of first and second compounds result in a therapeutic effect.    
   
   
       25 . A method for treating atherosclerosis of  claim 24  wherein the second compound is an HMG-CoA reductase inhibitor or a CETP inhibitor.  
   
   
       26 . A method for treating atherosclerosis of  claim 25  wherein the second compound is rosuvastatin, pitavastatin, lovastatin simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, or [2R, 4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester or a prodrug of said compound or a pharmaceutically acceptable salt of said compound or prodrug.  
   
   
       27 . A kit for achieving a therapeutic effect in a mammal comprising packaged in association a first therapeutic agent comprising a therapeutically effective amount of a compound of  claim 33 , or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable carrier, a second therapeutic agent comprising a therapeutically effective amount of an HMG CoA reductase inhibitor, a CETP inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, slow-release niacin, a combination of niacin and lovastatin, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant and a pharmaceutically acceptable carrier and directions for administration of said first and second agents to achieve the therapeutic effect.  
   
   
       28 . A kit of  claim 27  wherein said second compound is an HMG-CoA reductase inhibitor or CETP inhibitor.  
   
   
       29 . A kit of  claim 28  wherein said second compound is rosuvastatin, pitavastatin, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, or [2R, 4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester or a prodrug of said compound or a pharmaceutically acceptable salt of said compound or prodrug.  
   
   
       30 . A method for treating negative energy balance in ruminants by administering to a ruminant in need of such treatment a therapeutically effective amount of a compound of  claim 33 , or a pharmaceutically acceptable salt of said compound.  
   
   
       31 - 32 . (canceled)  
   
   
       33 . A compound having a Formula I  
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt of said compound, wherein  
       Q is carbon;  
       each R 1  is independently hydrogen, halo, (C 1 -C 5 )alkyl optionally substituted with one or more halo or with (C 1 -C 3 )alkoxy, (C 1 -C 5 )alkoxy optionally substituted with one to eleven halo, (C 1 -C 5 )alkylthio optionally substituted with one or more halo or R 1  in conjunction with the two adjacent carbon atoms forms a C 5 -C 6 fused fully saturated, partially unsaturated or fully unsaturated five or six membered carbocyclic ring wherein each carbon in the carbon chain may optionally be replaced with one heteroatom selected from oxygen and sulfur;  
       R 2  is hydrogen or (C 1 -C 5 )alkyl optionally substituted with C 1 -C 3  alkoxy;  
       X is —COOR 4 , —O—(CR 3   2 )—COOR 4 , —S—(CR 3   2 )—COOR 4 , —CH 2 —(CR 5   w )—COOR 4 , 1H-tetrazol-5-yl-E- or thiazolidinedione-5-yl-G-; wherein w is 0, 1 or 2; E is (CH 2 ), and r is 0, 1, 2 or 3, and G is (CH 2 ) s  or methylidene and s is 0 or 1;  
       each R 3  is independently hydrogen, (C 1 -C 4 )alkyl optionally substituted with one to nine halo or with (C 1 -C 3 )alkoxy optionally substituted with one or more halo, or R 3  and the carbon to which it is attached form a 3, 4, 5, or 6 membered carbocyclic ring;  
       R 4  is H, (C 1 -C 4 )alkyl; benzyl or p-nitrobenzyl;  
       each R 5  is independently hydrogen, (C 1 -C 4 )alkyl optionally substituted with one to nine halo or with (C 1 -C 3 )alkoxy, (C 1 -C 4 )alkoxy optionally substituted with one to nine halo, (C 1 -C 4 )alkylthio optionally substituted with one to nine halo or with (C 1 -C 3 )alkoxy, or R 5  and the carbon to which it is attached form a 3, 4, 5, or 6 membered carbocyclic ring wherein any carbon of a 5- or 6-membered ring may be replaced by an oxygen atom;  
       Ar 1  is phenyl or phenyl fused to oxazolyl or thiazolyl wherein Ar 1  is optionally mono- or di-substituted independently with: halo, (C 1 -C 3 )alkyl optionally substituted with one to nine halo or (C 1 -C 3 )alkoxy optionally substituted with one to nine halo or (C 1 -C 3 )alkylthio optionally substituted with one to nine halo:  
       B is a bond, CO, (CY 2 ) n , CYOH, CY═CY, -L(CY 2 ) n —, —(CY 2 ) n -L-, -L-(CY 2 ) 2 -L-, NY—OC—, —CONY—, —SO 2 NY—, —NY—SO 2 — wherein each L is independently O, S, SO, or SO 2 , each Y is independently hydrogen or (C 1 -C 3 ) alkyl, and n is 0, 1, 2 or 3;  
       Ar 2  is phenyl or phenyl fused to a ring selected from the group consisting of: phenyl, pyridinyl, thienyl, thiazolyl, oxazolyl, and imidazolyl;  
       each J is independently hydrogen, hydroxy, halo, (C 1 -C 8 )alkyl optionally substituted with one to eleven halo, (C 1 -C 8 )alkoxy optionally substituted with one to eleven halo. (C 1 -C 8 )alkylthio optionally substituted with one to eleven halo, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkoxy, (C 3 -C 7 )cycloalkylthio, or phenyl optionally substituted with one to four substituents from the group consisting of: halo, (C 1 -C 8 )alkyl optionally substituted with one to five halo, (C 1 -C 8 )alkoxy optionally substituted with one to five halo, (C 1 -C 3 )alkylthio optionally substituted with one to five halo:  
       p and q are each independently 0, 1, 2 or 3; and with the provisos. 
 a) if Ar 1  is phenyl, B is a bond, Ar 2  is a bond or phenyl, and X is —COOH then q is other than 0 and J is other than hydrogen, halo, (C 1 -C 8 )alkyl or unsubstituted phenyl;  
 b) if Ar 2  is phenyl, B is not a bond, Ar 2  is phenyl and X is —COOR 4  then B is attached to Ar 1  para to NR 2 ; and  
 c) if B is O, S, SO, NH, CO, CH 2 , or SO 2  then R 1  is not H.  
 
