Novel heterocyclic analogs of diphenylethylene compounds

Abstract

Novel diphenylethylene compounds and derivatives thereof containing thiazolidinedione or oxazolidinedione moieties are provided which are effective in lowering blood glucose level, serum insulin, triglyceride and free fatty acid levels in animal models of Type II diabetes. The compounds are disclosed as useful for a variety of treatments including the treatment of inflammation, inflammatory and immunological diseases, insulin resistance, hyperlipidemia, coronary artery disease, cancer and multiple sclerosis.

1 . A compound represented by the following formula 1:  
     
       
         
         
             
             
         
       
       wherein Z is  
       
         
           
           
               
               
           
         
       
       n, m, q and r independently represent integers from zero to 4 provided that n+m≦4 and q+r≦4; p and s independently represent integers from zero to 5 provided that p+s≦5; a, b and c represent double bonds which may be present or absent; when present, the double bonds may be in the E or Z configuration and, when absent, the resulting stereocenters may have the R- or S-configuration;  
       R and R′ each independently represent a hydrogen atom; linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; —CO 2 Z′; —CO 2 R′″; —NH 2 ; —NHR′″; —NR 2 ′″; —OH; —OR′″; —CONR 2 ″″; halogen atom; optionally substituted linear or branched C 1 -C 20 alkyl; optionally substituted linear or branched C 2 -C 20  alkenyl;  
       R″ independently represents a hydrogen atom; linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; —CO 2 Z′; —CO 2 R′″; —NH 2 ; —NHR′″; —NR 2 ′″; —OH; —OR′″; halogen atom; optionally substituted linear or branched C 1 -C 20  alkyl; optionally substituted linear or branched C 2 -C 20  alkenyl;  
       R′″ independently represents a linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; or —(CH 2 ) x —Ar, where x represents an integer from 1 to 6 and Ar represents aryl;  
       R″″ independently represents a hydrogen atom; optionally substituted C 1 -C 20  alkyl; optionally substituted C 1 -C 20  alkoxy; optionally substituted C 2 -C 20  alkenyl; optionally substituted C 6 -C 10  aryl; or NR 2 ″″ represents a cyclic moiety;  
       Z′ represents a hydrogen atom or a pharmaceutically acceptable counter-ion;  
       A, A′ and A″ each independently represent a hydrogen atom; C 1 -C 20  acylamino; C 1 -C 20  acyloxy; C 1 -C 20  alkanoyl;C 1 -C 20  alkoxycarbonyl; C 1 -C 20  alkoxy; C 1 -C 20  alkylamino; C 1 -C 20  alkylcarboxylamino; carboxyl; cyano; halo; or hydroxy;  
       B, B′ and B″ each independently represent; C 2 -C 20 alkenoyl; aroyl; aralkanoyl; nitro; optionally substituted, linear or branched C 1 -C 20  alkyl; or optionally substituted, linear or branched C 2 -C 20  alkenyl;  
       or A and B jointly, A′ and B′ jointly, or A″ and B″ jointly, independently represent a methylenedioxy or ethylenedioxy group; and  
       X and X′ independently represent >NH, >NR′″, —O—, or —S—.  
     
   
   
       2 . A compound represented by the following formula 1:  
     
       
         
         
             
             
         
       
       wherein Z is  
       
         
           
           
               
               
           
         
       
