Methods, compounds, and compositions for reducing body fat and modulating fatty acid metabolism

Abstract

Methods, pharmaceutical compositions, and compounds for reducing body weight, modulating body lipid metabolism, and reducing food intake in mammals are provided. The compounds of the invention include fatty acid ethanolamide compounds, homologues and analogs of which the prototype is the endogenous fatty acid ethanolamide, oleoylethanolamide.

1 . A method of modulating lipid metabolism in a mammal in need thereof, said method comprising administering to said mammal a fatty acid alkanolamide, wherein said administering is in an effective amount to modulate lipid metabolism. 
     
     
         2 . The method according to  claim 1 , wherein the fatty acid alkanolamide is oleoylethanolamide. 
     
     
         3 . The method of  claim 1 , wherein the fatty acid alkanolamide comprises a fatty acid moiety covalently bonded to an ethanolamine moiety via an amide linkage. 
     
     
         4 . The method of  claim 3 , wherein the fatty acid moiety is monounsaturated or polyunsaturated. 
     
     
         5 . The method of  claim 1 , wherein the administering is via a dermal patch. 
     
     
         6 . The method of  claim 4 , wherein the fatty acid moiety is oleic acid. 
     
     
         7 . The method of  claim 3 , wherein the fatty acid moiety has from 12 to 20 carbon atoms. 
     
     
         8 . The method of  claim 3 , wherein the fatty acid is selected from the group consisting of elaidic acid, palmitoleic acid, palmitic acid, linoleic acid, alpha-linolenic acid, and gamma-linolenic acid. 
     
     
         9 . (canceled) 
     
     
         10 . The method of  claim 3 , wherein the hydroxy group of the ethanolamine moiety is bound to a the carboxylate group of a lower (C 2 -C 6 ) alkyl carboxylic acid to form the corresponding ester. 
     
     
         11 . (canceled) 
     
     
         12 . The method according to  claim 1 , wherein the mammal is human. 
     
     
         13 . The method according to  claim 1 , wherein the fatty acid alkanolamide is palmitoylethanolamide. 
     
     
         14 . (canceled) 
     
     
         15 . The method according to  claim 1 , wherein said fatty acid alkanolamide is administered with a pharmaceutically acceptable carrier by an oral, rectal, topical, or parenteral route. 
     
     
         16 . A method of reducing or controlling body fat or body weight in a mammal in need thereof, said method comprising administering to said mammal, in an effective amount to reduce body fat or body weight, a compound of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein n is from 0 to 5, the sum of a and b can be from 0 to 4; Z is a member selected from the group consisting of C(O)N(Ro); (Ro)NC(O); OC(O); (O)CO; O; NRo; and S; and wherein Ro and R2 are members independently selected from the group consisting of unsubstituted or unsubstituted alkyl, hydrogen, C 1 -C 6  alkyl, and lower (C 1 -C 6 ) acyl, and wherein up to four hydrogen atoms of the fatty acid portion and alkanol portion thereof are substituted by methyl or a double bond, and the bond between carbons c and d may be unsaturated or saturated. 
     
     
         17 . A method of  claim 16 , wherein said compound is of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein n is from 0 to 4, the sum of a and b is from 1 to 3, and R 1  and R 2  are members independently selected from the group comprising hydrogen, C 1 -C 6  alkyl, and lower (C 1 -C 6 ) acyl, and wherein up to four hydrogen atoms of the fatty acid portion and alkanolamine portion thereof are substituted by methyl or a double bond, and the bond between carbons c and d may be unsaturated or saturated. 
     
     
         18 - 25 . (canceled) 
     
     
         26 . The method of  claim 16 , wherein the mammal is a human. 
     
     
         27 . The method of  claim 16 , wherein the compound is according to one of the following formulae: 
       
         
           
           
               
               
           
         
       
       wherein n is from 1-5 and the sum of a and b is from 0 to 4; R 2  is selected from the group consisting of hydrogen, C 1 -C 6  alkyl, and lower (C 1 -C 6 ) acyl; and up to four hydrogen atoms of the fatty acid portion and alkanol portion thereof may also be substituted by methyl or a double bond. 
     
     
         28 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein n is from 0 to 5, the sum of a and b can be from 0 to 4; Z is a member selected from the group consisting of C(O)N(R o )—; —(R o )NC(O)—; —OC(O)—; —(O)CO—; O; NR o ; and S; and wherein R 1  and R 2  are members independently selected from the group consisting of unsubstituted or unsubstituted alkyl, hydrogen, C 1 -C 6  alkyl, and lower (C 1 -C 6 ) acyl, and wherein up to four hydrogen atoms of the fatty acid portion and alkanol portion thereof are substituted by methyl or a double bond, and the bond between carbons c and d may be unsaturated or saturated. 
       
     
     
         29 . A pharmaceutical composition of  claim 28 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt of the compound, wherein n is from 1 to 3, the sum of a and b is from 1 to 3, and R 1  and R 2  are members independently selected from the group consisting of hydrogen, C 1 -C 6  alkyl, and lower (C 1 -C 6 ) acyl and wherein up to four hydrogen atoms of the fatty acid portion and alkanol portion thereof are substituted by methyl or a double bond, and the bond between carbons c and d may be unsaturated or saturated. 
     
     
         30 - 48 . (canceled) 
     
     
         49 . The method of  claim 1 , wherein the modulating increases fat and fatty acid catabolism in the mammal. 
     
     
         50 . The method of  claim 17 , wherein the modulating increases fat and fatty acid catabolism in the mammal.