Novel use of sesquiterpene derivative

Abstract

The present disclosure relates to a novel use of a sesquiterpene derivative, more particularly to a composition for preventing, improving or treating macular degeneration or macular edema caused by vascular leakage in the eye, the composition containing a sesquiterpene derivative compound represented by Chemical Formula 1 of the present disclosure or a pharmaceutically acceptable salt thereof as an active ingredient. Whereas the intraocular disease-related treating agents available in the market should be injected directly into the vitreous cavity, thus causing pain and side effects, the sesquiterpene derivative compound of the present disclosure is delivered to the target tissue (eye) via different administration routes (oral, intraperitoneal, etc.) other than the intravitreal route. Accordingly, the sesquiterpene derivative compound provides excellent therapeutic effect without being restricted by the administration routes.

1 . A pharmaceutical composition for preventing or treating macular degeneration or macular edema, comprising a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient: 
       
         
           
           
               
               
           
         
         wherein 
         the broken line denotes a single bond or a double bond, wherein 
         i) if the bond between C-3 and C-4 and the bond between C-5 and C-6 are single bonds, R 2b  is nonexistent and R 2a  is CH 2 ; 
         ii) if the bond between C-3 and C-4 is a double bond, the bond between C-5 and C-6 is a single bond, R 2b  is nonexistent and R 2a  is CH 3 ; or 
         iii) if the bond between C-5 and C-6 is a double bond, the bond between C-3 and C-4 is a single bond and R 2a  and R 2b  are CH 3 , 
         R 1  is H or CH 3 , 
         R 3  is a functional group selected from a group consisting of R 3a  through R 3d , 
       
       
         
           
           
               
               
           
         
         in R 3a , 
         i) each of R 4  and R 7  is OH or OCH 3  and R 5 , R 6  and R 8  are H; or 
         ii) R 5  is COOCH 3 , R is H or OH, R 8  is OH and R 4  and R are H, 
         in R 3b , 
         R 9  is a functional group selected from a group consisting of H, NH 2 , C 1 -C 8  alkoxy and R 9a  through R 9j  and R 10  is H or OH, 
       
       
         
           
           
               
               
           
         
         in R 3c , 
         each of R 11  and R 12  is OH or OAc and R 3  is H; or 
         each of R 11  and R 12  is OH or OCH 3  and R 13  is CH 3  and 
         in R 3d , 
         R 14  is OCH 3  and R 15  and R 16  are CH 3 . 
       
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein, if the bond between C-3 and C-4 and the bond between C-5 and C-6 are single bonds, R 2b  is nonexistent, R 2a  is CH 2  and R 3  is a functional group selected from a group consisting of R 3b  through R 3d . 
     
     
         3 . The pharmaceutical composition according to  claim 2 , wherein, in the functional group selected from a group consisting of R 3b  through R 3d ,
 in R 3b , R 9  is selected from a group consisting of ethoxy, methoxy and R 9a ;   in R 3c , R 11  is OH, R 12  is OCH 3  and R 13  is CH 3 ; or   in R 3d , R 14  is OCH 3  and R 15  and R 16  are CH 3 .   
     
     
         4 . The pharmaceutical composition according to  claim 3 , wherein the compound of Chemical Formula 1 is a compound selected from a group consisting of:
 3-[[(1R,2S,4aS,8aS)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-4-hydroxy-5-(2-phenylethylamino)cyclohexa-3,5-diene-1,2-dione;   3-[[(1R,2S,4aS,8aS)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-2-hydroxy-5-methoxycyclohexa-2,5-diene-1,4-dione;   3-[[(1 S,2R,4aR,8aR)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-5-ethoxy-2-hydroxycyclohexa-2,5-diene-1,4-dione;   18-methoxy-22-methyl-16-[{(5 S,8S,9R,10S)-5,8,9-trimethyl-4-methylenedecahydronaphthalen-9-yl}methyl]benzo[d]-oxazol-17-ol; and   18-methoxy-22,22-dimethyl-16-[{(5R,8S,9R,10S)-5,8,9-trimethyl-4-methylenedecahydronaphthalen-9-yl}methyl]benzo[d]-oxazol-17(2H)-one.   
     
     
         5 . The pharmaceutical composition according to  claim 1 , wherein the composition is prepared into a formulation selected from a group consisting of an oral medication, an injection, an eye drop and an ointment. 
     
     
         6 . A pharmaceutical composition for inhibiting vascular leakage in the eye, comprising a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient: 
       
         
           
           
               
               
           
         
         wherein 
         the broken line denotes a single bond or a double bond, 
         wherein 
         i) if the bond between C-3 and C-4 and the bond between C-5 and C-6 are single bonds, R 2b  is nonexistent and R 2a  is CH 2 ; 
         ii) if the bond between C-3 and C-4 is a double bond, the bond between C-5 and C-6 is a single bond, R 2b  is nonexistent and R 2a  is CH 3 ; or 
         iii) if the bond between C-5 and C-6 is a double bond, the bond between C-3 and C-4 is a single bond and R 2a  and R 2b  are CH 3 , 
         R 1  is H or CH 3 , 
         R 3  is a functional group selected from a group consisting of R 3a  through R 3d , 
       
       
         
           
           
               
               
           
         
         in R 3a , 
         i) each of R 4  and R 7  is OH or OCH 3  and R 5 , R 6  and R 8  are H; or 
         ii) R 5  is COOCH 3 , R 7  is H or OH, R 8  is OH and R 4  and R 6  are H, 
         in R 3b , 
         R 9  is a functional group selected from a group consisting of H, NH 2 , C 1 -C 8  alkoxy and R 9a  through R 9j  and R 10  is H or OH, 
       
       
         
           
           
               
               
           
         
         in R 3c , 
         each of R 11  and R 12  is OH or OAc and R 13  is H; or 
         each of R 11  and R 12  is OH or OCH 3  and R 13  is CH 3  and 
         in R 3d , 
         R 14  is OCH 3  and R 15  and R 16  are CH 3 . 
       
