Helianthrone derivatives as anti-cancer agents

Abstract

Hypericin and helianthrone derivatives of general formula (I) wherein the dotted line between positions 11 and 12 represent an optional C11-C12 bond; R is independently selected from the group consisting of hydroxy, C 1 -C 10 alkoxy, NH—C 1 -C 10 alkyl, and NH-hydroxy(C 1 -C 10 )alkyl; R′ is independently selected from the group consisting of hydroxy and C 1 -C 10 alkoxy; R″ is independently selected from the group consisting of hydrogen, hydroxy, C 1 -C 10 alkoxy, NH—C 1 -C 10 alkyl, and NH-hydroxy(C 1 -C 10 )alkyl; and R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of hydrogen, hydroxy, chloro, bromo, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, and C 1 -C 10 alkoxycarbonyl, provided that R″ is not hydrogen when there is a C11-C12 bond and when there is a C11-C12 bond and both R′ are hydroxy, both R″ groups are not hydroxy. These compounds and pharmaceutical compositions containing them as active agents are useful as inhibitors of angiogenesis and can be used to prevent formation of metastases and restenosis and for the treatment of angiogenesis-associated ophthalmologic disorders. In addition, the helianthrone derivatives of formula (I) can be used for the treatment of tumors in the absence of light irradiation.

1 . A pharmaceutical composition for the treatment or inhibition of angiogenesis comprising, as an active ingredient, a therapeutically effective amount of a compound of the general formula (I):  
       
         
           
           
               
               
           
         
       
       wherein the dotted line between positions 11 and 12 represent an optional C11-C12 bond; R is independently selected from the group consisting of hydroxy, C 1 -C 10  alkoxy, NH—C 1 -C 10  alkyl, and NH-hydroxy(C 1 -C 10 )alkyl; R′ is independently selected from the group consisting of hydroxy and C 1 -C 10  alkoxy; R″ is independently selected from the group consisting of hydrogen, hydroxy, C 1 -C 10  alkoxy, NH—C 1 -C 10  alkyl, and NH-hydroxy(C 1 -C 10 )alkyl; and R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are independently selected from the group consisting of hydrogen, hydroxy, chloro, bromo, C 1 -C 10  alkyl, C 1 -C 10  alkoxy, and C 1 -C 10  alkoxycarbonyl, provided that when there is a C11-C12 bond and both R′ are hydroxy, both R″ groups are not hydroxy.  
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the compound is administered with a carrier or diluent.  
     
     
         3 . The pharmaceutical composition of  claim 2 , wherein the active agent is present in an amount of between about 0.1 micrograms and 1 mg per kg of patient body weight.  
     
     
         4 . The pharmaceutical composition of  claim 1 , where each R is the same and each R″ is the same, provided that each R″ is not hydrogen when a C11-C12 bond is present.  
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the each R is hydroxyl, methoxy, butylamino or hydroxyethylamino, each R′ is hydroxyl or methoxycarbonyl, R 2  and R 5  are hydrogen and R 3  and R 6  are hydrogen or bromo.  
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein each R or each R″ is hydroxy or methoxy.  
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the compound of formula I to be administered is selected from the group consisting of: 
 10,13-dimethyl-1,3,4,6-tetramethoxyhelianthrone,    1,3,4,6-tetrahydroxyhelianthrone,    1,3,4,6-tetramethoxyhelianthrone,    10,13 -dimethyl-1,3,4,6-tetrahydroxyhelianthrone,    10,13-di(methoxycarbonyl)-1,3,4,6-tetramethoxyhelianthrone,    1,6-di-N-butylamino-3,4-dimethoxy-helianthrone,    1,6-di-N-butylamino-3,4-dimethoxy-10,13-dimethyl-helianthrone,    1,6-di-(N-hydroxyethylamino)-3,4-dimethoxy-helianthrone,    2,5-dibromo-1,3,4,6-tetrahydroxyhelianthrone, and    2,5-dibromo-10,13-dimethyl-1,3,4,6-tetrahydroxyhelianthrone.    
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the active agent is 10,13-dimethyl-1,3,4,6-tetramethoxyhelianthrone.  
     
     
         9 . A method of making a pharmaceutical composition for the treatment or inhibition of angiogenesis which comprises mixing an effective amount of the compound of formula (I) according to  claim 1  with at least one pharmaceutically acceptable carrier or diluent for administration to a patient in need of such treatment or inhibition.  
     
     
         10 . The method of  claim 9 , wherein the compound is present in an amount of between about 0.1 micrograms and 1 mg per kg of patient body weight.  
     
     
         11 . A method of making a pharmaceutical composition for the treatment of tumor metastases which comprises mixing an effective amount of the compound of formula (I) according to  claim 1  with at least one pharmaceutically acceptable carrier or diluent for administration to a patient in need of such treatment.  
     
     
         12 . The method of  claim 11 , wherein the active agent is present in an amount of between about 0.1 micrograms and 1 mg per kg of patient body weight.  
     
     
         13 . A method of making a pharmaceutical composition for the treatment of angiogenesis-associated ophthalmologic disorders which comprises mixing an effective amount of the compound of formula (I) according to  claim 1  with at least one pharmaceutically acceptable carrier or diluent for administration to a patient in need of such treatment.  
     
     
         14 . The method of  claim 13 , wherein the active agent is present in an amount of between about 0.1 micrograms and 1 mg per kg of patient body weight.  
     
     
         15 . A method of making a pharmaceutical composition for the treatment of diabetic retinopathy, macular degeneration or eye infection which comprises mixing an effective amount of the compound of formula (I) according to  claim 1  with at least one pharmaceutically acceptable carrier or diluent for administration to a patient in need of such treatment.  
     
     
         16 . The method of  claim 15 , wherein the active agent is present in an amount of between about 0.1 micrograms and 1 mg per kg of patient body weight.  
     
     
         17 . A method of making a pharmaceutical composition for the treatment or prevention inhibition of restenosis which comprises mixing an effective amount of the compound of formula (I) according to  claim 1  with at least one pharmaceutically acceptable carrier or diluent for administration to a patient in need of such treatment or inhibition.  
     
     
         18 . The method of  claim 17 , wherein the active agent is present in an amount of between about 0.1 micrograms and 1 mg per kg of patient body weight.  
     
     
         19 . A method of making a pharmaceutical composition for the inhibition of transduction of cell proliferation which comprises mixing an effective amount of the compound of formula (I) according to  claim 1  with at least one pharmaceutically acceptable carrier or diluent for administration to a patient in need of such inhibition.  
     
     
         20 . The method of  claim 19 , wherein the active agent is present in an amount of between about 0.1 micrograms and 1 mg per kg of patient body weight.