     
   
   
       34 . A compound according to  claim 33 , wherein B is a bond or -L-(CY 2 ) n — or —(CY 2 ) n -L-, and L is O or S, and n is 0, 1 or 2.  
   
   
       35 . A compound according to  claim 34  wherein Ar 1  is:  
     
       
         
         
             
             
         
       
     
   
   
       36 . A compound according to  claim 35 , wherein q is 1 or 2 and each J is independently halo, (C 1 -C 3 )alkyl optionally substituted with one to three halo, or (C 1 -C 3 )alkoxy optionally substituted with one to three halo.  
   
   
       37 . A compound according to  claim 36  wherein p is 1 and R 4  is H or (C 1 -C 3 )alkyl.  
   
   
       38 . A compound according to  claim 33 , wherein 
 X is —COOR 4 ;    B is -L-(CY 2 ) n — or —(CY 2 ) n -L- , and L is O or S, and n is 0, 1 or 2;    Ar 1  is phenyl or phenyl fused to oxazolyl or triazolyl; and    Ar 2  is phenyl or phenyl fused to a ring selected from the group consisting of: phenyl, pyridinyl, thienyl, thiazolyl, oxazolyl, and imidazolyl.    
   
   
       39 . A compound according to  claim 38 , wherein  
     
       
         
         
             
             
         
       
     
   
   
       40 . A compound according to  claim 39 , wherein q is 1 or 2 and each J is independently halo, (C 1 -C 3 )alkyl optionally substituted with one to three halo, or (C 1 -C 3 )alkoxy optionally substituted with one to three halo.  
   
   
       41 . A compound according to  claim 40  wherein p is 1 and R 4  is H or (C 1 -C 3 )alkyl.  
   
   
       42 . A compound according to  claim 41 , wherein L is S and n is 1.  
   
