VLA-4 inhibitory drug

Abstract

This invention relates to a VLA-4 inhibitory drug, having good oral absorbability and exhibiting sufficient anti-inflammatory effects when administered orally, wherein an active ingredient is represented by formula (I), or a salt thereof: Q represents an optionally-substituted monocyclic or bicyclic nitrogen-containing heterocyclic group having a nitrogen atom as the bonding site; Y represents an oxygen atom or CH 2 ; W represents an optionally-substituted bicyclic aromatic hydrocarbon ring group or an optionally-substituted bicyclic aromatic heterocyclic group; A 1 represents a nitrogen atom or C—R 3d wherein R 3d represents a hydrogen atom, a halogen atom, a C1-8 alkoxy group or a C1-8 alkyl group; R 1 represents H or a C1-8 alkyl group; R 2 represents H, a halogen, a C1-8 alkoxy

1 . A compound represented by the following formula (I): 
       
         
           
           
               
               
           
         
       
       wherein R 1  represents a hydrogen atom or a lower alkyl group; R 2  represents a hydrogen atom, a halogen atom, a lower alkoxy group, or a benzyloxy group which may be substituted with one or a plurality of substituents; Q represents a monocyclic or bicyclic nitrogen-containing heterocyclic group which may be substituted with one or a plurality of substituents, and has a nitrogen atom as the bonding site; Y represents an oxygen atom or CH 2 ; W represents a bicyclic aromatic hydrocarbon ring group which may be substituted with one or a plurality of substituents, or a bicyclic aromatic heterocyclic group which may be substituted with one or a plurality of substituents; R 3a , R 3b  and R 3c  each independently represent a hydrogen atom, a halogen atom, a lower alkoxy group or a lower alkyl group; and A represents a nitrogen atom or C—R 3d  (wherein R 3d  represents a hydrogen atom, a halogen atom, a lower alkoxy group or a lower alkyl group),
 or a salt thereof. 
 
     
     
         2 . The compound according to  claim 1 , wherein W in the formula (I) is a group represented by the following formula (I) or (ii): 
       
         
           
           
               
               
           
         
       
       wherein symbol “→” represents the position of attachment; R 4a  and R 4b  each independently represent a hydrogen atom, a halogen atom, a lower alkoxy group or a lower alkyl group; A 2a  represents an oxygen atom, a sulfur atom or N—R 4c  (wherein R 4c  represents a hydrogen atom or a lower alkyl group); A 2b  represents a nitrogen atom or C—R 4d  (wherein R 4d  represents a hydrogen atom or a lower alkyl group);
 R 5a  and R 5b  each independently represent a hydrogen atom, a halogen atom, a lower alkoxy group or a lower alkyl group; A 3a  represents a nitrogen atom or C—R 5c  (wherein R 5c  represents a hydrogen atom or a lower alkyl group); and A 3b  represents a nitrogen atom or C—R 5d  (wherein R 5d  represents a hydrogen atom or a lower alkyl group), 
 or a salt thereof. 
 
     
     
         3 . The compound according to  claim 1 , wherein W in the formula (I) is any one group among the groups represented by the following formulas (iii-a) to (iii-h): 
       
         
           
           
               
               
           
         
       
       wherein symbol “→” represents the position of attachment; R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , R 6i , R 6j , R 6k , R 6l , R 6m , R 6n , R 6o  and R 6p  each independently represent a hydrogen atom, a halogen atom, a lower alkoxy group or a lower alkyl group; and R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 7g  and R 7h  each independently represent a hydrogen atom or a lower alkyl group,
 or a salt thereof. 
 
     
     
         4 . The compound according to  claim 3 , wherein W in the formula (I) is a group represented by the formula (iii-a), (iii-b), (iii-c), (iii-d) or (iii-g),
 or a salt thereof.   
     
     
         5 . The compound according to  claim 3 , wherein W in the formula (I) is a group represented by the following formula (iii-a), (iii-b) or (iii-c),
 or a salt thereof.   
     
