Compositions and methods for topical delivery of prostaglandins to subcutaneous fat

Abstract

Described herein are compositions comprising a prostaglandin FP receptor agonist (PFPRA) compound and a fatty acid ester (e.g., isopropyl myristate), optionally comprising an ointment base such as a hydrocarbon base (e.g., petroleum jelly) and/or an organic alcohol (e.g., propylene glycol), that, when topically applied to the skin, locally delivers a therapeutically effective amount of the PFPRA compound to subcutaneous fat under the skin, and methods of preparation. The therapeutic effect is, for example, reduction of the subcutaneous fat under the skin. Further provided are methods of reducing body fat in a subject comprising topically administering the composition to the subject.

1 - 20 . (canceled) 
     
     
         21 . A composition comprising a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; wherein:
 each instance of   independently represents a single bond or a double bond, which can be in the cis or trans configuration; 
 A is optionally substituted C 1-10  alkylene, optionally substituted C 2-10  alkenylene, or optionally substituted C 2-10  alkynylene, wherein the alkylene, alkenylene, or alkynylene group is optionally interrupted by one or more —O— or —S— groups; 
 B is hydrogen, optionally substituted C 3-7  carbocyclyl, optionally substituted 3-8-membered heterocyclyl, optionally substituted 5-14-membered heteroaryl, optionally substituted C 6-10  aryl, optionally substituted C 1-30  alkyl, optionally substituted C 2-30  alkenyl, or optionally substituted C 2-30  alkynyl; 
 X is —OR 4 , —SR 4 , or —N(R 4 ) 2 , wherein each instance of R 4  is independently hydrogen, optionally substituted C 1-30  alkyl, optionally substituted C 2-30  alkenyl, optionally substituted C 2-30  alkynyl, —C(═O)R 5 , or —C(═O)OR 5 , wherein R 5  is optionally substituted C 1-30  alkyl, optionally substituted C 2-30  alkenyl, or optionally substituted C 2-30  alkynyl, or two R 4  groups are joined to form an optionally substituted 3-8-membered heterocyclyl or optionally substituted 5-14-membered heteroaryl ring; 
 Z is ═O, ═S, or ═NR Z , wherein R Z  is selected from hydrogen, an amino protecting group, —OH, substituted hydroxyl, optionally substituted C 1-10  alkyl, optionally substituted C 2-10  alkenyl, optionally substituted C 2-10  alkynyl, optionally substituted C 3-7  carbocyclyl, optionally substituted 3-8-membered heterocyclyl, optionally substituted C 6-10  aryl, or optionally substituted 5-14-membered heteroaryl, or Z represents two hydrogen atoms; and 
 one of R 1  and R 2  is ═O, —OH, or a —O(CO)R 6  group, and the other one is —OH or —O(CO)R 6 , or R 1  is ═O and R 2  is H, wherein R 6  is an optionally substituted C 1-20  alkyl, optionally substituted C 2-20  alkenyl, optionally substituted C 2-20  alkynyl, or —(CH 2 ) m R 7 , wherein m is 0 or an integer of between 1-10, inclusive, and R 7  is optionally substituted C 3-7  carbocyclyl, optionally substituted 3-8-membered heterocyclyl, optionally substituted C 6-10  aryl, or optionally substituted 5-14-membered heteroaryl; 
 and a fatty acid ester. 
 
       
     
     
         22 . The composition of  claim 21 , wherein the fatty acid ester is of formula: 
       
         
           
           
               
               
           
         
         wherein:
 R FA1  is optionally substituted C 1 -C 6  alkyl; and 
 R FA2  is optionally substituted C 10 -C 20  alkyl or optionally substituted C 10 -C 20  alkenyl. 
 
       
     
     
         23 . The composition of  claim 22 , wherein R FA1  is unsubstituted C 1 -C 6  alkyl. 
     
     
         24 . The composition of  claim 22 , wherein R FA1  is unsubstituted C 1 -C 3  alkyl. 
     
     
         25 . The composition of  claim 22 , wherein R FA2  is optionally substituted C 1 -C 20  alkyl. 
     
     
         26 . The composition of  claim 22 , wherein R FA2  is unsubstituted C 10 -C 20  alkyl. 
     