       n, m, q and r independently represent integers from zero to 4 provided that n+m≦4 and q+r≦4; p and s independently represent integers from zero to 5 provided that p+s≦5; a, b and c represent double bonds which may be present or absent; when present, the double bonds may be in the E or Z configuration and, when absent, the resulting stereocenters may have the R- or S-configuration;  
       R independently represents a hydrogen atom; linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; —CO 2 Z′; —CO 2 R′″; —NH 2 ; —NHR′″; —NR 2 ′″; —OH; —OR′″; —CONR 2 ″″; halogen atom; optionally substituted linear or branched C 1 -C 20  alkyl; optionally substituted linear or branched C 2 -C 20  alkenyl;  
       R′ independently represents a hydrogen atom; linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; —CO 2 Z′; —CO 2 R′″; —NH 2 ; —NHR′″; —NR 2 ′″; —OR′″; —CONR 2 ″″; halogen atom; optionally substituted linear or branched C 1 -C 20  alkyl; optionally substituted linear or branched C 2 -C 20  alkenyl;  
       R″ independently represents a hydrogen atom; linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; —CO 2 Z′; —CO 2 R′″; —NH 2 ; —NHR′″; —NR 2 ′″; —OH; —OR′″; halogen atom; optionally substituted linear or branched C 1 -C 20  alkyl; optionally substituted linear or branched C 2 -C 20  alkenyl;  
       R′″ independently represents a linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; or —(CH 2 ) x —Ar, where x represents an integer from 1 to 6 and Ar represents aryl;  
       R″″ independently represents a hydrogen atom; optionally substituted C 1 -C 20  alkyl; optionally substituted C 1 -C 20  alkoxy; optionally substituted C 2 -C 20  alkenyl; optionally substituted C 6 -C 10  aryl; or NR 2 ″″ represents a cyclic moiety;  
       Z′ represents a hydrogen atom or a pharmaceutically acceptable counter-ion;  
       A, A′ and A″ each independently represent a hydrogen atom; C 1 -C 20  acylamino; C 1 -C 20  acyloxy; C 1 -C 20  alkanoyl;C 1 -C 20  alkoxycarbonyl; C 1 -C 20  alkoxy; C 1 -C 20  alkylamino; C 1 -C 20  alkylcarboxylamino; carboxyl; cyano; halo; or hydroxy;  
       B, B′ and B″ each independently represent; C 2 -C 20  alkenoyl; aroyl; aralkanoyl; nitro; optionally substituted, linear or branched C 1 -C 20  alkyl; or optionally substituted, linear or branched C 2 -C 20  alkenyl;  
       or A and B jointly, A′ and B′ jointly, or A″ and B″ jointly, independently represent a methylenedioxy or ethylenedioxy group; and  
       X and X′ independently represent >NH, >NR′″, —O—, or —S—.  
     
   
   
       3 . A pharmaceutical composition comprising: 
 a therapeutically effective amount of a compound represented by the following formula 1:                          wherein Z is                          n, m, q and r independently represent integers from zero to 4 provided that n+m≦4 and q+r≦4; p and s independently represent integers from zero to 5 provided that p+s≦5; a, b and c represent double bonds which may be present or absent; when present, the double bonds may be in the E or Z configuration and, when absent, the resulting stereocenters may have the R- or S-configuration;    R and R′ each independently represent a hydrogen atom; linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; —CO 2 Z′; —CO 2 R′″; —NH 2 ; —NHR′″; —NR 2 ′″; —OH; —OR′″; —CONR 2 ″″; halogen atom; optionally substituted linear or branched C 1 -C 20  alkyl; optionally substituted linear or branched C 2 -C 20  alkenyl;    R″ independently represents a hydrogen atom; linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; —CO 2 Z′; —CO 2 R′″; —NH 2 ; —NHR′″; —NR 2 ′″; —OH; —OR′″; halogen atom; optionally substituted linear or branched C 1 -C 20  alkyl; optionally substituted linear or branched C 2 -C 20  alkenyl;    R′″ independently represents a linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; or —(CH 2 ) x —Ar, where x represents an integer from 1 to 6 and Ar represents aryl;    R″″ independently represents a hydrogen atom; optionally substituted C 1 -C 20  alkyl; optionally substituted C 1 -C 20  alkoxy; optionally substituted C 2 -C 20  alkenyl; optionally substituted C 6 -C 10  aryl; or NR 2 ″″ represents a cyclic moiety;    Z′ represents a hydrogen atom or a pharmaceutically acceptable counter-ion;    A, A′ and A″ each independently represent a hydrogen atom; C 1 -C 20  acylamino; C 1 -C 20  acyloxy; C 1 -C 20  alkanoyl;C 1 -C 20  alkoxycarbonyl; C 1 -C 20  alkoxy; C 1 -C 20  alkylamino; C 1 -C 20  alkylcarboxylamino; carboxyl; cyano; halo; or hydroxy;    B, B′ and B″″ each independently represent; C 2 -C 20  alkenoyl; aroyl; aralkanoyl; nitro; optionally substituted, linear or branched C 1 -C 20  alkyl; or optionally substituted, linear or branched C 2 -C 20  alkenyl;    or A and B jointly, A′ and B′ jointly, or A″ and B″ jointly, independently represent a methylenedioxy or ethylenedioxy group; and    X and X′ independently represent >NH, >NR′″, —O—, or —S—;    in a physiologically acceptable carrier.    
   
