Ribofuranosyl purine compounds, methods for preparing the same and use thereof

Abstract

The present invention relates to the compounds of the formulae (I) and (I-1) and the process for preparing the same, uses of the compounds for the treatment of diseases associated with platelet aggregation and in the manufacture of a medicament for the treatment of diseases associated with platelet aggregation, and relates to a pharmaceutical composition and a pharmaceutical formulation containing the compounds, wherein the definitions of R 1 , R 2 , R 3 and R 2a in the formulae are the same as those in the description.

1 . A compound represented by the formula (I-1) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  represents an unsubstituted or R 4 -substituted C 1 -C 8  hydrocarbyl, or an unsubstituted or R 5 -substituted 5- to 6-membered cyclic group; 
 R 2a  represents an unsubstituted or R 5 -substituted C 3 -C 8  saturated or unsaturated aliphatic hydrocarbyl, an unsubstituted or R 5 -substituted C 3 -C 8  alicyclic group, an unsubstituted or R 6 -substituted C 6 -C 10  aryl-C 2 -C 4  alkyl, an unsubstituted or R 6 -substituted 5- to 10-membered heterocyclyl-C 1 -C 4  alkyl, or an unsubstituted or R 6 -substituted 5- to 10-membered heteroaryl-C 1 -C 4  alkyl; 
 R 3  represents H or R 2a ; 
 R 4  represents halogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxyl, halogenated C 1 -C 4  alkyl, halogenated C 1 -C 4  alkoxyl, hydroxyl, hydroxyl C 1 -C 4  alkyl, carboxyl, nitro, cyano, C 1 -C 4  alkylthio, or C 1 -C 4  alkyl-CO—; 
 R 5  represents C 1 -C 4  alkyl, C 1 -C 4  alkoxyl, hydroxyl, hydroxyl C 1 -C 4  alkyl, carboxyl, nitro, cyano, C 1 -C 4  alkylthio or C 1 -C 4  alkyl-CO—; and 
 R 6  represents halogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxyl, hydroxyl, hydroxyl C 1 -C 4  alkyl, carboxyl, nitro, cyano, C 1 -C 4  alkylthio, or C 1 -C 4  alkyl-CO—; 
 provided that 
 when R 1  is —CH 3  and R 3  is H, R 2a  is not cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl, 3-methyl-2-pentenyl, 2-methyl-3-hydroxyl-1-propenyl, 3-methyl-4-hydroxyl-1-butenyl, furfurylmethylene, 3-methyl-1-butenyl, 3-methyl-2-butenyl, 3-methylbutyl, 3-methyl-4-hydroxylbutyl, 3-methyl-4-hydroxyl-2-butenyl or 3-methyl-4-hydroxyl-3-butenyl; or 
 when R 1  is propyl, R 2a  is not cyclopentyl, isopropyl, n-propyl or n-butyl. 
 
     
     
         2 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 1  represents an unsubstituted or R 4 -substituted C 1 -C 6  alkyl, wherein R 4  represents halogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxyl, halogenated C 1 -C 4  alkyl, halogenated C 1 -C 4  alkoxyl, hydroxyl, hydroxyl C 1 -C 4  alkyl, carboxyl, nitro, cyano, C 1 -C 4  alkylthio, or C 1 -C 4  alkyl-CO—. 
     
     
         3 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 2a  represents an unsubstituted or R 5 -substituted C 3 -C 6  alkyl, an unsubstituted or R 5 -substituted C 3 -C 6  cycloalkyl, an unsubstituted or R 6 -substituted 5- to 6-membered heteroaryl-C 1 -C 4  alkyl, an unsubstituted or R 6 -substituted phenyl-C 2 -C 4  alkyl, or an unsubstituted or R 6 -substituted 5- to 6-membered heterocyclyl-C 1 -C 4  alkyl, wherein R 5  is selected from the group consisting of C 1 -C 4  alkyl, C 1 -C 4  alkoxyl, hydroxyl, hydroxyl C 1 -C 4  alkyl, carboxyl, nitro, cyano, C 1 -C 4  alkylthio and C 1 -C 4  alkyl-CO—; and R 6  is selected from the group consisting of halogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxyl, hydroxyl, hydroxyl C 1 -C 4  alkyl, carboxyl, nitro, cyano, C 1 -C 4  alkylthio, and C 1 -C 4  alkyl-CO—. 
     
     
         4 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 1  represents C 1 -C 6  alkyl; R 2a  represents C 3 -C 6  alkyl, C 3 -C 6  cycloalkyl, an unsubstituted or R 6 -substituted phenyl-C 2 -C 4  alkyl, an unsubstituted or R 6 -substituted 5- to 6-membered heteroaryl-C 1 -C 4  alkyl, or an unsubstituted or R 6 -substituted 5- to 6-membered heterocyclyl-C 1 -C 4  alkyl, wherein R 6  is selected from the group consisting of halogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxyl, hydroxyl, hydroxyl C 1 -C 4  alkyl, carboxyl, nitro, cyano, C 1 -C 4  alkylthio and C 1 -C 4  alkyl-CO—. 
     
     
         5 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 1  represents C 1 -C 4  alkyl; R 2a  represents C 3 -C 6  alkyl, C 5 -C 6  cycloalkyl, unsubstituted or C 1 -C 4  alkyl-substituted or C 1 -C 4  alkoxyl-substituted phenyl-C 2 -C 4  alkyl, unsubstituted or C 1 -C 4  alkyl-substituted or C 1 -C 4  alkoxyl-substituted 5- to 6-membered heteroaryl-C 1 -C 4  alkyl, or unsubstituted or C 1 -C 4  alkyl-substituted or C 1 -C 4  alkoxyl-substituted 5- to 6-membered heterocyclyl-C 1 -C 4  alkyl. 
     
     
         6 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 1  represents methyl, ethyl, n-propyl, isopropyl or butyl; R 2a  represents n-hexyl, cyclohexyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, methoxylphenylethyl, 2-thienylethyl, furylmethyl, or tetrahydrofurylmethyl. 
     
     
         7 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 3  represents H or C 3 -C 6  alkyl. 
     
     
         8 . (canceled) 
     
     
         9 . A process for preparing the compound according to  claim 1 , 
       
         
           
           
               
               
           
         
       
       wherein R is acyl; R 1 , R 2  and R 3  are as defined in  claim 1 ;
 which comprises: using guanosine 1 as the starting material, firstly conducting the conventional esterification protection of three hydroxyl groups on the ribose ring of guanosine with an acid anhydride or an acyl halide, then halogenating the isomerized hydroxyl group at 6-position using the conventional halogenating reagent to obtain 2-amino-6-halogenated-9-(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosyl) purine 3, then under an anhydrous condition diazotizing the amino at 2-position of 3 with a conventional diazotization reagent, and then reacting with disulfide to obtain the corresponding 2-alkylthio-6-halogenated-9-(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosyl)purine 4, eventually conducting the nucleophilic substitution reaction with amine under the action of an alkaline, and removing the protecting group by the catalysis of alkali metal alkoxides to obtain the final product compound of the formula (I-1). 
 
     
     
         10 . A pharmaceutical composition, comprising the compound according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         11 . A pharmaceutical formulation, comprising the compound according to  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         12 - 16 . (canceled)