   
       43 . A compound selected from the group consisting of; 
 2-Methyl-5-(4′-trifluoromethoxy-biphenyl-4-ylsulfamoyl)-benzoic acid;    2-Ethyl-5-[4-(6-methyl-benzothiazol-2-yl)-phenylsulfamoyl]-benzoic acid;    2-Methyl-5-(4′-trifluoromethyl-biphenyl-4-ylsulfamoyl)-benzoic acid;    2-Isopropyl-5-[propyl-(4′-trifluoromethoxy-biphenyl-4-yl)-sulfamoyl]-benzoic acid;    2-Methyl-5-[(4′-propoxy-biphenyl-4-yl)-propyl-sulfamoyl]-benzoic acid;    2-Methyl-5-(4′-propoxy-biphenyl-4-ylsulfamoyl)-benzoic acid;    5-(4′-tert-Butyl-biphenyl-4-ylsulfamoyl)-2-methyl-benzoic acid;    5-[4-(4-Chloro-benzylsulfanyl)-phenylsulfamoyl]-2-methyl-benzoic acid;    2-Methyl-5-[4-(3-trifluoromethoxy-benzylsulfanyl)-phenylsulfamoyl]-benzoic acid;    2-Methyl-5-[2-(4-trifluoromethyl-phenyl)-benzooxazol-5-ylsulfamoyl]-benzoic acid;    2-Methyl-5-[4-(5-phenyl-benzooxazol-2-yl)-phenylsulfamoyl)-benzoic acid; and    2-Isopropyl -5-[4-(5-methyl-benzooxazol-2-yl)-phenylsulfamoyl]-benzoic acid;    or a pharmaceutically acceptable salt of said compound.    
   
   
       44 . A compound having a Formula II  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein 
 R 3  is hydrogen or (C 1 -C 4 )alkyl;  
 Ar 1  is phenyl optionally mono-, di- or tri-substituted independently with: halo, (C 1 -C 3 )alkyl optionally substituted with one to five halo or (C 1 -C 3 )alkoxy optionally substituted with one to five halo or (C 1 -C 3 )alkylthio optionally substituted with one to five halo;  
 B is (CY 2 ) n , O, S; —CH 2 S— or —CH 2 O and n is 1 or 2;  
 Ar 2  is phenyl or phenyl fused to a ring selected from the group consisting of; phenyl, pyrimidinyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, and imidazolyl;  
 each J is independently hydrogen, hydroxy, halo; (C 1 -C 8 )alkyl optionally substituted with one to eleven halo. (C 1 -C 8 )alkoxy optionally substituted with one to eleven halo; (C 1 -C 8 )alkylthio optionally substituted with one to eleven halo; (C 3 -C 8 )cycloalkyl; (C 3 -C 7 )cycloalkoxy; (C 3 C 8 )cycloalkylthio; or phenyl optionally substituted with one or more halo or (C 1 -C 3 )alkyl optionally substituted with one to five halo or (C 1 -C 3 )alkoxy optionally substituted with one to five halo or (C 1 -C 3 )alkylthio optionally substituted with one to five halo; and  
 q is 0, 1, 2 or 3.  
 
   
   
       45 . A compound according to  claim 44 , wherein the compound is: 
 4-(5-Chloro-benzooxazol-2-yl)-phenylamine;    4-(4-Trifluoromethyl-benzylsulfanyl)-phenylamine;    4-(4-tert-Butyl-benzylsulfanyl)-phenylamine;    4-(4-Ethyl-benzylsulfanyl)-phenylamine;    4-(3,4-Difluoro-benzylsulfanyl)-phenylamine;    4-(3,4-Dimethyl-benzylsulfanyl)-phenylamine;    4-(5,7-Difluoro-benzothiazol-2-ylmethylsulfanyl)-phenylamine:    4′-Trifluoromethoxy-biphenyl-4-ylamine;    4-(4-Trifluoromethoxy-benzylsulfanyl)-phenylamine; or    4-Trifluoromethoxy-phenyl)-benzooxazol-5-ylamine;    or a pharmaceutically acceptable salt thereof.