Ester pro-drugs of [3-(1-(1h-imidazol-4-yl)ethyl)-2-methylphenyl] methanol for lowering intraocular pressure

Abstract

The present invention relates to method of lowering intraocular pressure in a subject in need of such treatment, which comprises administering a therapeutically effective amount of a composition comprising a ester pro-drugs of [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, of enantiomers thereof, of tautomers thereof, pharmaceutical compositions containing them and their use as pharmaceuticals.

What is claimed is: 
     
         1 . A pharmaceutical composition for lowering intraocular pressure, administered topically to the eye of a subject in need of such treatment, comprising a compound having a structure of Formula II 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is H or optionally substituted C 1-3  alkyl; 
         R 2  is H or optionally substituted C 1-3  alkyl; 
         R 3  is H, optionally substituted C 1-10  alkyl, optionally substituted heterocycle or optionally substituted aryl; and 
         R is optionally substituted C 1-10  alkyl, optionally substituted heterocycle or optionally substituted aryl; or 
         a pharmaceutically acceptable salt thereof; and 
       
       pharmaceutically acceptable carriers, preservatives, co-solvents, buffering agents, viscosity building agents, purified water. 
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein the compound having a structure of Formula II is selected from:
 iso-Butyric acid 3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester;   2,2-Dimethyl-propionic acid 3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester;   Acetic acid 3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester;   Benzoic acid 3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester;   3-Methyl-butyric acid 3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester;   3-Phenyl-propionic acid 3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester;   2-Amino-3-methyl-butyric acid 3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester;   2-(2-Amino-3-methyl-butyrylamino)-3-methyl-butyric acid 3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester;   2-(2-Amino-acetylamino)-3-methyl-butyric acid 3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester; and   2-Amino-3-phenyl-propionic acid 3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester.   
     
     
         3 . The pharmaceutical composition according to  claim 1 , wherein the buffering agents include: sodium chloride, potassium chloride, calcium chloride dihydrate, magnesium chloride hexahydrate, boric acid and sodium borate decahydrate. 
     
     
         4 . The pharmaceutical composition according to  claim 1 , wherein the viscosity building agents include: polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose and hydroxypropyl cellulose. 
     
     
         5 . The pharmaceutical composition according to  claim 1 , wherein the co-solvents include: polysorbate 20, polysorbate 60, polysorbate 80, Pluronic F-84, Pluronic F-68, Pluronic P-103, cyclodextrin, Solutol. 
     
     
         6 . The pharmaceutical composition according to  claim 1 , wherein the preservatives include: stabilized oxychloro complex, stabilized chlorine dioxide, benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, Onamer M. 
     
     
         7 . The pharmaceutical composition according to  claim 1 , further formulated as a solution in water at a pH of 5.5 to 8.0. 
     
     
         8 . The pharmaceutical composition according to  claim 1 , wherein the compound having a structure of Formula II is comprised from 0.01 to 5 percent. 
     
     
         9 . The pharmaceutical composition according to  claim 6 , wherein the preservative will range from 0.001% to 1%. 
     
     
         10 . The pharmaceutical composition according to  claim 5 , wherein the co-solvents are employed at a level of from 0.01% to 2% by weight. 
     
     
         11 . The pharmaceutical composition according to  claim 4 , wherein the viscosity building agents are employed at a level of from 0.01% to 2% by weight. 
     
     
         12 . A pharmaceutical composition for lowering intraocular pressure comprising 0.01 to 5 percent of a compound having a structure of Formula II 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is H or optionally substituted C 1-3  alkyl; 
         R 2  is H or optionally substituted C 1-3  alkyl; 
         R 3  is H, optionally substituted C 1-10  alkyl, optionally substituted heterocycle or optionally substituted aryl; and 
         R is optionally substituted C 1-10  alkyl, optionally substituted heterocycle or optionally substituted aryl; or 
         a pharmaceutically acceptable salt thereof; and 
       
       a pH of 5.5 to 8.0 and at least one co-solvent from 0.01% to 2% by weight, and at least one viscosity building agent from 0.01% to 2% by weight and at least one preservative from 0.001% to 1%, wherein said pharmaceutical composition is an aqueous liquid formulated as an eye drop suitable for topical administration.