New 3-aryl propionic acid derivatives and analogs

Abstract

Novel 3-aryl propionic acid derivatives and analogs, process and intermediate for their manufacture, pharmaceutical preparations containing them and the use of the compounds in clinical conditions associated with insulin resistance.

1 . A compound having the general formula  
       
         
           
           
               
               
           
         
       
       and stereo- and optical isomers and racemates thereof as well as pharmaceutically acceptable salts, solvates and crystalline forms thereof, in which formula A is situated in the ortho, meta or para position and represents  
       
         
           
           
               
               
           
         
         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, alkenyl, alkynyl, 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 a , wherein R a  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 
 —OSO 2 R d , wherein R d  is as defined above;  
 —OCONR f R a , wherein R f  and R a  are as defined above;  
 —NR c COOR d , wherein R c  and R d  are as defined above;  
 —NR c COR a , wherein R c  and R a  are as defined above;  
 —NR c R d , wherein R c  and R d  are as defined above;  
 —NR c SO 2 R d , wherein R c  and R d  are as defined above;  
 —NR c CONR a R k , wherein R a , R c  and R k  are the same or different and each represents hydrogen, alkyl, aryl, or alkylaryl;  
 —NR c CSNR a R k , wherein R a , R c  and R k  are the same or different and each represents hydrogen, alkyl, aryl or alkylaryl;  
 —SO 2 R d , wherein R d  is as defined above;  
 —SOR d , wherein R d  is as defined above;  
 —SR c , wherein R c  is as defined above;  
 —SO 2 NR a R f , wherein R f  and R a  are as defined above;  
 —SO 2 OR a , wherein R a  is as defined above;  
 —CN,  
 —CONR c R a , wherein R c  and R a  are 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;  
 
         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 according to  claim 1  with the exception of (S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid, and 3-{4-[2-(4-tert-butoxycarbonylaminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid.  
     
     
         3 . A compound according to any of claims  1  or  2 , wherein 
 A is situated in the meta or para position and represents,                          R is hydrogen; 
 —OR a , wherein R a  is as defined in  claim 1;   
 —NR a R b , wherein R a  and R b  are the same or different and R a  is as defined in  claim 1  and R b  represents hydrogen, alkyl, aryl, alkylaryl, cyano, —OH, —Oalkyl or —Oalkylaryl;  
   R 1  is cyano; 
 —OR d , wherein R d  is as defined in  claim 1;   
 —O—[CH 2 ] m —OR a , wherein m and R a  are as defined in  claim 1;   
   R 2  is hydrogen or alkyl;    R 3  is hydrogen or alkyl;    R 4  is hydrogen;    n is an integer 1-3;    D is situated in the ortho, meta or para position and represents 
 —OSO 2 R d , wherein R d  is as defined in  claim 1;   
 —OCONR a R c , wherein R a  and R c  are as defined in  claim 1;   
 —NR c COOR d , wherein R c  and R d  are as defined in  claim 1;   
 —NR c COR a , wherein R c  and R a  are as defined in  claim 1;   
 —NR c COR a , wherein R c  and R a  are as defined in  claim 1;   
 —NR c R d , wherein R c  and R d  are as defined in  claim 1;   
 —NR c CSNR a R k , wherein R a , R c  and R k  are as defined in  claim 1;   
 —SO 2 R d , wherein R d  is as defined in  claim 1;   
 —SR c , wherein R c  is as defined in  claim 1;   
 —CN;  
 —CONR a R c , wherein R a  and R c  are as defined in  claim 1;   
   D′ is situated in the ortho, meta or para position and represents 
 hydrogen, alkyl, alkylaryl halogen, —CN or —NO 2 ;  
 —OR h , wherein R h  is hydrogen or alkyl;  
   D″ is situated in the ortho, meta or para position and represents 
 hydrogen, alkyl, alkylaryl, halogen, —CN or —NO 2 ;  
 —OR h , wherein R h  is as above.  
   
     
     
         4 . A compound according to  claim 3 , 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 1-3,    D is situated in the ortho, meta or para position and represents 
 —NR c COOR d , wherein R c , and R d  are as defined in  claim 1;   
   D′ is hydrogen.    D″ is hydrogen.    
     
