Novel Process for the Preparation of Hexacyclic Compounds

Abstract

This invention relates to novel processes for the preparation of compounds of the formula [1], wherein R 1 , R 2 , R 3 and R 4 are as defined in the claims and description as well as pharmaceutically acceptable salts thereof. The compounds of the formula [1] are hexacyclic compounds having potent anti-tumor activity.

1 . A compound of formula [2]: 
       
         
           
           
               
               
           
         
         or a salt thereof; wherein: 
         R 1  and R 2  are independently hydrogen, halogen, (C 1 -C 5 )-alkyl or (C 1 -C 5 )-alkoxy; 
         R 3  is hydrogen; or
 (C 1 -C 5 )-alkyl optionally substituted with one to three moieties independently selected from the group consisting of (C 1 -C 5 )-alkoxy, hydroxy, halogen, amino, (C 3 -C 7 )-cycloalkyl, heterocyclic ring or and aryl in which the aryl ring is optionally substituted with one to three moieties independently selected from the group consisting of hydroxy, (C 1 -C 5 )-alkoxy, amino, mono-(C 1 -C 5 )-alkylamino and di-(C 1 -C 5 )-alkylamino; 
 
         R 4  is hydrogen; or
 (C 1 -C 10 )-alkyl, optionally substituted with one to three moieties independently selected from the group consisting of (C 1 -C 5 )-alkoxy, hydroxy, halogen, amino, mono-(C 1 -C 5 )-alkylamino, di-(C 1 -C 5 )-alkylamino, (C 3 -C 7 )-cycloalkyl, a heterocyclic ring and aryl in which the aryl ring is optionally substituted with one to three moieties independently selected from the group consisting of hydroxy, alkoxy, halogen, amino, mono-(C 1 -C 5 )-alkylamino and di-(C 1 -C 5 )-alkylamino; and 
 
         R 5  is —OH or —O—(C 1 -C 5 )-alkyl. 
       
     
     
         2 . A compound according to  claim 1 , which is a compound of formula [2A]: 
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         3 . A process of preparing a compound of  claim 1 , or a salt thereof, comprising:
 a) ozonolysis of a compound of formula [4]:   
       
         
           
           
               
               
           
         
       
       or a salt thereof, in order to obtain a compound of formula [5]: 
       
         
           
           
               
               
           
         
       
       or a salt thereof;
 b) cyclizing the compound of formula [5] with an amine R 4 —NH 2  to obtain a compound of formula [6]: 
 
       
         
           
           
               
               
           
         
       
       or a salt thereof; and
 c) hydrogenating the nitro group of the compound of formula [6], or a salt thereof, in order to obtain a compound of formula [2]: 
 
       
         
           
           
               
               
           
         
       
       or a salt thereof; wherein: 
       R 1  and R 2  are independently hydrogen, halogen, (C 1 -C 5 )-alkyl or (C 1 -C 5 )-alkoxy; 
       R 3  is hydrogen; or
 (C 1 -C 5 )-alkyl optionally substituted with one to three moieties independently selected from the group consisting of (C 1 -C 5 )-alkoxy, hydroxy, halogen, amino, (C 3 -C 7 )-cycloalkyl, heterocyclic ring and aryl in which the aryl ring is optionally substituted with one to three moieties independently selected from the group consisting of hydroxy, (C 1 -C 5 )-alkoxy, amino, mono-(C 1 -C 5 )-alkylamino and di-(C 1 -C 5 )-alkylamino; 
 
       R 4  is hydrogen; or
 (C 1 -C 10 )-alkyl, optionally substituted with one to three moieties independently selected from the group consisting of (C 1 -C 5 )-alkoxy, hydroxy, halogen, amino, mono-(C 1 -C 5 )-alkylamino, di-(C 1 -C 5 )-alkylamino, (C 3 -C 7 )-cycloalkyl, a heterocyclic ring and aryl in which the aryl ring is optionally substituted with one to three moieties independently selected from the group consisting of hydroxy, alkoxy, halogen, amino, mono-(C 1 -C 5 )-alkylamino and di-(C 1 -C 5 )-alkylamino; and 
 
       R 5  is —OH or —O—(C 1 -C 5 )-alkyl. 
     
     
         4 . A process of preparing a compound of  claim 2 , or a salt thereof, wherein said process comprises:
 a′) ozonolysis of a compound of formula [4A]:   
       
         
           
           
               
               
           
         
       
       or a salt thereof, in order to obtain a compound of formula [5A]: 
       
         
           
           
               
               
           
         
       
       or a salt thereof;
 b′) cyclizing the compound of formula [5A], or a salt thereof, with n-pentylamine in order to obtain a compound of formula [6A]: 
 
       
         
           
           
               
               
           
         
       
       or a salt thereof; and
 c′) hydrogenating the nitro group of the compound of formula [6A], or a salt thereof, in order to obtain a compound of formula [2A]: 
 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         5 . A process of preparing a compound of  claim 1 , or a salt thereof, comprising:
 a) ozonolysis of a compound of formula [4]:   
       
         
           
           
               
               
           
         
       
       or a salt thereof, in order to obtain a compound of formula [5]: 
       
         
           
           
               
               
           
         
       
       or a salt thereof,
 d) hydrogenating the nitro group of the compound of formula [5], or a salt thereof, in order to obtain a compound of formula [7]: 
 
       
         
           
           
               
               