   
       4 . A pharmaceutical composition comprising: 
 a therapeutically effective amount of a compound represented by the following formula 1:                          wherein Z is                          n, m, q and r independently represent integers from zero to 4 provided that n+m≦4 and q+r≦4; p and s independently represent integers from zero to 5 provided that p+s≦5; a, b and c represent double bonds which may be present or absent; when present, the double bonds may be in the E or Z configuration and, when absent, the resulting stereocenters may have the R- or S-configuration;    R independently represents a hydrogen atom; linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; —CO 2 Z′; —CO 2 R′″; —NH 2 ; —NHR′″; —NR 2 ′″; —OH; —OR′″; —CONR 2 ″″; halogen atom; optionally substituted linear or branched C 1 -C 20  alkyl; optionally substituted linear or branched C 2 -C 20  alkenyl;    R′ independently represents a hydrogen atom; linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; —CO 2 Z′; —CO 2 R′″; —NH 2 ; —NHR′″; —NR 2 ′″; —OR′″; —CONR 2 ″″; halogen atom; optionally substituted linear or branched C 1 -C 20  alkyl; optionally substituted linear or branched C 2 -C 20  alkenyl;    R″ independently represents a hydrogen atom; linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; —CO 2 Z′; —CO 2 R′″; —NH 2 ; —NHR′″; —NR 2 ′″; —OH; —OR′″; halogen atom; optionally substituted linear or branched C 1 -C 20  alkyl; optionally substituted linear or branched C 2 -C 20  alkenyl;    R′″ independently represents a linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; or —(CH 2 ) x —Ar, where x represents an integer from 1 to 6 and Ar represents aryl;    R″″ independently represents a hydrogen atom; optionally substituted C 1 -C 20  alkyl; optionally substituted C 1 -C 20  alkoxy; optionally substituted C 2 -C 20  alkenyl; optionally substituted C 6 -C 10  aryl; or NR 2 ″″represents a cyclic moiety;    Z′ represents a hydrogen atom or a pharmaceutically acceptable counter-ion;    A, A′ and A″ each independently represent a hydrogen atom; C 1 -C 20  acylamino; C 1 -C 20  acyloxy; C 1 -C 20  alkanoyl;C 1 -C 20  alkoxycarbonyl; C 1 -C 20  alkoxy; C 1 -C 20  alkylamino; C 1 -C 20  alkylcarboxylamino; carboxyl; cyano; halo; or hydroxy;    B, B′ and B″ each independently represent; C 2 -C 20  alkenoyl; aroyl; aralkanoyl; nitro; optionally substituted, linear or branched C 1 -C 20  alkyl; or optionally substituted, linear or branched C 2 -C 20  alkenyl;    or A and B jointly, A′ and B′ jointly, or A″ and B″ jointly, independently represent a methylenedioxy or ethylenedioxy group; and    X and X′ independently represent >NH, >NR′″, —O—, or —S—;    in a physiologically acceptable carrier.    
   
