2,6-quinolinyl and 2,6-naphthyl derivatives, processes for preparing them and their uses as vla-4 inhibitors

Abstract

The present invention concerns 2,6-quinolinyl and 2,6-naphthyl derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals.

1 . A compound of formula I or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein
 X is CH; 
 R 1  is cycloalkyl, aryl, heterocycle, aralkyl, heterocycle-alkyl, or a group of the formula: 
 
     
       
         
         
             
             
         
       
       R 2  is —NR 4 R 5 , —OR 4  or —C(═O)NR 5 R 6 ; 
       R 3  is tetrazole, —CN, —CH 2 OH or —CO—R 7 ; 
       R 4  is H, -G 1 -R 8 , or a group of the formula: 
     
     
       
         
         
             
             
         
       
       R 5  is H or C 1 -C 4 -alkyl; 
       or —NR 4 R 5  represents a heterocycle or —N═CR 9 R 10 ; 
       R 6  is aryl, heterocycle, cycloalkyl or aralkyl; 
       R 7  is hydroxy, amino, hydroxylamino, an oxy derivative or an amino derivative; 
       G 1  is CO, CH 2 , or SO 2 ; 
       R 8  is aryl, heterocycle, cycloalkyl, aralkyl or —NH-aryl; 
       R 9  is aryl; and 
       R 10  is ether; or 
       R 1  is cycloalkyl; 
       R 2  is —NR 4 R 5 ; 
       R 3  is —CO—R 7 ; 
       R 4  is H or -G 1 -R 8 ; 
       R 5  is H or C 1 -C 4 -alkyl; 
       G 1  is CO, CH 2 , or SO 2 ; 
       R 8  is an optionally substituted phenyl, cycloalkyl or —NH-optionally-substituted phenyl and 
       R 7  is neither an oxy derivative of formula —O—CHR b R c , wherein R b  is H, C 1 -C 6 -alkyl alkyl or an optionally substituted phenyl, and R c  is an optionally substituted phenyl, nor is R 7  an amino derivative of formula —NR d —CHR b R c  where R b  and R c  have the same definitions above, and R d  is H or C 1 -C 6 -alkyl. 
     
   
   
       2 . The compound according to  claim 1 , wherein
 R 1  is cycloalkyl, aryl, aromatic heterocycle or aralkyl;   R 2  is —NR 4 R 5 ;   R 3  is —CO—R 7 ;   R 4  is -G 1 -R 8 ;   R 7  is hydroxy, amino, hydroxylamino or an oxy derivative;   G 1  is CO; and   R 8  is aryl, heterocycle, cycloalkyl or —NH-aryl.   
   
   
       3 . The compound according to  claim 2 , wherein
 R 1  is 2,6-dichlorophenyl, 2,4-dichlorophenyl, 2,6-dimethoxyphenyl, 2-nitrophenyl, 2-(trifluoromethyl)phenyl, 2-bromophenyl, 2-(1,3-benzodioxol-5-yl)-1-methylethyl, 2-methoxyphenyl, 4-(methylsulfonyl)phenyl, 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl, 2,6-dimethylphenyl, 2-chloro-6-nitrophenyl, 3,5-dichloro-4-pyridinyl, 2-chloro-6-fluorophenyl, 2-methoxy-1-naphthyl, or 2-mesityl;   R 2  is —NHR 4 ;   R 7  is hydroxy, amino or C 1 -C 4 -alkyloxy;   and   R 8  is 2,6-dichlorophenyl, 1-carboxy-1,2,2-trimethyl-3-cyclopentyl, 1-((4-methylphenyl)sulfonyl)-2-piperidinyl, 1-[(4-methylphenyl)sulfonyl]-octahydro-1H-indol-2-yl, 1-(4-chlorophenyl)cyclopentyl, 2-chloro-4-(methylsulfonyl)phenyl, 2-chloro-6-methylphenyl, 3-acetyl-1,3 thiazolidin-4-yl, 2,6-dimethoxyphenyl, 2,6-dimethylphenyl, 2,6-difluorophenyl, 2-chloro-4-(methylsulfonyl)phenyl, 1-(methylsulfonyl)-2-piperidinyl, 2-methyltetrahydro-2-furanyl, 1-acetyl-2-pyrrolidinyl, 1-(phenylsulfonyl)-2-pyrrolidinyl, 2,4-dichloro-6-methyl-3-pyridinyl, 1-benzyl-5-oxo-2-pyrrolidinyl, 3-acetyl-1,1-dioxido-1,3-thiazolidin-4-yl or 1-[2-(diethylamino)ethyl]cyclopentyl.   
   
   
       4 . The compound according to  claim 3 , wherein
 R 1  is 2,6-dichlorophenyl, 2,6-dimethoxyphenyl, 3,5-dichloro-4-pyridinyl, 2-nitrophenyl, 2-chloro-6-fluorophenyl, 2-methoxy-1-naphthyl or 2-chloro-6-nitrophenyl;   R 7  is hydroxy or C 1 -C 4 -alkyloxy; and   R 8  is 2,6-dichlorophenyl, 1-carboxy-1,2,2-trimethyl-3-cyclopentyl, 1-((4-methylphenyl)sulfonyl)-2-piperidinyl, 1-[(4-methylphenyl)sulfonyl]octahydro-1H-indol-2-yl, 1-(4-chlorophenyl)cyclopentyl, 2-chloro-4-(methylsulfonyl)phenyl, 2-chloro-6-methylphenyl, 1-(phenylsulfonyl)-2-pyrrolidinyl, 2,4-dichloro-6-methyl-3-pyridinyl or 1-benzyl-5-oxo-2-pyrrolidinyl.   
   
