Therapeutic agent for meibomian gland dysfunction

Abstract

A compound represented by the formula (1): wherein R 1 represents a hydroxyl group, a dimethylphosphynoyloxy group, etc.; and R 2 and R 3 represent a methoxy group, etc., or a pharmaceutically acceptable salt thereof can reduce a score of telangiectasia around the meibomian gland orifices and a number of obstruction at the orifices, so that it is useful as a prophylactic and/or therapeutic agent for meibomian gland dysfunction.

1 . A method for prophylaxis and/or treatment of meibomian gland dysfunction in a mammalian subject, the method comprising: 
       administering to the mammalian subject a therapeutically effective amount of a compound represented by formula (1): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  represents a hydroxyl group, a methoxy group, a hydroxymethoxy group, an ethoxy group, a 1-hydroxyethoxy group, a 2-hydroxyethoxy group, a 2-methoxyethoxy group, a 2-ethoxyethoxy group, a formyloxy group, a carboxyoxy group, an acetoxy group, a hydroxyacetoxy group, a propionyloxy group, a 2-hydroxypropionyloxy group, a 3-hydroxypropionyloxy group, a 2-methylpropionyloxy group, a 2-(hydroxymethyl)-propionyloxy group, a 3-hydroxy-2-(hydroxymethyl)propionyloxy group, a 2,2-dimethylpropionyloxy group, a 2-(hydroxymethyl)-2-methylpropionyloxy group, a 2,2-bis(hydroxymethyl)propionyloxy group, a methylphosphynoyloxy group, a dimethylphosphynoyloxy group or a 1H-tetrazol-1-yl group; 
         R 2  represents a hydrogen atom, a hydroxyl group, a methoxy group, a mercapto group or a methylthio group; 
         R 3  represents a hydrogen atom, a hydroxyl group or a methoxy group; 
         a wavy line represents that the carbon atom bonded to R 1 , R 2  or R 3  can take either configuration of S or R, 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The method according to  claim 1 , wherein the compound represented by formula (1) is further characterized in that:
 R 1  represents a hydroxyl group, a 2-hydroxyethoxy group, a 2-ethoxyethoxy group, a 2,2-bis(hydroxymethyl)propionyloxy group, a dimethylphosphynoyloxy group or a 1H-tetrazol-1-yl group;   R 2  represents a hydrogen atom, a hydroxyl group, a methoxy group or a methylthio group; and   R 3  represents a hydrogen atom or a methoxy group   
       in the above-mentioned formula (1). 
     
     
         3 . The method according to  claim 1 , wherein the compound represented by formula (1) is further characterized in that:
 R 1  represents a hydroxyl group or a dimethylphosphynoyloxy group;   R 2  represents a methoxy group; and   R 3  represents a methoxy group   
       in the above-mentioned formula (1). 
     
     
         4 . The method according to  claim 1 , wherein the compound represented by the formula (1) is sirolimus, deforolimus, everolimus, temsirolimus, zotarolimus, biolimus, novolimus, 7-epi-rapamycin, 7-thiomethyl-rapamycin, 7-epi-thiomethyl-rapamycin, 7-demethoxy-rapamycin or 32-demethoxy-rapamycin. 
     
     
         5 . The method according to  claim 1 , wherein the compound represented by the formula (1) is sirolimus. 
     
     
         6 . The method according to  claim 1 , wherein the compound represented by the formula (1) is deforolimus. 
     
     
         7 . The method according to  claim 1 , wherein the meibomian gland dysfunction is low-delivery state meibomian gland dysfunction. 
     
     
         8 . The method according to  claim 1 , wherein the compound represented by formula (1) is administered to the mammalian subject by instillation administration. 
     
     
         9 . The method according to  claim 1 , wherein the compound represented by formula (1) is administered to the mammalian subject by an eye drop or an ophthalmic ointment. 
     
     
         10 . The method according to  claim 9 , wherein the eye drop is a suspension or an emulsion. 
     
     
         11 . The method according to  claim 1 , wherein the compound represented by formula (1) is administered to the mammalian subject by administrating to the eyelid skin. 
     
     
         12 . The method according to  claim 1 , wherein the compound represented by formula (1) is administered to the mammalian subject by an ointment (excluding an ophthalmic ointment). 
     
     
         13 . A method for suppressing obstruction of meibomian gland in a mammalian subject, the method comprising:
 administering to the mammalian subject an effective amount of a compound represented by a formula (1):   
       
         
           
           
               
               
           
         
         wherein 
         R 1  represents a hydroxyl group, a methoxy group, a hydroxymethoxy group, an ethoxy group, a 1-hydroxyethoxy group, a 2-hydroxyethoxy group, a 2-methoxyethoxy group, a 2-ethoxyethoxy group, a formyloxy group, a carboxyoxy group, an acetoxy group, a hydroxyacetoxy group, a propionyloxy group, a 2-hydroxypropionyloxy group, a 3-hydroxypropionyloxy group, a 2-methylpropionyloxy group, a 2-(hydroxymethyl)-propionyloxy group, a 3-hydroxy-2-(hydroxymethyl)propionyloxy group, a 2,2-dimethylpropionyloxy group, a 2-(hydroxymethyl)-2-methylpropionyloxy group, a 2,2-bis(hydroxymethyl)propionyloxy group, a methylphosphynoyloxy group, a dimethylphosphynoyloxy group or a 1H-tetrazol-1-yl group; 
         R 2  represents a hydrogen atom, a hydroxyl group, a methoxy group, a mercapto group or a methylthio group; 
         R 3  represents a hydrogen atom, a hydroxyl group or a methoxy group; and 
         a wavy line represents that the carbon atom bonded to R 1 , R 2  or R 3  can take either configuration of S or R, 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         14 . A method for suppressing telangiectasia around meibomian gland orifices in a mammalian subject, the method comprising:
 administering to the mammalian subject an effective amount of a compound represented by a formula (1):   
       
         
           
           
               
               
           
         
         wherein 
         R 1  represents a hydroxyl group, a methoxy group, a hydroxymethoxy group, an ethoxy group, a 1-hydroxyethoxy group, a 2-hydroxyethoxy group, a 2-methoxyethoxy group, a 2-ethoxyethoxy group, a formyloxy group, a carboxyoxy group, an acetoxy group, a hydroxyacetoxy group, a propionyloxy group, a 2-hydroxypropionyloxy group, a 3-hydroxypropionyloxy group, a 2-methylpropionyloxy group, a 2-(hydroxymethyl)-propionyloxy group, a 3-hydroxy-2-(hydroxymethyl)propionyloxy group, a 2,2-dimethylpropionyloxy group, a 2-(hydroxymethyl)-2-methylpropionyloxy group, a 2,2-bis(hydroxymethyl)propionyloxy group, a methylphosphynoyloxy group, a dimethylphosphynoyloxy group or a 1H-tetrazol-1-yl group; 
         R 2  represents a hydrogen atom, a hydroxyl group, a methoxy group, a mercapto group or a methylthio group; 
         R 3  represents a hydrogen atom, a hydroxyl group or a methoxy group; 
         a wavy line represents that the carbon atom bonded to R 1 , R 2  or R 3  can take either configuration of S or R, 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The method according to  claim 13 , wherein the compound represented by the formula (1) is sirolimus or deforolimus. 
     
     
         16 . The method according to  claim 14 , wherein the compound represented by the formula (1) is sirolimus or deforolimus.