Novel anthranilic acid derivatives

Abstract

The invention is concerned with novel anthranilic acid derivatives of formula (I) wherein R 1 to R 14 and n are as defined in the description and in the claims, as well as physiologically acceptable salts and esters thereof. These compounds are HM74A agonists and can be used as medicaments.

1 . A compound of formula (I):  
     
       
         
         
             
             
         
       
       wherein  
       R 1  is hydrogen or lower-alkyl;  
       R 2 , R 3 , R 4  and R 5 , independently from each other, are hydrogen, halogen, lower-alkyl or fluoro-lower-alkyl, with the proviso that R 4 is not bromine;  
       R 6 , R 7 , R 8  and R 9 , independently from each other, are hydrogen, lower-alkyl, lower-alkoxy, cycloalkyl, halogen, lower-alkoxy-lower-alkyl, fluoro-lower-alkyl, fluoro-lower-alkoxy, lower alkenyl, lower alkinyl or cyano;  
       R 10 , R 11 , R 12  and R 13  independently from each other are hydrogen, lower-alkyl or fluoro-lower-alkyl, or R 10  and R 11  are bound together to form a cycloalkyl together with the carbon atom to which they are attached and —R 10 —R 11 — is —(CH 2 ) 2-6 —, or R 12  and R 13  are bound together to form a cycloalkyl together with the carbon atom to which they are attached and —R 12 —R 13 — is —(CH 2 ) 2-6 —;  
       R 14  is phenyl or heteroaryl, which phenyl or heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, lower-alkyl, hydroxy-lower-alkyl, lower-alkoxy, fluoro-lower-alkoxy, carboxy, carboxy-lower-alkyl, lower-alkoxy-carbonyl, lower-alkoxy-carbonyl-lower-alkyl, R 15 R 16 NC(O), R 15 R 16 NC(O)-lower-alkyl, fluoro-lower-alkyl, R 15 R 16 N-lower-alkyl, R 15 R 16 N, lower-alkyl-SO 2 , lower-alkyl-SO 2 O, lower-alkyl-SO 2 -NR 15 , R 15 R 16 NSO 2 , cyano, heteroaryl, cycloalkyl, lower-alkoxy-lower-alkyl, lower-alkenyl, lower-alkinyl, fluoro-lower-alkoxy-lower-alkyl, cyano-lower-alkyl;  
       R 15  and R 16  independently from each other are hydrogen or lower-alkyl;  
       m is 0 or 1;  
       n is 0 or 1;  
       and pharmaceutically acceptable salts and pharmaceutically acceptable esters thereof;  
       with the proviso that the compound of formula (I) is not selected from the group consisting of:  
       5-chloro-2-[[2,3-dimethyl-4-[1-[4-(2-methylpropyl)phenyl]ethoxy]benzoyl]amino]-benzoic acid,  
       2-[[4-[(4-bromophenoxy)methyl]benzoyl]amino]-benzoic acid methyl ester,  
       2-[(4-phenoxybenzoyl)amino]-benzoic acid,  
       2-[[4-[(3-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl ester,  
       2-[[4-[(4-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid,  
       2-[[4-[(2-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl ester,  
       2-[[4-[(2,4-dichlorophenoxy)methyl]benzoyl]amino]-benzoic acid methyl ester,  
       2-[[4-[[4-(1,1-dimethylethyl)phenoxy]methyl]benzoyl]amino]-benzoic acid methyl ester,  
       2-[[4-[(2-chloro-6-fluorophenyl)methoxy]benzoyl]amino]-benzoic acid methyl ester,  
       2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid methyl ester,  
       2-[[4-[(2-chlorophenyl)methoxy]benzoyl]amino]-benzoic acid methyl ester,  
       2-[[4-[(4-propylphenoxy)methyl]benzoyl]amino]-benzoic acid methyl ester, and  
       2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid 1-methylethyl ester.  
     
   
   
       2 . The compound according to  claim 1 , wherein R 1  is hydrogen.  
   
