Anti-inflammatory compounds and uses thereof

Abstract

Compounds of the general formula are disclosed with activity towards treating diseases related to inflammation, such as cancer, neurodegenerative and cardiovascular diseases. Pharmaceutical compositions and methods of use are also disclosed.

1 . A pharmaceutical composition comprising a compound of Formula I 
       
         
           
           
               
               
           
         
         or an enantiomer, a diasteromer, a racemate, a tautomer thereof, or a prodrug, salt, hydrate or ester thereof, and a pharmaceutically acceptable excipient, 
         wherein A is an optionally substituted aliphatic, alicyclic, aryl, aralkyl, heteroaliphatic, heterocyclic, or heteroaromatic group, 
         wherein X 1  is selected from the group consisting of —O—, —NH—, and —S—; 
         wherein B is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, aralkyl, or heteroaromatic group, wherein
 B is optionally substituted with one or more X 2  which is independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkoxyl, —CN; an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, aralkyl, heteroaromatic moiety; —OR R , —S(═O) n R d , —NR b R c , —C(═O)R a  and —C(═O)OR a ; wherein
 n is 0-2, 
 R a , for each occurrence, is independently selected from the group consisting of hydrogen and an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, aralkyl, or a heteroaromatic moiety; 
 R b  and R c , for each occurrence, are independently selected from the group consisting of hydrogen; hydroxy; SO 2 R d ; and aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, aralkyl, heteroaromatic or an acyl moiety; 
 R d , for each occurrence, is independently selected from the group consisting of hydrogen; —N(R e ) 2 ; aliphatic, aryl and heteroaryl; 
 
 R e , for each occurrence, is independently hydrogen or aliphatic; and
 R R  is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, aralkyl, heteroaromatic or acyl moiety; 
 
 
         and 
         wherein D is phosphate ester (—O—P(O)(OR f ) 2 ), wherein each R f  independently is an H, alkyl, alkenyl, an alkynyl group, an aryl, or an aralkyl group, which may in turn be substituted or unsubstituted, provided that at least one R f  is not H. 
       
     
     
         2 . The pharmaceutical composition of  claim 1  wherein A is 
       
         
           
           
               
               
           
         
         where Y is (—C—) n , wherein n is 0 to 4, optionally containing one or more unsaturated bonds in the (—C—) n  moiety when n is 2 or greater and X 2  is as defined in  claim 1 . 
       
     
     
         3 . The pharmaceutical composition of  claim 1  wherein A is 
       
         
           
           
               
               
           
         
       
       wherein R 2  is at least one halogen, R 3  and R 4  are independently hydrogen or an aliphatic group and X 2  is as defined in  claim 1 . 
     
     
         4 . The pharmaceutical composition of  claim 1  wherein A is 
       
         
           
           
               
               
           
         
       
     
     
         5 . The pharmaceutical composition of  claim 1  wherein A is 
       
         
           
           
               
               
           
         
       
       and X 2  is as defined in  claim 1 . 
     
     
         6 . The pharmaceutical composition of  claim 1  wherein A is 
       
         
           
           
               
               
           
         
       
       where R 5  and R 6  are independently hydrogen, —OH, alkoxy, halide, trifluoroalkyl, alpha-haloalkyl, trifluoroalkoxy, or R a , wherein R a  is independently hydrogen or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl or aralkyl, or a heteroaromatic moiety and X 2  is as defined in  claim 1 . 
     
     
         7 . The pharmaceutical composition of  claim 1  wherein A is 
       
         
           
           
               
               
           
         
       
       wherein R 5  and R 6  are independently hydrogen, —OH, alkoxy, halide, trifluoroalkyl, alpha-haloalkyl, trifluoroalkoxy, or R a , wherein R a  is hydrogen or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, or a heteroaromatic moiety. 
     
     
         8 . The pharmaceutical composition of  claim 1  wherein A is a straight chain or branched aliphatic moiety. 
     
     
         9 . The pharmaceutical composition of  claim 1  wherein X 2  is 
       
         
           
           
               
               
           
         
       
       wherein R 5  and R 6  are independently hydrogen, —OH, alkoxy, halide, trifluoroalkyl, alpha-haloalkyl, trifluoroalkoxy, or R a  where R a , for each occurrence, is independently hydrogen or an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl or aralkyl, or a heteroaromatic moiety and X 2  is as defined in  claim 1 . 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein A is a non-steroidal anti-inflammatory drug. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein A is a derivative of acetylsalicylic acid, or a derivative of arylalkanoic acid. 
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein A is a derivative of sulindac, of ibuprofen, of naproxen, or of valproic acid. 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein A is 
       
         
           
           
               
               
           
         
       
     
     
         14 . The pharmaceutical composition of  claim 12 , wherein A is 
       
         
           
           
               
               
           
         
       
     
     
         15 . The pharmaceutical composition of  claim 12 , wherein A is 
       
         
           
           
               
               
           
         
       
     
     
         16 . The pharmaceutical composition of  claim 12 , wherein A is 
       
         
           
           
               
               
           
         
       
     
     
         17 . The pharmaceutical composition of  claim 1 , wherein said compound has anti-cancer activity. 
     
