Novel salicylic anilides

Abstract

Novel salicylic anilides are chemical uncouplers useful e.g. for the treatment of obesity.

1 - 19 . (canceled) 
   
   
       20 . A method of treating obesity, atherosclerosis, hypertension, type 2 diabetes, dyslipidemia, coronary heart disease, osteoarthritis, gallbladder diseases, endometrial, breast, prostate or colon cancer, or preventing of weight gain or maintaining a weight loss, or treating diabetic microvascular diseases in the retina, renal glomerulus or peripheral nerve cell apoptosis, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according, formula I 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein X represent and m is 0, 1 or 2;
 R1 represents branched C 1-6 alkyl or phenyl; 
 R2 and R4 independently represent, hydrogen, C 1-6 alkyl, C 1-6 alkynyl or C 1-6 alkoxy; 
 R5, R6 and R7 together constitute a substitution pattern selected from the group consisting of 2-chloro-4-nitro; 2-chloro-4-cyano; 2-trifluoromethoxy-4-nitro; 2-trifluoromethoxy-4-cyano; 2-trifluoromethyl-4-(1-imidazolyl); and 2-methyl-4-(1-imidazolyl; 
 R3 represents C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 haloalkyl, arylC 1-6 alkyl, arylC 1-6 alkenyl, arylC 1-6 alkynyl, heteroarylC 1-6 alkyl, heteroarylC 1-6 alkenyl, heteroarylC 1-6 alkynyl, C 3-8 cycloalkyl, aryl, or heteroaryl; wherein R3 may optionally be substituted with up to four substituents, R10, R11, R12, and R13, wherein R10, R11, R12, and R13 independently represent C 1-6 alkyl, C 1-6 alkylaryl, halogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, oxo, cyano, nitro, —(CH2) r O R14, —SH, —S(O) p R15, —S(O) p N(R14)(R15), —C(O)OR14, —OC(O)R14, —C(O)R14, —C(O)N(R14)(R15), —(CH2) r N(R14)C(O)R15, —B(OR14)(OR15), —(CH2) r N(R14)(R15), or phenyl, wherein said phenyl is optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cyano, nitro, —OR16, —S(O) s R16, —C(O)OR16, —OC(O)R16, —C(O)R16, —C(O)N(R16)(R17), —N(R16)(R17), —(CH 2 ) s)N(R 16)C(O)R17, —B(OR16)(OR17), —(CH2) t OR16, or —(CH 2 ) t N(R16)(R17);
 each R14 independently represents hydrogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 3-8 cycloalkyl, or phenyl optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl and cyano; 
 R15 represents C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkyl, C 1-6 alkenyl, C 3-8 cycloalkyl, or phenyl optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl and cyano; 
 or wherein R14 and R15, when attached to a nitrogen atom, together with said nitrogen atom form a C 3-8 cycloalkyl or heteroaryl ring, optionally substituted with one or more C 1-6 alkyl substituents; 
 each R16 and R17 independently represents hydrogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl or C 3-8 cycloalkyl; or R16 and R17 when attached to a nitrogen atom together with said nitrogen atom form a cycloalkyl or heteroaryl ring, optionally substituted with one or more alkyl substituents; 
 p and s, independently of each other, are an integer of 0, 1, or 2; 
 r and t, independently of each other, are an integer of 0, 1, 2, or 3; 
 q is 0, 1, 2; 
 provided that the compound is not N-(2-chloro-4-nitrophenyl)-3-tert-butyl-6-methylsalicylanilide, 3,5-Di-tert-butyl-N-(2-chloro-4-nitro-phenyl)-2-hydroxy-benzamide or 3-tert-Butyl-N-(2-chloro-4-nitro-phenyl)-2-hydroxy-5-methyl-benzamide; 
 or a pharmaceutically acceptable salt or solvate thereof; 
 
 optionally in combination with other therapeutically active compounds, wherein said other compound may be administered either concomitantly or sequentially. 
 
   
   
       21 . The method according to  claim 20 , wherein the disease is selected from atherosclerosis, hypertension, type 2 diabetes, dyslipidemia, and wherein the patient is obese. 
   
   
       22 . The method according to  claim 20  for the prevention of weight gain or the maintenance of a weight loss. 
   
   
       23 . The method according to  claim 20 , wherein the disease is obesity. 
   
   
       24 - 25 . (canceled) 
   
   
       26 . The method of  claim 20 , wherein m is 0. 
   
   
       27 . A compound according to  claim 20 , wherein m is 1. 
   
   
       28 . A compound according to  claim 20 , wherein m is 2. 
   
   
       29 . A compound according to  claim 20 , wherein R1 represents phenyl, neopentyl, tert-butyl, isopropyl or 1,1-dimethylpropyl. 
   
   
       30 . A compound according to  claim 29 , wherein R1 represents tert-butyl. 
   
   
       31 . A compound according to  claim 20 , wherein R2 and R4 independently represent hydrogen or methyl. 
   
   
       32 . A compound according to  claim 20 , wherein R3 represents C 1-6 alkenyl or C 1-6 alkynyl, both of which are optionally substituted. 
   
   
       33 . A compound according to  claim 32 , wherein R3 represents styryl. 
   
   
       34 . A compound according to  claim 20  selected from the group consisting of
 5-tert-Butyl-4-hydroxy-2-methyl-biphenyl-3-carboxylic acid (2-chloro-4-nitrophenyl)-amide;   (E) 3-tert-Butyl-N-(2-chloro-4-cyano-phenyl)-2-hydroxy-5-styryl-benzamide;   5-tert-Butyl-4-hydroxy-2-methyl-biphenyl-3-carboxylic acid (4-cyano-2-trifluoromethoxy-phenyl)-amide;   5-tert-Butyl-4′-cyano-4-hydroxy-2-methyl-biphenyl-3-carboxylic acid (4-cyano-2-trifluoromethoxy-phenyl)-amide;   3-tert-Butyl-N-(2-chloro-4-cyano-phenyl)-5-(5-cyano-thiophen-2-yl)-2-hydroxy-benzamide; and   5-Benzo[b]thiophen-2-yl-3-tert-butyl-N-(2-chloro-4-cyano-phenyl)-2-hydroxy-benzamide;   or a pharmaceutically acceptable salt or solvate thereof.