Compounds for the treatment of metabolic disorders

Abstract

Compounds useful for the treatment of various metabolic disorders, such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, cachexia, obesity, atherosclerosis and arteriosclerosis, are disclosed.

1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 n is 1 or 2;  
 m is 0 or 1;  
 q is 0 or 1;  
 t is 0 or 1;  
 R 5  is alkyl having from 1 to 3 carbon atoms;  
 A is phenyl, unsubstituted or substituted by 1 or 2 groups selected from: halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy; and  
 R 9  is halo, or alkoxy having from 1 to 3 carbon atoms; and  
 X is —CH 2 —, Q is OR 1  and R 1  is ethyl; or X is —CH 2 CR 12 R 13 —or —CH 2 CH(NHAc)—wherein each of R 12  and R 13  is independently hydrogen or methyl, Q is OR 1  and R 1  is hydrogen or alkyl having from 1 to 7 carbon atoms; or X is —CH 2 CH 2 — and Q is NR 10 R 11  wherein one of R 10  and R 11  is hydrogen, alkyl having from 1 to 3 carbon atoms or hydroxy, and the other is hydrogen or alkyl having from 1 to 3 carbon atoms; or  
 R 9  is hydrogen: and  
 X is —CH 2 CR 12 R 13 —or —CH 2 CH(NHAc)—wherein one of R 12  and R 13  is methyl and the other is hydrogen or methyl 0 is OR 1  and R is hydrogen or alkyl having from 1 to 7 carbon atoms: or X is —CH 2 CH 2 — and Q is NR 10 R 11  wherein one of R 10  and R 11  is hydrogen, alkyl having from 1 to 3 carbon atoms or hydroxy, and the other is hydrogen or alkyl having from 1 to 3 carbon atoms,  
 or when R 1  is hydrogen, a pharmaceutically acceptable salt of the compound.  
 
     
     
         2 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 n is 1 or 2;  
 m is 0 or 1;  
 q is 0 or 1;  
 t is 0 or 1;  
 R 5  is alkyl having from 1 to 3 carbon atoms;  
 A is phenyl, unsubstituted or substituted by 1 or 2 groups selected from: halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy; and  
 X is —CH 2 — and R 1  is ethyl; or X is CH 2 CH 2 — or —CH 2 CH(NHAc)- and R 1  is hydrogen or alkyl having from 1 to 7 carbon atoms;  
 or when R 1  is hydrogen, a pharmaceutically acceptable salt of the compound.  
 
     
     
         3 . The compound or salt of  claim 2 , wherein R 1  is hydrogen or ethyl.  
     
     
         4 . The compound or salt of  claim 2 , wherein q is 0.  
     
     
         5 . The compound or salt of  claim 2 , wherein X is —CH 2 CH 2 —.  
     
     
         6 . The compound or salt of  claim 2 , wherein A is phenyl, unsubstituted or substituted by 1 or 2 groups selected from: halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy;  
       wherein each halo is independently fluoro or chloro.  
     
     
         7 . The compound or salt of  claim 6 , wherein each halo substituent on phenyl ring A is fluoro.  
     
     
         8 . The compound or salt of  claim 7 , wherein phenyl ring A is substituted by 2 fluoro groups.  
     
     
         9 . The compound or salt of  claim 2 , wherein A is phenyl, unsubstituted or substituted by 1 or 2 groups selected from: halo, alkyl having 1 carbon atom, perfluoromethyl, alkoxy having 1 carbon atom, and perfluoromethoxy.  
     
     
         10 . The compound of  claim 2 , having the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 n is 1 or 2;  
 m is 0 or 1;  
 q is 0 or 1;  
 t is 0 or 1;  
 R 2  and R 3  are each independently selected from hydrogen, halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy;  
 R 5  is alkyl having from 1 to 3 carbon atoms; and  
 X is —CH 2 —and R 1  is ethyl; or X is H 2 CH 2 — or CH 2 CH(NHAc)- and R 1  is hydrogen or alkyl having from 1 to 7 carbon atoms;  
 or when R 1  is hydrogen, a pharmaceutically acceptable salt of the compound.  
 
     
     
         11 . The compound or salt of  claim 10 , wherein R 1  is hydrogen or ethyl.  
     
     
         12 . The compound or salt of  claim 11 , wherein the compound is 4-[4-(2-(N-(2-fluorobenzyl)-N-methylamino)ethoxy)phenyl)]-4-oxobutyric acid.  
     
     
         13 . The compound or salt of  claim 11 , wherein the compound is (2RS), 2-N-acetyl)(2,6-difluorobenzyloxy)phenyl)-4-oxobutyric acid.  
     
     
         14 . The compound or salt of  claim 11 , wherein the compound is 4(3-(4trifluoromethylbenzyloxy)phenyl)-4-oxobutyric acid.  
     
