Anti-cancer nitro- and thia-fatty acids

Abstract

The present invention relates to pharmaceutical compositions comprising, as an anticancer agent (a) one or more compounds having the formula NO 2 -A-B, wherein A is a saturated or unsaturated hydrocarbon chain of 14-26 double bonds, and B is (CH 2 ) m (COOH) n in which n is an integer from 0 to 2 and m is an integer from 0 to 2; or a derivative thereof in which the hydrocarbon chain has one or more than one substitution selected from the group consisting of hydroxy, hydroperoxy, epoxy and peroxy; (b) one or more compounds selected from polyunsaturated fatty acids (PUFA's) having a 16 to 26 carbon atom chain and 3 to 6 double bonds, and wherein the PUFA is covalently coupled at the carboxylic acid group to an amino acid selected from glycine and aspartic acid; (c) one or more compounds selected from unsaturated fatty acids having an 18 to 25 carbon atom chain and 1 to 6 double bonds and wherein the fatty acid has one or two β-oxa, γ-oxa, β-thia, γ-thia substitutions; or (d) one or more compounds having formula (I) wherein A′ is a saturated or unsaturated hydrocarbon chain of 9-26 carbon atoms, X is oxygen or is absent and B′ is (CH 2 ) j (COOH) k in which j is an integer from 1 to 3 and k is 0 or 1; or a derivative thereof in which the hydrocarbon chain has one or more than one substitution selected from the group consisting of hydroxy, hydroperoxy, epoxy and peroxy; and a pharmaceutically acceptable carrier or diluent.

1 . An anti-cancer pharmaceutical composition comprising, as an anti-cancer agent, one or more compounds having the formula NO 2 -A-B, wherein A is a saturated or unsaturated hydrocarbon chain of 14 to 26 carbon atoms and B is (CH 2 ) n  (COOH) m  in which n is an integer from 0 to 2 and m is an integer from 0 to 2, and a pharmaceutically acceptable carrier or diluent.  
     
     
         2 . A pharmaceutical composition according to  claim 1 , in which the hydrocarbon chain of the compound(s) includes one or more than one substitution selected from the group consisting of hydroxy, hydroperoxy, epoxy and peroxy.  
     
     
         3 . A pharmaceutical composition according to  claim 1 , in which the hydrocarbon chain of the compound(s) is either saturated or unsaturated and has 18 to 22 carbon atoms.  
     
     
         4 . A pharmaceutical composition according to  claim 1 , in which the hydrocarbon chain of the compound(s) has from 3 to 6 double bonds.  
     
     
         5 . A pharmaceutical composition according to  claim 1 , in which the hydrocarbon chain of the compound(s) is unsaturated and has eighteen carbon atoms and three double bonds separated by methylene groups, with the first double bond relative to the omega carbon atom being between the 3<rd>and  4 <th>or  6 <th>and  7 <th>carbon atoms.  
     
     
         6 . An anti-cancer pharmaceutical composition comprising, as an anti-cancer agent, the compound (all-Z)-4-nitrotricosa-8,11,14,17-tetraenoic acid or 4-[(all-Z)-Nonadeca-4,7,10,13-tetraenyl]-4-nitroheptane-1,7-dicarboxylic acid.  
     
     
         7 . A pharmaceutical composition according to any one of  claims 1  to  6 , in which the cancer is prostate cancer.  
     
     
         8 . A pharmaceutical composition according to any one of  claims 1  to  6 , in which the cancer is breast cancer.  
     
     
         9 . A method of treating cancer in a subject, said method comprising administering to the subject a therapeutic amount of a compound having the formula NO 2 -A-B, wherein A is a saturated or unsaturated hydrocarbon chain of 14 to 26 carbon atoms and B is (CH 2 )n(COOH)m in which n is an integer from 0 to 2 and m is an integer from 0 to 2.  
     
     
         10 . A method according to  claim 9 , in which the hydrocarbon chain of the compound includes one or more than one substitution selected from the group consisting of hydroxy, hydroperoxy, epoxy and peroxy.  
     
     
         11 . A method according to  claim 9 , in which the hydrocarbon chain of the compound is either saturated or unsaturated and has 18 to 22 carbon atoms  
     
     
         12 . A method according to  claim 9 , in which the hydrocarbon chain of the compound has from 3 to 6 double bonds.  
     
     
         13 . A method according to  claim 9 , in which the hydrocarbon chain of the compound is unsaturated and has eighteen carbon atoms and three double bonds separated by methylene groups, with the first double bond relative to the omega carbon atom being between the 3rd and 4th or 6th and 7th carbon atoms.  
     
     
         14 . A method according to  claim 9 , wherein the compound is (all-Z)-4-nitrotricosa-8,11,14,17-tetraenoic acid or 4-[(all-Z)-Nonadeca-4,7, 10,13-tetraenyl]-4-nitroheptane-1,7-dicarboxylic acid.  
     
     
         15 . A method according to any one of  claims 9  to  14 , in which the cancer is prostate cancer.  
     
     
         16 . A method according to any one of  claims 9  to  14 , in which the cancer is breast cancer.  
     
     
         17 . Use of a compound having the formula NO 2 -A-B, wherein A is a saturated or unsaturated hydrocarbon chain of 14 to 26 carbon atoms and B is (CH 2 ) n  (COOH) m  in which n is an integer from 0 to 2 and m is an integer from 0 to 2, for the preparation of a pharmaceutical composition for the treatment of cancer.  
     
