Use of 2,5-Dihydroxybenzene Derivatives for Treating Actinic Keratosis

Abstract

The present invention relates to the use of a 2,5-dihydroxybenzene derivative represented by Formula (I) or a pharmaceutically acceptable salt, solvate, isomer, or prodrug thereof for the therapeutic and/or phrophylactic treatment of, inter alia, actinic keratosis.

1 . A method for the treatment or prophylaxis of actinic keratosis, comprising administering to a subject in need thereof, an effective amount of a 2,5-dihydroxybenzene derivative represented by Formula (I) or a pharmaceutically acceptable salt, solvate, isomer, or prodrug thereof, wherein the compound of Formula (I) is: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is —(CH 2 ) a Y or —CH═CH—(CH 2 ) p Y; 
 Y is —SO 3 H, —SO 3   − .X + , —SO 3 R 3 , —PO 3 H, —PO 3 —.X + , —PO 3 R 3 , —CO 2 H, —CO 2   − .X +  or —CO 2 R 3 ; 
 X +  is an organic cation or an inorganic cation, such that the general charge of the compound of Formula (I) is neutral; 
 R 9  and R 9′  are independently selected from —OH and —OR 2 , wherein when R 9  and R 9′  are both —OR 2 , then said R 9  and R 9′  can be the same or different; 
 R 2  is a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkylsulfonyl group, a substituted or unsubstituted arylsulfonyl group, a substituted or unsubstituted alkylcarbonyl group or a substituted or unsubstituted arylcarbonyl group; 
 R 3  is a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group; 
 a is a number selected from 0, 1, 2, 3, 4, 5 and 6; and 
 p is a number selected from 0, 1, 2, 3, 4, 5 and 6. 
 
     
     
         2 . The method of  claim 1 , wherein Y is selected from —SO 3 H, —SO 3   − .X, —SO 3 R 3 , —CO 2 H, —CO 2   − .X +  and —CO 2 R 3 . 
     
     
         3 . The method of  claim 1  or  claim 2 , wherein at least one of R 9  and R 9′  are, independently, a substituted or unsubstituted alkylsulfonyloxy group, a substituted or unsubstituted arylsulfonyloxy group, a substituted or unsubstituted alkylcarbonyloxy group or a substituted or unsubstituted arylcarbonyloxy group 
     
     
         4 . The method of  claim 2 , wherein R 2  is selected from methylcarbonyl, phenylsulfonyl, 4-methylphenylsulfonyl, benzylsulfonyl, benzyl and phenyl. 
     
     
         5 . The method of  claim 1 , wherein the compound of Formula (I) is selected from the group consisting of: 
       2,5-dihydroxybenzenesulfonic acid (Dobesilate), 
       5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid; 
       2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid; 
       2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzenesulfonic acid; 
       2-(acetyloxy)-5-hydroxybenzenesulfonic acid; 
       5-(acetyloxy)-2-hydroxybenzenesulfonic acid; 
       2,5-bis(acetyloxy)benzenesulfonic acid; 
       2-(benzyloxy)-5-hydroxybenzenesulfonic acid; 
       5-(benzyloxy)-2-hydroxybenzenesulfonic acid; 
       2,5-bis(benzyloxy)benzenesulfonic acid; 
       2,5-dihydroxybenzene homosulfonic acid (homodobesilate) 
       5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid; 
       2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid; 
       2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzenehomosulfonic acid; 
       2-(acetyloxy)-5-hydroxybenzenehomosulfonic acid; 
       5-(acetyloxy)-2-hydroxybenzenehomosulfonic acid; 
       2,5-bis(acetyloxy)benzenehomosulfonic acid; 
       2-(benzyloxy)-5-hydroxybenzenehomosulfonic acid; 
       5-(benzyloxy)-2-hydroxybenzenehomosulfonic acid; 
       2,5-bis(benzyloxy)benzenehomosulfonic acid; 
       2,5-dihydroxybenzoic acid (gentisic acid), 
       5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}benzoic acid; 
       2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}benzoic acid; 
       2,5-bis{[(4-methylphenyl)sulfonyl]oxy}benzoic acid; 
       2-(acetyloxy)-5-hydroxybenzoic acid; 
       5-(acetyloxy)-2-hydroxybenzoic acid; 
       2,5-bis(acetyloxy)benzoic acid; 
       2-(benzyloxy)-5-hydroxybenzoic acid; 
       5-(benzyloxy)-2-hydroxybenzoic acid; 
       2,5-bis(benzyloxy)benzoic acid; 
       2,5-dihydroxyhomobenzoic acid (homogentisic acid), 
       5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid; 
       2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid; 
       2,5-bis{[(4-methylphenyl)sulfonyl]oxy}homobenzoic acid; 
       2-(acetyloxy)-5-hydroxyhomobenzoic acid; 
       5-(acetyloxy)-2-hydroxyhomobenzoic acid; 
       2,5-bis(acetyloxy)homobenzoic acid; 
       2-(benzyloxy)-5-hydroxyhomobenzoic acid; 
       5-(benzyloxy)-2-hydroxyhomobenzoic acid; 
       2,5-bis(benzyloxy)homobenzoic acid; 
       3-(2,5-dihydroxyphenyl)-2-propenoic acid (2,5-dihydroxycinnamic acid) 
       3-(5-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic acid; 
       3-(2-hydroxy-5-{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic acid; 
       3-(2,5-bis{[(4-methylphenyl)sulfonyl]oxy}phenyl)-2-propenoic acid; 
       3-(2-(acetyloxy)-5-hydroxyphenyl)-2-propenioc acid; 
       3-(5-(acetyloxy)-2-hydroxyphenyl)-2-propenoic acid; 
       3-(2,5-bis(acetyloxy)phenyl)-2-propenoic acid; 
       3-(2-(benzyloxy)-5-hydroxyphenyl)-2-propenoic acid; 
       3-(5-(benzyloxy)-2-hydroxyphenyl)-2-propenoic acid; 
       3-(2,5-bis(benzyloxy)phenyl)-2-propenoic acid; 
       and pharmaceutically acceptable salts, solvates and prodrugs thereof. 
     