   
       5 . A method of treating diabetes comprising: 
 administering to a subject suffering from a diabetic condition, a therapeutically effective amount of a compound represented by the following formula 1:                          wherein Z is                          n, m, q and r independently represent integers from zero to 4 provided that n+m≦4 and q+r≦4; p and s independently represent integers from zero to 5 provided that p+s≦5; a, b and c represent double bonds which may be present or absent; when present, the double bonds may be in the E or Z configuration and, when absent, the resulting stereocenters may have the R- or S-configuration;    R and R′ each independently represent a hydrogen atom; linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; —CO 2 Z′; —CO 2 R′″; —NH 2 ; —NHR′″; —NR 2 ′″; —OH; —OR′″; —CONR 2 ″″; halogen atom; optionally substituted linear or branched C 1 -C 20  alkyl; optionally substituted linear or branched C 2 -C 20  alkenyl;    R″ independently represents a hydrogen atom; linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; —CO 2 Z′; —CO 2 R′″; —NH 2 ; —NHR′″; —NR 2 ′″; —OH; —OR′″; halogen atom; optionally substituted linear or branched C 1 -C 20  alkyl; optionally substituted linear or branched C 2 -C 20  alkenyl;    R′″ independently represents a linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; or —(CH 2 ) x —Ar, where x represents an integer from 1 to 6 and Ar represents aryl;    R″″ independently represents a hydrogen atom; optionally substituted C 1 -C 20  alkyl; optionally substituted C 1 -C 20  alkoxy; optionally substituted C 2 -C 20  alkenyl; optionally substituted C 6 -C 10  aryl; or NR 2 ″″ represents a cyclic moiety;    Z′ represents a hydrogen atom or a pharmaceutically acceptable counter-ion;    A, A′ and A″ each independently represent a hydrogen atom; C 1 -C 20  acylamino; C 1 -C 20  acyloxy; C 1 -C 20  alkanoyl;C 1 -C 20  alkoxycarbonyl; C 1 -C 20  alkoxy; C 1 -C 20  alkylamino; C 1 -C 20  alkylcarboxylamino; carboxyl; cyano; halo; or hydroxy;    B, B′ and B″ each independently represent; C 2 -C 20  alkenoyl; aroyl; aralkanoyl; nitro; optionally substituted, linear or branched C 1 -C 20  alkyl; or optionally substituted, linear or branched C 2 -C 20  alkenyl;    or A and B jointly, A′ and B′ jointly, or A″ and B″ jointly, independently represent a methylenedioxy or ethylenedioxy group; and    X and X′ independently represent >NH, >NR′″, —O—, or —S—;    in a physiologically acceptable carrier.    
   
   
       6 . A method of treating diabetes comprising: 
 administering to a subject suffering from a diabetic condition, a therapeutically effective amount of a compound represented by the following formula 1:                          wherein Z is                          n, m, q and r independently represent integers from zero to 4 provided that n+m≦4 and q+r≦4; p and s independently represent integers from zero to 5 provided that p+s≦5; a, b and c represent double bonds which may be present or absent; when present, the double bonds may be in the E or Z configuration and, when absent, the resulting stereocenters may have the R- or S-configuration;    R independently represents a hydrogen atom; linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; —CO 2 Z′; —CO 2 R′″; —NH 2 ; —NHR′″; —NR 2 ′″; —OH; —OR′″; —CONR 2 ″″; halogen atom; optionally substituted linear or branched C 1 -C 20  alkyl; optionally substituted linear or branched C 2 -C 20  alkenyl;    R′ independently represents a hydrogen atom; linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; —CO 2 Z′; —CO 2 R′″; —NH 2 ; —NHR′″; —NR 2 ′″; —OR′″; —CONR 2 ″″; halogen atom; optionally substituted linear or branched C 1 -C 20  alkyl; optionally substituted linear or branched C 2 -C 20  alkenyl;    R″ independently represents a hydrogen atom; linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; —CO 2 Z′; —CO 2 R′″; —NH 2 ; —NHR′″; —NR 2 ′″; —OH; —OR′″; halogen atom; optionally substituted linear or branched C 1 -C 20  alkyl; optionally substituted linear or branched C 2 -C 20  alkenyl;    R′″ independently represents a linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; or —(CH 2 ) x —Ar, where x represents an integer from 1 to 6 and Ar represents aryl;    R″″ independently represents a hydrogen atom; optionally substituted C 1 -C 20  alkyl; optionally substituted C 1 -C 20  alkoxy; optionally substituted C 2 -C 20  alkenyl; optionally substituted C 6 -C 10  aryl; or NR 2 ″″ represents a cyclic moiety;    Z′ represents a hydrogen atom or a pharmaceutically acceptable counter-ion;    A, A′ and A″ each independently represent a hydrogen atom; C 1 -C 20  acylamino; C 1 -C 20  acyloxy; C 1 -C 20  alkanoyl;C 1 -C 20  alkoxycarbonyl; C 1 -C 20  alkoxy; C 1 -C 20  alkylamino; C 1 -C 20  alkylcarboxylamino; carboxyl; cyano; halo; or hydroxy;    B, B′ and B″ each independently represent; C 2 -C 20 alkenoyl; aroyl; aralkanoyl; nitro; optionally substituted, linear or branched C 1 -C 20  alkyl; or optionally substituted, linear or branched C 2 -C 20  alkenyl;    or A and B jointly, A′ and B′ jointly, or A″ and B″ jointly, independently represent a methylenedioxy or ethylenedioxy group; and    X and X′ independently represent >NH, >NR′″, —O—, or —S—;    in a physiologically acceptable carrier.    
   
