Benzamide derivatives and pharmaceutical compositions containing same

Abstract

The novel benzamide derivative represented by formula (1) and the novel anilide derivative represented by formula (13) of this invention has differentiation-inducing effect, and are, therefore, useful a therapeutic or improving agent for malignant tumors, autoimmune diseases, dermatologic diseases and parasitism. In particular, they are highly effective as an anticancer drug, specifically to a hematologic malignancy and a solid carcinoma.

1. A benzamide compound represented by formula (1): 
                 
 wherein A is an optionally substituted phenyl group or an optionally substituted heterocyclic group wherein the substituent(s) for the phenyl group or the heterocyclic group is (are) 1 to 4 substituents selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, an alkyl group having 1 to 4 carbons, an alkoxy group having 1 to 4 carbons, an aminoalkyl group having 1 to 4 carbons, an alkylamino group having 1 to 4 carbons, an acyl group having 1 to 4 carbons, an acylamino group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, a perfluoroalkyl group having 1 to 4 carbons, a perfluoroalkyloxy group having 1 to 4 carbons, a carboxyl group, an alkoxycarbonyl group having 1 to 4 carbons, a phenyl group and a heterocyclic group;  
 X is a bond or a moiety having a structure selected from those illustrated in formula (2): 
                 
 
  wherein e is an integer of 1 to 4; g and m are independently an integer of 0 to 4; R 4  is a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbons, or the acyl group represented by formula (3) 
                 
 
  wherein R 6  is an optionally substituted alkyl group having 1 to 4 carbons, a perfluoroalkyl group having 1 to 4 carbons, a phenyl group or a heterocyclic group;  
 R 5  is a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbons;  
 n is an integer of 0-4 , provided that when X is a bond, n is not zero ;  
 Q is a moiety having a structure selected from those illustrated in formula (4) 
                 
 
  wherein R 7  and R 8  are independently a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbons;  
 R 1  and R 2  are independently a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, an alkyl group having 1 to 4 carbons, an alkoxy group having 1 to 4 carbons, an aminoalkyl group having 1 to 4 carbons, an alkylamino group having 1 to 4 carbons, an acyl group having 1 to 4 carbons, an acylamino group having 1 to 4 carbons, an alkylthio group having 1 to 4 carbons, a perfluoroalkyl group having 1 to 4 carbons, a perfluoroalkyloxy group having 1 to 4 carbons, a carboxyl group or an alkoxycarbonyl group having 1 to 4 carbons;  
 R 3  is a hydroxyl or  an amino group; or a pharmaceutically acceptable salt thereof.  
 
     
     
       2. A benzamiode derivative or a pharmaceutically acceptable salt thereof as claimed in  claim 1 , wherein n is an integer of 1 to 4. 
     
     
       3. A benzamide derivative  compound or a pharmaceutically acceptable salt thereof as claimed in claim  2    1 , wherein Q is selected from the structures illustrated in formula (5): 
                 
 
       wherein R 7  and R 8  are as defined above. 
     
     
       4. A benzamide derivative  compound or a pharmaceutically acceptable salt thereof as claimed in  claim 3 , wherein A is an optionally substituted hetero ring. 
     
     
       5. A benzamide derivative  compound or a pharmaceutically acceptable salt thereof as claimed in  claim 4 , wherein A is an optionally substituted pyridyl group. 
     
     
       6. A benzamide derivative  compound or a pharmaceutically acceptable salt thereof as claimed in  claim 4 , wherein X is a direct bond. 
     
     
       7. A benzamide derivative  compound or a pharmaceutically acceptable salt thereof as claimed in  claim 6 , wherein R 1  and R 2  are a hydrogen atom. 
     
     
       8. A benzamide derivative or a pharmaceutically acceptable salt thereof  compound of formula (   1   ) as claimed in  claim 7 , wherein R 1  is an amino group . 
     
     
       9. A benzamide derivative  compound or a pharmaceutically acceptable salt thereof as claimed in  claim 5 , wherein X is the structure represented by formula (6):
   —(CH 2 )e—  (6)  
 
       wherein e is an integer of 1 to 4. 
     
     
       10. A benzamide derivative  compound or a pharmaceutically acceptable salt thereof as claimed in  claim 9 , wherein n is 1; and R 1  and R 2  are a hydrogen atom. 
     
