Derivatives of octahydro-6, 10-dioxo-6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxylic acid, their preparation process and their use in the preparation of therapeutically active compounds

Abstract

A compound of the formula of SR configuration or a SR+SS wherein R is selected from the group consisting of hydrogen, alkyl of up to 18 carbon atoms and aryl and aralkyl of up to 18 carbon atoms and the —NH 2 is free or protected useful as intermediates.

1 ) The compounds of formula (I):  
       
         
           
           
               
               
           
         
       
       of SR configuration or in the form of an SR+SS mixture, in which R represents a hydrogen atom, an alkyl or aralkyl radical containing up to 18 carbon atoms, the amine function being able to be free or protected.  
     
     
         2 ) The compounds of formula (I) defined in  claim 1 , corresponding to formula (IA):  
       
         
           
           
               
               
           
         
       
       of SR configuration or in the form of an SR+SS mixture, in which R is as defined in  claim 1  and either R 1  represents a  
       
         
           
           
               
               
           
         
       
       radical 
 Ra, Rb, Rc and Rd representing an alkyl or aryl radical containing up to 18 carbon atoms, or a mono or polycyclic radical containing one or more heteroatoms, X representing a hydrogen atom, an alkyl radical containing up to 8 carbon atoms or an aryl radical containing up to 14 carbon atoms, and R 2  represents a hydrogen atom,  
 or R 1  and R 2  form together a mono or polycyclic radical containing one or more heteroatoms.  
 
     
     
         3 ) The compounds of formula (IA) defined in  claim 1  or  2  in which R 1  and R 2  form together a polycyclic radical containing one or more heteroatoms of SR configuration or in the form of an SR+SS mixture.  
     
     
         4 ) The compounds of formula (IA) defined in  claim 3 , corresponding to formula (IA 1 ):  
       
         
           
           
               
               
           
         
       
       of SR configuration or in the form of an SR+SS mixture.  
     
     
         5 ) The compounds of formula (I) defined in any one of  claims 1  to  4 , in which R represents a methyl radical.  
     
     
         6 ) The racemic mixture of the compounds of formula (I) defined in  claim 1  the names of which follow: 
 (1S-cis) methyl-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate and  
 (1R-trans) methyl-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2] diazepine-1-carboxylate.  
 
     
     
         7 ) Process for the preparation of the compounds of formula (I) defined in any one of the previous claims, characterized in that a compound of formula (II):  
       
         
           
           
               
               
           
         
       
       in which alk represents an alkyl radical containing up to 8 carbon atoms and Hal represents a halogen atom, is subjected to the action of a compound of formula (III):  
       
         
           
           
               
               
           
         
       
       in which Aryl represents an aryl radical containing co to 14 carbon atoms, in order to obtain the compound of formula (IV):  
       
         
           
           
               
               
           
         
       
       which is subjected to the action of a basic agent, in order to obtain the compound of formula (V):  
       
         
           
           
               
               
           
         
       
       which is optionally subjected to the action of an alkylation agent in order to obtain the compound of formula (VI):  
       
         
           
           
               
               
           
         
       
       which is subjected to the action of a compound of formula (VII):  
       
         
           
           
               
               
           
         
       
       in which Hal 1  represents a halogen atom and Ar represents an aryl or aralkyl radical containing up to 18 carbon atoms, R 1  and R 2  retain the same definition as in  claim 2 , in order to obtain the compound of formula (VIII):  
       
         
           
           
               
               
           
         
       
       of SR configuration or in the form of an SR+SS mixture, which is subjected to the action of a hydrogenation agent in order to obtain the compound of formula (IX):  
       
         
           
           
               
               
           
         
       
       of SR configuration or in the form of an SR+SS mixture, which is subjected to the action of a condensation agent in order to obtain the corresponding compound of formula (IA), then if desired, the amine function is released in order to obtain the compound of formula (I) in which the amine function is free.  
     
     
         8 ) As new chemical products, the compounds of formulae (IV), (VIII) and (IX) defined in  claim 7 .  
     
     
         9 ) Use of the compounds of formula (I) defined in any one of  claims 1  to  6 , in the form of SS,SR mixtures or in SR form, characterized in that a compound of formula (I) is subjected to the action of a deracemization agent of the asymmetric carbon carried by the ring with 6 members, in order to obtain the compound of formula (Iopt):  
       
         
           
           
               
               
           
         
       
       in SS form, in which the amine function is free or protected and R is as defined in  claim 1 .  
     
     
         10 ) Use of the compounds of formula (IA) defined in any one of  claims 2  to  6 , for the preparation of the compounds of formula (IAopt):  
       
         
           
           
               
               
           
         
       
       in SS form, in which R, R 1  and R 2  retain the same definition as in  claim 2 .  
     
     
         11 ) Use according to  claim 9  or  10 , characterized in that R represents a methyl radical.  
     
     
         12 ) Use according to  claim 9 ,  10  or  11 , characterized in that the amine function is protected in the form of phthalimido.  
     
     
         13 ) Use according to any one of  claims 9  to  12 , characterized in that the deracemization agent is a base.  
     
     
         14 ) Use according to  claim 13 , characterized in that the strong base is an alkaline or alkaline-earth alcoholate or a lithiated amine.  
     
     
         15 ) Use according to any one of  claims 10  to  14 , characterized in that the starting product is the racemic mixture according to  claim 6  and the prepared product is: 
 (1s-cis) methyl-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-3,4,7,8,9,10-hexahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepine-1-methyl carboxylate.