2' or 3' -deoxy and 2', 3' -dideoxy-beta-L-pentofuranonucleo-side compounds, method of preparation and application in therapy, especially as anti- viral agents

Abstract

Method for the sterospecific preparation of 2′ or 3′ deoxy and 2′, 3′-dideoxy-β-L-pentofuranonucleoside compounds. 2′ or 3′ deoxy and 2′, 3′-dideoxy-β-L-pentofuranonucleoside compounds are also described. Finally, the invention concerns the use of these compounds, and particularly 2′, 3′ dideoxy-β-L-fluorocytidine, as drugs, and especially as anti-viral agents.

1 . Method for the preparation of 2′- or 3′-deoxy-and 2′,3′-dideoxy-β-L-pentofuranocucleoside compounds of formula I:  
       
         
           
           
               
               
           
         
       
       in which 
 B represents a purine or pyrimidine base;  
 R 1  represents OH;  
 R 2  and R 3  represent, independently of each other, H or OH;  
 at least one of R 2  and R 3  represents H;  
 characterized in that the following steps are carried out: 
 1) a compound of formula (II) is condensed with the base B in order to obtain the compound of formula (III) according to the scheme  
                     
  in which formulae (II) and (III)  
 
 R′ 1  and R′ 2  have the meanings given for R 1  and R 2  except that when R 1  and R 2  represent OH, the said OH group is protected by a protecting group such as an acyl, benzoyl, benzyl or silyl group,  
 R′ 3  represents a C 1  to C 5  alkyl group or a phenyl radical, which are optionally substituted,  
 X is a leaving group such as Cl, Br, I or a C 1  to C 5  acyloxy or alkoxy group,  
 B′ is a purine or pyrimidine base B which is optionally appropriately protected, p 2  2) the R′ 3  CO group at the 2′ position is removed by deacetylation so as to obtain an OH group and a 
  compound of formula  
                     
 3) optionally, the OH group at the 2′ position is removed; and  
 4) where appropriate, the R′ 1  and R′ 2  groups and the B′ base are deprotected so as to obtain the compounds of formula (I).  
 
 
     
     
         2 . Method according to  claim 1 , characterized in that in the compounds (II) and (III), R′ 3  represents a C 1  to C 5  alkyl group, preferably CH 3 .  
     
     
         3 . Method according to  claim 1  or  2 , characterized in that the compound (II), di-O-acetylated at the 1,2 position, in which X and R′ 3 COO represent an O-acetyl group, is prepared by acetolysis of the 1,2-isopropylidene-L-xylofuranose compound of formula (V)  
       
         
           
           
               
               
           
         
       
     
     
         4 . Method according to one of  claims 1  to  3 , characterized in that R′ 2  and R′ 3 COO are different, in particular R′ 2  is an O-benzoyl group and R′ 3  is an alkyl group.  
     
     
         5 . Method according to one of  claims 1  to  4 , characterized in that the compounds of formula (I) are prepared in which R 2  and R 3  represent H or OH.  
     
     
         6 . Method according to one of  claims 1  to  4 , characterized in that B represents one of the adenine, guanine, hypoxanthine, uracil, thymine or cytosine bases, it being possible for these bases to be substituted especially by a halogen at the 5 position for cytosine and uracil.  
     
     
         7 . Method for the preparation of a compound of formula (I) in which B is cytosine according to one of  claims 1  to  6 , characterized in that a compound of formula (I) is prepared in which B is uracil according to the method of  claims 1  to  6  and the uridine derivative is converted to a cytidine derivative by converting uracil to cytosine.  
     
     
         8 . Stereoisomeric β-L-pentofuranonucleoside compounds corresponding to the following formula  
       
         
           
           
               
               
           
         
       
       in which 
 B has the meaning given in one of claims  1  and  6 , R 1  represents OH and,  
 either R 2  represents OH and R 3  represents H,  
 or R 2  represents H and R 3  represents OH.  
 
     
     
         9 . Compounds according to  claim 7 , characterized in that B represents uracil, 5-fluorouracil, hypoxanthine, 5-fluorocytosine, guanine or adenine.  
     
     
         10 . Stereoisomeric 2′,3′-dideoxy-β-L-pentofuranonucleoside compounds corresponding to the formula (I)  
       
         
           
           
               
               
           
         
       
       in which: 
 R 1  represents OH  
 R 2  and R 3  represent H and  
 B represents uracil, guanine, hypoxanthine, b fluorocytosine, fluorocytosine.  
 
     
     
         11 . Compound according to  claim 10 , which is chosen from β-L-ddU, β-L-5 fluoro-ddU, β-L-5-fluoro ddC.  
     
     
         12 . Use of the compounds according to one of  claims 8  to  11 , as a drug.  
     
     
         13 . Use of the compounds according to one of  claims 8  to  11 , as an antiviral drug.  
     
     
         14 . Use of the compounds according to one of  claims 8  to  11 , as an antiviral drug which is useful for the treatment of AIDS.  
     
     
         15 . Use of β-L-5-fluoro ddC according to  claim 14 , as antiviral agent.  
     
     
         16 . Use of β-L-5-fluoro ddC according to  claim 15 , as anti-HIV agent.