   
       3 . The compound according to  claim 1 , wherein R 2 , R 3 , R 4  and R 5 , independently from each other, are hydrogen or halogen, with the proviso that R 4  is not bromine.  
   
   
       4 . The compound according to  claim 1 , wherein R 2  is hydrogen or fluorine.  
   
   
       5 . The compound according to  claim 1 , wherein R 3  is hydrogen.  
   
   
       6 . The compound according to  claim 1 , wherein R 4  is hydrogen or fluorine.  
   
   
       7 . The compound according to  claim 1 , wherein R 5  is hydrogen.  
   
   
       8 . The compound according to  claim 1 , wherein R 6 , R 7 , R 8  and R 9 , independently from each other, are hydrogen, lower-alkyl or lower-alkoxy.  
   
   
       9 . The compound according to  claim 1 , wherein R 6  is hydrogen, methyl or methoxy.  
   
   
       10 . The compound according to  claim 1 , wherein R 7  is hydrogen or methyl.  
   
   
       11 . The compound according to  claim 1 , wherein R 8  is hydrogen.  
   
   
       12 . The compound according to  claim 1 , wherein R 9  is hydrogen.  
   
   
       13 . The compound according to  claim 1 , wherein R 14  is pyridinyl, quinolinyl or phenyl which is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, lower-alkyl, lower-alkoxy, lower-alkyl-SO 2 , lower-alkoxy-carbonyl, cyano, fluoro-lower-alkyl, R 15 R 16 NC(O) and triazolyl, wherein R 15  and R 16  independently from each other are hydrogen or lower-alkyl.  
   
   
       14 . The compound according to  claim 1 , wherein R 14  is phenyl, 2-methyl-phenyl, 2-fluoro-phenyl, 2-chloro-phenyl, 3-fluoro-phenyl, 3-methyl-phenyl, quinolin-8-yl, 4-[1,2,4]-triazol-1-yl-phenyl, 2,4-difluoro-phenyl, pyridin-2-yl or 2,5-difluoro-phenyl.  
   
   
       15 . The compound according to  claim 1 , wherein m is 0.  
   
   
       16 . The compound according to  claim 1 , wherein n is 0 or 1 and R 12  and R 13  are hydrogen.  
   
   
       17 . The compound according to  claim 1 , wherein n is 0.  
   
