Bengamides with a substituted caprolactame cycle, method for the preparation thereof, compositions containing them and use thereof

Abstract

The invention relates to the preparation of substituted caprolactams, a method for the preparation thereof, compositions containing them and the use thereof as a medicament, particularly as anticancer agents.

1 . A product of general formula (I) below:  
       
         
           
           
               
               
           
         
       
       wherein 
 (i) R1 is independently selected from the group consisting of H, —(C1-C24)alkyl, —(C3-C9)cycloalkyl, heterocycloalkyl, —(C3-C24)alkylene, heterocycloalkylene, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylalkylene, heteroarylalkylene, —(C1-C8)alkylaryl-(C1-C24)alkyl, —(C1-C8)alkylaryl-O—(C1-C24)alkyl,  
 (ii) R2 is independently selected from the group consisting of H, OR7, OCO(R7), in which R7 is selected from the group consisting of —(C1-C24)alkyl, (C3-C9)cycloalkyl, heterocycloalkyl, —(C3-C24)alkylene, heterocycloalkylene, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylalkylene, heteroarylalkylene, —(C1-C8)alkylaryl-(C1-C24)alkyl, —(C1-C8)alkylaryl-O—(C1-C24)alkyl,  
 (iii) R4, R5 and R6 are each independently selected from the group consisting of H, —(C1-C6)acyl, —(C1-C6)alkyl, —(C1-C6)alkylaryl, —(C1-C6)alkyl-heteroaryl, -aryl, -heteroaryl, -arylalkylene, -heteroarylalkylene, with the proviso that when R4, R5 and R6 are each H, and R1 is H or methyl, then R2 is not H or OH.  
 
     
     
         2 . The product according to  claim 1 , wherein R4, R5 and R6 are each independently selected from the group consisting of H and —(C1-C6)acyl.  
     
     
         3 . The product according to  claim 2 , wherein each of R4, R5 and R6 is H.  
     
     
         4 . The product according to  claim 1 , wherein R2 is chosen from H and OH.  
     
     
         5 . The product according to  claim 4 , wherein R2 is H.  
     
     
         6 . The product according to  claim 1 , of general formula (II) below:  
       
         
           
           
               
               
           
         
       
       in which each R8 is independently selected from the group consisting of H, halogen, OH, CN, O(C1-C24)alkyl, OCO(C1-C24)alkyl, —(C1-C4)alkylaryl, —(C1-C4)alkyl-heteroaryl; in which p=0, 1, 2, 3, 4 or 5, and in which R2 is selected from the group consisting of H, OH, O(C1-C24)alkyl, OCO(C1-C24)alkyl, OCO(C3-C9)cycloalkyl, —OCO(C1-C8)alkylaryl-(C1-C24)alkyl, —OCO(C1-C8)alkylaryl-O—(C1-C24)alkyl,  
       
         
           
           
               
               
           
         
       
       in which each Rz is independently selected from the group consisting of H, COO(R10), CONH(R10), CO(R10), and R10; in which each R10 is independently selected from —(C1-C4)alkyl, —(C1-C4)alkyl halogen, —(C1-C4)alkylaryl, and —(C1-C4)alkyl-heteroaryl, in which each R10 is optionally substituted with a substituent chosen from OH, halogen, —(C1-C4)alkyl, —O—(C1-C4)alkyl, —(C1-C4)alkylaryl, aryl, —(C1-C4)alkyl-heteroaryl, and -heteroaryl.  
     
     
         7 . The product according to  claim 1 , wherein R1 is —(C1-C8)alkylaryl substituted with 0 to 5 substituents R8, which may be identical or different, chosen from H, halogen, alkyl, haloalkyl, O-haloalkyl, NH 2 , aryl and heteroaryl.  
     
     
         8 . The product according to  claim 1 , wherein R8 is independently selected from the group consisting of H, —C(CH 3 ) 3 , F, CF 3  and OCF 3 , and in which n=0, 1, 2, 3, 4 or 5.  
     
     
         9 . The product according to  claim 1 , wherein n=4 or 5.  
     