     
         5 . A compound according to  claim 4 , wherein 
 A is situated in the para position;    R is —OH, —Oalkyl or —Oalkylaryl; 
 —NH 2 , —NHOalkylaryl or —NHCN;  
   R 1  is —Oalkyl, preferably —Olower alkyl;    R 2  is hydrogen;    R 3  is hydrogen;    n is the integer 1;    D is situated in the para position, and represents —NR h COOR d , wherein 
 R d  is as defined in  claim 1  and R h  represents hydrogen or alkyl.  
   
     
     
         6 . A compound according to  claim 5 , wherein 
 D is —NR j COOalkyl, wherein R j  represents hydrogen or lower alkyl.    
     
     
         7 . A compound according to  claim 3 , 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 1-3;    D is situated in the ortho, meta or para position and represents 
 —NR c COR a , wherein R c  and R a  are as defined in  claim 1;   
   D′ is hydrogen.    D″ is hydrogen.    
     
     
         8 . A compound according to  claim 7 , wherein 
 A is situated in the para position;    R is —OH, —Oalkyl or —Oalkylaryl; 
 —NH 2 , —NHOalkylaryl or —NHCN;  
   R 1  is —Oalkyl, preferably —Olower alkyl;    R 2  is hydrogen;    R 3  is hydrogen;    n is the integer 1;    D is situated in the para position, and represents —NR h COR d , wherein R d  is and as defined in  claim 1  and R h  represents hydrogen or alkyl.    
     
     
         9 . A compound according to  claim 8 , wherein 
 D is —NHCOR d  alkyl, wherein R d  is as defined in  claim 1 .    
     
     
         10 . A compound according to  claim 3 , 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;    R 3  is hydrogen or alkyl;    R 4  is hydrogen;    n is an integer 1-3;    D is situated in the ortho, meta or para position and represents 
 —SO 2 R d , wherein R d  is as defined in  claim 1;   
   D′ is hydrogen;    D″ is hydrogen.    
     
     
         11 . A compound according to  claim 10 , wherein 
 A is situated in the para position;    R is —OH, —Oalkyl or —Oalkylaryl; 
 —NH 2 , —NHOalkylaryl or —NHCN;  
   R 1  is —Oalkyl, preferably —Olower alkyl;    R 3  is hydrogen;    n is the integer 1;    D is situated in the para position and represents —SO 2 R d , wherein R d  is as defined in  claim 1 .    
     
     
         12 . A compound according to  claim 3 , 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;    R 3  is hydrogen or alkyl,    R 4  is hydrogen;    n is an integer 1-3,    D is situated in the ortho, meta or para position and represents 
 —SR d , wherein R d  is as defined in  claim 1;   
   D′ is hydrogen;    D″ is hydrogen.    
     
     
         13 . A compound according to  claim 12 , wherein 
 A is situated in the para postion;    R is —OH, —Oalkyl, —Oalkylaryl; 
 —NH 2 , —NHOalkylaryl or —NHCN;  
   R 1  is —Oalkyl, preferably —Olower alkyl;    R 3  is hydrogen;    n is the integer 1;    D is situated in the para position and represents —SR d , wherein R d  is as defined in  claim 1 .    
     
     
         14 . A compound according to  claim 3 , wherein 
 A is situated in the meta or para position,    R is —OR a , wherein R a  is hydrogen, alkyl, 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 1-3,    D is situated in the ortho, meta or para position and represents 
 —OCONR a R b , wherein R a  and R c  are as defined in  claim 1;   
   D′ is hydrogen;    D″ is hydrogen.    
     
     
         15 . A compound according to  claim 14 , wherein 
 A is situated in the para position;    R is —OH, —Oalkyl, —Oalkylaryl; 
 —NH 2 , —NHOalkylaryl, —NHCN;  
   R 2  is hydrogen;    R 3  is hydrogen;    n is the integer 1;    D is situated in the para position, and represents 
 —OCONHR d , wherein R d  is as defined in  claim 1 .  
   
     
     
         16 . A compound according to  claim 15 , wherein 
 R 1  is —Oalkyl, preferably —Olower alkyl;    D is —OCONHalkyl.    
     
