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 .- 17 . (canceled) 
   
   
       18 . A compound of the general formula: 
     
       
         
         
             
             
         
       
     
     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): 
 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 ; 
       a prodrug, a pharmaceutically acceptable salt, or a solvate thereof. 
     
   
   
       19 . The compound of  claim 18 , 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 C6H 5 )—, and   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 3  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; and 
       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. 
     
   
   
       20 . The compound of  claim 18  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. 
 
   
   
       21 . The compound of  claim 18 , 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. 
 
   
   
       22 . The compound of  claim 21 , wherein R 5  is —CH 2 —R 18 , wherein R 18  is represented by the formula: 
     
       
         
         
             
             
         
       
     
     wherein β is —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. 
 
   
   
       23 . The compound of  claim 18 , 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. 
   
   
   
       24 . The compound of  claim 18  wherein R 2  is hydrogen atom;
 a prodrug, a pharmaceutically acceptable salt, or a solvate thereof.   
   
   
       25 . The compound of  claim 18  wherein R 6  is C4-C6 alkyl;
 a prodrug, a pharmaceutically acceptable salt, or a solvate thereof.   
   
   
       26 . The compound of  claim 18  wherein R A  is —CH 2 CONH 2  or —COCONH 2 ;
 a prodrug, a pharmaceutically acceptable salt, or a solvate thereof.   
   
   
       27 . A compound of the general formula (IV): 
     
       
         
         
             
             
         
       
     
     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 ) 1-6 —; R 19  is hydrogen, C1-C3 alkyl, or halogen; E is a single bond, —CH 2 —, or —O—; and 
       R 24  is hydrogen or C1-C6 alkyl; 
       a prodrug, a pharmaceutically acceptable salt, or a solvate thereof. 
     
   
   
       28 . A pharmaceutical composition which comprises a compound of  claim 18  together with a pharmaceutically acceptable carrier or diluent. 
   
   
       29 . A method for inhibiting type X sPLA 2  enzyme, which comprises contacting type X sPLA2 enzyme protein with an effective amount of a compound of  claim 18 . 
   
   
       30 . A method for preparing a pharmaceutical composition, which comprises mixing a compound of  claim 18  with a pharmaceutically acceptable carrier or diluent. 
   
   
       31 . A pharmaceutical composition which comprises a compound of  claim 27  together with a pharmaceutically acceptable carrier or diluent. 
   
   
       32 . A method for inhibiting type X sPLA2 enzyme, which comprises contacting type X sPLA2 enzyme protein with an effective amount of a compound of  claim 27 . 
   
   
       33 . A method for preparing a pharmaceutical composition, which comprises mixing a compound of  claim 27  with a pharmaceutically acceptable carrier or diluent.