Compounds exhibiting type X sPLA2 inhibiting effect

Abstract

A compound represented by the general formula: wherein R 20 is —CH 2 COOH and the like; R 21 is —COCONH 2 and the like; R 22 is C4-C6 alkyl; and the like; R 23 is —CH 2 —R 18 wherein R 18 is aryl and the like; R 24 is hydrogen or C1-C6 alkyl and the like; an optical active compound, a prodrug thereof, or a pharmaceutically acceptable salt, or a solvate having type X sPLA 2 inhibitory effect was found.

1 . A compound of the general formula (I):  
     
       
         
         
             
             
         
       
       wherein A ring is a ring represented by the formula (a) to (c):  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are each independently selected from hydrogen atom, non-interfering substituents, or -(L 1 )-(acidic group) wherein L 1  is an acid linker having an acid linker length of 1 to 5, provided that at least one of the R 1  and R 2  is -(L 1 )-(acidic group); 
 R 3  and R 4  are each independently selected from hydrogen atom, non-interfering substituents, carbocyclic groups, carbocyclic groups substituted with a non-interfering substituent(s), heterocyclic groups, or heterocyclic groups substituted with a non-interfering substituent(s);  
 —B— is represented by the formula (d) to (e):  
                     
 
       wherein R 5  is (f) C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, a carbocyclic group, or a heterocyclic group, (g) the groups represented by (f) each substituted independently with at least one group selected from non-interfering substituents, or -(L 2 )-R 8  wherein L 2  is a divalent linking group of 1 to 18 atom(s) selected from hydrogen atom(s), nitrogen atom(s), carbon atom(s), oxygen atom(s), and sulfur atom(s), and R 8  is a group selected from the groups (f) and (g);  
       R 6  is optionally substituted C4-C8 alkyl, C3-C8 cycloalkyl C1-C4 alkyl, or aryl C1-C4 alkyl;  
       R A  is represented by the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 9  and R 10  are each independently hydrogen atom, C1-C3 alkyl, or halogen;  
       X and Y are each independently oxygen atom or sulfur atom; and  
       Z is —NH 2  or —NHNH 2 ;  
       provided that —B— is (e), when A ring is (a);  
       a prodrug, a pharmaceutically acceptable salt, or a solvate thereof.  
     
   
   
       2 . A compound of  claim 1  wherein R 1  is hydrogen atom or -(L 3 )-R 11  wherein L 3  is —OCH 2 —, —SCH 2 —, —NH—CH 2 —, —CH 2 CH 2 —, —O—CH(CH 3 )—, or —O—CH(CH 2 CH 2 C 6 H 5 )—, R 11  is represented by the formula:  
     
       
         
         
             
             
         
       
       wherein R 38  is C1-C6 alkyl, C1-C3 haloalkyl, or aryl optionally substituted with C1-C6 alkyl, halogen, optionally substituted amino or nitro; 
 R 2  is hydrogen atom or -(L 4 )-R 12  wherein L 4  is represented by the formula:  
                     
 
       wherein R 13  and R 14  are each independently hydrogen atom, C1-C10 alkyl, aryl C1-C10 alkyl, carboxy, alkyloxycarbonyl, or halogen; R 12  is —COOH, —SO 3 H, or —P(O)(OH) 2 ; provided that R 1  and R 2  are not hydrogen atoms at the same time;  
       a prodrug, a pharmaceutically acceptable salt, or a solvate thereof.  
     
   
   
       3 . A compound of  claim 1  wherein R 3  is hydrogen atom, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, or a heterocyclic group, and R 4  is hydrogen atom or halogen; 
 a prodrug, a pharmaceutically acceptable salt, or a solvate thereof.    
   
   
       4 . A compound of  claim 1  wherein R 5  is —(CH 2 ) 1-6 —R 15  wherein R 15  is represented by the formula:  
     
       
         
         
             
             
         
       
       wherein b, d, f, h, j, m, and o are each independently an integer from 0 to 2, R 16  and R 17  are each independently halogen, C1-C10 alkyl, C1-C10 alkyloxy, C1-C10 alkylthio, aryloxy, or C1-C10 haloalkyl, α is oxygen atom or sulfur atom, β is —CH 2 — or —(CH 2 ) 2 —, γ is oxygen atom or sulfur atom, c, i, and p are each independently an integer from 0 to 5, e is an integer from 0 to 7, g is an integer from 0 to 4, k and n are each independently an integer from 0 to 3;  
       a prodrug, a pharmaceutically acceptable salt, or a solvate thereof.  
     