     
         17 . A compound according to  claim 3 , wherein 
 A is situated in the meta or para position,    R is —OR a , wherein R a  is hydrogen, alkyl, 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 1-3;    D is situated in the ortho, meta or para position and represents 
 —NR c SO 2 R d , wherein R c  and R d  are as defined in  claim 1;   
   D′ is hydrogen;    D″ is hydrogen.    
     
     
         18 . A compound according to  claim 17 , wherein 
 A is situated in the para position;    R is —OH, —Oalkyl, —Oalkylaryl; 
 —NH 2 , —NHOalkylaryl or —NHCN;  
   R 2  is hydrogen;    R 3  is hydrogen;    n is the integer 1,    D is situated in the para position, and represents 
 —NR h SO 2 R d , wherein R d  is as defined in  claim 1  and R h  is hydrogen or alkyl.  
   
     
     
         19 . A compound according to  claim 18 , wherein 
 R 1  is —Oalkyl, preferably —Olower alkyl;    D is —NR h SO 2 alkyl wherein R h  is hydrogen or alkyl.    
     
     
         20 . A compound according to  claim 3 , 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 1-3;    D is situated in the ortho, meta or para position and represents 
 —NR c R d , wherein R c  and R d  are as defined in  claim 1;   
   D′ is hydrogen;    D″ is hydrogen.    
     
     
         21 . A compound according to  claim 20 , wherein 
 A is situated in the para position;    R is —OH, —Oalkyl, —Oalkylaryl; 
 —NH 2 , —NHOalkylaryl or —NHCN;  
   R 2  is hydrogen;    R 3  is hydrogen;    n is the integer 1;    D is situated in the para position, and represents 
 —NR h R d  wherein R d  is as defined in  claim 1  and R h  is hydrogen or alkyl.  
   
     
     
         22 . A compound according to  claim 21 , wherein 
 R 1  is —Oalkyl, preferably —Olower alkyl;    D is —NR h alkyl wherein R h  is hydrogen or alkyl.    
     
     
         23 . A compound according to  claim 3 , 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 1-3;    D is situated in the ortho, meta or para position and represents 
 —NR c CONR a R k , wherein R a , R c  and R k  are as defined in  claim 1;   
   D′ is hydrogen;    D″ is hydrogen.    
     
     
         24 . A compound according to  claim 23 , wherein 
 A is situated in the para position;    R is —OH, —Oalkyl, —Oalkylaryl; 
 —NH 2 , —NHOalkylaryl or —NHCN;  
   R 2  is hydrogen;    R 3  is hydrogen;    n is the integer 1;    D is situated in the para position, and represents 
 —NHCONHR d , wherein R d  is as defined in  claim 1 .  
   
     
     
         25 . A compound according to  claim 24 , wherein 
 R 1  is —Oalkyl, preferably —Olower alkyl;    D is —NHCONHalkyl.    
     
     
         26 . A compound according to  claim 3 , 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 1-3;    D is situated in the ortho, meta or para position and represents 
 —NR c CSNR a R k , wherein R a , R c  and R k  are as defined in  claim 1;   
   D′ is hydrogen;    D″ is hydrogen.    
     
     
         27 . A compound according to  claim 26 , wherein 
 A is situated in the para position;    R is —OH, —Oalkyl, —Oalkylaryl; 
 —NH 2 , —NHOalkylaryl or —NHCN;  
   R 2  is hydrogen;    R 3  is hydrogen;    n is the integer 1;    D is situated in the para position, and represents 
 —NHCSNHR d , wherein R d  is as defined in  claim 1 .  
   
     
     
         28 . A compound according to  claim 27 , wherein 
 R 1  is —Olower alkyl;    D is —NHCSNHalkyl.    
     
     
         29 . A compound according to  claim 3 , wherein 
 A is situated in the meta or para position,    R is —OR a , wherein R a  is hydrogen, alkyl, 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 1-3,    D is situated in the ortho, meta or para position and represents 
 —OSO 2 R d , wherein R d  is as defined in  claim 1;   
   D′ is hydrogen;    D″ is hydrogen.    
     
