Solid phase synthesis of LXR ligands

Abstract

The invention provides solid support synthetic methods for producing combinatorial libraries of modulators of LXRs. The combinatorial libraries thus produced are useful both as diagnostic indicators of LXRα function and as pharmacologically active agents. The combinatorial libraries find particular use in the treatment of disease states associated with cholesterol metabolism, particularly atherosclerosis and hypercholesterolemia.

What is claimed is:  
     
         1 . A method for preparing LXR ligands on a solid support, said method comprising: 
 (a) attaching an aniline derivative to said solid support to provide a support-bound aniline derivative;    (b) contacting said support-bound aniline derivative with an aldehyde or ketone under reductively aminating conditions to provide a support-bound substituted aniline derivative; and    (c) contacting said support-bound substituted aniline derivative with an acylating agent to provide an LXR ligand on said solid support.    
     
     
         2 . A method in accordance with  claim 1 , further comprising: 
 (d) removing said LXR ligand from said solid support.    
     
     
         3 . A method in accordance with  claim 1 , wherein said aniline derivative has the formula:  
       
         
           
           
               
               
           
         
       
       wherein PG is a protecting group, and said method further comprises a step between steps (a) and (b) of removing said protecting group.  
     
     
         4 . A method in accordance with  claim 1 , wherein said aldehyde or ketone of step (b) is selected from the group consisting of an optionally substituted (C 1 -C 8 )alkyl aldehyde and an optionally substituted dialkylketone.  
     
     
         5 . A method in accordance with  claim 1 , wherein said aldehyde or ketone of step (b) is selected from the group consisting of optionally substituted aryl aldehyde and a ketone having the formula R 3 —C(O)—R 4  
 wherein R 3  and R 4  are members each independently selected form the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl and optionally substituted alkyl.  
 
     
     
         6 . A method in accordance with  claim 1 , wherein said acylating agent has the formula:  
       R 1 —Y  
       wherein 
 R 1  is a member selected from the group consisting of optionally substituted (C 8 -C 18 )bicycloalkyl, optionally substituted (C 8 -C 18 )tricycloalkyl, optionally substituted (C 8 -C 18 )heterobicycloalkyl and optionally substituted (C 8 -C 18 )heterotricycloalkyl; and  
 Y is a member selected from the group consisting of a carboxylic acid, a carboxylate ester, a carboxylic acid chloride and other activated forms of carboxylic acids.  
 
     
     
         7 . A method in accordance with  claim 1 , wherein said solid support is selected from the group consisting of 4-(bromomethyl)phenoxymethyl polystyrene, Merrifield resin, Rink amide resin and Sieber resin.  
     
     
         8 . A method in accordance with  claim 4 , wherein said acylating agent has the formula:  
       R 1 —Y  
       wherein 
 R 1  is a member selected from the group consisting of optionally substituted (C 8 -C 18 )bicycloalkyl, optionally substituted (C 8 -C 18 )tricycloalkyl, optionally substituted (C 8 -C 18 )heterobicycloalkyl and optionally substituted (C 8 -C 18 )heterotricycloalkyl; and  
 Y is a member selected from the group consisting of a carboxylic acid, a carboxylate ester, a carboxylic acid chloride and other activated forms of carboxylic acids.  
 
     
     
         9 . A method in accordance with  claim 2 , wherein said LXR ligands have the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is a member selected from the group consisting of optionally substituted (C 8 -C 18 )bicycloalkyl, optionally substituted (C 8 -C 18 )tricycloalkyl, optionally substituted (C 8 -C 18 )heterobicycloalkyl and optionally substituted (C 8 -C 18 )heterotricycloalkyl;  
 R 2  is a member selected from the group consisting of optionally substituted (C 1 -C 8 )alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl and optionally substituted heteroarylalkyl; and  
 X is a member selected from the group consisting of —CO 2 R 11 , —CH 2 OR 11 , —C(O)R 11 , —C(O)NR 11 R 12  and —CH 2 NR 11 R 12 , wherein R 11  and R 12  are each members independently selected from the group consisting of hydrogen and optionally substituted (C 1 -C 8 )alkyl.  
 