   
   
       5 . A compound of  claim 4  wherein R 5  is —CH 2 —R 18  wherein R 18  is represented by the formula:  
     
       
         
         
             
             
         
       
       whereβ in —CH 2 —, or —(CH 2 ) 2 —; R 19  is hydrogen atom, C1-C3 alkyl or halogen; E is a bond, —CH 2 —, or —O—;  
       a prodrug, a pharmaceutically acceptable salt, or a solvate thereof.  
     
   
   
       6 . A compound of  claim 1  wherein R 1  is —OCH 2 COOH or —OCH 2 CONHSO 2 R 38  wherein R 38  is C1-C6 alkyl, C1 haloalkyl, or aryl; 
 a prodrug, a pharmaceutically acceptable salt, or a solvate thereof.    
   
   
       7 . A compound of  claim 1  wherein R 2  is hydrogen atom; 
 a prodrug, a pharmaceutically acceptable salt, or a solvate thereof.    
   
   
       8 . A compound of  claim 1  wherein R 6  is C4-C6 alkyl; 
 a prodrug, a pharmaceutically acceptable salt, or a solvate thereof.    
   
   
       9 . A compound of  claim 1  wherein R A  is —CH 2 CONH 2  or —COCONH 2 ; 
 a prodrug, a pharmaceutically acceptable salt, or a solvate thereof.    
   
   
       10 . A compound of the general formula (II):  
     
       
         
         
             
             
         
       
       wherein R 20  is —OCH 2 COOH, —OCH 2 CONHSO 2 CH 3 , or —OCH 2 CONHSO 2 C 6 H 5 ; R 21  is —COCONH 2 , —CH 2 CONH 2 , or —CH 2 CONHNH 2 ; R 22  is C4-C6 alkyl; R 23  is —CH 2 —R 18  wherein R 18  is represented by the formula:  
       
         
           
           
               
               
           
         
       
       wherein β is —(CH 2 ) 16 —; R 19  is hydrogen, C1-C3 alkyl, or halogen; E is a single bond, —CH 2 —, or —O—; R 24  is hydrogen or C1-C6 alkyl;  
       a prodrug, a pharmaceutically acceptable salt, or a solvate thereof.  
     
   
   
       11 . A compound of the general formula (III):  
     
       
         
         
             
             
         
       
       wherein R 20 , R 21 , R 22 , R 23 , and R 24  are as defined in  claim 10;   
       a prodrug, a pharmaceutically acceptable salt, or a solvate thereof.  
     
   
   
       12 . A compound of the general formula (IV):  
     
       
         
         
             
             
         
       
       wherein R 20 , R 21 , R 22 , R 23 , and R 24  are as defined in  claim 10;   
       a prodrug, a pharmaceutically acceptable salt, or a solvate thereof.  
     
   
   
       13 . A pharmaceutical composition which comprises a compound of any one of claims  1 ,  10 ,  11  or  12  together with a pharmaceutically acceptable carrier or diluent.  
   
   
       14 - 16 . (canceled)  
   
   
       17 . A method of treating a mammal for diminishing influence caused by cancer, liver cirrhosis, Alzheimer's disease and/or arteriosclerosis comprising administering to said mammal including human a therapeutically effective amount of a compound of any one of claims  1 ,  10 ,  11  or  12 .  
   
   
       18 . A method for inhibiting type X sPLA 2  enzyme, which comprises contacting type X sPLA 2  enzyme protein with an effective amount of a compound of any one of claims  1 ,  10 ,  11  or  12 .  
   
   
       19 . A method for preventing or treating cancer, liver cirrhosis, Alzheimer's disease and/or arteriosclerosis, which comprises administering to a mammal including a human a therapeutically effective amount of a compound of any one of claims  1 ,  10 ,  11  or  12 .  
   
   
       20 . A method for preparing a pharmaceutical composition, which comprises mixing a compound of any one of claims  1 ,  10 ,  11  or  12  with a pharmaceutically acceptable carrier or diluent.