   
       18 . The compound according to  claim 1 , selected from the group consisting of 
 2-(4-Benzyloxy-benzoylamino)-benzoic acid,    2-[4-(4-Fluoro-phenoxy)-benzoylamino]-benzoic acid,    2-[4-(3,4-Dichloro-phenoxy)-benzoylamino]-benzoic acid,    2-(4-p-Tolyloxy-benzoylamino)-benzoic acid,    2-[4-(3-Methoxy-phenoxy)-benzoylamino]-benzoic acid,    2-(4-o-Tolyloxy-benzoylamino)-benzoic acid,    2-[4-(4-Methoxy-phenoxy)-benzoylamino]-benzoic acid,    2-[4-(4-Chloro-phenoxy)-benzoylamino]-benzoic acid,    2-[4-(3,4-Difluoro-phenoxy)-benzoylamino]-benzoic acid,    2-[4-(4-Methanesulfonyl-phenoxy)-benzoylamino]-benzoic acid,    2-[4-[4-Methoxycarbonyl)phenoxy]benzoyl]aminobenzoic acid,    2-[4-(3,5-Dichloro-phenoxy)-benzoylamino]-benzoic acid,    2-[4-(4-Cyano-phenoxy)-benzoylamino]-benzoic acid,    2-[4-(2-Fluoro-phenoxy)-benzoylamino]-benzoic acid,    2-[4-(2-Chloro-phenoxy)-benzoylamino]-benzoic acid,    2-[4-(3-Fluoro-phenoxy)-benzoylamino]-benzoic acid,    2-[4-(3-Chloro-phenoxy)-benzoylamino]-benzoic acid,    2-(4-m-Tolyloxy-benzoylamino)-benzoic acid,    2-[4-(Quinolin-8-yloxy)-benzoylamino]-benzoic acid,    2-[4-(4-Trifluoromethyl-phenoxy)-benzoylamino]-benzoic acid,    2-[4-(4-Carbamoyl-phenoxy)-benzoylamino]-benzoic acid,    2-[4-(4-Dimethylaminomethyl-phenoxy)-benzoylamino]-benzoic acid,    2-[4-(4-[1,2,4]Triazol-1-yl-phenoxy)-benzoylamino]-benzoic acid,    2-[4-(2,4-Difluoro-phenoxy)-benzoylamino]-benzoic acid,    2-[4-(Pyridin-2-yloxy)-benzoylamino]-benzoic acid,    2-[4-(Pyridin-3-yloxy)-benzoylamino]-benzoic acid,    2-[4-(3,4-Dimethyl-phenoxy)-benzoylamino]-benzoic acid,    2-[4-(2,3-Difluoro-phenoxy)-benzoylamino]-benzoic acid,    2-[4-(2,5-Difluoro-phenoxy)-benzoylamino]-benzoic acid,    2-(3-Methyl-4-phenoxy-benzoylamino)-benzoic acid,    2-(2-Methyl-4-phenoxy-benzoylamino)-benzoic acid,    2-(2-Methoxy-4-phenoxy-benzoylamino)-benzoic acid,    5-Fluoro-2-(4-phenoxy-benzoylamino)-benzoic acid,    4-Fluoro-2-(4-phenoxy-benzoylamino)-benzoic acid, and    2-Fluoro-6-(4-phenoxy-benzoylamino)-benzoic acid,    and pharmaceutically acceptable salts and esters thereof.    
   
   
       19 . The compound according to  claim 1 , selected from the group consisting of 
 2-(4-o-Tolyloxy-benzoylamino)-benzoic acid,    2-[4-(2-Fluoro-phenoxy)-benzoylamino]-benzoic acid,    2-[4-(2-Chloro-phenoxy)-benzoylamino]-benzoic acid,    2-[4-(3-Fluoro-phenoxy)-benzoylamino]-benzoic acid,    2-(4-m-Tolyloxy-benzoylamino)-benzoic acid,    2-[4-(Quinolin-8-yloxy)-benzoylamino]-benzoic acid,    2-[4-(4-[1,2,4]Triazol-1-yl-phenoxy)-benzoylamino]-benzoic acid,    2-[4-(2,4-Difluoro-phenoxy)-benzoylamino]-benzoic acid,    2-[4-(Pyridin-2-yloxy)-benzoylamino]-benzoic acid,    2-[4-(2,5-Difluoro-phenoxy)-benzoylamino]-benzoic acid,    2-(3-Methyl-4-phenoxy-benzoylamino)-benzoic acid,    4-Fluoro-2-(4-phenoxy-benzoylamino)-benzoic acid, and    2-Fluoro-6-(4-phenoxy-benzoylamino)-benzoic acid    and pharmaceutically acceptable salts and esters thereof.    
   
   
       20 . The compound according to  claim 1 , selected from the group consisting of 
 2-[4-(3-Fluoro-phenoxy)-3-methyl-benzoylamino]-benzoic acid,    2-[4-(2-Fluoro-phenoxy)-3-methyl-benzoylamino]-benzoic acid,    2-[4-(2,4-Difluoro-phenoxy)-3-methyl-benzoylamino]-benzoic acid,    4-Chloro-5-fluoro-2-(4-phenoxy-benzoylamino)-benzoic acid, and    2-(4-Phenoxy-benzoylamino)-5-trifluoromethyl-benzoic acid,    and pharmaceutically acceptable salts and esters thereof.    
   
