Tricyclic condensed heterocyclic compound, method for producing same, and use thereof

Abstract

A compound derived from the culture product of an actinomycete and having an antitumor activity is provided. Provided is a compound represented by any one of formulas (I), (II) and (III) or an optical isomer thereof or a pharmaceutically acceptable salt thereof which can be isolated from the culture fluid of an actinomycete which belongs to the genus Streptomyces , wherein R 1 , R 2 , R 5 and R 6 each independently represent a hydrogen atom, a methyl group, a hydroxymethyl group, a hydroxyl group, or a double bond by which R 1 and R 2 or R 5 and R 6 are bonded; R 3 , R 4 , R 7 and R 8 each independently represent a methyl group or a hydroxymethyl group; and R 9 represents a hydrogen atom or a hydroxyl group.

1 . A compound represented by any one of formulas (I), (II) and (III) 
       
         
           
           
               
               
           
         
         or an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 5  and R 6  each independently represent a hydrogen atom, a methyl group, a hydroxymethyl group, a hydroxyl group, or represent a double bond by which R 1  and R 2  or R 5  and R 6  are bonded; R 3 , R 4 , R 7  and R 8  each independently represent a methyl group or a hydroxymethyl group; and R 9  represents a hydrogen atom or a hydroxyl group. 
       
     
     
         2 . The compound of  claim 1  represented by any one of formulas (IV), (V) and (VI) 
       
         
           
           
               
               
           
         
         or an optical isomer thereof or a pharmaceutically acceptable salt thereof, 
         wherein R 5  and R 6  each independently represent a hydrogen atom, a methyl group, a hydroxymethyl group or a hydroxyl group; R 3 , R 4 , R 7  and R 8  each independently represent a methyl group or a hydroxymethyl group; and R 9  represents a hydrogen atom or a hydroxyl group. 
       
     
     
         3 . The compound of  claim 2  represented by formula (IV) or an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein each of R 3 , R 4 , R 5 , R 6 , R 7  and R 8  is a methyl group. 
     
     
         4 . The compound of  claim 2  represented by formula (IV) or an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein R 3  is a hydroxymethyl group, and each of R 4 , R 5 , R 6 , R 7  and R 8  is a methyl group. 
     
     
         5 . The compound of  claim 2  represented by formula (IV) or an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein R 4  is a hydroxymethyl group, and each of R 3 , R 5 , R 6 , R 7  and R 8  is a methyl group. 
     
     
         6 . The compound of  claim 2  represented by formula (IV) or an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein R 5  is a hydroxymethyl group, and each of R 3 , R 4 , R 6 , R 7  and R 8  is a methyl group. 
     
     
         7 . The compound of  claim 2  represented by formula (IV) or an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein R 6  is a hydroxymethyl group, and each of R 3 , R 4 , R 5 , R 7  and R 8  is a methyl group. 
     
     
         8 . The compound of  claim 2  represented by formula (V) or an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein R 9  is a hydroxyl group, and each of R 3 , R 5 , R 6 , R 7  and R 8  is a methyl group. 
     
     
         9 . A pharmaceutical composition comprising as an active ingredient the compound of  claim 1  or an optical isomer thereof or a pharmaceutically acceptable salt thereof. 
     
     
         10 . (canceled) 
     
     
         11 . A process of producing the compound of  claim 1 , comprising:
 culturing a microorganism capable of producing the compound of  claim 1 ; and   isolating the compound of  claim 1  from a product of the culturing,   wherein the microorganism capable of producing the compound of  claim 1  is a microorganism which belongs to the genus  Streptomyces.      
     
     
         12 . The process of  claim 11 , wherein the microorganism capable of producing the compound of  claim 1  is  Streptomyces  sp. NPS643 or a variant thereof. 
     
     
         13 . A process of producing a compound represented by formula (VII) 
       
         
           
           
               
               
           
         
         or an optical isomer thereof or a pharmaceutically acceptable salt thereof, comprising deriving a compound represented by formula (VII) or an optical isomer thereof or a pharmaceutically acceptable salt thereof from the compound of  claims 1  or an optical isomer thereof or a pharmaceutically acceptable salt thereof used as a starting material, wherein R 1 , R 4 , R 7 , R 10 , R 11  and R 13  are each independently and arbitrarily selected from —CH 2 OH, —CH 2 O-lower alkyl, —CH 2 NH 2 , —CH 2 NH-lower alkyl, —CH 2 N(lower alkyl) 2 , —CH 2 -halogen, —COOH, —CO 2 -alkyl, —CONH 2  and COH;
 R 2  and R 3  are arbitrarily selected from combinations of (hereinafter, a halogen is referred to as “X”) (X,X), (H,X), (H 2 OH), (OH,H) and (H,NH 2 ) (the substituents in the parentheses may be in any order) and an epoxy in which R 2  and R 3  are bonded to —O—; 
 R 5  and R 6 , R 8  and R 9 , and R 12  and R 14  are each independently and arbitrarily selected from combinations of (X,X), (H,X), (H 2 OH), (OH,X) and (H,NH 2 ) (the substituents in the parentheses may be in any order) and an epoxy in which R 5  and R 6 , R 8  and R 9 , or R 12  and R 14  are bonded to —O—; and 
 bonds indicated with a to f are each independently a single bond or a double bond.