Compounds and methods of treating obesity

Abstract

The present invention relates to novel fatty acid derivatives, methods for their preparation, pharmaceutical compositions including such compounds, and methods of using these compounds and compositions, especially as agents for the treatment of obesity and related disorders, and for improving cognition.

1 .- 33 . (canceled) 
     
     
         34 . A compound represented by formula (A): 
       
         
           
           
               
               
           
         
       
       wherein:
 FA is a residue of a fatty acid selected from the group consisting of oleic acid (oleoyl), elaidic acid (elaidoyl), linoleic acid (linoleoyl), gamma-linolenic acid (gamma-linolenoyl), alpha-linolenic acid (alpha-linolenoyl), eicosapentaenoic acid (eicosapentaenoyl), docosahexaenoic acid (docosahexaenoyl), arachidonic acid (arachidonyl), palmitic acid (palmitoyl), palmitoleic acid (palmitoleoyl), stearic acid (stearoyl), myristic acid (myristoyl), lauric acid (lauroyl), and tetradec-7-enoic acid (tetradec-7-enoyl), or the residue of an alcohol derivative of any of the foregoing fatty acids; 
 X is O or a bond 
 le is H or CH 3 ; 
 R 2  is selected from the group consisting of: 
 1) the residue of an (L)- or (D)-amino acid when R 1  is H, or of an (L)- or (D)-N-methyl amino acid when R 1  is CH 3 , provided that the amino acid or N-methyl amino acid is not glycine, alanine, serine, tyrosine, phenylalanine, cysteine or sarcosine; 
 
       further provided that:
 (i) when X is a bond, R 1  is H and FA is the residue of palmitic acid or lauric acid, the amino acid is not valine; 
 (ii) when X is a bond, R 1  is H and FA is the residue of alpha-linolenic acid, the amino acid is not leucine; and 
 (iii) when X is a bond, R 1  is H and FA is the residue of palmitoleic acid, the amino acid is not leucine or isoleucine; 
 2) when R 1  is H, the residue of an unnatural amino acid selected from the group consisting of Dap, dimethyl Dap, dimethylamino lysine, Dab, 2-pyridyl alanine, 3-pyridyl alanine, 1-napththyl alanine, 2-naphthyl alanine, homoarginine, citrulline, ornithine, 4-halo phenyl alanine, 4-amino phenyl alanine and 4-nitro phenylalanine; or when R 1  is CH 3 , the N-methyl derivatives of the any of the foregoing amino acids, or R 1  and R 2 , together with the nitrogen and carbon to which they are respectively attached, can form a heterocycle selected from: 
 
       
         
           
           
               
               
           
         
       
       including salts, hydrates, solvates, polymorphs, optical isomers, geometrical isomers, enantiomers, diastereomers, and mixtures thereof. 
     
     
         35 . The compound of  claim 34 , wherein FA is the residue of oleic acid (oleoyl) or oleyl alcohol. 
     
     
         36 . The compound of  claim 34 , wherein the amino acid is selected from the group consisting of valine, leucine, isoleucine, methionine, threonine, tryptophan, histidine, aspartic acid, asparagine, glutamic acid, glutamine, γ-carboxyglutamic acid, arginine, ornithine and lysine, and N-methyl derivatives of any of the foregoing. 
     
     
         37 . The compound of  claim 36 , wherein the amino acid is selected from the group consisting of glutamic acid, valine, arginine, ornithine, lysine, theronine, methionine, tryptophan, histidine, aspartic acid and isoleucine. 
     
     
         38 . The compound of  claim 36 , wherein the amino acid is valine, leucine or isoleucine. 
     
     
         39 . The compound of  claim 34 , wherein X is a bond, and the compound is represented by the structure: 
       
         
           
           
               
               
           
         
       
     
     
         40 . The compound of  claim 39 , wherein R 1  is H. 
     