     
         30 . A compound according to  claim 29 , wherein 
 A is situated in the para position,    R is —OH, —Oalkyl, —Oalkylaryl; 
 —NH 2 , —NHOalkylaryl or —NHCN;  
   R 2  is hydrogen;    R 3  hydrogen;    n is the integer 1;    D is situated in the para position and represents 
 —OSO 2 alkyl or —OSO 2 alkylaryl.  
   
     
     
         31 . A compound according to  claim 30 , wherein 
 R 1  is —Oalkyl, preferably —Olower alkyl;    D is —OSO 2  alkyl.    
     
     
         32 . A compound according to any of the preceding claims being 
 2-Ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid;    3-{4-[2-(4-tert-Butoxycarbonylaminophenyl)ethoxy]phenyl}-2-ethoxypropanoic acid;    2-Ethoxy-3-{4-[2-(4-methanesulfonylphenyl)ethoxy]phenyl}propanoic acid;    2-Ethoxy-3-{4-[2-(4-methylsulfanylphenyl)ethoxy]phenyl}propanoic acid;    2-Ethoxy-3-[4-(2-{4-isobutyrylaminophenyl}ethoxy)phenyl]propanoic acid;    3-{4-[2-(4-tert-Butylcarbamoyloxyphenyl)ethoxy]phenyl}-2-ethoxypropanoic acid ethyl ester,    2-Ethoxy-3-{4-[2-(4-methanesulfonylaminophenyl)ethoxy]phenyl}propanoic acid;    N-Cyano-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic amide;    N-Benzyloxy-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic amide;    2-Ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic amide;    2-Ethoxy-3-{4-[3-(3-methanesulfonyloxyphenyl)propoxy]phenyl}propanoic acid ethyl ester;    2-Ethoxy-3-(4-{2-[4-(2-propanesulfonyloxy)phenyl]ethoxy}phenyl)propanoic acid;    3-[4-{2-(4-[tert-Butoxycarbonyl(methyl)amino]phenyl)ethoxy}phenyl]-(S)-2-ethoxypropanoic acid;    (S)-2-Ethoxy-3-[4-{2-[4-(methoxycarbonylamino)phenyl)ethoxy]phenyl}propanoic acid;    2-Ethoxy-3-{4-[2-(4-methylcarbamoyloxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester;    3-[4-{2-(4-[Benzyloxycarbonylamino]phenyl)ethoxy}phenyl]-(S)-2-ethoxypropanoic acid;    3-{4-[2-(4-tert-Butoxycarbonylaminophenyl)ethoxy]-3-methoxyphenyl}-2-ethoxypropanoic acid;    3-[4-(2-{4-tert-Butoxycarbonylaminophenyl}ethoxy)phenyl]-2-(2,2,2-trifluoroethoxy)propanoic acid methyl ester,    (S)-2-Ethoxy-3-(4-{2-[4-(phenylsulfonyl)phenyl]ethoxy}phenyl)propanoic acid; 
 and, where applicable, stereo- and optical isomers and racemates thereof as well as pharmaceutically acceptable salts, solvates and crystalline forms thereof.  
   
     
     
         33 . A compound according to any of the preceding claims wherein the compound is one of the possible enantiomers.  
     