   
       7 . A method of treating inflammation or inflammatory disease comprising: 
 administering to a subject suffering from such condition, a therapeutically effective amount of a compound represented by the following formula 1:                          wherein Z is                          n, m, q and r independently represent integers from zero to 4 provided that n+m≦4 and q+r≦4; p and s independently represent integers from zero to 5 provided that p+s≦5; a, b and c represent double bonds which may be present or absent; when present, the double bonds may be in the E or Z configuration and, when absent, the resulting stereocenters may have the R- or S-configuration;    R and R′ each independently represent a hydrogen atom; linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; —CO 2 Z′; —CO 2 R′″; —NH 2 ; —NHR′″; —NR 2 ′″; —OH; —OR′″; —CONR 2 ″″; halogen atom; optionally substituted linear or branched C 1 -C 20  alkyl; optionally substituted linear or branched C 2 -C 20  alkenyl;    R″ independently represents a hydrogen atom; linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; —CO 2 Z′; —CO 2 R ′″; —NH 2 ; —NHR′″; —NR 2 ′″; —OH; —OR′″; halogen atom; optionally substituted linear or branched C 1 -C 20  alkyl; optionally substituted linear or branched C 2 -C 20  alkenyl;    R′″ independently represents a linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; or —(CH 2 ) x —Ar, where x represents an integer from 1 to 6 and Ar represents aryl;    R″″ independently represents a hydrogen atom; optionally substituted C 1 -C 20  alkyl; optionally substituted C 1 -C 20  alkoxy; optionally substituted C 2 -C 20  alkenyl; optionally substituted C 6 -C 10  aryl; or NR 2 ″″ represents a cyclic moiety;    Z′ represents a hydrogen atom or a pharmaceutically acceptable counter-ion;    A, A′ and A″ each independently represent a hydrogen atom; C 1 -C 20  acylamino; C 1 -C 20  acyloxy; C 1 -C 20  alkanoyl;C 1 -C 20  alkoxycarbonyl; C 1 -C 20  alkoxy; C 1 -C 20  alkylamino; C 1 -C 20  alkylcarboxylamino; carboxyl; cyano; halo; or hydroxy;    B, B′ and B″ each independently represent; C 2 -C 20  alkenoyl; aroyl; aralkanoyl; nitro; optionally substituted, linear or branched C 1 -C 20  alkyl; or optionally substituted, linear or branched C 2 -C 20  alkenyl;    or A and B jointly, A′ and B′ jointly, or A″ and B″ jointly, independently represent a methylenedioxy or ethylenedioxy group; and    X and X′ independently represent >NH, >NR′″, —O—, or —S—;    in a physiologically acceptable carrier.    
   