     
     
         7 . The pharmaceutical composition according to  claim 6 , wherein, if the bond between C-3 and C-4 and the bond between C-5 and C-6 are single bonds, R 2b  is nonexistent, R 2a  is CH 2  and R 3  is a functional group selected from a group consisting of R 3b  through R 3d . 
     
     
         8 . The pharmaceutical composition according to  claim 7 , wherein, in the functional group selected from a group consisting of R 3b  through R 3d ,
 in R 3b , R 9  is selected from a group consisting of ethoxy, methoxy and R 9a ;   in R 3c , R 11  is OH, R 12  is OCH 3  and R 13  is CH 3 ; or   in R 3d , R 14  is OCH 3  and R 15  and R 16  are CH 3 .   
     
     
         9 . The pharmaceutical composition according to  claim 8 , wherein the compound of Chemical Formula 1 is a compound selected from a group consisting of:
 3-[[(1R,2S,4aS,8aS)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-4-hydroxy-5-(2-phenylethylamino)cyclohexa-3,5-diene-1,2-dione;   3-[[(1R,2S,4aS,8aS)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-2-hydroxy-5-methoxycyclohexa-2,5-diene-1,4-dione;   3-[[(1 S,2R,4aR,8aR)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-5-ethoxy-2-hydroxycyclohexa-2,5-diene-1,4-dione;   18-methoxy-22-methyl-16-[{(5 S,8S,9R,10S)-5,8,9-trimethyl-4-methylenedecahydronaphthalen-9-yl}methyl]benzo[d]-oxazol-17-ol; and   18-methoxy-22,22-dimethyl-16-[{(5R,8S,9R,10S)-5,8,9-trimethyl-4-methylenedecahydronaphthalen-9-yl}methyl]benzo[d]-oxazol-17(2H)-one.   
     
     
         10 . A food composition for preventing or improving macular degeneration or macular edema, comprising a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient: 
       
         
           
           
               
               
           
         
         wherein 
         the broken line denotes a single bond or a double bond, wherein 
         i) if the bond between C-3 and C-4 and the bond between C-5 and C-6 are single bonds, R 2b  is nonexistent and R 2a  is CH 2 ; 
         ii) if the bond between C-3 and C-4 is a double bond, the bond between C-5 and C-6 is a single bond, R 2b  is nonexistent and R 2a  is CH 3 ; and 
         iii) if the bond between C-5 and C-6 is a double bond, the bond between C-3 and C-4 is a single bond and R 2a  and R 2b  are CH 3 , 
         R 1  is H or CH 3 , 
         R 3  is a functional group selected from a group consisting of R 3a  through R 3d , 
       
       
         
           
           
               
               
           
         
         in R 3a , 
         i) each of R 4  and R 7  is OH or OCH 3  and R 5 , R 6  and R 8  are H; or 
         ii) R 5  is COOCH 3 , R 7  is H or OH, R 8  is OH and R 4  and R 6  are H, 
         in R 3b , 
         R 9  is a functional group selected from a group consisting of H, NH 2 , C 1 -C 8  alkoxy and R 9a  through R 9j  and R 10  is H or OH, 
       
       
         
           
           
               
               
           
         
         in R 3c , 
         each of R 11  and R 12  is OH or OAc and R 13  is H; or 
         each of R 11  and R 12  is OH or OCH 3  and R 13  is CH 3  and 
         in R 3d , 
         R 14  is OCH 3  and R 15  and R 16  are CH 3 . 
       
     
     
         11 . The food composition according to  claim 10 , wherein, if the bond between C-3 and C-4 and the bond between C-5 and C-6 are single bonds, R 2b  is nonexistent, R 2a  is CH 2  and R 3  is a functional group selected from a group consisting of R 3b  through R 3d . 
     
     
         12 . The food composition according to  claim 11 , wherein, in the functional group selected from a group consisting of R 3b  through R 3d ,
 in R 3b , R 9  is selected from a group consisting of ethoxy, methoxy and R 9a ;   in R 3c , R 11  is OH, R 12  is OCH 3  and R 13  is CH 3 ; or   in R 3d , R 14  is OCH 3  and R 15  and R 16  are CH 3 .   
     
     
         13 . The food composition according to  claim 12 , wherein the compound of Chemical Formula 1 is a compound selected from a group consisting of:
 3-[[(1R,2S,4aS,8aS)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-4-hydroxy-5-(2-phenylethylamino)cyclohexa-3,5-diene-1,2-dione;   3-[[(1R,2S,4aS,8aS)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-2-hydroxy-5-methoxycyclohexa-2,5-diene-1,4-dione;   3-[[(1 S,2R,4aR,8aR)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-5-ethoxy-2-hydroxycyclohexa-2,5-diene-1,4-dione;   18-methoxy-22-methyl-16-[{(5 S,8S,9R,10S)-5,8,9-trimethyl-4-methylenedecahydronaphthalen-9-yl}methyl]benzo[d]-oxazol-17-ol; and   18-methoxy-22,22-dimethyl-16-[{(5R,8S,9R,10S)-5,8,9-trimethyl-4-methylenedecahydronaphthalen-9-yl}methyl]benzo[d]-oxazol-17(2H)-one.