     
         18 . Use according to  claim 17 , in which the hydrocarbon chain of the compound includes one or more than one substitution selected from the group consisting of hydroxy, hydroperoxy, epoxy and peroxy.  
     
     
         19 . Use according to  claim 17 , in which the hydrocarbon chain of the compound is either saturated or unsaturated and has 18 to 22 carbon atoms.  
     
     
         20 . Use according to  claim 17 , in which the hydrocarbon chain of the compound has from 3 to 6 double bonds.  
     
     
         21 . Use according to  claim 17 , in which the hydrocarbon chain of the compound is unsaturated and has eighteen carbon atoms and three double bonds separated by methylene groups, with the first double bond relative to the omega carbon atom being between the 3rd and 4th or 6th and 7th carbon atoms.  
     
     
         22 . Use according to  claim 17 , wherein the compound is (all-Z)-4-nitrotricosa-8,11,14,17-tetraenoic acid or 4-[(all-Z)-Nonadeca-4,7, 10,13-tetraenyl]-4-nitroheptane-1,7-dicarboxylic acid.  
     
     
         23 . Use according to any one of  claims 17  to  22 , wherein the cancer is prostate cancer.  
     
     
         24 . Use according to any one of  claims 17  to  22 , wherein the cancer is breast cancer.  
     
     
         25 . An anti-cancer pharmaceutical composition comprising, as an anti-cancer agent, one or more compounds selected from polyunsaturated fatty acids having a 16 to 26 carbon atom chain and 3 to 6 double bonds, and wherein the polyunsaturated fatty acid is covalently coupled at the carboxylic acid group to an amino acid selected from glycine and aspartic acid, and a pharmaceutically acceptable carrier or diluent.  
     
     
         26 . A method of treating cancer in a subject, said method comprising administering to the subject a therapeutic amount of a compound selected from polyunsaturated fatty acids having a 16 to 26 carbon atom chain and 3 to 6 double bonds, and wherein the polyunsaturated fatty acid is covalently coupled at the carboxylic acid group to an amino acid selected from glycine and aspartic acid.  
     
     
         27 . Use of a compound selected from polyunsaturated fatty acids having a 16 to 26 carbon atom chain and 3 to 6 double bonds, and wherein the polyunsaturated fatty acid is covalently coupled at the carboxylic acid group to an amino acid selected from glycine and aspartic acid, for the preparation of a pharmaceutical composition for the treatment of cancer.  
     
     
         28 . An anti-cancer pharmaceutical composition comprising, as an anti-cancer agent, one or more compounds selected from unsaturated fatty acids having an 18 to 25 carbon atom chain and 1 to 6 double bonds and wherein the fatty acid has one or two substitutions selected from the group consisting of [beta]-oxa, [gamma]-oxa, [beta]-thia and [gamma]-thia, and a pharmaceutically acceptable carrier or diluent.  
     
     
         29 . A method of treating cancer in a subject, said method comprising administering to the subject a therapeutic amount of a compound selected from unsaturated fatty acids hasting an 18 to 25 carbon atom chain and 1 to 6 double bonds and wherein the fatty acid has one or two substitutions selected from the group consisting of [beta]-oxa, [gamma]-oxa, [beta]-thia and [gamma]-thia.  
     
     
         30 . Use of a compound selected from unsaturated fatty acids having an 18 to 25 carbon atom chain and 1 to 6 double bonds and wherein the fatty acid has one or two substitutions selected from the group consisting of [beta]-oxa, [gamma]-oxa, [beta]-thia and [gamma]-thia, for the preparation of a pharmaceutical composition for the treatment of cancer.  
     
     
         31 . An anti-cancer pharmaceutical composition comprising, as an anti-cancer agent, one or more compounds selected from compounds having the formula  
       
         
           
           
               
               
           
         
       
       wherein A is a saturated or unsaturated hydrocarbon chain of 9 to 26 carbon atoms, X is oxygen or is absent and U is (CH 2 )j(COOH)k in which j is an integer from 1 to 3 and k is 0 or 1, and derivatives thereof in which the hydrocarbon chain includes one or more substitution selected from the group consisting of hydroxy, hydroperoxy, epoxy and peroxy, and a pharmaceutically acceptable carrier or diluent.  
     
     
         32 . A method of treating cancer in a subject said method comprising administering to the subject a therapeutic amount of a compound having the formula  
       
         
           
           
               
               
           
         
       
       wherein A is a saturated or unsaturated hydrocarbon chain of 9 to 26 carbon atoms, X is oxygen or is absent and B is (CH 2 ) j  (COOH) k  in which j is an integer from 1 to 3 and k is 0 or 1, or a derivative thereof in which the hydrocarbon chain includes one or more substitution selected from the group consisting of hydroxy, hydroperoxy, epoxy and peroxy.  
     
     
         33 . Use of a compound selected from compounds having the formula  
       
         
           
           
               
               
           
         
       
       wherein A is a saturated or unsaturated hydrocarbon chain of 9 to 26 carbon atoms, X is oxygen or is absent and B is (CH 2 )j(COOH)k in which j is an integer from 1 to 3 and k is 0 or 1, or a derivative thereof in which the hydrocarbon chain includes one or more substitution selected from the group consisting of hydroxy, hydroperoxy, epoxy and peroxy, for the preparation of a pharmaceutical composition for the treatment of cancer.