           
         
       
       or a salt thereof,
 e) cyclizing the compound of formula [7], or a salt thereof, with an amine R 4 —NH 2  in order to obtain a compound of formula [2]: 
 
       
         
           
           
               
               
           
         
       
       or a salt thereof; wherein: 
       R 1  and R 2  are independently hydrogen, halogen, (C 1 -C 5 )-alkyl or (C 1 -C 5 )-alkoxy; 
       R 3  is hydrogen; or
 (C 1 -C 5 )-alkyl optionally substituted with one to three moieties independently selected from the group consisting of (C 1 -C 5 )-alkoxy, hydroxy, halogen, amino, (C 3 -C 7 )-cycloalkyl, heterocyclic ring and aryl in which the aryl ring is optionally substituted with one to three moieties independently selected from the group consisting of hydroxy, (C 1 -C 5 )-alkoxy, amino, mono-(C 1 -C 5 )-alkylamino and di-(C 1 -C 5 )-alkylamino; 
 
       R 4  is hydrogen; or
 (C 1 -C 10 )-alkyl, optionally substituted with one to three moieties independently selected from the group consisting of (C 1 -C 5 )-alkoxy, hydroxy, halogen, amino, mono-(C 1 -C 5 )-alkylamino, di-(C 1 -C 5 )-alkylamino, (C 3 -C 7 )-cycloalkyl, a heterocyclic ring and aryl in which the aryl ring is optionally substituted with one to three moieties independently selected from the group consisting of hydroxy, alkoxy, halogen, amino, mono-(C 1 -C 5 )-alkylamino and di-(C 1 -C 5 )-alkylamino; and 
 
       R 5  is —OH or —O—(C 1 -C 5 )-alkyl. 
     
     
         6 . A process of preparing a compound of  claim 2 , or salt thereof, wherein said process comprises:
 a′) ozonolysis of a compound of formula [4A]:   
       
         
           
           
               
               
           
         
       
       or a salt thereof, in order to obtain a compound of the formula [5A]: 
       
         
           
           
               
               
           
         
       
       or a salt thereof;
 d′) hydrogenating the nitro group of the compound of formula [5A], or a salt thereof, in order to obtain a compound of formula [7A]: 
 
       
         
           
           
               
               
           
         
       
       or a salt thereof, and
 e′) cyclizing the compound of formula [7A], or a salt thereof, with n-pentylamine in order to obtain a compound of formula [2A], or a salt thereof. 
 
     
     
         7 . A compound according to  claim 1 , or a salt thereof, wherein R 3  is hydrogen, methyl, ethyl, propyl, hydroxymethyl, aminomethyl, chloromethyl, or trifluoromethyl. 
     
     
         8 . A compound according to  claim 1 , or a salt thereof, wherein R 4  is methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1,1-dimethylethyl, 2-methylpropyl, 2,2-dimethylpropyl, n-pentyl, 3-methylbutyl, 2-n-hexyl, 3,3-dimethylbutyl, n-heptyl, n-octyl, benzyl, phenethyl, 2-(dimethylamino)ethyl, 2-(4-morpholino)ethyl, 3-(dimethylamino)propyl, 2-(pyridin-2-yl)ethyl, 2-(pyridin-3-yl)ethyl, 2-(4-methoxyphenyl)ethyl, 2-(4-chlorophenyl)ethyl, 2-(4-fluorophenyl)ethyl, or 3-phenylpropyl. 
     
     
         9 . A compound according to  claim 1 , or a salt thereof, wherein:
 R 1  is hydrogen; and   R 2  is hydrogen or (C 1 -C 3 )-alkyl;   R 3  is hydrogen; or
 (C 1 -C 5 )-alkyl optionally substituted with one to three moieties independently selected from the group consisting of (C 1 -C 5 )-alkoxy, hydroxy, halogen, amino, 
 (C 3 -C 7 )-cycloalkyl, a heterocyclic ring and aryl; 
   R 4  is hydrogen; or
 (C 1 -C 8 )-alkyl which is optionally substituted with one to three moieties independently selected from the group consisting of (C 1 -C 3 )-alkoxy, hydroxy, halogen, amino, mono-(C 1 -C 3 )-alkylamino, di-(C 1 -C 3 )-alkylamino, (C 3 -C 7 )-cycloalkyl, a heterocyclic ring and aryl in which the aryl ring is optionally substituted with one to three moieties independently selected from the group consisting of hydroxy, alkoxy and halogen; and 
   R 5  is —OH or —O—(C 1 -C 5 )-alkyl.   
     
     
         10 . A compound according to  claim 1 , or a salt thereof, wherein:
 R 1  and R 2  are hydrogen;   R 3  is hydrogen, methyl, ethyl, propyl, hydroxymethyl, aminomethyl, chloromethyl, or trifluoromethyl; and   R 4  is methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1,1-dimethylethyl, 2-methylpropyl, 2,2-dimethylpropyl, n-pentyl, 3-methylbutyl, 2-n-hexyl, 3,3-dimethylbutyl, n-heptyl, n-octyl, benzyl, phenethyl, 2-(dimethylamino)ethyl, 2-(4-morpholino)ethyl, 3-(dimethylamino)propyl, 2-(pyridin-2-yl)ethyl, 2-(pyridin-3-yl)ethyl, 2-(4-methoxyphenyl)ethyl, 2-(4-chlorophenyl)ethyl, 2-(4-fluorophenyl)ethyl, or 3-phenylpropyl; and   R 5  is —OH or —O—(C 1 -C 5 )-alkyl.