Use Of 2,5-Dihydroxybenzene Compounds And Derivatives For The Treatment Of Rosacea

Abstract

The present invention relates to the use of a 2,5-dihydroxybenzene derivative of formula (I) or a pharmaceutically acceptable salt, solvate, isomer, or prodrug thereof for the treatment and/or prophylaxis of, inter alia, rosacea.

What is claimed is: 
     
         1 . A method for inhibiting mitogenesis induced by FGF-1 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 )aY or —CH═CH—(CH 2 ) p Z; 
         Y is —SO 3 H, —SC 3 X—SO 3 R 3 , —PO 3 H, —PO 3 —.X + , or —PO 3 R 3 , wherein when Y is —SO 3 H, —SO 3   − .X +  or —SO 3 R 3 , then R 9  and R 9′ , are independently selected from —OH and —OR 2 , 
         wherein at least one of R 9  and R 9′ , is 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; 
         Z is —SO 3 H, —SO 3   − X + , —SO 3 R 3 , —PO 3 H, —P0 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 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 an integer selected from 0, 1, 2, 3, 4, 5 and 6. 
       
     
     
         2 . The method of  claim 1 , wherein R 1  is —(CH 2 )aY or —CH═CH—(CH 2 ) p Y. 
     
     
         3 . The method of  claim 2 , wherein Y is selected from —SO 3 H, —SO 3   − .X + , —SO 3 R 3 . 
     
     
         4 . The method of  claim 2 , wherein R 3  is selected from methyl and ethyl. 
     
     
         5 . The method of  claim 1 , wherein 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. 
     
     
         6 . The method of  claim 1 , wherein R 2  is selected from methylcarbonyl, phenylsulfonyl, 4-methylphenylsulfonyl, benzylsulfonyl, benzyl and phenyl. 
     
     
         7 . The method of  claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:
 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;   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;   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;   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;   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.   
     
     
         8 . The method of  claim 7 , wherein the compound of Formula (I) is selected from: 2-(acetyloxy)-5-hydroxybenzenesulfonic acid; 5-(acetyloxy)-2-hydroxybenzene-sulfonic acid and 2,5-bis(acetyloxy)benzenesulfonic acid. 
     
     
         9 . The method of  claim 1 , wherein the compound of Formula (I) is administered topically. 
     
     
         10 . The method of  claim 9 , wherein the compound of Formula (I) is administered orally, buccally, transdermally, by inhalation, rectally, intraocularly, or otically. 
     
     
         11 . The method of  claim 1 , further comprising administration of at least one additional therapeutic agent. 
     
     
         12 . The method of  claim 11 , wherein the at least one additional therapeutic agent is selected from the group consisting of: a steroid; a retinoid; an antimicrobial compound; an antioxidant; an anti-inflammatory compound; a vitamin D analog; salicylic acid; an endothelin antagonist; an immunomodulating agent; an angiogenesis inhibitor; an inhibitor of FGF, VEGF, EGF or HGF; an inhibitor of an EGF, FGF, VEGF or HGF receptor; a tyrosine kinase inhibitor; a protein kinase C inhibitor; metronidazole; dapsone; a vasoconstricting agent; and a combination of two or more thereof. 
     
     
         13 . The method of  claim 12 , wherein the at least one additional therapeutic agent is metronidazole. 
     
     
         14 . The method of  claim 9 , wherein the compound is administered at least once per week. 
     
     
         15 . The method of  claim 14 , wherein the compound is administered at least once per day. 
     
     
         16 . The method of  claim 15 , wherein the compound is administered at least twice per day. 
     
     
         17 . The method of  claim 9 , wherein the compound is present in a pharmaceutical composition an amount of at least about 1% w/w. 
     
     
         18 . The method of  claim 17 , wherein the compound is present in a pharmaceutical composition in an amount of at least about 2.5% w/w. 
     
     
         19 . The method of  claim 18 , wherein the compound is present in a pharmaceutical composition in an amount of at least about 5% w/w. 
     
     
         20 . A method for inhibiting proliferation of cancer cells 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 )aY or —CH═CH—(CH 2 ) p Z; 
         Y is —SO 3 H, —SC 3 X—SO 3 R 3 , —PO 3 H, —PO 3 —.X + , or —PO 3 R 3 , wherein when Y is —SO 3 H, —SO 3   − .X +  or —SO 3 R 3 , then R 9  and R 9′ , are independently selected from —OH and —OR 2 , 
         wherein at least one of R 9  and R 9′ , is 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; 
         Z 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 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 an integer selected from 0, 1, 2, 3, 4, 5 and 6 
         with the proviso that when a is 0 and Y is —SO 3 H, R 9  and R 9′  are not both —OH.