     
         15 . The compound of  claim 10 , having the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 n is 1 or 2;  
 m is 0 or 1;  
 p is 1 and R 1  is ethyl; or p is 2 and R 1  is hydrogen or alkyl having from 1 to 7 carbon atoms;  
 R 2  and R 3  are each independently selected from hydrogen, halo, alkyl having 1 or 2 carbon atoms, perfluoromethyl, alkoxy having 1 or 2 carbon atoms, and perfluoromethoxy;  
 or when R 1  is hydrogen, a pharmaceutically acceptable salt of the compound.  
 
     
     
         16 . The compound or salt  claim 15 , wherein R 1  is hydrogen or ethyl.  
     
     
         17 . The compound or salt of  claim 16 , wherein the compound is 4-(3-(2,6-Dimethoxybenzyloxy)phenyl)-4-oxobutyric acid.  
     
     
         18 . The compound or salt of  claim 15 , wherein one of R 2  and R 3  is hydrogen or halo and the other is halo.  
     
     
         19 . The compound or salt of  claim 18 , wherein the compound is 4-(4-(3-fluorobenzyloxy)phenyl)-4-oxobutyric acid.  
     
     
         20 . The compound salt of  claim 18 , wherein the compound is 4-(4-(4-fluorobenzyloxy)phenyl)-4-oxobutyric acid.  
     
     
         21 . The compound or salt of  claim 18 , wherein the compound is 4-(4-(2-chlorobenzyloxy)phenyl)-4-oxobutyric acid.  
     
     
         22 . The compound or salt of  claim 18 , wherein R 2  is fluoro and R 3  is hydrogen.  
     
     
         23 . The compound or salt of  claim 22 , wherein the compound is 4-(4-(2-fluorobenzyloxy)phenyl)-4-oxobutyric acid.  
     
     
         24 . The compound or salt of  claim 22 , wherein the compound is 4-(4-(2-(2-fluorophenyl)ethoxy)phenyl)-4-oxobutyric acid.  
     
     
         25 . The compound or salt of  claim 22 , wherein the compound is ethyl 4-(4-(2-fluorobenzyloxyl)phenyl)-4-oxobutyrate  
     
     
         26 . The compound of  claim 22 , ethyl 4-(3-(2-fluorobenzyloxyl)phenyl)-4-oxobutyrate.  
     
     
         27 . The compound or salt of  claim 16 , wherein R 2  is fluoro and R 3  is fluoro.  
     
     
         28 . The compound or salt of  claim 27 , wherein the compound is 4-(4-(2,5-difluorobenzyloxy)phenyl)-4-oxobutyric acid.  
     
     
         29 . The compound or salt of  claim 27 , wherein the compound is 4-(4-(2,4-difluorobenzyloxy)phenyl)-4-oxobutyric acid.  
     
     
         30 . The compound of  claim 27 , Ethyl 4-(4-(2,6-fluorobenzyloxy)phenyl)-3-oxobutyrate.  
     
     
         31 . The compound or salt of  claim 16 , wherein R 2  is methyl.  
     
     
         32 . The compound or salt of  claim 31 , wherein the compound is 4-(3-(2-Fluoro-6-methylbenzyloxy)phenyl)-4-oxobutyric acid.  
     
     
         33 . The compound of  claim 31 , Ethyl 4-(3-(2,6-dimethylbenzyloxyl)phenyl)-4-oxobutyrate.  
     
     
         34 . The compound or salt of  claim 31 , wherein the compound is 4-(4-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutyric acid.  
     
     
         35 . The compound or salt of  claim 1 , wherein A is 2,6-dimethylphenyl; t is 0, q is 0, n is 1, m is 0, x is —C 2 CR 12 R 13 —, wherein each of R 12  and R 13  is independently hydrogen or methyl.  
     
     
         36 . The compound or salt of  claim 35 , wherein the compound is 4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxo-2,2-dimethylbutyric acid.  
     
     
         37 . The compound or salt of  claim 35 , wherein the compound is 4-[[4(2,6-dimethylbenzyloxy)-3-methoxy]phenyl]-4-oxobutyric acid.  
     
     
         38 . The compound or salt of  claim 1 , wherein the compound is 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutanecarbohydroxamic acid.  
     
     
         39 . The compound or salt of  claim 1 , wherein the compound is 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyramide.  
     
     
         40 . The compound of  claim 27 , having the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 n is 1 or 2;  
 m is 0;  
 R 1  is H or alkyl having from 1 to 7 carbon atoms;  
 or when R 1  is hydrogen, a pharmaceutically acceptable salt of the compound.  
 
     
     
         41 . The compound or salt of  claim 40 , wherein the compound is 4-(4-(2,6-difluorobenzyloxy)phenyl)-4-oxobutyric acid.  
     
     
         42 . The compound of  claim 40 , Ethyl 4-(4-(2,6-difluorobenzyloxyl)phenyl)-4-oxobutyrate.  
     
     
         43 . The compound or salt of  claim 40 , wherein the compound is 4-(3-(2,6-difluorobenzyloxy)phenyl)-4-oxobutyric acid.  
     
     
         44 . The compound or salt of  claim 40 , wherein the compound is 4-(2-(2,6-difluorobenzyloxy)phenyl)-4-oxobutyric acid.