     
         10 . The product according to  claim 1 , wherein R1 is —(C1-C8)alkylaryl in which aryl is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
     
     
         11 . The product according to  claim 1 , wherein the absolute conformation of the carbons bearing the substituents OCH 3 , OR4, OR5 and OR6 is as shown in the general formula (III) below:  
       
         
           
           
               
               
           
         
       
     
     
         12 . The product according to  claim 6 , wherein it is:  
       
         
           
           
               
               
           
         
       
     
     
         13 . The product according to  claim 1 , wherein it is selected from: 
 N—[(S)-1-(4-benzyl)-2-oxoperhydroazepin-3-yl]-(E)-(2R,3R,4S,5R)-3,4,5-tri hydroxy-2-methoxy-8-methyldec-6-enamide,    N—[(S)-1-(4-tert-butylbenzyl)-2-oxoperhydroazepin-3-yl]-(E)-(2R,3R,4S,5R)-3,4,5-tri hydroxy-2-methoxy-8-methyldec-6-enamide,    N—[(S)-2-oxo-1-(3-trifluoromethylbenzyl)perhydroazepin-3-yl]-(E)-(2R,3R,4S,5R)-3,4,5-tri hydroxy-2-methoxy-8-methyldec-6-enamide,    N—[(S)-2-oxo-1-(4-trifluoromethoxybenzyl)perhydroazepin-3-yl]-(E)-(2R, 3R,4S,5R)-3,4,5-trihydroxy-2-methoxy-8-methyldec-6-enamide,    N—[(S)-1-(4-fluoro-3-trifluoromethyl benzyl)-2-oxoperhydroazepin-3-yl]-(E)-(2R, 3R,4S,5R)-3,4,5-trihydroxy-2-methoxy-8-methyldec-6-enamide,    N—[(S)-1-(4-fluorobenzyl)-2-oxoperhydroazepin-3-yl]-(E)-(2R,3R,4S,5R)-3,4,5-trihydroxy-2-methoxy-8-methyldec-6-enamide,    N—[(S)-2-oxo-1-(3,5-difluorobenzyl)perhydroazepin-3-yl]-(E)-(2R,3R,4S,5R)-3,4,5-trihydroxy-2-methoxy-8-methyldec-6-enamide,    N—[(S)-1-(3,4-difluorobenzyl)-2-oxoperhydroazepin-3-yl]-(E)-(2R,3R,4S,5R)-3,4,5-trihydroxy-2-methoxy-8-methyldec-6-enamide,    N—[(S)-1-(2,3,5,6-tetrafluorobenzyl)-2-oxoperhydroazepin-3-yl]-(E)-(2R, 3R,4S,5R)-3,4,5-trihydroxy-2-methoxy-8-methyldec-6-enamide,    N—[(S)-1-(2,3,4,5,6-pentafluorobenzyl)-2-oxoperhydroazepin-3-yl]-(E)-(2R,3R,4S,5R)-3,4,5-trihydroxy-2-methoxy-8-methyldec-6-enamide,    N—[(S)-1-(4-cyano-3-fluorobenzyl)-2-oxoperhydroazepin-3-yl]-(E)-(2R,3R,4S,5R)-3,4,5-trihydroxy-2-methoxy-8-methyldec-6-enamide,    N—[(S)-1-(3-cyano-4-fluorobenzyl)-2-oxoperhydroazepin-3-yl]-(E)-(2R,3R,4S,5R)-3,4,5-trihydroxy-2-methoxy-8-methyldec-6-enamide,    N—[(S)-1-(3-amino-1H-indazol-6-ylmethyl)-2-oxoperhydroazepin-3-yl]-(E)-(2R, 3R,4S,5R)-3,4,5-trihydroxy-2-methoxy-8-methyldec-6-enamide, and    N—[(S)-1-(3-amino-1H-indazol-5-ylmethyl)-2-oxoperhydroazepin-3-yl]-(E)-(2R, 3R,4S,5R)-3,4,5-trihydroxy-2-methoxy-8-methyldec-6-enamide.    
     