     
         6 . The compound according to any one of  claims 1  to  5 , wherein Q in the formula (I) is any one of groups represented by the following formulas (iv-a) to (iv-x): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein symbol “→” represents the position of attachment;
 R 9a  and R 9b  each independently represent a hydrogen atom, a halogen atom or a lower alkyl group; 
 R 10a  represents a hydrogen atom or a lower alkyl group; R 10b  represents a lower alkyl group; 
 R 11  represents a substituted lower alkyl group; 
 R 12a  represents a hydrogen atom or a lower alkyl group; R 12b  and R 12c  each independently represent a lower alkyl group or a lower cycloalkyl group which may be substituted with one or a plurality of substituents; or R 12b  and R 12c , together with the nitrogen atom to which they are bound, form an azetidin-1-yl group which may be substituted with one or a plurality of substituents, a pyrrolidin-1-yl group which may be substituted with one or a plurality of substituents, a piperidin-1-yl group which may be substituted with one or a plurality of substituents, or a morpholin-1-yl group which may be substituted with one or a plurality of substituents; 
 R 13a  and R 13b  each independently represent a hydrogen atom, a lower alkyl group or a lower alkoxymethyl group; 
 R 14a  and R 14b  each independently represent a lower alkyl group or a lower alkoxymethyl group; 
 R 15  represents a hydrogen atom, a lower alkyl group which may be substituted with one or a plurality of substituents, or a carbamoyl group which may be substituted with one or two substituents; 
 R 16a  represents a lower alkyl group; R 16b  and R 16c  each independently represent a hydrogen atom, a halogen atom or a lower alkoxy group; 
 R 17  represents a halogen atom, a lower alkoxy group or an amino group which may be substituted with one or two substituents; 
 R 18a  and R 18b  each independently represent a lower alkyl group; 
 R 19a  and R 19b  each independently represent a halogen atom, or R 19a  and R 19b , together with the carbon atoms on the pyrrolidine ring to which they are bound, form a C3 to C6 cycloalkyl ring; R 20a  represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group; A 5a  represents a nitrogen atom or C—R 20b  (wherein R 20b  represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group); A 5b  represents a nitrogen atom or C—R 20c  (wherein R 20c  represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group); A 5c  represents a nitrogen atom or C—R 20d  (wherein R 20d  represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group); 
 R 21  represents a hydrogen atom, or one or a plurality of lower alkyl groups; A 6  represents an oxygen atom, a sulfur atom or S(O) 2 ; 
 R 22a  represents a hydrogen atom, or one or a plurality of lower alkyl groups; A 7a  and A 7c  are directly bound to represent an oxygen atom or CH 2 ; A 7b  represents 1) an oxygen atom, a sulfur atom or S(O) 2  when A 7a  and A 7c  together form CH 2 , 2) represents CH 2  when A 7a  and A 7c  together form a direct bond, or 3) represents C(—R 22b )—R 22c  (wherein R 22b  and R 22c  each independently represent a hydrogen atom or a lower alkyl group) when A 7a  and A 7c  together form an oxygen atom; 
 R 23  represents a hydrogen atom, or one or a plurality of lower alkyl groups; A 8  represents an oxygen atom, a sulfur atom, S(O) 2  or CF 2 ; 
 R 24a  represents a hydrogen atom, or one or a plurality of lower alkyl groups; R 24b  represents a lower alkyl group; 
 R 25a  represents a hydrogen atom, or one or a plurality of lower alkyl groups; R 25b  represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxymethyl group which may be substituted with one or a plurality of substituents, a lower alkoxyethyl group which may be substituted with one or a plurality of substituents, a lower alkoxy group which may be substituted with one or a plurality of substituents, a phenoxy group which may be substituted with one or a plurality of substituents, a carbamoyl group which may be substituted with one or two substituents, a lower alkylsulfonyl group which may be substituted with one or a plurality of substituents, an amino group which may be substituted with one or two substituents, or a morpholin-4-yl group which may be substituted with one or a plurality of substituents; 
 R 26  represents a hydrogen atom, or one or a plurality of lower alkyl groups; A 9  represents an oxygen atom or S(O) 2 ; 
 R 27a  represents a hydrogen atom, or one or a plurality of lower alkyl groups; R 27b  represents a hydrogen atom, a lower alkyl group, a fluoro-lower alkyl group, a lower cycloalkylmethyl group, a lower alkoxyethyl group which may be substituted with one or a plurality of substituents, or a benzyl group which may be substituted with one or a plurality of substituents; 
 R 28a  represents a hydrogen atom, or one or a plurality of lower alkyl groups; R 28b  represents a lower cycloalkyl group which may be substituted with one or a plurality of substituents, or a pyridyl group which may be substituted with one or a plurality of substituents; 
 R 29a  represents a hydrogen atom, or one or a plurality of lower alkyl groups; A 10  represents C(O) or S(O) 2 ; R 29b  represents a lower alkyl group, a benzyl group which may be substituted with one or a plurality of substituents, or an amino group which may be substituted with one or two substituents; 
 R 30a  represents a hydrogen atom, or one or a plurality of lower alkyl groups; R 30b  represents a hydrogen atom, a lower alkyl group, or a benzyl group which may be substituted with one or a plurality of substituents; R 31a  represents a hydrogen atom, or one or a plurality of lower alkyl groups; A 11  represents an oxygen atom, CH—R 31b  (wherein R 31b  represents a hydrogen atom or a lower alkyl group), or N—R 31c  (wherein R 31c  represents a hydrogen atom, a lower alkyl group which may be substituted with one or a plurality of substituents, a lower cycloalkyl group which may be substituted with one or a plurality of substituents, or a lower alkylsulfonyl group which may be substituted with one or a plurality of substituents); and 
 A 12  represents an oxygen atom or N—R 32  (wherein R 32  represents a hydrogen atom, a lower alkyl group or a lower cycloalkyl group), 
 or a salt thereof. 
 