   
       21 . A process for the manufacture of compounds of formula (I) as defined in  claim 1 , which process comprises 
 a) reacting a compound of formula (II)                          with a compound of formula (III),                          wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , m and n are as defined in any of claims  1 - 20  and R 17  is OH, Cl, Br, or a carboxylic acid moiety to form an anhydride; or    b) hydrolysis of a compound of formula (Ia)                          wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , m and n are as defined in any of claims  1 - 20  and R 1  is lower-alkyl.    
   
   
       22 . A pharmaceutical composition, comprising a therapeutically effecitve amount of a compound according to— claim 1  or a compound selected from the group consisting of: 
 5-chloro-2-[[2,3-dimethyl-4-[1-[4-(2-methylpropyl)phenyl]ethoxy]benzoyl]amino]-benzoic acid,    2-[[4-[(4-bromophenoxy)methyl]benzoyl]amino]-benzoic acid methyl ester,    2-[(4-phenoxybenzoyl)amino]-benzoic acid,    2-[[4-[(3-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl ester,    2-[[4-[(4-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid,    2-[[4-[(2-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl ester,    2-[[4-[(2,4-dichlorophenoxy) methyl]benzoyl]amino]-benzoic acid methyl ester,    2-[[4-[[4-(1,1-dimethylethyl) phenoxy]methyl]benzoyl]amino]-benzoic acid methyl ester,    2-[[4-[(2-chloro-6-fluorophenyl)methoxy]benzoyl]amino]-benzoic acid methyl ester,    2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid methyl ester,    2-[[4-[(2-chlorophenyl)methoxy]benzoyl]amino]-benzoic acid methyl ester,    2-[[4-[(4-propylphenoxy)methyl]benzoyl]amino]-benzoic acid methyl ester, and    2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid 1-methyl ethyl ester,    and a pharmaceutically acceptable carrier and/or adjuvant.    
   
   
       23 . A method for the treatment and/or prevention of diseases which are modulated by HM74A agonists, comprising the step of administering a therapeutically effective amount of a compound according to—claim 1 or a compound selected from the group consisting of: 
 5-chloro-2-[[2,3-dimethyl-4-[1-[4-(2-methylpropyl)phenyl]ethoxy]benzoyl]amino]-benzoic acid,    2-[[4-[(4-bromophenoxy)methyl]benzoyl]amino]-benzoic acid methyl ester,    2-[(4-phenoxybenzoyl)amino]-benzoic acid,    2-[[4-[(3-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl ester,    2-[[4-[(4-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid,    2-[[4-[(2-methoxyphenoxy)methyl]benzoyl]amino]-benzoic acid methyl ester,    2-[[4-[(2,4-dichlorophenoxy)methyl]benzoyl]amino]-benzoic acid methyl ester,    2-[[4-[[4-(1,1-dimethylethyl)phenoxy]methyl]benzoyl]amino]-benzoic acid methyl ester,    2-[[4-[(2-chloro-6-fluorophenyl)methoxy]benzoyl]amino]-benzoic acid methyl ester,    2-[[4-[(2-chlorophenoxy)methyl]benzoyl]amino]-benzoic acid methyl ester,    2-[[4-[(2-chlorophenyl)methoxy]benzoyl]amino]-benzoic acid methyl ester,    2-[[4-[(4-propylphenoxy)methyl]benzoyl]amino]-benzoic acid methyl ester, and    2-[[4-[(2-chlorophenoxy) methyl]benzoyl]amino]-benzoic acid 1-methylethyl ester,    to a human being or animal in need thereof.    
   
   
       24 . The method according to  claim 23 , wherein said disease is increased lipid levels, increased cholesterol levels, atherosclerotic diseases, dyslipidemia, low HDL-cholesterol, hypertriglyceridemia, thrombosis, angina pectoris, peripheral vascular disease, stroke, diabetes, non-insulin dependent diabetes mellitus, metabolic syndrome, Alzheimer's disease, Parkinson's disease, schizophrenia, impaired or improvable cognitive function, sepsis, inflammatory diseases, colitis, pancreatitis or cholestasisfibrosis of the liver.