     
         18 . A method for treating an inflammation-related disease, said method comprising the step of administering to a subject in need thereof a compound of Formula (I) 
       
         
           
           
               
               
           
         
         or an enantiomer, a diasteromer, a racemate, a tautomer thereof, or a prodrug, salt, hydrate or ester thereof, 
         wherein A is an optionally substituted aliphatic, alicyclic, aryl, aralkyl, heteroaliphatic, heterocyclic, or heteroaromatic group, 
         wherein X 1  is selected from the group consisting of —O—, —NH—, and —S—; 
         wherein B is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, aralkyl, or heteroaromatic group, wherein
 B is optionally substituted with one or more —X 2  which is independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkoxyl, —CN; an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, aralkyl, heteroaromatic moiety; —OR R , —S(═O) n R d , —NR b R c , —C(═O)R a  and —C(═O)OR a ; wherein
 n is 0-2, 
 R a , for each occurrence, is independently selected from the group consisting of hydrogen and an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, aralkyl, or a heteroaromatic moiety; 
 R b  and R c , for each occurrence, are independently selected from the group consisting of hydrogen; hydroxy; SO 2 R d ; and aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, aralkyl, heteroaromatic or an acyl moiety; 
 R d , for each occurrence, is independently selected from the group consisting of hydrogen; —N(R e ) 2 ; aliphatic, aryl and heteroaryl; 
 
 R e , for each occurrence, is independently hydrogen or aliphatic; and
 R R  is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, aralkyl, heteroaromatic or acyl moiety; 
 
 
         and 
         wherein D is phosphate ester (—O—P(O)(OR f ) 2 ), wherein each R f  independently is an H, alkyl, alkenyl, an alkynyl group, an aryl, or an aralkyl group, which may in turn be substituted or unsubstituted, provided that at least one R f  is not H. 
       
     
     
         19 . The method according to  claim 18 , wherein the inflammation related disease is selected from the group consisting of rheumatologic disease, a cardiovascular disease, a neurodegenerative disease, a cerebrovascular disease, an autoimmune disease, chronic inflammation of an organ, a neoplastic and pre-neoplastic disease. 
     
     
         20 . The method according to  claim 19 , wherein the disease is selected from the group consisting of rheumatoid arthritis, Sjogren's syndrome, coronary artery disease, peripheral vascular disease, hypertension, Alzheimer's disease and its variants, lupus erythematosus, chronic bronchitis, and chronic sinusitis. 
     
     
         21 . The method according to  claim 18 , wherein the subject is a human. 
     
     
         22 . A method for treating cancer, said method comprising the step of administering to a subject in need thereof a compound of Formula (I) 
       
         
           
           
               
               
           
         
         or an enantiomer, a diasteromer, a racemate, a tautomer thereof, or a prodrug, salt, hydrate or ester thereof, 
         wherein A is an optionally substituted aliphatic, alicyclic, aryl, aralkyl, heteroaliphatic, heterocyclic, or heteroaromatic group, 
         wherein X 1  is selected from the group consisting of —O—, —NH—, and —S—; 
         wherein B is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, aralkyl, or heteroaromatic group, wherein
 B is optionally substituted with one or more X 2  which is independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkoxyl, —CN; an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, aralkyl, heteroaromatic moiety; —OR R , —S(═O) n R d , —NR b R c , —C(═O)R a  and —C(═O)OR a ; wherein
 n is 0-2, 
 R a , for each occurrence, is independently selected from the group consisting of hydrogen and an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, aralkyl, or a heteroaromatic moiety; 
 R b  and R c , for each occurrence, are independently selected from the group consisting of hydrogen; hydroxy; SO 2 R d ; and aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, aralkyl, heteroaromatic or an acyl moiety; 
 R d , for each occurrence, is independently selected from the group consisting of hydrogen; —N(R e ) 2 ; aliphatic, aryl and heteroaryl; 
 
 R e , for each occurrence, is independently hydrogen or aliphatic; and
 R R  is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, aralkyl, heteroaromatic or acyl moiety; 
 
 
         and 
         wherein D is phosphate ester (—O—P(O)(OR f   2 ), wherein each R f  independently is an H, alkyl, alkenyl, an alkynyl group, an aryl, or an aralkyl group, which may in turn be substituted or unsubstituted, provided that at least one R f  is not H. 
       
     
     
         23 . The method of  claim 22 , wherein the cancer is selected from the group consisting of benign prostatic hypertrophy, prostate cancer, colon adenomas, colon cancer, cancer of the lung, lymphoma and leukemia. 
     
     
         24 . The method according to  claim 22 , wherein the subject is a human. 
     
     
         25 . A compound of Formula (I) 
       
         
           
           
               
               
           
         
         or an enantiomer, a diasteromer, a racemate, a tautomer thereof, or a prodrug, salt, hydrate or ester thereof, 
         wherein A is an optionally substituted aliphatic, alicyclic, aryl, aralkyl, heteroaliphatic, heterocyclic, or heteroaromatic group, 
         wherein X 1  is —NH—; 
         wherein B is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, aralkyl, or heteroaromatic group, wherein
 B is optionally substituted with one or more X 2  which is independently selected from the group consisting of hydrogen, halogen, hydroxyl, alkoxyl, —CN; an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, aralkyl, heteroaromatic moiety; —OR R , —S(═O) n R d , —NR b R c , —C(═O)R a  and —C(═O)OR a ; wherein
 n is 0-2, 
 R a , for each occurrence, is independently selected from the group consisting of hydrogen and an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, aralkyl, or a heteroaromatic moiety; 
 R b  and R c , for each occurrence, are independently selected from the group consisting of hydrogen; hydroxy; SO 2 R d ; and aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, aralkyl, heteroaromatic or an acyl moiety; 
 R d , for each occurrence, is independently selected from the group consisting of hydrogen; —N(R e ) 2 ; aliphatic, aryl and heteroaryl; 
 
 R e , for each occurrence, is independently hydrogen or aliphatic; and
 R R  is an optionally substituted aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, aralkyl, heteroaromatic or acyl moiety; 
 
 
         and 
         wherein D is phosphate ester (—O—P(O)(OR f ) 2 ), wherein each R f  independently is an H, alkyl, alkenyl, an alkynyl group, an aryl, or an aralkyl group, which may in turn be substituted or unsubstituted, provided that at least one R f  is not H, and at least one R g  is not H.