   
       8 . A method of treating inflammation or inflammatory disease comprising: 
 administering to a subject suffering from such condition, a therapeutically effective amount of a compound represented by the following formula 1:                          wherein Z is                          n, m, q and r independently represent integers from zero to 4 provided that n+m≦4 and q+r≦4; p and s independently represent integers from zero to 5 provided that p+s≦5; a, b and c represent double bonds which may be present or absent; when present, the double bonds may be in the E or Z configuration and, when absent, the resulting stereocenters may have the R- or S-configuration;    R independently represents a hydrogen atom; linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; —CO 2 Z′; —CO 2 R′″; —NH 2 ; —NHR′″; —NR 2 ′″; —OH; —OR′″; —CONR 2 ″″; halogen atom; optionally substituted linear or branched C 1 -C 20  alkyl; optionally substituted linear or branched C 2 -C 20  alkenyl;    R′ independently represents a hydrogen atom; linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; —CO 2 Z′; —CO 2 R′″; —NH 2 ; —NHR′″; —NR 2 ′″; —OR′″; —CONR 2 ″″; halogen atom; optionally substituted linear or branched C 1 -C 20  alkyl; optionally substituted linear or branched C 2 -C 20  alkenyl;    R″ independently represents a hydrogen atom; linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; —CO 2 Z′; —CO 2 R′″; —NH 2 ; —NHR′″; —NR 2 ′″; —OH; —OR′″; halogen atom; optionally substituted linear or branched C 1 -C 20  alkyl; optionally substituted linear or branched C 2 -C 20  alkenyl;    R′″ independently represents a linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; or —(CH 2 ) x —Ar, where x represents an integer from 1 to 6 and Ar represents aryl;    R″″ independently represents a hydrogen atom; optionally substituted C 1 -C 20  alkyl; optionally substituted C 1 -C 20  alkoxy; optionally substituted C 2 -C 20  alkenyl; optionally substituted C 6 -C 10  aryl; or NR 2 ″″ represents a cyclic moiety;    Z′ represents a hydrogen atom or a pharmaceutically acceptable counter-ion;    A, A′ and A″ each independently represent a hydrogen atom; C 1 -C 20  acylamino; C 1 -C 20  acyloxy; C 1 -C 20  alkanoyl;C 1 -C 20  alkoxycarbonyl; C 1 -C 20  alkoxy; C 1 -C 20  alkylamino; C 1 -C 20  alkylcarboxylamino; carboxyl; cyano; halo; or hydroxy;    B, B′ and B″ each independently represent; C 2 -C 20  alkenoyl; aroyl; aralkanoyl; nitro; optionally substituted, linear or branched C 1 -C 20  alkyl; or optionally substituted, linear or branched C 2 -C 20  alkenyl;    or A and B jointly, A′ and B′ jointly, or A″ and B″ jointly, independently represent a methylenedioxy or ethylenedioxy group; and    X and X′ independently represent >NH, >NR′″, —O—, or —S—;    in a physiologically acceptable carrier.    
   
   
       9 . A method of treating immunological disease comprising: 
 administering to a subject suffering from an immunological disease a therapeutically effective amount of a compound represented by the following formula 1:                          wherein Z is                          n, m, q and r independently represent integers from zero to 4 provided that n+m≦4 and q+r≦4; p and s independently represent integers from zero to 5 provided that p+s≦5; a, b and c represent double bonds which may be present or absent; when present, the double bonds may be in the E or Z configuration and, when absent, the resulting stereocenters may have the R- or S-configuration;    R and R′ each independently represent a hydrogen atom; linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; —CO 2 Z′; —CO 2 R′″; —NH 2 ; —NHR′″; —NR 2 ′″; —OH; —OR′″; —CONR 2 ″″; halogen atom; optionally substituted linear or branched C 1 -C 20  alkyl; optionally substituted linear or branched C 2 -C 20  alkenyl;    R″ independently represents a hydrogen atom; linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; —CO 2 Z′; —CO 2 R′″; —NH 2 ; —NHR′″; —NR 2 ′″; —OH; —OR′″; halogen atom; optionally substituted linear or branched C 1 -C 20  alkyl; optionally substituted linear or branched C 2 -C 20  alkenyl;    R′″ independently represents a linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; or —(CH 2 ) x —Ar, where x represents an integer from 1 to 6 and Ar represents aryl;    R″″ independently represents a hydrogen atom; optionally substituted C 1 -C 20  alkyl; optionally substituted C 1 -C 20  alkoxy; optionally substituted C 2 -C 20  alkenyl; optionally substituted C 6 -C 10  aryl; or NR 2 ″″ represents a cyclic moiety;    Z′ represents a hydrogen atom or a pharmaceutically acceptable counter-ion;    A, A′ and A″ each independently represent a hydrogen atom; C 1 -C 20  acylamino; C 1 -C 20  acyloxy; C 1 -C 20  alkanoyl;C 1 -C 20  alkoxycarbonyl; C 1 -C 20  alkoxy; C 1 -C 20  alkylamino; C 1 -C 20  alkylcarboxylamino; carboxyl; cyano; halo; or hydroxy;    B, B′ and B″ each independently represent; C 2 -C 20  alkenoyl; aroyl; aralkanoyl; nitro; optionally substituted, linear or branched C 1 -C 20  alkyl; or optionally substituted, linear or branched C 2 -C 20  alkenyl;    or A and B jointly, A′ and B′ jointly, or A″ and B″ jointly, independently represent a methylenedioxy or ethylenedioxy group; and    X and X′ independently represent >NH, >NR′″, —O—, or —S—;    in a physiologically acceptable carrier.    
   
