Compounds having selective activity for Retinoid X Receptors, and means for modulation of processes mediated by Retinoid X Receptors

Abstract

Compounds, compositions, and methods for modulating processes mediated by Retinoid X Receptors using retinoid-like compounds which have activity selective for members of the subclass of Retinoid X Receptors (RXRs), in preference to members of the subclass of Retinoic Acid Receptors (RARs). Examples of such compounds are bicyclic benzyl, pyridinyl, thiophene, furanyl, and pyrrole derivatives. The disclosed methods employ compounds for modulating processes selectively mediated by Retinoid X Receptors.

1 - 3 . (canceled)  
   
   
       4 . A compound having the formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  and R 2 , each independently, represent hydrogen or lower alkyl or acyl having 1-4 carbon atoms;  
 Y represents C, O, S, N, CHOH, CO, SO, SO 2 ;  
 R 3  represents hydrogen or lower alkyl having 1-4 carbon atoms where Y is C or N;  
 R 4  represents hydrogen or lower alkyl having 1-4 carbon atoms where Y is C, but R 4  does not exist if Y is N, and neither R 3  or R 4  exist if Y is S, O, CHOH, CO, SO, or SO 2 ;  
 R′ and R″ represent hydrogen, lower alkyl or acyl having 1-4 carbon atoms, OH, alkoxy having 1-4 carbon atoms, thiol or thio ether, or amino,  
 or R′ or R″ taken together form an oxo (keto), methano, thioketo, HO—N═, NC—N═, (R 7 R 8 )N—N═, R 17 O—N═, R 17 N═, epoxy, cyclopropyl, or cycloalkyl group and wherein the epoxy, cyclopropyl, and cycloalkyl groups can be substituted with lower alkyl having 1-4 carbons or halogen;  
 R 5  represents hydrogen, a lower alkyl having 1-4 carbons, halogen, nitro, OR 7 , SR 7 , NR 7  R 8 , or (CF) n CF 3 , but R 5  cannot be hydrogen if Z, Z′, Z″, and Z′″, are all carbon, and R′ and R″ represent H, OH, C 1 -C 4  alkoxy or C 1 -C 4  acyloxy or R′ and R″ taken together form an oxo, methano, or hydroxyimino group;  
 R 7  represents hydrogen or a lower alkyl having 1-6 carbons;  
 R 8  represents hydrogen or a lower alkyl having 1-6 carbons;  
 R 9  represents a lower alkyl having 1-4 carbons, phenyl, aromatic alkyl, or q-hydroxy-phenyl, q-bromophenyl, q-chlorophenyl, q-fluorophenyl, or q-iodophenyl, where q=2-4;  
 R 17  represents hydrogen, lower alkyl having 1-8 carbons, alkenyl (including halogen, acyl, OR 7  and SR 7  substituted alkenes), R 9 , alkyl carboxylic acid (including halogen, acyl, OR 7  and SR 7  substituted alkyls), alkenyl carboxylic acid (including halogen, acyl, OR 7  and SR 7  substituted alkenes), alkyl amines (including halogen, acyl, OR 7  and SR 7  substituted alkyls), and alkenyl amines (including halogen, acryl, OR 7  and SR 7  substituted alkenes);  
 X is COOH, tetrazole, PO 3 H, SO 3 H, CHO, CH 2 OH, CONH 2 , COSH, COOR 9 , COSR 9 , CONHR 9 , or COOW where W is a pharmaceutically acceptable salt, and where X can originate from any C or N on the ring;  
 Z, Z′, Z″, and Z′″, each independently, represent C, S, O, N, but one of Z, Z′, Z″, and Z′″ is not O or S if attached by a double bond to another such Z or if attached to another such Z which is O or S, and is not N if attached by a single bond to another such Z which is N;  
 n=0-3; and  
 the dashed lines in the second and seventh structures shown depict optional double bonds; or a pharmaceutically acceptable salt thereof.  
 
   
   
       5 - 13 . (canceled)  
   
   
       14 . A pharmaceutical composition, comprising: 
 a pharmaceutically acceptable vehicle; and one or more compounds of  claim 4 .    
   
   
       15 - 18 . (canceled)  
   
   
       19 . A method for modulating a process mediated by one or more Retinoid X Receptors, said method comprising causing said process to be conducted in the presence of at least one compound as set forth in  claim 4 .  
   
   
       20 . The method of  claim 19 , wherein said Retinoid X Receptor is Retinoid X Receptor-alpha, Retinoid X Receptor-beta, or Retinoid X Receptor-gamma.  
   
   
       21 . The method of  claim 19 , wherein said process is the in vivo modulation of lipid metabolism, in vivo modulation of skin-related processes, in vivo modulation of autoimmune diseases, in vivo modulation of fatty acid metabolism, in vivo modulation of malignant cell development, in vivo modulation of premalignant lesions, or in vivo modulation of programmed cell death.  
   
   
       22 . The method of  claim 21 , wherein said process is the in vivo enhancement of programmed cell death.  
   
   
       23 . The method of  claim 21 , wherein said process is the in vivo inhibition of programmed cell death.  
   
   
       24 . The method of  claim 19 , wherein said process is in vivo or in vitro cellular growth and differentiation, or in vivo limb morphogenesis.  
   
   
       25 - 28 . (canceled)  
   
   
       29 . A method for treating a mammalian subject requiring Retinoid X Receptor therapy, comprising administering to such subject a pharmaceutically effective amount of one or more compounds of  claim 4 .  
   
   
       30 . A method for increasing plasma concentrations of high density lipoprotein in a mammalian subjects comprising administering to such subject a pharmaceutically effective amount of one or more compounds of  claim 4 .  
   
   
       31 - 44 . (canceled)  
   
   
       45 . The pharmaceutical composition of  claim 14 , wherein the pharmaceutically acceptable vehicle is suitable for enteral, parenteral, or topical administration.  
   
   
       46 . A compound selected from among 2-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl)thiophene-5-carboxylic acid (TTNCTC) and 2-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl)thiophene-5-carboxylic acid (TTNETC).