   
       5 . The compound according to  claim 1 , wherein, when the carbon atom to which R 2  and R 3  are attached is asymmetric, it is in the “S”-configuration. 
   
   
       6 . The compound according to  claim 1  selected from the group consisting of
 2-[(2,6-dichlorobenzoyl)amino]-3-[6-(2,6-dimethoxyphenyl)-2-naphthyl]propanoic acid;   (−)-methyl 2-[(2,6-dichlorobenzoyl)amino]-3-[6-(2,6-dimethoxyphenyl)-2-naphthyl]propanoate;   (−)-2-[(2,6-dichlorobenzoyl)amino]-3-[6-(2,6-dimethoxyphenyl)-2-naphthyl]propanoic acid;   (+)-2-[(2,6-dichlorobenzoyl)amino]-3-[6-(2,6-dimethoxyphenyl)-2-naphthyl]propanoic acid;   3-[6-(2,6-dimethoxyphenyl)-2-naphthyl]-2-({[(2S)-1-(phenylsulfonyl)pyrrolidinyl]carbonyl}amino)propanoic acid; and   methyl 3-[6-(2,6-dimethoxyphenyl)-2-naphthyl]-2-({[(2S)-1(phenylsulfonyl)pyrrolidinyl]carbonyl}amino)propanoate   
   
   
       7 . The compound:
 (−)-2-[(2,6-dichlorobenzoyl)amino]-3-[6-(2,6-dimethoxyphenyl)-2-naphthyl]propanoic acid.   
   
   
       8 . A composition comprising as active ingredient a therapeutically effective amount of a compound according to  claim 1  and a pharmaceutically acceptable adjuvant, diluent or carrier. 
   
   
       9 - 13 . (canceled) 
   
   
       14 . A compound of formula III: 
     
       
         
         
             
             
         
       
     
     wherein
 X is CH; 
 R 1  is cycloalkyl, aryl, heterocycle, aralkyl, heterocycle-alkyl, or a group of the formula: 
 
     
       
         
         
             
             
         
       
       R 7  is hydroxy or an oxy derivative. 
     
   
   
       15 . A compound of formula IV: 
     
       
         
         
             
             
         
       
     
     wherein
 X is CH; 
 R 1  is cycloalkyl, aryl, heterocycle, aralkyl, heterocycle-alkyl, or a group of the formula: 
 
     
       
         
         
             
             
         
       
       R 3  is —CO—R 7 ; 
       R 7  is hydroxy or an oxy derivative; and 
       P is an amine protecting group. 
     
   
   
       16 . A compound of formula VIII: 
     
       
         
         
             
             
         
       
     
     wherein
 X is CH; 
 R 1  is cycloalkyl, aryl, heterocycle, aralkyl, heterocycle-alkyl, or a group of the formula: 
 
     
       
         
         
             
             
         
       
       R 3  is —CO—R 7 ; 
       R 7  is hydroxy or an oxy derivative; and 
       P is an amine protecting group. 
     
   
   
       17 . A compound selected from the group consisting of:
 2-(benzyloxy)-6-(2,6-dimethoxyphenyl)naphthalene;   6-(2,6-dimethoxyphenyl)-2-naphthol; and   6-(2,6-dimethoxyphenyl)-2-naphthyl trifluoromethanesulfonate.   
   
   
       18 . A composition comprising as active ingredient a therapeutically-effective amount of a compound according to  claim 7  and a pharmaceutically-acceptable adjuvant, diluent or carrier. 
   
   
       19 . A method for the treatment of a VLA-4-dependent inflammatory disease, comprising administering a therapeutically-effective amount of a compound according to  claim 1  to a patient in need thereof. 
   
   
       20 . A method for the treatment of a VLA-4-dependent inflammatory disease, comprising administering a therapeutically-effective amount of a compound according to  claim 7  to a patient in need thereof. 
   
   
       21 . A method for the treatment of asthma, allergic rhinitis, sinusitis, conjunctivitis, food allergy, inflammatory skin disorders, autoimmune disorders, or atherosclerosis, comprising administering a therapeutically-effective amount of a compound according to  claim 1  to a patient in need thereof. 
   
   
       22 . The method according to  claim 21 , wherein the treatment is for an inflammatory skin disorder selected from dermatitis, psoriasis, urticaria, pruritus, and eczema. 
   
   
       23 . The method according to  claim 21 , wherein the treatment is for an autoimmune disorder selected from rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. 
   
   
       24 . The method according to  claim 23 , wherein the treatment is for an inflammatory bowel disease selected from Crohn's disease and ulcerative colitis. 
   
   
       25 . A method for the treatment of asthma, allergic rhinitis, sinusitis, conjunctivitis, food allergy, inflammatory skin disorders, autoimmune disorders, or atherosclerosis, comprising administering a therapeutically-effective amount of a compound according to  claim 7  to a patient in need thereof. 
   
   
       26 . The method according to  claim 25 , wherein the treatment is for an inflammatory skin disorder selected from dermatitis, psoriasis, urticaria, pruritus, and eczema. 
   
   
       27 . The method according to  claim 25 , wherein the treatment is for an autoimmune disorder selected from rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. 
   
   
       28 . The method according to  claim 26 , wherein the treatment is for an inflammatory bowel disease selected from Crohn's disease and ulcerative colitis.