Methods and compositions for reducing body fat and adipocytes

Abstract

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof, wherein X is —OR1, —SR2, or —NR3R4, and R1, R2, R3, R4, R5, R6, R7, R7′, 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 halosubstituted 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 8 , wherein the subject suffers from obesity. 
     
     
         10 . The method of  claim 8 , wherein the subject suffers from gynecomastia. 
     
     
         11 . The method of  claim 8 , wherein the subject suffers from HIV lipodystrophy. 
     
     
         12 . The method of  claim 8 , wherein the subject suffers from lipoma. 
     
     
         13 . The method of  claim 8 , wherein the subject suffers from excess fat on the chin. 
     
     
         14 . The method of  claim 8 , wherein the route of said administering is topical. 
     
     
         15 . The method of  claim 8 , wherein the route of said administering is selected from the group consisting of subcutaneous, intradermal, and intralesional. 
     
     
         16 . The method of  claim 8 , wherein the administering is to a body part selected from the group consisting of the abdomen, chest, breast, buttocks, hips, thighs, legs, knees, arms, chin, neck, and face. 
     
     
         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 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 . A pharmaceutical composition for reducing body fat, comprising a therapeutically effective amount of a compound of 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 halosubstituted 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. 
 
       
     
     
         25 . The composition of  claim 24 , wherein the composition is suitable for topical, subcutaneous, intradermal, or intralesional delivery. 
     
     
         26 . The composition of  claim 24 , wherein the composition comprises between about 0.01% to about 10% (w/w) or (w/v), inclusive, of the compound. 
     
     
         27 . The composition of  claim 24 , wherein the excipient is Lipoderm®.