     
         34 . A process for preparing a compound according to  claim 1 , characterized by 
 a) condensating a compound of the formula II                          with a compound of the formula III or IV                          in which formulas D, D′, D″, n, R, R 1  and R 3  are as defined in  claim 1  and L 1 =L 2 =L 3  are phenyl or L 1 =L 2  are OR (wherein R d  is as defined in  claim 1)  and L is ═O, whereafter, if desired, reducing the double bond and removing protective groups, to the formation of a compound of formula I wherein R 2  and R 4  are hydrogen, or    b) reacting a carbonyl compound of the formula II                          with a compound of the formula VII                          in which formulas D, D′, D″, n, R 1  and R 3  are as defined in  claim 1  and R 2  is alkyl, aryl or alkylaryl, followed by dehydroxylation and, if necessary, by removal of protective groups, to the formation of a compound of the formula I, where A is —CR 3 R 4 —CR 1 R 2 —COR, wherein R 4  is hydrogen, or    c) reacting a compound of the formula VIII                          with a compound of the formula VII                          in which formulas D, D′, D″, n, R, R 1 , R 2 , R 3  and R 4  are as defined in  claim 1  and X is a leaving group, whereafter, if necessary, removing protective groups to the formation of a compound of the formula I wherein A is —CR 3 R 4 —CR 1 R 2 —COR, or    d) reacting a compound of the formula V                          with a compound of the formula X                          in which formulas D, D′, D″, n and A are as defined in  claim 1  and R 1  is —OH or a leaving group, whereafter, if necessary, removing protective groups, or    e) converting a compound of the formula XI                          in which formula D, D′, D″, n, R, R 2 , R 3  and R 4  are as defined in  claim 1  and X″ is —OH followed, if necessary, by removal of protective groups, to the formation of a compound of the formula I, wherein A is —CR 3 R 4 —CR 1 R 2 —COR, wherein R 1  is    —OR e , wherein R e  is as defined in  claim 1 ,    —O—[CH 2 ] m —OR f , wherein m and R f  are as defined in  claim 1 ,    —OCONR a R c , wherein R a  and R c  are as defined in  claim 1 ,    f) reacting a compound of the formula XIII                          with a thiol, in which formula D, D′, D″, n, R, R 2 , R 3  and R 4  are as defined in  claim 1  and X′ is halogen, to the formation of a compound of the formula I wherein A is —CR 3 R 4 —CR 1 R 2 —COR, wherein R 1  is    —SR d , wherein R d  is as defined in  claim 1;  or    g) reacting a compound of the formula XIV                          with a suitable reagent and followed by removal of protective groups, in which formula D′, D″, n and A are as defined in  claim 1  and X 1  is —OH, —SH or —NR c H to the formation of a compound of the formula I, wherein D is —OSO 2 R d , —SR c , —OCONR f R a , —NR c COOR d , —NR c COR a , —NR c R d , —NR c CONR a R k , NR c SO 2 R d  and —NR c CSNR a R k ; wherein R a , R c , R d , R f , R g  and R k  are as defined in  claim 1 , or    h) hydrolysis of a compound of the formula I wherein R is —OR p , wherein R p  is a protective group, to the formation of a compound of the formula I wherein R is —OH, or    i) reacting a compound of the formula I, wherein R is —OH with a compound of the formula HNR a R b , wherein R a  and R b  are as defined in  claim 1 , to the formation of a compound of the formula I wherein R is —NR a R b , or    j) oxidizing a compound of the formula XV                          and if necessary followed by removal of protective groups, in which formula D′, D″, n and A are as defined in  claim 1  and X 2  is —SOR d  or —SR d  wherein R d  is as defined in  claim 1 , to the formation of a compound of the formula I wherein D is —SO 2 R d  or —SOR d ; whereafter, if desired, the compound obtained according to any of methods a)-j) is converted to a stereoisomer, a pharmaceutically acceptable salt thereof and/or a solvate, such as a hydrate, thereof.    
     
     
         35 . A process according to  claim 34 , characterized by the preparation of a compound according to any of claims  2 - 33 .  
     
     
         36 . A compound according to any of claims  1 - 33  for use in therapy.  
     
     
         37 . A pharmaceutical formulation containing a compound according to any of claims  1 - 33  as active ingredient optionally together with an acceptable carrier, adjuvant and/or diluent.  
     
     
         38 . The use of a compound according to any of claims  1 - 33  in the manufacture of a medicament for the prophylaxis and/or treatment of clinical conditions associated with insulin resistance.  
     
     
         39 . A method for the prophylaxis and/or treatment of clinical conditions associated with insulin resistance wherein a therapeutically active amount of a compound according to any of claims  1 - 33  administered to a mammal in the need of such prophylaxis and/or treatment.  
     
     
         40 . A method according to  claim 39  wherein the prophylaxis and/or treatment of clinical conditions associated with insulin resistance is the prophylaxis and/or treatment of dyslipidaemia in such conditions.  
     
     
         41 . A method according to  claim 39  wherein the prophylaxis and/or treatment of clinical conditions associated with insulin resistance is the prophylaxis and/or treatment of hyperglycaemia in non insulin dependent diabetes mellitus.  
     
     
         42 . A pharmaceutical formulation for use in the prophylaxis and/or treatment of clinical conditions associated with insulin resistance wherein the active ingredient is a compound according to any of claims  1 - 33 .