     
         41 . The compound of  claim 40 , wherein FA is the residue of oleic acid (oleoyl), and R 2  is the residue of an amino acid selected from the group consisting of glutamic acid, valine, arginine, ornithine, lysine, threonine, methionine, tryptophan, histidine, aspartic acid, leucine, and isoleucine. 
     
     
         42 . The compound of  claim 40 , wherein FA is the residue of oleic acid (oleoyl), and R 2  is the residue of an unnatural amino acid selected from the group consisting of Dap, dimethyl Dap, dimethylamino lysine, Dab, 2-pyridyl alanine, 3-pyridyl alanine, 1-napththyl alanine, 2-naphthyl alanine, homoarginine, citrulline, ornithine, 4-halo phenyl alanine, 4-amino phenyl alanine and 4-nitro phenyl alanine. 
     
     
         43 . The compound of  claim 40 , wherein FA is the residue of oleic acid (oleoyl), and R 1  and R 2 , together with the nitrogen and carbon to which they are respectively attached, form a heterocycle selected from: 
       
         
           
           
               
               
           
         
       
     
     
         44 . The compound of  claim 39 , wherein R 1  is CH 3 . 
     
     
         45 . The compound of  claim 39 , wherein FA is the residue of oleic acid (oleoyl), R 1  is H, and R 2  is the residue of (L)-valine. 
     
     
         46 . The compound of  claim 39 , which is ((Z-Octadec)-9-enoic acid 1-hydroxymethyl-2-methyl-propyl)-amide. 
     
     
         47 . The compound of  claim 34 , wherein X is O, and the compound is represented by the structure: 
       
         
           
           
               
               
           
         
       
     
     
         48 . The compound of  claim 34 , which is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or an enantiomer, diastereomer or mixtures thereof. 
     
     
         49 . The compound of  claim 48 , which is represented by the structure: 
       
         
           
           
               
               
           
         
       
       or an enantiomer, diastereomer or mixtures thereof. 
     
     
         50 . The compound of  claim 49 , which is represented by the structure: 
       
         
           
           
               
               
           
         
       
     
     
         51 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as an active ingredient a compound of  claim 34 , wherein the composition is in a form suitable for oral, parenteral or topical administration. 
     
     
         52 . A method for treating or reducing the severity of obesity or a complication of obesity, increasing or facilitating weight loss, suppressing, inhibiting or reducing appetite, decreasing body mass index (BMI), decreasing food consumption, or improving cognitive function in a subject, comprising the step of administering to the subject a compound of formula (A′) or a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (A′) or a salt, hydrate, solvate, polymorph, optical isomer, geometrical isomer, enantiomer, diastereomer, or mixture thereof, wherein formula (A′) is represented by the structure: 
       
         
           
           
               
               
           
         
       
       wherein
 FA is a residue of a fatty acid selected from the group consisting of oleic acid (oleoyl), elaidic acid (elaidoyl), linoleic acid (linoleoyl), gamma-linolenic acid (gamma-linolenoyl), alpha-linolenic acid (alpha-linolenoyl), eicosapentaenoic acid (eicosapentaenoyl), docosahexaenoic acid docosahexaenoyl), arachidonic acid arachidonyl), palmitic acid (palmitoyl), palmitoleic acid (palmitoleoyl), stearic acid (stearoyl), lauric acid (lauroyl), myristic acid (myristoyl), and tetradec-7-enoic acid (tetradec-7-enoyl), or the residue of an alcohol derivative of any of the foregoing fatty acids; 
 X is O or a bond; 
 R 1  is H or CH 3 ; 
 R 2  is selected from the group consisting of: 
 1) the residue of an (L)- or (D)-amino acid when R 1  is H, or of an (L)- or (D)-N-methyl amino acid when R 1  is CH 3 , provided that the amino acid or N-methyl amino acid is not glycine, alanine or sarcosine; 
 2) when R 1  is H, the residue of an unnatural amino acid selected from the group consisting of Dap, dimethyl Dap, dimethylamino lysine, Dab, 2-pyridyl alanine, 3-pyridyl alanine, 1-napththyl alanine, 2-naphthyl alanine, homoarginine, citrulline, phenylglycine, norleucine, ornithine, Abu, Apn, Ahx, 4-halo phenyl alanine, 4-amino phenyl alanine and 4-nitro phenylalanine; or when R 1  is CH 3 , the N-methyl derivatives of the any of the foregoing amino acids; 
 or R 1  and R 2 , together with the nitrogen and carbon to which they are respectively attached, can form a heterocycle selected from: 
 
