Organic Compounds

Abstract

The present invention relates to novel benzodiazepine compounds exhibiting RXR-antagonist efficacy, to the manufacture and to the use thereof.

1 . A method of treating a condition or disease associated with RXR-antagonism, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, 
     
       
         
         
             
             
         
       
     
     wherein R1 and R2, independently of each other, represent hydrogen, or C 1 -C 7 -alkyl, or R1 and R2 together with the carbon atoms of the phenyl ring to which they bind form a 5-, 6- or 7-membered cycloalkyl ring, which ring may optionally be substituted by one or more C 1 -C 7 -alkyl groups, which alkyl groups may also together form one or more 3-, 4-, 5-, 6- or 7-membered rings; R3 represents —CN, —CO—R 5 , or hydrogen, provided that, if R3 is hydrogen, R4 must represent C 3 -C 7 -alkenyl or C 3 -C 7 -alkynyl; R 5  represents aryl, or alkyl being unsubstituted or substituted by halogen, cyano, nitro, hydroxy, C 1 -C 7 -alkoxy, carboxyl or aryl; R4 represents C 1 -C 7 -alkyl, C 2 -C 7 -alkenyl or C 2 -C 7 -alkynyl or R4 represents C 2 -C 7 -alkanoyl; and X represents ligand (a), 
     
       
         
         
             
             
         
       
     
     wherein Y may be in ortho, meta or para position and wherein Y represents carboxyl, C 1 -C 7 -alkoxy-carbonyl, aryloxycarbonyl, tetrazolyl, SO 3 H or P(O)(OH) 2 ; and wherein Z represents hydrogen or a substituent selected from the group consisting of C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy, halogen, CF 3 , cyano and NO 2 . 
   
   
       2 . The method of  claim 1 , wherein the disease or condition is selected from the group consisting of diabetes, type-2-diabetes, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, hyperlipidemia, obesity, dyslipidemia, and osteoporosis. 
   
   
       2 . The method of  claim 1  wherein the compound is represented by formula (IIa), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
   
   
       3 . The method of  claim 2 , wherein the compound is represented by of formula (IIb), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein alk in each case represent C 1 -C 7 -alkyl and A is CH 2 , CH 2 CH 2 , or CH 2 CH 2 CH 2 . 
   
   
       4 . The method of  claim 3 , wherein the compound is represented by of formula (IIc), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
   
   
       5 . The method of  claim 1 , wherein X represents p-carboxyphenyl. 
   
   
       6 . The method of  claim 1 , wherein:
 R1 and R2 together with the two carbon atoms on the phenyl ring to which R1 and R2 bind form 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene ring;   X represents 4-carboxy-phenyl;   R3 is cyano or C 2 -C 5 -alkanoyl; and   R4 represents C 1 -C 7 -alkyl, C 2 -C 7 -alkenyl or C 2 -C 7 -alkynyl.   
   
   
       7 . The method of  claim 6 , wherein for R3 is in the para-position relative to N—R4 in formula (I). 
   
   
       8 . The method of  claim 6 , wherein R4 represents a C 1 -C 7 -alkyl. 
   
   
       9 . The method of  claim 6 , wherein R4 represents methyl or ethyl.