     
     
         10 . A method in accordance with  claim 9 , wherein 
 R 1  is a member selected from the group consisting of optionally substituted optionally substituted tricyclo[3.3.1.1 3,7 ]decanyl, optionally substituted bicyclo[3.2.1]octanyl, optionally substituted bicyclo[5.2.0]nonanyl, bicyclo[4.3.2]undecanyl, optionally substituted tricyclo[2.2.1.0 1 ]heptanyl, tricyclo[5.3.1.1 1 ]dodecanyl, optionally substituted tricyclo[5.4.0.0 2,9 ]undecanyl, optionally substituted tricyclo[5.3.2.0 4,9 ]dodecanyl, optionally substituted tricyclo[4.4.1.1 1,5 ]dodecanyl and optionally substituted tricyclo[5.5.1.0 3,11 ]tridecanyl group.    
     
     
         11 . A method in accordance with  claim 9 , wherein R 1  is a substituted or unsubstituted adamantyl group.  
     
     
         12 . A method in accordance with  claim 1 , wherein said solid support is selected from the group consisting of a 4-(bromomethyl)phenoxymethyl polystyrene and Merrifield resin; said aniline derivative has the formula:  
       
         
           
           
               
               
           
         
         wherein PG is a protecting group, and said method further comprises a step between steps (a) and (b) of removing said protecting group; said aldehyde or ketone of step (b) is selected from the group consisting of a optionally substituted (C 1 -C 5 )alkyl aldehyde or ketone; and said acylating agent of step (c) has the formula:  
         R 1 —Y  
         wherein  
         R 1  is a member selected from the group consisting of optionally substituted(C 8 -C 18 )bicycloalkyl, optionally substituted(C 8 -C 18 )tricycloalkyl, optionally substituted(C 8 -C 18 )heterobicycloalkyl and optionally substituted(C 8 -C 18 )heterotricycloalkyl; and  
         Y is a member selected from the group consisting of a carboxylic acid, a carboxylate ester, a carboxylic acid chloride and other activated forms of carboxylic acids.  
       
     
     
         13 . A method for preparing LXR ligands on a solid support, said method comprising: 
 (a) attaching a substituted aniline derivative to said solid support to provide a support-bound substituted aniline derivative; and    (b) contacting said support-bound substituted aniline derivative with an acylating agent to provide an LXR ligand on a solid support.    
     
     
         14 . A method in accordance with  claim 13 , further comprising: 
 (c) removing said LXR ligand from said solid support.    
     
     
         15 . A method in accordance with  claim 13 , wherein said substituted aniline derivative has the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 PG is a protecting group;  
 R 2  is a member selected from the group consisting of optionally substituted(C 1 -C 8 )alkyl, optionally substituted aryl and optionally substituted heteroaryl; and  
 said method further comprises a step between steps (a) and (b) of removing said protecting group.  
 
     
     
         16 . A method in accordance with  claim 13 , wherein said acylating agent has the formula:  
       R 1 —Y  
       wherein 
 R 1  is a member selected from the group consisting of optionally substituted(C 8 -C 18 )bicycloalkyl, optionally substituted(C 8 -C 18 )tricycloalkyl, optionally substituted(C 8 -C 18 )heterobicycloalkyl and optionally substituted(C 8 -C 18 )heterotricycloalkyl; and  
 Y is a member selected from the group consisting of carboxylic acid, carboxylate ester, carboxylic acid chloride and activated forms of carboxylic acids.  
 
     
     
         17 . A method in accordance with  claim 13 , wherein said solid support is selected from the group consisting of a 4-(bromomethyl)phenoxymethyl polystyrene, Merrifield resin, Rink amide resin and Sieber resin.  
     
     
         18 . A method in accordance with  claim 15 , wherein said acylating agent has the formula:  
       R 1 —Y  
       wherein 
 R 1  is a member selected from the group consisting of optionally substituted (C 8 -C 18 )bicycloalkyl, optionally substituted (C 8 -C 18 )tricycloalkyl, optionally substituted (C 8 -C 18 )heterobicycloalkyl and optionally substituted (C 8 -C 18 )heterotricycloalkyl; and  
 Y is a member selected from the group consisting of a carboxylic acid, a carboxylate ester, a carboxylic acid chloride and other activated forms of carboxylic acids.  
 
