Methods and compositions for reducing body fat and adipocytes

Abstract

Provided are methods of reducing body fat in a subject, comprising locally (e.g., topically) administering one or more compounds of the Formula (I) and/or (V): or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof, wherein X is —OR 1 , —SR 2 , or —NR 3 R 4 , and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 7 ′, Z, Y, n, y, and x, are as defined herein.

1 . A method for reducing fat in a body of a subject in need thereof, the method comprising administering locally to the subject a compound of the Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; 
         wherein:
 X is selected from:
 —OR 1 , wherein R 1  is selected from the group consisting of hydrogen, a hydroxyl protecting group, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl; 
 —SR 2 , wherein R 2  group consisting of hydrogen, a thiol protecting group, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl; 
 —NR 3 R 4 , wherein R 3  and R 4  are independently selected from the group consisting of hydrogen, an amino protecting group, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or R 3  and R 4  are joined to form an optionally substituted heterocyclyl ring. 
 
 
       
     
     
         2 . The method of  claim 1 , wherein the compound is of Formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof. 
       
     
     
         3 . The method of  claim 2 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, or isotopically enriched derivative thereof. 
       
     
     
         4 . The method of  claim 2 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, or isotopically enriched derivative thereof. 
       
     
     
         5 . The method of  claim 4 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The method of  claim 1 , wherein the compound is of Formula (III): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof. 
       
     
     
         7 . The method of  claim 1 , wherein the compound is of Formula (IV): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof. 
       
     
     
         8 . A method for reducing fat in a body of a subject in need thereof, the method comprising administering locally to the subject a compound of the Formula (V): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative thereof, or prodrug thereof; 
         wherein:
 X is:
 —OR 1 , wherein R 1  is selected from the group consisting of hydrogen, a hydroxyl protecting group, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl; 
 —SR 2 , wherein R 2  group consisting of hydrogen, a thiol protecting group, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl; or 
 —NR 3 R 4 , wherein R 3  and R 4  are independently selected from the group consisting of hydrogen, an amino protecting group, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or R 3  and R 4  are joined to form an optionally substituted heterocyclyl ring; 
 
 Z is ═O or represents two hydrogen atoms; 
 one of R 5  and R 6  is ═O, —OH, or a —O(CO)R 8  group and the other one is —OH or —O(CO)R 8 , or R 5  is ═O and R 6  is H, wherein R 8  is a saturated or unsaturated acyclic hydrocarbon group having from 1 to about 20 carbon atoms or —(CH 2 ) m R 9  wherein m is 0-10, and R 9  is cycloalkyl having from three to seven carbon atoms, aryl having from six to ten carbon atoms, or heteroaryl having from four to ten carbon atoms and one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur 
 R 7  is hydrogen, halogen, —OH or —O(CO)R 10 , wherein R 10  is a saturated or unsaturated acyclic hydrocarbon group having from 1 to about 20 carbon atoms or —(CH 2 ) m R 11 , wherein m is 0-10, and R 11  is cycloalkyl having from three to seven carbon atoms, aryl having from six to ten carbon atoms, or heteroaryl having from four to ten carbon atoms and one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; 
 R 7 ′ is hydrogen or halogen; 
 Y is selected from the group consisting of alkyl, halo, nitro, amino, thiol, hydroxy, alkyloxy, alkylcarboxy and halo-substituted alkyl, wherein said alkyl radical comprises from one to six carbon atoms; 
 y is 0 or 1, and x is 0 or 1, provided x and y are not both 1; and 
 n is 0 or an integer of from 1 to 3, inclusive. 
 
       
     
     
         9 . The method of  claim 1 , wherein the subject suffers from obesity gynecomastia, HIV lipodystrophy, lipoma, or excess fat on the chin. 
     
     
         10 . The method of  claim 8 , wherein the subject suffers from gynecomastia, obesity, HIV lipodystrophy, lipoma, or excess fat on the chin. 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 1 , wherein the route of said administering is topical. 
     
     
         15 . The method of  claim 1 , wherein the route of said administering is selected from the group consisting of subcutaneous, intradermal, and intralesional. 
     
     
         16 . (canceled) 
     
     
         17 . A pharmaceutical composition for reducing body fat, comprising a therapeutically effective amount of a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; and optionally one or more pharmaceutically acceptable excipients; 
         wherein:
 X is selected from:
 —OR 1 , wherein R 1  is selected from the group consisting of hydrogen, a hydroxyl protecting group, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl; 
 —SR 2 , wherein R 2  group consisting of hydrogen, a thiol protecting group, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally Response to Notice to File Missing Parts substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl; 
 —NR 3 R 4 , wherein R 3  and R 4  are independently selected from the group consisting of hydrogen, an amino protecting group, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or R 3  and R 4  are joined to form an optionally substituted heterocyclyl ring. 
 
 
       
     
     
         18 . The composition of  claim 17 , wherein the compound is of Formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof. 
       
     
     
         19 . The composition of  claim 18 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, or isotopically enriched derivative thereof. 
       
     
     
         20 . The composition of  claim 18 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, or isotopically enriched derivative thereof. 
       
     
     
         21 . The composition of  claim 20 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         22 . The composition of  claim 17 , wherein the compound is of Formula (III): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof. 
       
     
     
         23 . The composition of  claim 17 , wherein the compound is of Formula (IV): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof. 
       
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . The composition of  claim 17 , wherein the composition comprises between about 0.01% to about 10% (w/w) or (w/v), inclusive, of the compound. 
     
     
         27 . (canceled)