Guanidine and amidine acid derivatives and analogs and methods of using the same

Abstract

The present invention relates to certain novel guanidine or amidine acid derivatives and analogs, to a process for preparing such compounds, having the utility in clinical conditions associated with insulin resistance, to methods for their therapeutic use and to pharmaceutical compositions containing them.

1 . A compound of formula (I)  
     
       
         
         
             
             
         
       
     
     and stereo and optical isomers and racemates thereof as well as pharmaceutically acceptable salts, solvates, prodrugs, tautomers, and crystalline forms thereof, in which formula 
 A is situated in the ortho, meta or para position and represents  
                     
  wherein  
 R is hydrogen; 
 —OR a , wherein R a  represents hydrogen, alkyl, aryl or alkylaryl;  
 —NR a R b , wherein R a  and R b  are the same or different and R a  is as defined above and R b  represents hydrogen, alkyl, aryl, alkylaryl, cyano, —OH, -Oalkyl, -Oaryl, -Oalkylaryl, —COR c  or —SO 2 R d , wherein R c  represents hydrogen, alkyl, aryl or alkylaryl and R d  represents alkyl, aryl or alkylaryl;  
 
 R 1  is alkyl, aryl, alkene, alkyne, cyano; 
 —OR e , wherein R e  is alkyl, acyl, aryl or alkylaryl;  
 —O—[CH 2 ] m —OR f , wherein R f  represents hydrogen, alkyl, acyl, aryl or alkylaryl and m represents an integer 1-8;  
 
 —OCONR a R c , wherein R a  and R c  are as defined above; 
 —SR d , wherein R d  is as defined above;  
 —SO 2 NR a R f , wherein R f  and R a  are as defined above;  
 —SO 2 OR d , wherein R d  is as defined above;  
 COOR d , wherein R d  is as defined above;  
 
 R 2  is hydrogen, halogen, alkyl, aryl, or alkylaryl,  
 R 3  and R 4  are the same or different and each represents hydrogen, alkyl, aryl, or alkylaryl,  
 n is an integer 1-6,  
 D is situated in the ortho, meta or para position and represents  
   (U)(T)C(H)—NH— U is selected from ═NR f  or NR a R f , wherein R a  is as defined above and R f  is as defined above and may additionally comprise —COOR d , —CN, —OH, —SO 2 R d  and —COR a , wherein Ra and R d  are as defined above;    T is a group defined in U (except when U is ═NR f  then T cannot be ═NR f ) or is hydrogen, or a group selected from R 1 , wherein R 1  is defined above;    
 D′ is situated in the ortho, meta or para position and represents hydrogen, alkyl, acyl, aryl, alkylaryl, halogen, —CN, —NO 2 , —NR f R b , wherein R f  and R b  are as defined above; 
 —OR f , wherein R f  is as defined above;  
 —OSO 2 R d , wherein R d  is as defined above;  
 
 D″ is situated in the ortho, meta or para position and represents hydrogen, alkyl, acyl, aryl, alkylaryl, halogen, —CN, —NO 2 , —NR f R b  wherein R f  and R b  are as defined above; 
 —OR f , wherein R f  is as defined above;  
 —OSO 2 R d , wherein R d  is as defined above.  
 
 
   
   
       2 . A compound of formula I as claimed in  claim 1  wherein 
 A is situated in the meta or para position and represents,                           wherein    R is hydrogen; 
 —OR a ;  
 —NR a R b , wherein R b  represents hydrogen, alkyl, aryl, alkylaryl, cyano, —OH,  
 -Oalkyl or -Oalkylaryl;  
   R 1  is cyano; 
 —OR d ;  
 —O—[CH 2 ] m —OR a ;  
   R 2  is hydrogen or alkyl;    R 3  is hydrogen or alkyl;    R 4  is hydrogen;    n is an integer 2-4;    D is situated in the ortho, meta or para position and represents                          D′ is situated in the ortho, meta or para position and represents 
 hydrogen, alkyl, alkylaryl, halogen, —CN or —NO 2 ;  
 —OR b ;  
   D″ is situated in the ortho, meta or para position and represents 
 hydrogen, alkyl, alkylaryl, halogen, —CN or —NO 2 ;  
 —OR h ;  
   wherein R a , R b , R d , R f , R h  and m are as defined in.    
   