     
         14 . The product according to  claim 1 , wherein it is in: 
 1) racemic form, or    2) a form enriched in one stereoisomer, or    3) a form enriched in one enantiomer;    and in that it is optionally salified.    
     
     
         15 . A process for preparing a product of general formula (I) below:  
       
         
           
           
               
               
           
         
       
       in which R1, R2, R4, R5 and R6 are as defined above, characterized in that it comprises the following steps: 
 1) culturing and growth of  Myxococcus virescens,    
 2) extraction of a bengamide-rich fraction of said culture,  
 3) introduction of the substituents R1 to R6 onto a product derived from the bengamide-rich fraction, to obtain a product of general formula (I).  
 
     
     
         16 . The process as claimed in  claim 15 , further comprising a step of purifying the bengamide-rich fraction prior to step 3.  
     
     
         17 . The process according to  claim 15 , wherein the bengamide-rich fraction comprises a product of general formula (IV) below:  
       
         
           
           
               
               
           
         
       
       in which R9 is H or methyl, and R2 is H or OH.  
     
     
         18 . The process according to  claim 17 , wherein step 3 of introduction of the substituents R1 to R6 comprises a step in which the substituent R1 is introduced onto the product of general formula (IV) after protection of its free alcohol functions.  
     
     
         19 . A process for preparing a product of general formula (II) below:  
       
         
           
           
               
               
           
         
       
       in which R2 is H or OH, and R8 is selected from the group consisting of H, halogen, OH, CN, O(C1-C24)alkyl, OCO(C1-C24)alkyl, —(C1-C4)alkylaryl, and —(C1-C4)alkyl-heteroaryl; in which n=0, 1, 2, 3, 4 or 5, and in which R2 is selected from the group consisting of H, OH, O(C1-C24)alkyl, OCO(C1-C24)alkyl, OCO(C3-C9)cycloalkyl, —OCO(C1-C8)alkylaryl-(C0-C24)alkyl, —OCO(C1-C8)alkylaryl-O—(C1-C24)alkyl,  
       
         
           
           
               
               
           
         
       
       in which each Rz is independently selected from the group consisting of H, COO(R10), CONH(R10), CO(R10), and R10; in which each R10 is independently selected from —(C1-C4)alkyl, —(C1-C4)alkyl halogen, —(C1-C4)alkylaryl, and —(C1-C4)alkyl-heteroaryl, in which each R10 is optionally substituted with a substituent chosen from OH, halogen, —(C1-C4)alkyl, —O—(C1-C4)alkyl, —(C1-C4)alkylaryl, aryl, —(C1-C4)alkyl-heteroaryl, and -heteroaryl, 
 comprising a step in which a product of general formula (VI) below:  
                     
 in which R2 is H or OCOCH 3 , and R8 and n are as defined above, is saponified to obtain a product of general formula (II).  
 
     
     
         20 . The process according to  claim 19 , wherein the product of general formula (VI) is obtained by reaction between a product of general formula (V) below:  
       
         
           
           
               
               
           
         
       
       and a benzyl halide  
       
         
           
           
               
               
           
         
       
       in which X is a halogen and R8 and n are as defined above, in the presence of a base.  
     
     
         21 . The process according to  claim 21 , wherein the product of general formula (V) is obtained by acetylation of a product of general formula (IV) below:  
       
         
           
           
               
               
           
         
       
       in which R9 is H and R2 is H or OH.  
     
     
         22 . A process for preparing a product of general formula (VIII) below:  
       
         
           
           
               
               
           
         
         comprising a step in which the product of general formula (II′) below:  
         
           
             
             
                 
                 
             
           
         
         is placed in contact with NH 2 —NH 2  in a solvent such as ethanol or butanol and then heated, to obtain the product of general formula (VIII).  
       
     
     
         23 . A pharmaceutical composition comprising a product according to  claim 1 , in combination with a pharmaceutically acceptable excipient.  
     
     
         24 . A method of treating a cancer comprising: administering to a subject in need thereof an effective dose of a product according to  claim 1.