       
         
           
           
               
               
           
         
       
     
     
         53 . The method of  claim 52 , wherein X is a bond, and the compound is represented by the structure: 
       
         
           
           
               
               
           
         
       
     
     
         54 . The method of  claim 52 , wherein X is O, and the compound is represented by the structure: 
       
         
           
           
               
               
           
         
       
     
     
         55 . The method of  claim 54 , wherein the compound of formula (A′) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or an enantiomer, diastereomer or mixtures thereof. 
     
     
         56 . The method of  claim 55 , wherein the compound of formula (A′) is represented by the structure: 
       
         
           
           
               
               
           
         
       
       or an enantiomer, diastereomer or mixtures thereof. 
     
     
         57 . The method of  claim 56 , wherein the compound of formula (A′) is represented by the structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         58 . A method for treating or reducing the severity of obesity or a complication of obesity, increasing or facilitating weight loss, suppressing, inhibiting or reducing appetite, decreasing body mass index (BMI), decreasing food consumption, or improving cognitive function in a subject, comprising the step of administering to the subject a compound of formula (A) or a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (A) or a salt, hydrate, solvate, polymorph, optical isomer, geometrical isomer, enantiomer, diastereomer, or mixture thereof, wherein formula (A) is defined in  claim 34 . 
     
     
         59 . A compound according to  claim 34 , wherein the compound is represented by the structure of formula (A2): 
       
         
           
           
               
               
           
         
       
       wherein
 FA is a residue of an alcohol derivative of a fatty acid selected from the group consisting of oleic acid (oleoyl), elaidic acid (elaidoyl), linoleic acid (linoleoyl), gamma-linolenic acid (gamma-linolenoyl), alpha-linolenic acid (alpha-linolenoyl), eicosapentaenoic acid (eicosapentaenoyl), docosahexaenoic acid (docosahexaenoyl), palmitic acid (palmitoyl), palmitoleic acid (palmitoleoyl), stearic acid (stearoyl), myristic acid (myristoyl), lauric acid (lauroyl), and tetradec-7-enoic acid (tetradec-7-enoyl); 
 R 1  is H or CH 3 ; 
 R 2  is selected from the group consisting of: 
 1) the residue of an (L)- or (D)-amino acid when R 1  is H, or of an (L)- or (D)-N-methyl amino acid when R 1  is CH 3 , provided that the amino acid or N-methyl amino acid is not glycine, alanine, serine, tyrosine, phenylalanine, cysteine or sarcosine; 
 2) when R 1  is H, the residue of an unnatural amino acid selected from the group consisting of Dap, dimethyl Dap, dimethylamino lysine, Dab, 2-pyridyl alanine, 3-pyridyl alanine, 1-napththyl alanine, 2-naphthyl alanine, homoarginine, citrulline, ornithine, 4-halo phenyl alanine, 4-amino phenyl alanine and 4-nitro phenylalanine; or when R 1  is CH 3 , the N-methyl derivatives of the any of the foregoing amino acids; 
 or R 1  and R 2 , together with the nitrogen and carbon to which they are respectively attached, can form a heterocycle selected from: 
 
       
         
           
           
               
               
           
         
       
       including salts, hydrates, solvates, polymorphs, optical isomers, geometrical isomers, enantiomers, diastereomers, and mixtures thereof. 
     