   
       3 . A compound of formula I, as claimed in  claim 2 , wherein 
 A is situated in the meta or para position;    R is —OR a , wherein R a  is hydrogen, alkyl or alkylaryl; 
 —NHR b , wherein R b  is hydrogen, alkyl, alkylaryl, cyano, -Oalkyl or -Oalkylaryl;  
   R 1  is -Oalkyl;    R 2  is hydrogen or alkyl;    R 3  is hydrogen or alkyl;    R 4  is hydrogen;    n is an integer 2-4,    D is situated in the para position and represents                          wherein R a  and R f  are as defined in  claim 3;     D′ is hydrogen.    D″ is hydrogen.    
   
   
       4 . A compound of formula I, as claimed in  claim 3 , wherein 
 A is situated in the para position;    R is —OH, -Oalkyl or -Oalkylaryl; 
 —NH 2 , —NHOalkylaryl or —NHCN;  
   R 1  is -Oalkyl, -Olower alkyl;    R 2  is hydrogen;    R 3  is hydrogen;    n is the integer 2 to 3;    D is situated in the para position, and represents,                          wherein R a  is as defined in  claim 3  and R f  represents hydrogen, alkyl or —OCOR d , wherein R a  is as defined in  claim 3 .    
   
   
       5 . A compound of formula I, as claimed in  claim 4 , wherein 
 D represents                          wherein R a  is alkyl or aryl and R f  is as defined in  claim 4 .    
   
   
       6 . A compound of formula I, as claimed in  claim 5 , wherein R is —OH, -Oalkyl or -Oalkylaryl.  
   
   
       7 . A compound of formula I, as claimed in  claim 6 , wherein D represents  
     
       
         
         
             
             
         
       
     
     wherein R a  represents alkyl or aryl and R f  represents hydrogen, alkyl or —OCOR d , wherein R d  is as defined in  claim 6 .  
   
   
       8 . A compound of formula I, as claimed in  claim 7 , wherein D represents  
     
       
         
         
             
             
         
       
     
     wherein R a  is as defined in  claim 7  and R f  represents hydrogen, alkyl or —OCOR d , wherein R d  represents alkyl or aryl.  
   
   
       9 . A compound according to  claim 1  selected from: 
 3-{4-[(4-{[anilino(methylimino)methyl]amino}phenethyl)oxy]phenyl}-2-ethoxypropanoic acid;    3-{4-[(4-{[anilino(phenylimino)methyl]amino}phenethyl)oxy]phenyl}-2-ethoxypropanoic acid;    3-(4-{[4-({[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)-phenethyl]oxy}phenyl)-2-ethoxypropanoic acid;    3-(4-{[4-({[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)-phenethyl]oxy}phenyl)-2(S)-ethoxypropanoic acid;    (2S)-3-(4-{4-[4-({[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}-amino)phenyl]butoxy}phenyl)-2-ethoxypropanoic acid; or    (2S)-3-(4-{3-[4-({[(tert-Butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)phenyl]propoxy}phenyl)-2-ethoxypropanoic acid; and    pharmaceutically acceptable salts thereof.    
   
   
       10 . (canceled)  
   
   
       11 . A pharmaceutical formulation comprising a compound of formula I, as defined in any claim from 1 to 9 and a pharmaceutically acceptable adjuvant, diluent or carrier.  
   
   
       12 . (canceled)  
   
   
       13 . A method for the treatment or prophylaxis of a condition associated with a patient having reduced sensitivity to insulin comprising administering to the patient a compound of any one of  claims 1  to  9 .