Purine derivatives having, in particular, antiproliferative properties, and their biological uses

Abstract

This invention provides 2-, 6, and 9-substituted purine derivatives, particularly 2(1-R hydroxymethylpropylamino)-6-benzylamino-9-isopropyl purine, having, in particular, antiproliferative properties, and suitable for use as pharmaceutical compositions and herbicidal compositions. Also provided are pharmaceutical compositions and herbicidal compositions comprising the 2-, 6, and 9-substituted purine derivatives, and methods of treatment using the 2-, 6, and 9-substituted purine derivatives.

What is claimed is:  
     
         1 . A compound of formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 2  is R—NH, wherein R is saturated or unsaturated alkyl with a straight or branched chain;  
 R 6  is R—NH wherein R is aryl;  
 R 9  is saturated or unsaturated alkyl with a straight or branched chain;  
 each optionally substituted by one or more hydroxy, halogen, amino or alkyl groups;  
 with the proviso that when R 2  is hydroxyethyl amino, R 6  is not benzylamino or 3-hydroxybenzylamino.  
 
     
     
         2 . The compound of  claim 1 , wherein the halogen group is selected from the group consisting of chlorine, bromine or fluorine; 
 the alkyl radical is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and heptyl radicals; and    the aryl radical is a benzyl group.    
     
     
         3 . The compound of  claim 1 , wherein R in R 2  is a saturated, branched chain alkyl group.  
     
     
         4 . The compound of  claim 3 , wherein the alkyl chain of said branched chain alkyl group is substituted by a hydroxy group.  
     
     
         5 . The compound of  claim 1 , wherein R in R 2  is a saturated, straight chain alkyl group.  
     
     
         6 . The compound of  claim 5 , wherein the alkyl chain of said straight chain alkyl group is substituted by a hydroxy group.  
     
     
         7 . A compound as in one of claims  3 - 6 , wherein R in R 2  is chloro-substituted phenyl.  
     
     
         8 . The compound of  claim 1 , wherein R 2  is chosen from radicals that are capable of binding in a cdk2/ATP complex to a region of the bonding pocket of ATP occupied by ribose.  
     
     
         9 . The compound of  claim 8 , wherein R 2  is selected from the group consisting of methylamino, ethylamino, n-heptylamino, aminoethylamino, aminopropylamino, dimethylaminoethylamino, hydroxyethylamino, hydroxypropylamino, hydroxyisobutylamino, hydroxypentylamino, hydroxymethylpropylamino, (R,S)-aminohexanol, (R,S)-aminopentanol, (R)-aminopropanol and (S)-aminopropanol.  
     
     
         10 . The compound of  claim 9 , wherein R 2  is a hydroxypropylamino group.  
     
     
         11 . The compound of  claim 1 , wherein R 6  is-benzylamino.  
     
     
         12 . The compound of  claim 1 , wherein R 9  is selected from the group consisting of methyl, isopropyl and hydroxyethyl radicals.  
     
     
         13 . A purine derivative selected from the group consisting of 2-chloro-6-(3-hydroxybenzylamino)-9-methyl purine, 2-(3-hydroxypropylamino)-6-benzylamino-9-isopropyl purine, 2-D,L-(2-hydroxypropylamino)-6-benzylamino-9-isopropyl purine, 2-(5-hydroxypentylamino)-6-benzylamino-9-isopropyl purine, 2-(1-D,L-hydroxymethylpropyl-amino)-6-benzylamino-9-isopropyl purine, 2-(aminoethylamino)-6-benzylamino-9-isopropyl purine, 2-bis (2-hydroxyethylamino)-6-benzylamino-9-isopropyl purine, 2-(2-hydroxypropyl-amino)-6-isopentenylamino-9-isopropyl purine, 2-(2-hydroxyethylamino)-6-cyclohexyl-methylamino-9-methyl purine, 2-chloro-6-isopentenylamino-9-isopropyl purine, 2-(2-hydroxyethylamino-6-(3-hydroxybenzylamino)-9-methyl purine, non-crystalline 6-benzylamino-2-[(2R)-2-hydroxymethyl-pyrrolidine-1-yl]-9-isopropyl-(9H)-purine, 2-[6-benzylamino-9-isopropyl-(9H)-purine-2-yl]-N-benzylamino ethanol, 2-(R,S)-[6-benzylanmino-9-isopropyl-(9H)-purine-2-yl]amino-hexanol, 2-(S)-[6-benzylamino-9-isopropyl-(9H)-purine-2-yl]-amino-2-phenylethanol, 2-(R)-[6-benzylamino-9-isopropyl-(9H)-purine-2-yl]-amino-2-phenylethanol, 2-(R)-[6-benzylamino-9-isopropyl-(9H)-purine-2-yl]-amino-3-phenylpropanol, 2-(R,S)-[6-benzylamino-9-isopropyl-(9H)-purine-2-yl]-amino-pentanol, 2-(R)-[6-benzylamino-9-isopropyl-(9H)-purine-2-yl]-amino-propanol, 2-(S)-[benzylamino-9-isopropyl-(9H)-purine-2-yl]-amino-propanol, 2-(R)-(−)-[6-(3-iodo)-benzylamino-9-isopropyl-(9H)-purine-2-yl]-N-methanol pyrrolidine, 2-(R)-(˜)-[6-benzylamino-9-cyclopentyl-(9H)-purine-2-yl]-N-methanol pyrrolidine, 2-(2-hydroxypropylamino)-6-benzylamino-9-isopropyl purine, 2(2-hydroxypropylamino)-6-cyclohexylamino-9-methyl purine, and 2-chloro-6-isopentenylamino-9-isopropylpurine, or an optical isomer, a racemic mixture, or a geometric isomer thereof.  
     