     
         6 . The method of  claim 5 , wherein the compound of Formula (I) comprises an ester at position 1. 
     
     
         7 . The method of  claim 5 , wherein the compound of Formula (I) is selected from: 2-(acetyloxy)-5-hydroxybenzenesulfonic acid; 5-(acetyloxy)-2-hydroxybenzenesulfonic acid and 2,5-bis(acetyloxy)benzenesulfonic acid. 
     
     
         8 . The method of  claim 5 , wherein the compound of Formula (I) is selected from the group consisting of: 
       calcium 2,5-dihydroxybenzenesulfonate (calcium Dobesilate); 
       potassium 2,5-dihydroxybenzenesulfonate (potassium Dobesilate); 
       magnesium 2,5-dihydroxybenzenesulfonate (magnesium Dobesilate); 
       diethylamine 2,5-dihydroxybenzenesulfonate (Ethamsylate); 
     
     
         9 . The method of  claim 8 , wherein the compound of Formula (I) is calcium 2,5-dihydroxybenzenesulfonate (calcium Dobesilate). 
     
     
         10 . The method of  claim 8 , wherein the compound of Formula (I) is potassium 2,5-dihydroxybenzenesulfonate (potassium Dobesilate). 
     
     
         11 . The method of  claim 1 , wherein the actinic keratosis is selected from the group consisting of: hypertrophic, atrophic, bowenoid, and acantholythic keratosis. 
     
     
         12 . The method of  claim 1 , wherein the compound of Formula (I) is administered topically. 
     
     
         13 . The method of  claim 12 , wherein the compound of Formula (I) is administered orally, buccally, transdermally, by inhalation, rectally, intravaginally, or optically. 
     
     
         14 . The method of  claim 1 , further comprising administration of at least one additional therapeutic agent. 
     
     
         15 . The method of  claim 14 , wherein the at least one additional therapeutic agent is selected from the group consisting of: imiquimod, diclofenac, glycidic acid, trichloroacetic acid, colchicine, T4 endonuclease, 5-fluorouracil, isotretinoin, acitretin, cidofoir, 5-aminolevulinic acid, methyl aminolevulinate, hypericin, chemotherapeutic agent, a corticosteroid, an antibiotic, an analgesic, an immunomodulator, an immunosuppressant, an anti-angiogenic, a leukotriene modifier, an aminosalicylate, an anesthetic, a non-steroidal anti-inflammatory, a modifier of a solubilized interleukin receptor, a cytotoxic, an inhibitor of a tyrosine-kinase receptor, a protein kinase C inhibitor, and combinations of two or more thereof. 
     
     
         16 . The method of  claim 1 , further comprising at least one coadjuvant therapy selected from the group consisting of: photodynamic therapy, cryotherapy, curettage, and surgery. 
     
     
         17 . The method of  claim 12 , wherein the compound is administered at least once per week. 
     
     
         18 . The method of  claim 17 , wherein the compound is administered at least once per day. 
     
     
         19 . The method of  claim 18 , wherein the compound is administered at least twice per day. 
     
     
         20 . The method of  claim 12 , wherein the compound is present in a pharmaceutical composition in an amount of at least about 1% w/w. 
     
     
         21 . The method of  claim 20 , wherein the compound is present in a pharmaceutical composition in an amount of at least about 2.5% w/w. 
     
     
         22 . The method of  claim 21 , wherein the compound is present in a pharmaceutical composition in an amount of at least about 5% w/w. 
     
     
         23 . The method of  claim 22 , wherein the compound is present in a pharmaceutical composition in an amount of at least about 10% w/w. 
     
     
         24 . The method of  claim 23 , wherein the compound is present in a pharmaceutical composition in an amount of at least about 15% w/w. 
     
     
         25 . The method of  claim 12 , wherein the compound is administered over a period of at least about one week. 
     
     
         26 . The method of  claim 25 , wherein the compound is administered over a period of at least about four weeks.