   
       10 . A method of treating immunological disease comprising: 
 administering to a subject suffering from an immunological disease a therapeutically effective amount of a compound represented by the following formula 1:                          wherein Z is                          n, m, q and r independently represent integers from zero to 4 provided that n+m≦4 and q+r≦4; p and s independently represent integers from zero to 5 provided that p+s≦5; a, b and c represent double bonds which may be present or absent; when present, the double bonds may be in the E or Z configuration and, when absent, the resulting stereocenters may have the R- or S-configuration;    R independently represents a hydrogen atom; linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; —CO 2 Z′; —CO 2 R′″; —NH 2 ; —NHR′″; —NR 2 ′″; —OH; —OR′″; —CONR 2 ″″; halogen atom; optionally substituted linear or branched C 1 -C 20 alkyl; optionally substituted linear or branched C 2 -C 20  alkenyl;    R′ independently represents a hydrogen atom; linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; —CO 2 Z′; —CO 2 R′″; —NH 2 ; —NHR′″; —NR 2 ′″; —OR′″; —CONR 2 ″″; halogen atom; optionally substituted linear or branched C 1 -C 20  alkyl; optionally substituted linear or branched C 2 -C 20  alkenyl;    R″ independently represents a hydrogen atom; linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; —CO 2 Z′; —CO 2 R′″; —NH 2 ; —NHR′″; —NR 2 ′″; —OH; —OR′″; halogen atom; optionally substituted linear or branched C 1 -C 20  alkyl; optionally substituted linear or branched C 2 -C 20  alkenyl;    R′″ independently represents a linear or branched C 1 -C 20  alkyl; linear or branched C 2 -C 20  alkenyl; or —(CH 2 ) x —Ar, where x represents an integer from 1 to 6 and Ar represents aryl;    R″″ independently represents a hydrogen atom; optionally substituted C 1 -C 20  alkyl; optionally substituted C 1 -C 20  alkoxy; optionally substituted C 2 -C 20  alkenyl; optionally substituted C 6 -C 10  aryl; or NR 2 ″″ represents a cyclic moiety;    Z′ represents a hydrogen atom or a pharmaceutically acceptable counter-ion;    A, A′ and A″ each independently represent a hydrogen atom; C 1 -C 20  acylamino; C 1 -C 20  acyloxy; C 1 -C 20  alkanoyl;C 1 -C 20  alkoxycarbonyl; C 1 -C 20  alkoxy; C 1 -C 20  alkylamino; C 1 -C 20  alkylcarboxylamino; carboxyl; cyano; halo; or hydroxy;    B, B′ and B″ each independently represent; C 2 -C 20  alkenoyl; aroyl; aralkanoyl; nitro; optionally substituted, linear or branched C 1 -C 20  alkyl; or optionally substituted, linear or branched C 2 -C 20  alkenyl;    or A and B jointly, A′ and B′ jointly, or A″ and B″ jointly, independently represent a methylenedioxy or ethylenedioxy group; and    X and X′ independently represent >NH, >NR′″, —O—, or —S—;    in a physiologically acceptable carrier.    
   
   
       11 . A method of inhibiting the activity of TNF-alpha, IL-1, IL-6 or COX-2 which comprises administering to a host in need of such inhibition an effective amount of a compound according to  claim 1 .  
   
   
       12 . The method of inhibiting the undesired action of cytokine or cyclooxygenase which comprises administering to a host in need of such inhibition an effective amount of a compound according to  claim 1 .  
   
   
       13 . The method of treating a disease mediated by cytokines or cyclooxygenase which comprises administering to a host in need of such treatment a compound according to  claim 1 .  
   
   
       14 . The method of treating insulin resistance which comprises administering to a host in need of such treatment an effective amount of a compound according to  claim 1 .  
   
   
       15 . The method of treating hyperlipidemia which comprises administering to a host in need of such treatment an effective amount of a compound according to  claim 1 .  
   
   
       16 . The method of treating coronary heart disease which comprises administering to a host in need of such treatment an effective amount of a compound according to  claim 1 .  
   
   
       17 . The method of treating multiple sclerosis which comprises administering to a host in need of such treatment an effective amount of a compound according to  claim 1 .  
   