     
     
         19 . A method in accordance with  claim 14 , wherein said LXR ligands have the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is a member selected from the group consisting of optionally substituted(C 8 -C 18 )bicycloalkyl, optionally substituted (C 8 -C 18 )tricycloalkyl, optionally substituted (C 8 -C 18 )heterobicycloalkyl and optionally substituted (C 8 -C 18 )heterotricycloalkyl;  
 R 2  is a member selected from the group consisting of optionally substituted (C 1 -C 8 )alkyl, optionally substituted aryl and optionally substituted heteroaryl; and  
 X is a member selected from the group consisting of —CO 2 R 11 , —CH 2 OR 11 , —C(O)R 11 , —C(O)NR 11 R 12  and —CH 2 NR 11 R 12 , wherein R 11  and R 12  are each members independently selected from the group consisting of hydrogen and optionally substituted (C 1 -C 8 )alkyl.  
 
     
     
         20 . A method in accordance with  claim 13 , wherein said substituted aniline derivative has the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 PG is a protecting group;  
 R 2  is a member selected from the group consisting of optionally substituted (C 1 -C 8 )alkyl, optionally substituted aryl and optionally substituted heteroaryl; and  
 said method further comprises a step between step (a) and (b) of removing said protecting group; and said acylating agent has the formula:  
 R 1 —Y  
 wherein  
 R 1  is a member selected from the group consisting of optionally substituted (C 8 -C 18 )bicycloalkyl, optionally substituted (C 8 -C 18 )tricycloalkyl, optionally substituted (C 8 -C 18 )heterobicycloalkyl and optionally substituted (C 8 -C 18 )heterotricycloalkyl; and  
 Y is a member selected from the group consisting of carboxylic acid, carboxylate ester, carboxylic acid chloride and activated forms of carboxylic acids.  
 
     
     
         21 . A combinatorial library comprising compounds of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is a member selected from the group consisting of optionally substituted(C 8 -C 18 )bicycloalkyl, optionally substituted (C 8 -C 18 )tricycloalkyl, optionally substituted (C 8 -C 18 )heterobicycloalkyl and optionally substituted (C 8 -C 18 )heterotricycloalkyl;  
 R 2  is a member selected from the group consisting of optionally substituted (C 1 -C 8 )alkyl, optionally substituted aryl and optionally substituted heteroaryl; and  
 X is a member selected from the group consisting of —CO 2 R 11 , —CH 2 OR 11 , —C(O)R 11 , —C(O)NR 11 R 12  and —CH 2 NR 11 R 12 , wherein R 11  and R 12  are each members independently selected from the group consisting of a solid support, hydrogen and optionally substituted (C 1 -C 8 )alkyl.  
 
     
     
         22 . A method for synthesizing a combinatorial library comprising compounds of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is a member selected from the group consisting of optionally substituted(C 8 -C 18 )bicycloalkyl, optionally substituted (C 8 -C 18 )tricycloalkyl, optionally substituted (C 8 -C 18 )heterobicycloalkyl and optionally substituted (C 8 -C 18 )heterotricycloalkyl;  
 R 2 is a member selected from the group consisting of optionally substituted (C 1 -C 8 )alkyl, optionally substituted aryl and optionally substituted heteroaryl; and  
 X is a member selected from the group consisting of —CO 2 R 11 , —CH 2 OR 11 , —C(O)R 11 , —C(O)NR 11 R 12  and —CH 2 NR 11 R 12 , wherein R 11  and R 12  are each members independently selected from the group consisting of hydrogen and optionally substituted (C 1 -C 8 )alkyl; said method comprising:  
 (a) attaching an aniline derivative to a solid support to provide a support-bound aniline derivative;  
 (b) contacting said support-bound aniline derivative with an aldehyde or ketone under reductively aminating conditions to provide a support-bound substituted aniline derivative; and  
 (c) contacting said support-bound substituted aniline derivative with an acylating agent to provide an LXR ligand on said solid support.