     
     
         7 . The compound according to  claim 6 , wherein Q in the formula (I) is a group represented by the formula (Iv-a), (iv-b), (iv-c), (iv-d), (iv-h), (iv-i), (iv-j), (iv-n), (iv-o), (iv-p), (iv-q), (iv-s), (iv-t) or (iv-u),
 or a salt thereof.   
     
     
         8 . The compound according to  claim 6 , wherein Q in the formula (I) is a group represented by the formula (Iv-b), (iv-h), (iv-j), (iv-o), (iv-q), (iv-s) or (iv-t),
 or a salt thereof.   
     
     
         9 . The compound according to  claim 6 , wherein Q in the formula (I) is a group represented by the formula (Iv-j),
 or a salt thereof.   
     
     
         10 . The compound according to  claim 9 , wherein both R 18a  and R 18b  in the formula (Iv-j) are methyl groups or ethyl groups,
 or a salt thereof.   
     
     
         11 . The compound according to  claim 6 , wherein Q in the formula (I) is a group represented by the formula (Iv-o),
 or a salt thereof.   
     
     
         12 . The compound according to  claim 11 , wherein R 23  in the formula (Iv-o) is a hydrogen atom, a methyl group or a dimethyl group; and A 8  is an oxygen atom or S(O) 2 ,
 or a salt thereof.   
     
     
         13 . The compound according to  claim 6 , wherein Q in the formula (I) is a group represented by the formula (Iv-s),
 or a salt thereof.   
     
     
         14 . The compound according to  claim 13 , wherein R 27a  in the formula (Iv-s) is a hydrogen atom; and R 27b  is a fluoro-lower alkyl group,
 or a salt thereof.   
     
     
         15 . The compound according to any one of  claims 1  to  14 , wherein the formula (I) is a configuration represented by the following formula (I-a): 
       
         
           
           
               
               
           
         
       
       wherein R, R 2 , Q, Y, R 3a , R 3b , R 3c , A 1  and W represent the same as those in the formula (I),
 or a salt thereof. 
 
     
     
         16 . The compound according to any one of  claims 1  to  14 , wherein the formula (I) is a configuration represented by the following formula (I-b): 
       
         
           
           
               
               
           
         
       
       wherein R, R 2 , Q, Y, R 3a , R 3b , R 3c , A 1  and W represent the same as those in the formula (I),
 or a salt thereof. 
 
     
     
         17 . The compound according to any one of  claims 1  to  14 , wherein the formula (I) is a configuration represented by the following formula (I-c): 
       
         
           
           
               
               
           
         
       
       wherein R, R 2 , Q, Y, R 3a , R 3b , R 3c , A 1  and W represent the same as those in the formula (I),
 or a salt thereof. 
 
     
     
         18 . The compound according to any one of  claims 1  to  17 , wherein A 1  in the formula (I) is C—R 3d  (wherein R 3d  represents a hydrogen atom, a halogen atom, a lower alkoxy group or a lower alkyl group),
 or a salt thereof. 
 
     
     
         19 . The compound according to  claim 18 , wherein R 3d  is a hydrogen atom,
 or a salt thereof.   
     
