Compositions and methods for reducing body fat

Abstract

The present invention relates to compositions, such as bimatoprost, latanoprost and travoprost, and methods to reduce fat in the body of an individual, for example, by topical administration, injection, and/or implantation of such compositions.

1 . A method for reducing fat in a body of an individual, the method comprising administering to the skin of a body, in an amount sufficient to reduce fat in the body, a compound of formula I 
       
         
           
           
               
               
           
         
         wherein the dashed bonds represent a single or double bond which can be in the cis or trans configuration, A is alkylene or alkenylene radical having from two to six carbon atoms, which radical may be interrupted by one or more oxide radicals and substituted with one or more hydroxy, oxo, alkyloxy or alkylcarboxy groups wherein said alkyl radical comprises from one to six carbon atoms; B is a cycloalkyl radical having from three to seven carbon atoms or an aryl radical selected from the group consisting of hydrocarbyl aryl and heteroaryl radicals having from four to ten carbon atoms wherein a heteroatom may be selected from the group consisting of nitrogen, oxygen and sulfur atoms; X is a radical selected from the group consisting of —OR 4  and —N(R 4 ) 2  wherein R 4  is selected from the group consisting of hydrogen, a lower alkyl radical having from one to six carbon atoms, and 
       
       
         
           
           
               
               
           
         
         wherein R 5  is a lower alkyl radical having from one to six carbon atoms; Z is ═O or represents 2 hydrogen radicals; 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 a saturated or unsaturated acyclic hydrocarbon group having from 1 to about 20 carbon atoms or —(CH 2 ) m R 7  wherein m is 0-10 and R 7  is a cycloalkyl radical having from three to seven carbon atoms, or a hydrocarbyl aryl or heteroaryl radical, as defined above, or a pharmaceutically-acceptable salt thereof, optionally provided however that when B is not substituted with a pendant heteroatom-containing radical and Z is ═O, then X is not —OR 4 . 
       
     
     
         2 . The method of  claim 1  wherein the compound is represented by formula II 
       
         
           
           
               
               
           
         
         wherein y is 0 or 1, x is 0 or 1 and x and y are not both 1, Y is a radical 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, n is 0 or an integer of from 1 to 3 and R 3  is ═O, —OH or —O(CO)R 6 , and pharmaceutically acceptable salts thereof. 
       
     
     
         3 . The method of  claim 2  wherein said compound is represented by formula III 
       
         
           
           
               
               
           
         
         wherein hatched lines indicate the α configuration and solid triangles indicate the R configuration, and pharmaceutically acceptable salts thereof. 
       
     
     
         4 . The method of  claim 3 , wherein said compound is bimatoprost, represented by formula IV 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof. 
       
     
     
         5 . The method of  claim 3 , wherein said compound is latanoprost, represented by formula VII 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof. 
       
     
     
         6 . The method of  claim 3 , wherein said compound is travoprost, represented by formula VIII 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof. 
       
     
     
         7 . The method of  claim 1  wherein said compound is represented by formula V 
       
         
           
           
               
               
           
         
         wherein hatched lines indicate the α configuration and solid triangles indicate the β configuration, and wherein Y 1  is Cl or trifluoromethyl, and pharmaceutically acceptable salts thereof. 
       
     
     
         8 . The method of  claim 1  wherein said compound is represented by formula V 
       
         
           
           
               
               
           
         
         wherein Y 1  is Cl or trifluoromethyl, and the 9- and/or 11- and/or 15-esters the compound, and pharmaceutically acceptable salts thereof. 
       
     
     
         9 . A method for reducing fat in a body of an individual, the method comprising injecting into a fat deposit of a body, in an amount sufficient to reduce fat in the body, a compound of formula I 
       
         
           
           
               
               
           
         
         wherein the dashed bonds represent a single or double bond which can be in the cis or trans configuration, A is alkylene or alkenylene radical having from two to six carbon atoms, which radical may be interrupted by one or more oxide radicals and substituted with one or more hydroxy, oxo, alkyloxy or alkylcarboxy groups wherein said alkyl radical comprises from one to six carbon atoms; B is a cycloalkyl radical having from three to seven carbon atoms or an aryl radical selected from the group consisting of hydrocarbyl aryl and heteroaryl radicals having from four to ten carbon atoms wherein a heteroatom may be selected from the group consisting of nitrogen, oxygen and sulfur atoms; X is a radical selected from the group consisting of —OR 4  and —N(R 4 ) 2  wherein R 4  is selected from the group consisting of hydrogen, a lower alkyl radical having from one to six carbon atoms, and 
       
       
         
           
           
               
               
           
         
         wherein R 5  is a lower alkyl radical having from one to six carbon atoms; Z is ═O or represents 2 hydrogen radicals; 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 a saturated or unsaturated acyclic hydrocarbon group having from 1 to about 20 carbon atoms or —(CH 2 ) m R 7  wherein m is 0-10 and R 7  is a cycloalkyl radical having from three to seven carbon atoms, or a hydrocarbyl aryl or heteroaryl radical, as defined above, or a pharmaceutically-acceptable salt thereof, optionally provided however that when B is not substituted with a pendant heteroatom-containing radical and Z is ═O, then X is not —OR 4 . 
       
