Novel sulfonamides as l-cpt1 inhibitors

Abstract

The invention is concerned with novel sulfonamide derivatives of formula (I) wherein R 2 , R 3 , R 4 , A, X, Y 1 , Y 2 , Y 3 , Y 4 and Z 1 are as defined in the description and in the claims, as well as physiologically acceptable salts and esters thereof. These compounds inhibit L-CPT1 and can be used as medicaments.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         A is —C(O)OR 1  or selected from the group consisting of tetrazol-5-yl, 5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl, 2-oxo-2,3-dihydro-[1,2,3,5]oxathiadiazol-4-yl and 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl; 
         X is —N(R 5 )C(O)— or —C(O)N(R 5 )—; 
         V is N or C(R 6 ); 
         Y 2  is N or C(R 7 ); 
         Y 3  is N or C(H); 
         Y 4  is N or C(R 8 ); 
         Z 1  is N or C(R 9 ); 
         R 1  is hydrogen or lower-alkyl; 
         R 2  is hydrogen, halogen, hydroxy, cyano, lower-alkyl, fluoro-lower-alkyl, lower-alkoxy, fluoro-lower-alkoxy; NH 2 , N(H,lower-alkyl), N(lower-alkyl) 2 , or lower-alkyl-C(O)—O—, wherein lower-alkyl is optionally substituted with hydroxy, halogen, NH 2 , N(H,lower-alkyl), N(lower-alkyl) 2  or lower-alkoxy; 
         R 3  is hydrogen, lower-alkyl or lower-alkoxy-lower-alkyl; 
         R 4  is aryl or heteroaryl, which aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, cyano, lower-alkyl, fluoro-lower-alkyl, lower-alkoxy, fluoro-lower-alkoxy, lower-alkyl-C(O), lower-alkyl-C(O)—NH, lower-alkyl-C(O)—N(lower-alkyl), lower-alkyl-S(O) 2 , NH 2 —S(O) 2 , N(H,lower-alkyl)-S(O) 2  or N(lower-alkyl) 2 —S(O) 2 , NH 2 —C(O), N(H,lower-alkyl)-C(O), N(lower-alkyl) 2 —C(O), lower-alkoxy-C(O) or heteroaryl which is optionally substituted with lower-alkyl, halogen, thio-lower-alkoxy, or fluoro-lower-alkyl, 
         wherein lower-alkyl is optionally substituted with hydroxy, NH 2 , N(H,lower-alkyl) or N(lower-alkyl) 2 ; 
         R 5  is hydrogen, lower-alkyl or lower-alkoxy-lower-alkyl; 
         R 6 , R 7  and R 8  independently from each other are selected from the group consisting of hydrogen, halogen, hydroxy, cyano, lower-alkyl, fluoro-lower-alkyl, lower-alkoxy, fluoro-lower-alkoxy; NH 2 , N(H,lower-alkyl), N(lower-alkyl) 2 , or lower-alkyl-C(O)—O—, wherein lower-alkyl is optionally substituted with hydroxy, halogen, NH 2 , N(H,lower-alkyl), N(lower-alkyl) 2  and lower-alkoxy; 
         R 9  is hydrogen, halogen, hydroxy, cyano, lower-alkyl, fluoro-lower-alkyl, lower-alkoxy, fluoro-lower-alkoxy; NH 2 , N(H,lower-alkyl), N(lower-alkyl) 2 , or lower-alkyl-C(O)—O—, wherein lower-alkyl is optionally substituted with hydroxy, halogen, NH 2 , N(H,lower-alkyl), N(lower-alkyl) 2  or lower-alkoxy; 
         and pharmaceutically acceptable salts and esters thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein A is —C(O)OR 1  and R 1  is as defined in  claim 1 . 
     
     
         3 . The compound according to  claim 1 , wherein R 1  is hydrogen. 
     
     
         4 . The compound according to  claim 1 , wherein R 2  is hydrogen, halogen or lower-alkoxy. 
     
     
         5 . The compound according to  claim 1 , wherein R 2  is hydrogen. 
     
     
         6 . The compound according to  claim 1 , wherein R 3  is hydrogen. 
     