     
         20 . The compound according to any one of  claims 1  and  19 , wherein R 3a  in the formula (I) is a hydrogen atom, a fluorine atom or a chlorine atom; R 3b  is a hydrogen atom; and R 3c  is a fluorine atom, a chlorine atom, a methoxy group or a methyl group,
 or a salt thereof. 
 
     
     
         21 . The compound according to any one of  claims 1  to  17 , wherein the group represented by the following formula (v) in the formula (I) is any one of the groups represented by the following formulas (v-1) to (v-110): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein symbol “→” represents the position of attachment,
 or a salt thereof. 
 
     
     
         22 . The compound according to any one of  claims 1  to  21 , wherein R 2  in the formula (I) is a hydrogen atom,
 or a salt thereof. 
 
     
     
         23 . The compound according to any one of  claims 1  to  22 , wherein Y in the formula (I) is an oxygen atom,
 or a salt thereof. 
 
     
     
         24 . The compound according to any one of  claims 1  to  23 , wherein R 1  in the formula (I) is a hydrogen atom,
 or a salt thereof. 
 
     
     
         25 . A compound selected from the formulas represented by the following formulas (vi-1) to (vi-127): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a salt thereof, or a lower alkyl ester of the compound. 
       
     
     
         26 . The compound according to  claim 25 , represented by the formula (vi-26), (vi-27), (vi-28), (vi-29), (vi-30), (vi-31), (vi-32), (vi-35), (vi-45), (vi-47), (vi-48), (vi-50), (vi-51), (vi-53), (vi-54), (vi-55), (vi-58), (vi-88), (vi-89), (vi-90), (vi-91), (vi-92), (vi-93), (vi-94), (vi-95), (vi-96), (vi-97), (vi-98), (vi-99), (vi-100), (vi-123) or (vi-124),
 or a salt thereof, or a lower alkyl ester of the compound.   
     
     
         27 . A medicine comprising, as an active ingredient, the compound according to any one of  claims 1  to  26 , or a salt thereof. 
     
     
         28 . A VLA-4 inhibitory drug comprising, as an active ingredient, the compound according to any one of  claims 1  to  26 , or a salt thereof. 
     
     
         29 . A prophylactic and/or therapeutic drug for diseases caused by cellular adhesion, the drug comprising, as an active ingredient, the compound according to any one of  claims 1  to  26 , or a salt thereof. 
     
     
         30 . A prophylactic and/or therapeutic drug for diseases caused by the cellular adhesion involving VLA-4, the drug comprising, as an active ingredient, the compound according to any one of  claims 1  to  26 , or a salt thereof. 
     
     
         31 . The prophylactic and/or therapeutic drug according to  claim 29  or  30 , wherein the diseases caused by cellular adhesion include inflammatory diseases, autoimmune diseases, cancer metastasis, bronchial asthma, nasal congestion, diabetes mellitus, arthritis, psoriasis, multiple sclerosis, inflammatory bowel diseases, graft-versus-host disease, rejection on transplantation, acute myelogenous leukemia, chronic myelogenous leukemia, allergic granulomatous angiitis, atherosclerosis, eosinophilic pustular folliculitis, uveitis, glomerulonephritis, prometastatic breast cancer and malignant melanoma. 
     
     
         32 . Use of the compound according to any one of  claims 1  to  26 , or a salt thereof, for the manufacture of medicine. 
     
     
         33 . A method for preventing and/or treating diseases caused by cellular adhesion, the method comprising administering the compound according to any one of  claims 1  to  26 , or a salt thereof. 
     
     
         34 . A method for preventing and/or treating diseases caused by the cellular adhesion involving VLA-4, the method comprising administering the compound according to any one of  claims 1  to  26 , or a salt thereof. 
     
     
         35 . The method for preventing and/or treating according to  claim 33  or  34 , wherein the diseases caused by cellular adhesion include inflammatory diseases, autoimmune diseases, cancer metastasis, bronchial asthma, nasal congestion, diabetes mellitus, arthritis, psoriasis, multiple sclerosis, inflammatory bowel diseases, graft-versus-host disease, rejection on transplantation, acute myelogenous leukemia, chronic myelogenous leukemia, allergic granulomatous angiitis, atherosclerosis, eosinophilic pustular folliculitis, uveitis, glomerulonephritis, prometastatic breast cancer and malignant melanoma.