Green synthesis of imidazo pyrazole derivatives using polymer nanocomposite

Abstract

The present invention relates to novel fused imidazo pyrazole derivatives of formula (I), and formula (II), and methods for preparation thereof, in the presence of a chitosan-Al 2 O 3 nanocomposite film. The invention also relates to pharmaceutical compositions comprising compounds of the invention as active ingredients as well as the use of compounds of the invention for antimicrobial action.

1 . A compound of formula (I), 
       
         
           
           
               
               
           
         
         or a salt, solvate, tautomer or stereoisomer thereof, wherein: 
         R 1  is hydrogen, halogen, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl, 
         R 2  is hydrogen, halogen, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl, wherein R 2  does not have a pyrimidine or triazine ring directly bonded to the dihydropyrazole ring, 
         R 3  is hydrogen or an optionally substituted alkyl that has 1 to 3 carbons, and 
         R 4  is hydrogen, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl. 
       
     
     
         2 . The compound of  claim 1 , wherein R 1  is hydrogen, a 6-membered aryl, or a 5- or 6-membered heteroaryl, wherein the 6-membered aryl and the 5- or 6-membered heteroaryl are optionally substituted and optionally fused to a 5- or 6-membered carbocyclic group or a 5- or 6-membered heterocycle. 
     
     
         3 . The compound of  claim 1 , wherein R 2  is hydrogen, an optionally substituted (C 1 -C 7 )-alkyl, or an optionally substituted (C 3 -C 7 )-cycloalkyl. 
     
     
         4 . The compound of  claim 1 , wherein R 3  is hydrogen, methyl, ethyl or n-propyl, wherein the methyl, ethyl or n-propyl may be substituted by halogen. 
     
     
         5 . The compound of  claim 1 , wherein R 4  is hydrogen, an optionally substituted (C 1 -C 7 )-alkyl, an optionally substituted (C 3 -C 7 )-cycloalkyl, an optionally substituted 6-membered aryl, or an optionally substituted 5- or 6-membered heteroaryl. 
     
     
         6 . The compound of  claim 1 , wherein:
 R 1  is phenyl,   R 2  is methyl,   R 3  is hydrogen, and   R 4  is hydrogen.   
     
     
         7 . A compound of formula (II), 
       
         
           
           
               
               
           
         
         or a salt, solvate, tautomer or stereoisomer thereof, wherein: 
         R 1  is hydrogen, halogen, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl, 
         R 2  is hydrogen, halogen, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl, 
         R 3  is hydrogen or an optionally substituted alkyl that has 1 to 3 carbons, 
         X is S or NH, and 
         R 5  is an optionally substituted alkyl, an optionally substituted cycloalkyl, or an optionally substituted aryl. 
       
     
     
         8 . The compound of  claim 7 , wherein R 1  is hydrogen, a 6-membered aryl, or a 5- or 6-membered heteroaryl, wherein the 6-membered aryl and the 5- or 6-membered heteroaryl are optionally substituted and optionally fused to a 5- or 6-membered carbocyclic group or a 5- or 6-membered heterocycle. 
     
     
         9 . The compound of  claim 7 , wherein R 2  is hydrogen, an optionally substituted (C 1 -C 7 )-alkyl, or an optionally substituted (C 3 -C 7 )-cycloalkyl. 
     
     
         10 . The compound of  claim 7 , wherein R 3  is hydrogen, methyl, ethyl or n-propyl, wherein the methyl, ethyl or n-propyl may be substituted by halogen. 
     
     
         11 . The compound of  claim 7 , wherein:
 X is S, and   R 5  is an optionally substituted (C 1 -C 7 )-alkyl, an optionally substituted (C 3 -C 7 )-cycloalkyl, or benzyl, in which the benzyl is substituted by NO 2  or CF 3 .   
     
     
         12 . The compound of  claim 7 , wherein:
 X is NH, and   R 5  is CS-NR 6 R 7 , where   R 6  and R 7  are independently hydrogen, an optionally substituted (C 1 -C 7 )-alkyl, an optionally substituted (C 3 -C 7 )-cycloalkyl, a 6-membered aryl, or a 5- or 6-membered heteroaryl, in which the 6-membered aryl and the 5- or 6-membered heteroaryl are optionally substituted and optionally fused to a 5- or 6-membered carbocyclic group or a 5- or 6-membered heterocycle.   
     
     
         13 . The compound of  claim 7 , selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         14 . A method of preparing the compound of formula (I) of  claim 1 , comprising:
 reacting a compound of formula (III) with a compound of formula (IV) in the presence of a nanocomposite film comprising aluminum oxide dispersed in a chitosan matrix to form the compound of formula (I),   
       
         
           
           
               
               
           
         
       
     
     
         15 . The method of  claim 14 , further comprising forming the nanocomposite film by solution casting a mixture of chitosan and aluminum oxide nanoparticles. 
     
     
         16 . The method of  claim 15 , further comprising:
 dissolving chitosan in acetic acid to obtain a chitosan solution;   adjusting the pH of the chitosan solution to the range of 6-7;   adding a suspension of aluminum oxide nanoparticles in water portion-wise to the chitosan solution to form the mixture;   stirring the mixture;   casting the mixture onto a carrier substrate; and   drying the cast mixture to form the nanocomposite film.   
     
     
         17 . The method of  claim 16 , wherein the aluminum oxide nanoparticles have an average size of less than 50 nm. 
     
     
         18 . The method of  claim 14 , wherein the nanocomposite film is used as a heterogeneous base catalyst. 
     
     
         19 . The method of  claim 18 , further comprising:
 recycling the nanocomposite film; and   reusing the recycled nanocomposite film as the heterogeneous base catalyst to prepare the compound of formula (I).   
     
     
         20 . The method of  claim 14 , wherein R 1 , R 2 , R 3  and R 4  are phenyl, methyl, hydrogen and hydrogen, respectively, the method comprising:
 refluxing an equimolar quantity of pyrazole-5(4H)one and thiourea in ethanol in the presence of the nanocomposite film;   removing the nanocomposite film by filtration;   evaporating the ethanol so that a precipitant is formed; and   crystallizing the precipitant from ethanol to form the compound of formula (I).