     
       11. A benzamide derivative or a pharmaceutically acceptable salt thereof  compound of formula (   1   ) as claimed in  claim 10 , wherein R 3  is an amino group . 
     
     
       12. A benzamide derivative  compound or a pharmaceutically acceptable salt thereof as claimed in  claim 5 , wherein X is selected from the structure illustrated in formula (7): 
                 
 
       wherein e, g and R 4  are as defined above. 
     
     
       13. A benzamide derivative  compound or a pharmaceutically acceptable salt thereof as claimed in  claim 12 , wherein n is 1; and R 1  and R 2  are a hydrogen atom. 
     
     
       14. A benzamide derivative or a pharmaceutically acceptable salt thereof  compound of formula (   1   ) as claimed in  claim 13 , wherein R 3  is an amino group . 
     
     
       15. A benzamide derivative  compound or a pharmaceutically acceptable salt thereof as claimed in  claim 5 , wherein X is selected from the structures illustrated in formula (8): 
                 
 
       wherein g, m and R 5  are as defined above. 
     
     
       16. A benzamide derivative  compound or a pharmaceutically acceptable salt thereof as claimed in  claim 15 , wherein n is 1; and R 1  and R 2  are a hydrogen atom. 
     
     
       17. A benzamide derivative or a pharmaceutically acceptable salt thereof  compound of formula (   1   ) as claimed in  claim 16 , wherein R 3  is an amino group . 
     
     
       18. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in  claim 1 , wherein n is zero. 
     
     
       19. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in  claim 18 , wherein Q is selected from the structures illustrated in formula (5) 
                   
       
        
       
     
     
       20. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in  claim 19 , wherein A is an optionally substituted hetero ring. 
     
     
       21. A benzamide derivative or a pharmaceutically acceptable salt thereof as claimed in  claim 20 , wherein A is an optionally substituted pyridyl group. 
     
     
       22. A benzamide derivative  compound or a pharmaceutically acceptable salt thereof as claimed in claim  21    5 , wherein R 1  and R 2  are a hydrogen atom. 
     
     
       23. A benzamide derivative or a pharmaceutically acceptable salt thereof  compound of formula (   1   ) as claimed in  claim 22 , wherein R 1  is an amino group . 
     
     
       24. A benzamide derivative  compound or a pharmaceutically acceptable salt thereof as claimed in  claim 1   represented by formula (9) 
                 
 
     
     
       25. A benzamide derivative  compound or a pharmaceutically acceptable salt thereof as claimed in  claim 1   represented by formula (10) 
                 
 
     
     
       26. A benzamide derivative  compound or a pharmaceutically acceptable salt thereof as claimed in  claim 1   represented by formula (11) 
                 
 
     
     
       27. A benzamide derivative or a pharmaceutically acceptable salt thereof (as claimed in  claim 1 ) represented by formula (12) 
                   
       
        
       
     
     
       28. A composition suitable for the treatment of cancer which comprises a therapeutic effectively amount of a compound as set forth in  claim 1 , and a pharmaceutically acceptable carrier or excipient. 
     
     
       29. The composition of claim  28    31 , wherein said carrier or excipient is selected from the group consisting of lactose, glucose, starch, calcium carbonate, kaoline, crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, polyvinyl pyrrolidone, dried starch, sodium alginate, powdered agar, calcium carmelose, a mixture of starch and lactose, sucrose, butter, hydrogenated oil, a mixture of a quarternary ammonium base and sodium lauryl sulfate, glycerine and starch, lactose, bentonite, colloidal silicic acid, talc, stearates, and polyethylene glycol. 
     
     
       30. The composition of  claim 28 , which is in the form of a dosage formulation selected from the group consisting of a tablet, pill, powder, solution, suspension, emulsion, granule, capsule, injectable solution or suspension, and suppository. 
     