     
         7 . The compound according to  claim 1 , wherein R 4  is phenyl which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, fluoro-lower-alkyl, lower-alkoxy and fluoro-lower-alkoxy,
 or R 4  is thiophenyl which is substituted with a heteroaryl selected from the group consisting of isoxazolyl, pyrimidinyl and pyrazolyl, which heteroaryl is optionally substituted with 1 to 2 substituents selected from the group consisting of lower-alkyl, fluoro-lower-alkyl and thio-lower-alkoxy,   or R 4  is naphthalinyl.   
     
     
         8 . The compound according to  claim 1 , wherein R 4  is phenyl which is substituted with 1 to 2 substituents independently selected from the group consisting of halogen and lower-alkoxy. 
     
     
         9 . The compound according to  claim 1 , wherein R 4  is 3-chloro-phenyl, 3,4-dichloro-phenyl, 3,5-dichloro-phenyl or 5-chloro-2-methoxy-phenyl. 
     
     
         10 . The compound according to  claim 1 , wherein X is —C(O)N(R 5 )— and R 5  is as defined in  claim 1 . 
     
     
         11 . The compound according to  claim 10 , wherein R 5  is hydrogen. 
     
     
         12 . The compound according to  claim 1 , wherein Y 1  is C(R 6 ) and R 6  is as defined in  claim 1 . 
     
     
         13 . The compound according to  claim 12 , wherein R 6  is hydrogen, halogen or lower-alkoxy. 
     
     
         14 . The compound according to  claim 13 , wherein R 6  is hydrogen, chlorine or methoxy. 
     
     
         15 . The compound according to  claim 1 , wherein Y 2  is C(R 7 ) and R 7  is as defined in  claim 1 . 
     
     
         16 . The compound according to  claim 15 , wherein R 7  is hydrogen or lower-alkoxy. 
     
     
         17 . The compound according to  claim 16 , wherein R 7  is hydrogen or methoxy. 
     
     
         18 . The compound according to  claim 1 , wherein Y 3  is C(H). 
     
     
         19 . The compound according to  claim 1 , wherein Y 4  is C(R 8 ) and R 8  is as defined in  claim 1 . 
     
     
         20 . The compound according to  claim 19 , wherein R 8  is hydrogen. 
     
     
         21 . The compound according to  claim 1 , wherein Z 1  is N or C(R 9 ) and R 9  is hydrogen, halogen or lower-alkoxy. 
     
     
         22 . The compound according to  claim 21 , wherein Z 1  is C(R 9 ) and R 9  is hydrogen. 
     
     
         23 . The compound according to  claim 1 , selected from the group consisting of
 4-(3-Benzenesulfonylamino-benzoylamino)-benzoic acid,   4-[3-(4-Methoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[3-(3-Fluoro-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[3-(Naphthalene-2-sulfonylamino)-benzoylamino]-benzoic acid,   4-[3-(3,4-Dichloro-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[3-(2-Methoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[3-(3-Methoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[3-(2-Fluoro-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[3-(3-Chloro-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[3-(3-Trifluoromethyl-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[3-(3,5-Dichloro-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[3-(5-Chloro-2-methoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[3-(3-Difluoromethoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[3-(5-Isoxazol-3-yl-thiophene-2-sulfonylamino)-benzoylamino]-benzoic acid,   4-[3-[5-(2-Methylsulfanyl-pyrimidin-4-yl)-thiophene-2-sulfonylamino]-benzoylamino]-benzoic acid,   4-{3-[5-(2-Methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-thiophene-2-sulfonylamino]-benzoylamino}-benzoic acid,   2-Methoxy-4-[3-(3-trifluoromethyl-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[3-(3,5-Dichloro-benzenesulfonylamino)-benzoylamino]-2-methoxy-benzoic acid,   4-[3-(3,4-Dichloro-benzenesulfonylamino)-benzoylamino]-2-methoxy-benzoic acid,   4-[3-(3-Chloro-benzenesulfonylamino)-benzoylamino]-2-methoxy-benzoic acid,   4-[4-Chloro-3-(3-chloro-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[4-Chloro-3-(3,5-dichloro-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[4-Chloro-3-(3-trifluoromethyl-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[4-Chloro-3-(3-trifluoromethoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[4-Chloro-3-(5-chloro-2-methoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[4-Chloro-3-(3,4-dichloro-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[4-Chloro-3-(benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[4-Chloro-3-(2,5-dichloro-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[4-Chloro-3-(3-fluoro-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[4-Chloro-3-(2,5-dimethoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[3-(3-Chloro-benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid,   4-[3-(3,5-Dichloro-benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid,   4-[3,4-Dimethoxy-5-(3-trifluoromethyl-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[3-(5-Chloro-2-methoxy-benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid,   4-[3-(3,4-Dichloro-benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid,   4-[3-(benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid,   4-[3-(2,5-Dichloro-benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid,   4-[3-(3-Chloro-benzenesulfonylamino)-benzoylamino]-2-fluoro-benzoic acid, and   5-[3-(3-Chloro-benzenesulfonylamino)-benzoylamino]-pyridine-2-carboxylic acid,   and pharmaceutically acceptable salts and esters thereof.   
     