     
         14 . A pharmaceutical composition comprising a therapeutically effective amount of a purine derivative of  claim 13  and a pharmaceutical vehicle.  
     
     
         15 . A method of treating proliferative disorders in a patient, comprising administering to said patient the pharmaceutical composition of  claim 14 .  
     
     
         16 . A method of treating tumors in a patient, comprising administering to said patient the pharmaceutical composition of  claim 14 .  
     
     
         17 . The purine derivative according to  claim 13 , selected from the group consisting of 2-(3-hydroxypropylamino)-6-benzylamino-9-isopropyl purine, 2-DL-(2-hydroxypropylamino)-6-benzylamino-9-isopropyl purine, 2-(aminoethylamino)-6-benzylamino-9-isopropyl purine, 2-bis-(2-hydroxyethylamino)-6-benzylamino-9-isopropyl purine, 2-(2-hydroxypropylamino)-6-isopentenylamino-9-isopropyl purine, non-crystalline 6-benzylamino-2[(2R)-2-hydroxymethyl-pyrrolidin-1-yl]-9-isopropyl-(9H)-purine, 2-[6-benzylamino-9-isopropyl-(9H)-purin-2-yl]-N-benzylamino ethanol, 2-(R,S)-[6-benzylamino-9-isopropyl-(9H)-purin-2-yl]-amino-hexanol, 2-(S)-[6-benzylamino-9-isopropyl-(9H)-purine-2-yl]-amino-2-phenylethanol, 2-(R)-[6-benzylamino-9-isopropyl-(9H)-purine-2-yl]-amino-2-phenylethanol, 2-(R)-[6-benzylamino-9-isopropyl-(9H)-purine-2-yl]-amino-3-phenylpropanol, 2-(R,S)-[6-benzylamino-9-isopropyl-(9H)-purine-2-yl]-amino-pentanol, 2-(R)-[6-benzylamino-9-isopropyl-(9H)-purine-2-yl]-amino-propanol, 2-(S)-[benzylamino-9-isopropyl-(9H)-purine-2-yl[-amino-propanol, 2-(R)-(−)-[6-(3-iodo)-benzylamino-9-isopropyl-(9II)-purine-2-yl]-N-pyrrolidine methanol, 2-(R)-(−)-[6-benzylamino-9-cyclopentyl-(9H)-purin-2-yl]-N-pyrrolidine methanol, 2-(2-hydroxypropylamino)-6-benzylamino-9-isopropyl purine, 2(2-hydroxypropylamino)-6-cyclohexylamino-9-methyl purine, and 2-chloro-6-isopentenylamino-9-isopropylpurine or an optical isomer, a racemic mixture, or a geometric isomer thereof.  
     
     
         18 . A pharmaceutical composition comprising a therapeutically effective amount of a purine derivative of  claim 17  and a pharmaceutical vehicle.  
     
     
         19 . A method of treating proliferative disorders in a patient, comprising administering to said patient the pharmaceutical composition of  claim 18 .  
     
     
         20 . A method of treating tumors in a patient, comprising administering to said patient the pharmaceutical composition of  claim 18 .  
     
     
         21 . A method of treating proliferative disorders in a patient, comprising administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of the compound 2-(1-D,L-hydroxymethylpropylamino)-6-benzylamino-9-isopropylpurine and a pharmaceutical vehicle.  
     
     
         22 . A method of treating proliferative disorders in a patient, comprising administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of the compound 6-benzylamino-2-R-(1-ethyl-2-hydroxyethylamino)-9-isopropylpurine and a pharmaceutical vehicle.  
     
     
         23 . The method of  claim 21 , where said proliferative disorder is selected from the group consisting of cancer, psoriasis, parasitoses, Alzheimer's disease, and neuronal apoptosis.  
     
     
         24 . The method of  claim 22 , where said proliferative disorder is selected from the group consisting of cancer, psoriasis, parasitoses, Alzheimer's disease, and neuronal apoptosis.  
     
     
         25 . A method of treating tumors in a patient, comprising administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of the compound 2-(1-D,L-hydroxymethylpropylamino)-6-benzylamino-9-isopropylpurine and a pharmaceutical vehicle.  
     
     
         26 . A method of treating tumors in a patient, comprising administering to said patient a pharmaceutical composition comprising a therapeutically effective amount of the compound 6-benzylamino-2-R-(1-ethyl-2-hydroxyethylamino)-9-isopropylpurine and a pharmaceutical vehicle.  
     
     
         27 . The method of  claim 25 , wherein said pharmaceutical composition is administered orally or parenterally.  
     
     
         28 . The method of  claim 26 , wherein said pharmaceutical composition is administered orally or parenterally.