     
         60 . A compound according to  claim 34 , wherein the compound is represented by the structure of formula (A1): 
       
         
           
           
               
               
           
         
       
       wherein
 FA is a residue of a fatty acid selected from the group consisting of oleic acid (oleoyl), elaidic acid (elaidoyl), linoleic acid (linoleoyl), eicosapentaenoic acid (eicosapentaenoyl), docosahexaenoic acid (docosahexaenoyl), arachidonic acid (arachidonyl), palmitic acid (palmitoyl), stearic acid (stearoyl), myristic acid (myristoyl), lauric acid (lauroyl), and tetradec-7-enoic acid (tetradec-7-enoyl); 
 R 1  is H or CH 3 ; 
 R 2  is selected from the group consisting of: 
 1) the residue of an (L)- or (D)-amino acid when R 1  is H, or of an (L)- or (D)-N-methyl amino acid when R 1  is CH 3 : 
 
       wherein the amino acid is selected from the group consisting of valine, leucine, isoleucine, methionine, threonine, tryptophan, histidine, aspartic acid, asparagine, glutamic acid, glutamine, γ-carboxyglutamic acid, arginine, ornithine and lysine, and N-methyl derivatives of any of the foregoing, provided that when R 1  is H and FA is the residue of palmitic acid or lauric acid, the amino acid is not valine;
 2) when R 1  is H, the residue of an unnatural amino acid selected from the group consisting of Dap, dimethyl Dap, dimethylamino lysine, Dab, 2-pyridyl alanine, 3-pyridyl alanine, 1-napththyl alanine, 2-naphthyl alanine, homoarginine, citrulline, ornithine, 4-halo phenyl alanine, 4-amino phenyl alanine and 4-nitro phenylalanine; or 
 when R 1  is CH 3 , the N-methyl derivatives of the any of the foregoing amino acids; 
 or R 1  and R 2 , together with the nitrogen and carbon to which they are respectively attached, can form a heterocycle selected from: 
 
       
         
           
           
               
               
           
         
       
       including salts, hydrates, solvates, polymorphs, optical isomers, geometrical isomers, enantiomers, diastereomers, and mixtures thereof. 
     
     
         61 . A compound according to  claim 34 , wherein the compound is represented by the structure of formula (A1): 
       
         
           
           
               
               
           
         
       
       wherein
 FA is a residue of a fatty acid selected from the group consisting of oleic acid (oleoyl), linoleic acid (linoleoyl), palmitic acid (palmitoyl) and stearic acid (stearoyl); 
 R 1  is H or CH 3 ; 
 R 2  is selected from the group consisting of: 
 1) when R 1  is H, the residue of an (L)- or (D)-amino acid selected from the group consisting of glutamic acid, valine, arginine, ornithine, lysine, threonine, methionine, tryptophan, histidine, aspartic acid, leucine, and isoleucine, or when R 1  is CH 3 , the N-methyl derivative of any of the foregoing amino acids, provided that when R 1  is H and FA is the residue of palmitic acid, the amino acid is not valine,; 
 2) when R 1  is H, the residue of an unnatural amino acid selected from the group consisting of Dap, dimethyl Dap, dimethylamino lysine, Dab, 2-pyridyl alanine, 3-pyridyl alanine, 1-napththyl alanine, 2-naphthyl alanine, homoarginine, citrulline, ornithine, 4-halo phenyl alanine, 4-amino phenyl alanine and 4-nitro phenylalanine; or when R 1  is CH 3 , the N-methyl derivatives of the any of the foregoing amino acids; 
 or R 1  and R 2 , together with the nitrogen and carbon to which they are respectively attached, can form a heterocycle selected from: 
 
       
         
           
           
               
               
           
         
       
       including salts, hydrates, solvates, polymorphs, optical isomers, geometrical isomers, enantiomers, diastereomers, and mixtures thereof. 
     
     
         62 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or an enantiomer, diastereomer or mixtures thereof.