     
         27 . The composition of  claim 21 , wherein the total number of carbons atoms in the fatty acid ester is between 15 and 19, inclusive. 
     
     
         28 . The composition of  claim 21 , wherein the total number of carbon atoms in the fatty acid ester approximates the length of the compound of Formula (I). 
     
     
         29 . The composition of  claim 21 , wherein the predicted length of the fatty acid ester by molecular modeling is similar to the predicted length of the compound of Formula (I) by molecular modeling. 
     
     
         30 . The composition of  claim 29 , wherein the predicted length of the fatty acid ester by molecular modeling is within ±3 Å of the predicted length of the compound of Formula (I) by molecular modeling. 
     
     
         31 . The composition of  claim 21  further comprising an ointment base. 
     
     
         32 . The composition of  claim 31 , wherein the ointment base is a hydrocarbon base. 
     
     
         33 . The composition of  claim 31 , wherein the composition consists essentially of the compound of Formula (I), or a pharmaceutically acceptable salt thereof; the fatty acid ester; and an ointment base. 
     
     
         34 . The composition of  claim 21 , wherein the concentration of the compound of Formula (I), or the pharmaceutically acceptable salt thereof, is between about 0.001% and about 1% w/w, inclusive. 
     
     
         35 . The composition of  claim 21 , wherein the concentration of the fatty acid ester is between about 1% and about 20% w/w, inclusive. 
     
     
         36 . The composition of  claim 21 , wherein the concentration the compound of Formula (I), or the pharmaceutically acceptable salt thereof, is between about 0.001% and 1% w/w, inclusive; and the concentration of the fatty acid ester is between about 1% and about 10% w/w, inclusive. 
     
     
         37 . The composition of  claim 31 , wherein the concentration of the compound of Formula (I), or the pharmaceutically acceptable salt thereof, is between about 0.001% and 1% w/w, inclusive; the concentration of the fatty acid ester is between about 1% and about 10% w/w, inclusive; and the concentration of the ointment base is between about 70% and about 99% w/w, inclusive. 
     
     
         38 . The composition of  claim 21 , wherein the compound of Formula (I) is of Formula (I-a): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; wherein:
 each instance of   independently represents a single bond or a double bond which can be in the cis or trans configuration; 
 each instance of R 3  and R 3 ′ is independently hydrogen, halogen, —OH, substituted hydroxyl, or —O(CO)R 8 , wherein R 8  is optionally substituted C 1-20  alkyl, optionally substituted C 2-20  alkenyl, optionally substituted C 2-20  alkynyl, or —(CH 2 ) m R 9 , wherein m is 0 or an integer between 1-10, inclusive; and R 9  is optionally substituted C 3-7  carbocyclyl, optionally substituted C 6-10  aryl, or optionally substituted 5-14-membered-heteroaryl, or R 3  and R 3 ′ are joined to form ═O; 
 Y is selected from the group consisting of optionally substituted C 1-10  alkyl, C 1-10  perhaloalkyl, optionally substituted C 2-10  alkenyl, optionally substituted C 2-10  alkynyl, halo, nitro, cyano, thiol, substituted thiol, hydroxyl, substituted hydroxyl, amino, monosubstituted amino, and disubstituted amino; 
 G is —O— or —S—; 
 y is 0, 1, or 2; 
 x is 0 or 1; and 
 n is 0 or an integer between 1-5, inclusive. 
 
       
     
     
         39 . The composition of  claim 38 , wherein the compound of Formula (I-a) is of Formula (I-d): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         40 . The composition of  claim 38 , wherein the compound of Formula (I-a) is of Formula (I-d3): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         41 . The composition of  claim 38 , wherein the compound of Formula (I-a) is of Formula (I-h): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         42 . The composition of  claim 38 , wherein the compound of Formula (I-a) is of Formula (I-j): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         43 . The composition of  claim 38 , wherein the compound of Formula (I-a) is of Formula (I-j): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         44 . The composition of  claim 21 , wherein the compound of Formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof. 
       
     
     
         45 . A method for reducing body fat in a subject, the method comprising administering to the subject a composition of  claim 21 .