     
     
         10 . The method of  claim 9  wherein the compound is represented by formula II 
       
         
           
           
               
               
           
         
         wherein y is 0 or 1, x is 0 or 1 and x and y are not both 1, Y is a radical 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, n is 0 or an integer of from 1 to 3 and R 3  is ═O, —OH or —O(CO)R 6 , and pharmaceutically acceptable salts thereof. 
       
     
     
         11 . The method of  claim 10  wherein said compound is represented by formula III 
       
         
           
           
               
               
           
         
         wherein hatched lines indicate the α configuration and solid triangles indicate the β configuration, and pharmaceutically acceptable salts thereof. 
       
     
     
         12 . The method of  claim 11 , wherein said compound is bimatoprost, represented by formula IV 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof. 
       
     
     
         13 . The method of  claim 11 , wherein said compound is latanoprost, represented by formula VII 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof. 
       
     
     
         14 . The method of  claim 11 , wherein said compound is travoprost, represented by formula VIII 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof. 
       
     
     
         15 . The method of  claim 9  wherein said compound is represented by formula V 
       
         
           
           
               
               
           
         
         wherein hatched lines indicate the α configuration and solid triangles indicate the β configuration, and wherein Y 1  is Cl or trifluoromethyl, and pharmaceutically acceptable salts thereof. 
       
     
     
         16 . The method of  claim 9  wherein said compound is represented by formula VI 
       
         
           
           
               
               
           
         
         wherein Y 1  is Cl or trifluoromethyl, and the 9- and/or 11- and/or 15-esters of the compound, and pharmaceutically acceptable salts thereof. 
       
     
     
         17 . A method for reducing fat in a body of an individual, the method comprising implanting into a body, in an amount sufficient to reduce fat in the body, an implantable depot comprising a compound of formula I 
       
         
           
           
               
               
           
         
         wherein the dashed bonds represent a single or double bond which can be in the cis or trans configuration, A is alkylene or alkenylene radical having from two to six carbon atoms, which radical may be interrupted by one or more oxide radicals and substituted with one or more hydroxy, oxo, alkyloxy or alkylcarboxy groups wherein said alkyl radical comprises from one to six carbon atoms; B is a cycloalkyl radical having from three to seven carbon atoms or an aryl radical selected from the group consisting of hydrocarbyl aryl and heteroaryl radicals having from four to ten carbon atoms wherein a heteroatom may be selected from the group consisting of nitrogen, oxygen and sulfur atoms; X is a radical selected from the group consisting of —OR 4  and —N(R 4 ) 2  wherein R 4  is selected from the group consisting of hydrogen, a lower alkyl radical having from one to six carbon atoms, and 
       
       
         
           
           
               
               
           
         
         wherein R 5  is a lower alkyl radical having from one to six carbon atoms; Z is ═O or represents 2 hydrogen radicals; 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 a saturated or unsaturated acyclic hydrocarbon group having from 1 to about 20 carbon atoms or —(CH 2 ) m R 7  wherein m is 0-10 and R 7  is a cycloalkyl radical having from three to seven carbon atoms, or a hydrocarbyl aryl or heteroaryl radical, as defined above, or a pharmaceutically-acceptable salt thereof, optionally provided however that when B is not substituted with a pendant heteroatom-containing radical and Z is ═O, then X is not —OR 4 . 
       
     
     
         18 . The method of  claim 17  wherein the compound is represented by formula II 
       
         
           
           
               
               
           
         
         wherein y is 0 or 1, x is 0 or 1 and x and y are not both 1, Y is a radical 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, n is 0 or an integer of from 1 to 3 and R 3  is ═O, —OH or —O(CO)R 6 , and pharmaceutically acceptable salts thereof. 
       
     
     
         19 . The method of  claim 18  wherein said compound is represented by formula III 
       
         
           
           
               
               
           
         
         wherein hatched lines indicate the α configuration and solid triangles indicate the R configuration, and pharmaceutically acceptable salts thereof. 
       
     
     
         20 . The method of  claim 19 , wherein said compound is bimatoprost, represented by formula IV 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof. 
       
     
     
         21 - 44 . (canceled)