   
       18 . The method of treating cancer which comprises administering to a host in need of such treatment an effective amount of a compound according to  claim 1 .  
   
   
       19 . A compound according to  claim 1  selected from the group consisting of: 
 2-{4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-3-p-tolylacrylic acid,    2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-3-p-tolylacrylic acid,    2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-3-p-tolylacrylic acid methyl ester,    3-(3,5-dimethylphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-acrylic acid,    3-(3,5-dimethylphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-acrylic acid,    3-(3,5-dimethylphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-acrylic acid methyl ester,    5-(4-{4-[2-(3,5-dimethylphenyl)-1-(morpholine-4-carbonyl)-vinyl]-phenoxy}-benzyl)-thiazolidine-2,4-dione,    5-(4-{4-[2-(4-methoxyphenyl)-vinyl]-phenoxy}-benzyl)-thiazolidine-2,4-dione,    5-(4-{4-[2-(3,5-dimethoxyphenyl)-vinyl]-phenoxy}-benzyl)-thiazolidine-2,4-dione,    5-[4-(4′-methoxybiphenyl-3-yloxy)-benzylidene]-thiazolidine-2,4-dione,    5-[4-(4′-methoxybiphenyl-3-yloxy)-benzyl]-thiazolidine-2,4-dione,    5-[4-(2′,4′-dimethoxybiphenyl-3-yloxy)-benzylidene]-thiazolidine-2,4-dione, and    5-[4-(3′,5′-dimethoxybiphenyl-3-yloxy)-benzyl]-thiazolidine-2,4-dione.    
   
   
       20 . A pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of: 
 2-{4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-3-p-tolylacrylic acid,    2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-3-p-tolylacrylic acid,    2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-3-p-tolylacrylic acid methyl ester,    3-(3,5-dimethylphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)-phenoxy]-phenyl}-acrylic acid,    3-(3,5-dimethylphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-acrylic acid,    3-(3,5-dimethylphenyl)-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-acrylic acid methyl ester,    5-(4-{4-[2-(3,5-dimethylphenyl)-1-(morpholine-4-carbonyl)-vinyl]-phenoxy}-benzyl)-thiazolidine-2,4-dione,    5-(4-{4-[2-(4-methoxyphenyl)-vinyl]-phenoxy}-benzyl)-thiazolidine-2,4-dione,    5-(4-{4-[2-(3,5-dimethoxyphenyl)-vinyl]-phenoxy}-benzyl)-thiazolidine-2,4-dione,    5-[4-(4′-methoxybiphenyl-3-yloxy)-benzylidene]-thiazolidine-2,4-dione,    5-[4-(4′-methoxybiphenyl-3-yloxy)-benzyl]-thiazolidine-2,4-dione,    5-[4-(2′,4′-dimethoxybiphenyl-3-yloxy)-benzylidene]-thiazolidine-2,4-dione, and    5-[4-(3′,5′-dimethoxybiphenyl-3-yloxy)-benzyl]-thiazolidine-2,4-dione,    together with a physiologically acceptable carrier therefor.    
   
   
       21 . A method for treating diabetes, comprising: co-administering an effective amount of a compound of  claim 1  and an agent selected from the group consisting of: 
 insulin or an insulin mimetic,    a sulfonylurea or other insulin secretagogue,    a thiazolidinedione,    a fibrate or other PPAR-alpha agonist,    a PPAR-delta agonist,    a biguanide,    a statin or other hydroxymethylglutaryl (HMG) CoA reductase inhibitor,    an alpha-glucosidase inhibitor,    a bile acid-binding resin,    apoA1,    niacin,    probucol,    and nicotinic acid.    
   
   
       22 . A method for treating inflammatory or immunological disease, comprising: co-administering an effective amount of a compound of  claim 1  and an agent selected from the group consisting of: 
 a nonsteroidal anti-inflammatory drug (NSAID),    a cyclooxygenase-2 inhibitor,    a corticosteroid or other immunosuppressive agent,    a disease-modifying antirheumatic drug (DMARD),    a TNF-alpha inhibitor,    other cytokine inhibitor,    other immune modulating agent,    and a narcotic agent.    
   
   
       23 . The compound of  claim 1  wherein Z is represented by:  
     
       
         
         
             
             
         
       
     
   
   
       24 . The pharmaceutical composition of  claim 3  wherein Z is represented by: