5-Amidino-N-(2-aminophenethyl)-2-hydroxybenzenesulfonamide derivative, medicinal composition containing the same, pharmaceutical use thereof, and intermediate therefor

Abstract

The present invention relates to a 5-amidino-N-(2-aminophenethyl)-2-hydroxybenzenesulfonamide derivative represented by the general formula: wherein R 1 is a hydrogen atom or a lower alkyl group; R 2 represents a hydrogen atom, an optionally substituted lower alkyl group, etc.; R 3 is a di(lower alkyl)amino group, a lower alkyl group, a cycloalkyl group, etc.; Q is a hydrogen atom or an optionally substituted lower alkyl group; and Z is a hydrogen atom or a hydroxy group, etc., or a pharmaceutically acceptable salt thereof, which exerts a potent and selective activated blood coagulation factor X inhibitory activity and is useful as an agent for the prevention or treatment of a disease occurred associating an activated blood coagulation factor X, a pharmaceutical composition comprising the same, a pharmaceutical use thereof and an intermediate thereof.

1 - 13 . (canceled)  
   
   
       14 . A 5-cyano-N-(2-aminophenethyl)-2-hydroxybenzenesulfonamide derivative represented by the general formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  represents a hydrogen atom or a lower alkyl group;  
 R 22  represents a hydrogen atom, a lower alkyl group, —Y 1 —COOR A  in which Y 1  represents a lower alkylene group or a single bond; and R A  represents a hydrogen atom, or a lower alkyl group, —COCOOR B  in which R B  represents a hydrogen atom or lower alkyl group, —Y 2 —CONH—R C  in which Y 2  represents a lower alkylene group or a single bond; and R C  represents a hydrogen atom, or a lower alkyl group which may have a substituent selected from the following group (i), —COCONH—R D  in which R D  is a hydrogen atom or a lower alkyl group which may have a substituent selected from the following group (ii), —CO—Y 3 —R E  in which Y 3  is a lower alkylene group or a single bond; and R E  represents a 5 to 10-membered aromatic heterocyclic group which may have a lower alkyl group, —CO—Y 41 —R F  in which Y 41  is a lower alkylene group which may have one or two optionally protected hydroxy groups; and R F  represents —COOR F1  in which R F1  is a hydrogen atom or a lower alkyl group, or a lower alkyl group which may have —COOR G  in which R G  is a hydrogen atom or a lower alkylsulfonyl group;  
 (i) —COOR C1  in which R C1  is a hydrogen atom and a lower alkyl group;  
 (ii) —COOR D1  in which R D1  is a hydrogen atom and a lower alkyl group;  
 R 3  represents a di(lower alkyl)amino group, a lower alkyl group, a 3 to 10-membered cycloalkyl group, a 6 to 10-membered aryl group which may have one to three substituents selected from the following group (A), a 3 to 10-membered heterocycloalkyl group which may have an oxo group or a 5 to 10-membered aromatic heterocyclic group which may have a substituent selected from the following group (B); 
 (A) an oxo group, a lower alkyl group, a halo(lower alkyl)group, —Y 5 —R H , a halogen atom, a nitro group, an amino group, —COOR I , a carbamoyl group, a sulfamoyl group, a loweralkylsulfonyl group, a mono(lower alkyl)sulfamoyl group which may have —COOR H , and a loweralkylsulfonylamino-substituted (lower alkyl) group; 
 wherein Y 5  represents an oxygen atom or a sulfur atom;  
 R H  represents a hydrogen atom, a halo(lower alkyl)group, or a lower alkyl group which may have —COOR H1  in which R H1  is a hydrogen atom, a 3 to 10-membered cycloalkyl group or a lower alkyl group;  
 R 1  represents a hydrogen atom or a 3 to 10-membered cycloalkyl group or a lower alkyl group;  
 R J  represents a hydrogen atom, a 3 to 10-membered cycloalkyl group or a lower alkyl group;  
 
 (B) a lower alkyl group, an amino group and —COOR K ; 
 wherein R K  represents a hydrogen atom, a 3 to 10-membered cycloalkyl group or a lower alkyl group;  
 
 
 Q represents a hydrogen atom or a lower alkyl group which may have a substituent selected from the following group (C); 
 (C) —OR L , —COOR M , —CONR N R O , a 6 to 10-membered aryl group which may have one to three substituents selected from the following group (iii), and a 5 to 10-membered aromatic heterocyclic group which may have one to three substituents selected from the following group (iv); 
 wherein R L  represents a hydrogen atom or a lower alkyl group which may have —OR L1    
 where R L1  represents a hydrogen atom or a lower alkyl group;  
 R M  represents a hydrogen atom, a 3 to 10-membered cycloalkyl group, or a lower alkyl group which may have a substituent selected from the following group (v);  
 R N  and R O  independently represent a hydrogen atom, a 6 to 10-membered aryl group which may have a carbamoyl group, a 5 to 10-membered aromatic heterocyclic group which may have a substituent selected from the following group (vi), or a lower alkyl group which may have a substituent selected from the following group (vii), or —NR N R O  forms a cyclic amino group which may have a substituent selected from the following group (viii);  
 (v) —COOR M1  in which R M1  is a hydrogen atom, a 3 to 10-membered cycloalkyl group or a lower alkyl group, —OCOR M2  in which R M2  is a 3 to 10-membered cycloalkyl group or a lower alkyl group, —OCOOR M3  in which R M3  is a 3 to 10-membered cycloalkyl group or a lower alkyl group, —OR M4  in which R M4  is a hydrogen atom, a 3 to 10-membered cycloalkyl group or a lower alkyl group, —CONR M5 R M6  in which R M5  and R M6  are independently a hydrogen atom or a lower alkyl group, or —NR M5 R M6  forms a cyclic amino group, a 3 to 10-membered cycloalkyl group, a 6 to 10-membered aryl group, a 3 to 10-membered heterocycloalkyl group, and a 5 to 10-membered aromatic heterocyclic group;  
 (vi) a halogen atom, a lower alkyl group, a carbamoyl group and —COOR N1  in which R N1  represents a hydrogen atom, or a lower alkyl group;  
 (vii) —OR N2  in which R N2  is a hydrogen atom or a lower alkyl group, and a 5 to 10-membered aromatic heterocyclic group;  
 (viii) a hydroxy group, a lower alkyl group, a hydroxy(lower alkyl) group, a carbamoyl group, a di(lower alkyl)amino group, a lower acyl group, and —COOR N3  in which R N3  represents a hydrogen atom or a lower alkyl group;  
 (iii) a halogen atom, a nitro group, a lower alkyl group, —OR P  in which R P  is a hydrogen atom or a lower alkyl group, and —COOR Q  in which R Q  is a hydrogen atom or a lower alkyl group;  
 (iv) a halogen atom, an oxo group, a lower alkyl group and a phenyl group;  
 or salt thereof.