     
         24 . The compound according to  claim 1 , selected from the group consisting of
 4-[3-(3,4-Dichloro-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[3-(3-Chloro-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[3-(3,5-Dichloro-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[3-(5-Chloro-2-methoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[4-Chloro-3-(3-chloro-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[4-Chloro-3-(3,5-dichloro-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[4-Chloro-3-(5-chloro-2-methoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid,   4-[3-(3,5-Dichloro-benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid, and   4-[3-(5-Chloro-2-methoxy-benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid,   and pharmaceutically acceptable salts and esters thereof.   
     
     
         25 . The compound according to  claim 1 , selected from the group consisting of
 3-(3-Chloro-benzenesulfonylamino)-[4-(tetrazol-5-yl)-phenyl]-benzamide,   3-(5-Chloro-2-methoxy-benzenesulfonylamino)-[4-(tetrazol-5-yl)-phenyl]-benzamide,   3-(5-Chloro-2-methoxy-benzenesulfonylamino)-N-[4-(5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-benzamide,   3-(5-Chloro-2-methoxy-benzenesulfonylamino)-N-[4-(2-oxo-2,3-dihydro-[1,2,3,5]oxathiadiazol-4-yl)-phenyl]-benzamide,   3-(5-Chloro-2-methoxy-benzenesulfonylamino)-N-[4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-benzamide,   and pharmaceutically acceptable salts and esters thereof.   
     
     
         26 . A process for the manufacture of a compound of formula (I) as defined in  claim 1 , comprising the steps of:
 a) reacting a compound of formula (II)   
       
         
           
           
               
               
           
         
         with a compound LG-S(O) 2 —R 4 , 
         wherein R 2 , R 3 , R 4 , A, X, Y 1 , Y 2 , Y 3 , Y 4  and Z 1  are as defined in any of  claims 1 - 25  and LG is a leaving group, 
         or 
         b) reacting a compound of formula (III) 
       
       
         
           
           
               
               
           
         
         with a compound of formula (IV) 
       
       
         
           
           
               
               
           
         
         wherein R 2 , R 3 , R 4 , R 5 , A, X, Y 1 , Y 2 , Y 3 , Y 4  and Z 1  are as defined in any of  claims 1 - 25 , 
         or 
         c) reacting a compound of formula (V) 
       
       
         
           
           
               
               
           
         
         with a compound of formula (VI) 
       
       
         
           
           
               
               
           
         
         wherein R 2 , R 3 , R 4 , R 5 , A, X, Y 1 , Y 2 , Y 3 , Y 4  and Z 1  are as defined in  claim 1 . 
       
     
     
         27 . A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to  claim 1 , and a pharmaceutically acceptable carrier and/or adjuvant. 
     
     
         28 . A method for the therapeutic and/or prophylactic treatment of diseases which are modulated by L-CPT1 inhibitors, comprising the step of administering a therapeutically effective amount of a compound according to  claim 1  to a human being or animal in need thereof. 
     
     
         29 . The method according to  claim 28 , wherein said disease is hyperglycemia, glucose tolerance disorders, diabetes and associated pathologies, non insulin dependent diabetes mellitus, obesity, hypertension, insulin resistance syndrome, metabolic syndrome, hyperlipidemia, hypercholesterolemia, fatty liver disease, atherosclerosis, congestive heart failure or renal failure.