     
       31. A pharmaceutical composition which comprises a pharmaceutically effective amount of a compound according to  claim 1   benzamide compound represented by formula (   1   ): 
                 
   wherein A is an optionally substituted phenyl group or an optionally substituted heterocyclic group wherein the substituent ( s )  for the phenyl group or the heterocyclic group is  ( are )    1  to  4  substituents selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, an alkyl group having  1  to  4  carbons, an alkoxy group having  1  to  4  carbons, an aminoalkyl group having  1  to  4  carbons, an alkylamino group having  1  to  4  carbons, an acyl group having  1  to  4  carbons, an acylamino group having  1  to  4  carbons, an alkylthio group having  1  to  4  carbons, a perfluoroalkyl group having  1  to  4  carbons, a perfluoroalkyloxy group having  1  to  4  carbons, a carboxyl group, an alkoxycarbonyl group having  1  to  4  carbons, a phenyl group and a heterocyclic group;    
   X is a bond or a moiety having a structure selected from those illustrated in formula  (   2   ): 
                   
   wherein e is an integer of  1  to  4 ; g and m are independently an integer of  0  to  4 ; R   4    is a hydrogen atom or an optionally substituted alkyl group having  1  to  4  carbons, or the acyl group represented by formula  (   3   ) 
                   
   wherein R   6    is an optionally substituted alkyl group having  1  to  4  carbons, a perfluoroalkyl group having  1  to  4  carbons, a phenyl group or a heterocyclic group; R   5    is a hydrogen atom or an optionally substituted alkyl group having  1  to  4  carbons;    
   n is an integer of  0  to  4 , provided that when X is a bond, n is not zero;    
   Q is a moiety having a structure selected from those illustrated in formula  (   4   ) 
                   
   wherein R   7    and R   8    are independently a hydrogen atom or an optionally substituted alkyl group having  1  to  4  carbons;    
   R   1    and R   2    are independently a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, an alkyl group having  1  to  4  carbons, an alkoxy group having  1  to  4  carbons, an aminoalkyl group having  1  to  4  carbons, an alkylamino group having  1  to  4  carbons, an acyl group having  1  to  4  carbons, an acylamino group having  1  to  4  carbons, an alkylthio group having  1  to  4  carbons, a perfluoroalkyl group having  1  to  4  carbons, a perfluoroalkyloxy group having  1  to  4  carbons, a carboxyl group or an alkoxycarbonyl group having  1  to  4  carbons;    
   R   3    is an amino group;    
   or a pharmaceutically acceptable salt thereof; and    
   ii. a pharmaceutically acceptable carrier or excipient.    
 
     
     
       32. The composition of  claim 31 , which is a pharmaceutically acceptable formulation selected from the group consisting of a tablet, pill, powder, solution, suspension, emulsion, granule, capsule, injectable solution or suspension, and suppository. 
     
     
       33. A benzamide compound of formula (   9   ) 
                   
       
        
       
     
     
       34. A pharmaceutical composition which comprises a pharmaceutically effective amount of a benzamide compound according to  claim 33  and a pharmaceutically acceptable carrier or excipient. 
     
     
       35. A pharmaceutical composition which comprises a pharmaceutically effective amount of a benzamide compound or pharmaceutically acceptable salt thereof according to  claim 24 , and a pharmaceutically acceptable carrier or excipient. 
     
     
       36. A benzamide compound of formula (   10   ) 
                   
       
        
       
     
     
       37. A pharmaceutical composition which comprises a pharmaceutically effective amount of a benzamide compound according to  claim 36 , and a pharmaceutically acceptable carrier or excipient. 
     
     
       38. A pharmaceutical composition which comprises a pharmaceutically effective amount of a benzamide compound or pharmaceutically acceptable salt thereof according to  claim 25 , and a pharmaceutically acceptable carrier or excipient. 
     
     
       39. A benzamide compound of formula (   11   ) 
                   
       
        
       
     
     
       40. A pharmaceutical composition which comprises a pharmaceutically effective amount of a benzamide compound according to  claim 39 , and a pharmaceutically acceptable carrier or excipient. 
     
     
       41. A pharmaceutical composition which comprises a pharmaceutically effective amount of a benzamide compound or pharmaceutically acceptable salt thereof according to  claim 26 , and a pharmaceutically acceptable carrier or excipient. 
     
     
       42. A pharmaceutical composition which comprises a pharmaceutically effective amount of a benzamide compound of formula (   12   ) 
                   
       
         and a pharmaceutically acceptable carrier or excipient. 
       
     
     
       43. A pharmaceutical composition which comprises a pharmaceutically effective amount of a benzamide compound represented by formula (   12   ) 
                   
       
         or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.