Substituted nitrogen heterocyclic derivatives and pharmaceutical use thereof

Abstract

Various substituted nitrogen heterocyclic derivatives and their pharmaceutically acceptable salt derivatives are provided for use as medicaments, and particularly, as antimitotic, anti-viral, anti-cancer, anti-degenerative, immunosuppressive, and anti-microbial drugs or, vaccines. These heterocyclic derivatives can be used as an active agent in a pharmaceutical, as well as a diagnostic utility. To this end, several families of heterocyclic derivatives are provided including pyrrolopyrimidines, pyrazolopyrimidines, purines, and imidazopyridines. In particular, certain tri-substituted and tetra-substituted purines and pyrazolopyrimidines and their deaza analogues are provided for inhibiting cyclin-dependent kinase (“cdk”) proteins, viruses, and immunostimulation.

What is claimed is:  
     
         1 . Substituted nitrogen heterocyclic derivatives of the formula I— 
       
         
           
           
               
               
           
         
       
       wherein, 
 A is a divalent group  
                     
 Z is N;  
 R2 and R6 are independent of one another, represent H, halogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkyl alkyl, arylalkyl, heteroalkyl, heteroarylalkyl, heterocycloalkyl alkyl or R6′-X wherein  
 X is an —NH—, —N(C 1 -C 6 -alkyl)-, —O— or —S— moiety;  
 R6′ is H, alkyl, substituted alkyl, acyl, amido, sulpho, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heteroaryl, arylalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroarylalkyl, heteroalkyl, cycloalkyl alkyl and heterocycloalkyl alkyl;  
 R8 is halogen, hydroxyl, amino, carboxyl, cyano, nitro, amido, sulpho, sulphamino, carbamino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, arylalkyl, heteroalkyl, heteroarylalkyl, cycloalkyl alkyl, heterocycloalkyl alkyl or  
 R8′-X wherein  
 X is —NH—, —N(alkyl)—, —O— or —S— moiety, and  
 R8′ is according to any one of the substituents defined above for R2′ or R6′;  
 R9 is alkyl, substituted alkyl, acyl, carboxyl, amido, sulphamino, cycloalkyl, substituted cycloalkyl, cycloalkyl alkyl, heteroalkylcycloalkyl alkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heteroaryl, arylalkyl, heteroarylalkyl, heteroalkyl or —B-R9′ wherein  
 B is —CH 2 —, —(CH 2 ) 2 —, —CH(CH 3 )CH 2 —, —CH(CH 2 F)CH 2 —, —CH(CH 2 OH)CH 2 , or the groups of the following structure,  
                     
 wherein the left hand bond is linked to nitrogen of 5-membered ring of compounds of the formula I;  
 R4 and R5, that are independent of one another, represent hydrogen, hydroxyl, halogen, amino, acyloxy substituent having 1-5 carbon atoms, alkoxy substituent having 1-5 carbon atoms, alkylmercapto substituent having 1-5 carbon atoms, alkylamino substituent having 1-5 carbon atoms and dialkylamino in which each alkyl substituent has 1-5 carbon atoms;  
 R7 and R10, that are independent of one another, represent H or alkyl substituent having 1-10 carbon atoms;  
 or R9 is —(CH 2 ) n -R9′, wherein n=1-2 and the  
 R9′ is -X(CH 2 ) m Y wherein  
 X is —O—, —S—, —NH— or —N (alkyl)- substituent having 1-6 carbon atoms;  
 m=1-2;  
 Y is carboxyl, amido, sulpho, sulphamino, hydroxyl, carboxyl, mercapto, carbylmercapto, amino, alkylamino, carbamino —PO(OH) 2 , —PO(O-C 1 -C 6 -alkyl) 2 , —PO(NH-C 1 -C 6 -alkyl) 2 , —PO(O-C 1 -C 6 -alkyl) (NH-C 1 -C 6 -alkyl) —PO(OH) (O-C 1 -C 6 -alkyl), —PO(OH)(NH-C 1 -C 6 -alkyl) or —(CH 2 CHD)-R9′, wherein  
 D is alkyl, substituted alkyl, —PO(OH) 2 ,  
 —PO(OH) (O-C 1 -C 6 -alkyl), —PO(OH) (NH-C 1 -C 6 -alkyl)  
 wherein: 
 “halogen” is fluorine, bromine, chlorine, and iodine atoms;  
 “alkyl” is: 
 a) a branched or unbranched alkyl group having 1-6 carbon atoms,  
 b) a branched or unbranched alkenyl group having 2-6 carbon atoms, and  
 c) a branched or unbranched alkinyl group having 2-6 carbon atoms;  
 “substituted alkyl” is a branched or unbranched alkyl, alkenyl or alkinyl group having 1-6 carbon atoms and having substituted by one or more substituents selected from the group consisting of hydroxyl, mercapto, carbylmercapto, halogen, carbyloxy, amino, amido, carboxyl, cycloalkyl, sulpho or acyl;  
 “carbyloxy” is the group —OR a , where R a  is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl or substituted heterocycloalkyl whereas these generic groups have meanings being identical with definitions of the corresponding groups as defined in this legend;  
 
 
 “carbylmercapto” is the group -SR b  where R b  is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl or substituted heterocycloalkyl whereas these general groups have meanings being identical with definitions of the corresponding groups as defined in this legend;  
 “sulpho” is the group —SO 3 R c  where R c  is: 
 a) hydrogen,  
 b) a branched or unbranched alkyl group having 1-6 carbon atoms,  
 c) a branched or unbranched alkenyl group having 2-6 carbon atoms,  
 d) a branched or unbranched alkinyl group having 2-6 carbon atoms, and  
 e) a branched or unbranched alkyl, alkenyl or alkinyl group having 1-6 carbon atoms and being substituted by one or more substituents selected from the group consisting of hydroxyl, mercapto, carbylmercapto, halogen, carbyloxy, amino, amido, carboxyl, cycloalkyl, sulpho or acyl, whereas these generic groups have meanings being identical with the definitions of the corresponding groups as defined in this legend;  
 
 “sulphamino” is the group —NHSO 3 R d  wherein R d  is: 
 a) hydrogen,  
 b) a branched or unbranched alkyl group having 1-6 carbon atoms,  
 c) a branched or unbranched alkenyl group having 2-6 carbon atoms,  
 d) a branched or unbranched alkinyl group having 2-6 carbon atoms, and  
 e) a branched or unbranched alkyl, alkenyl or alkinyl group having 1-6 carbon atoms and being substituted by one or more substituents selected from the group consisting of hydroxyl, mercapto, carbylmercapto, halogen, carbyloxy, amino, amido, carboxyl, cycloalkyl, sulpho or acyl, whereas these generic substituents have meanings being identical with definitions of the corresponding groups as defined in this legend;  
 
 “acyl” is the group —C(O)R e  where R e  is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl whereas these generic groups have meanings being identical with definitions of the corresponding groups as defined in this legend;  
 “aryloxy” is the group —OAr, where Ar is an aryl, substituted aryl, heteroaryl or substituted heteroaryl whereas these generic groups have meanings being identical with definitions of the corresponding groups as defined in this legend;  
 “alkylamino” is the group —NR f R g  where R f  and R g , that are independent of one another, represent hydrogen, alkyl, substituted alkyl, provided that R f  and R g  are not both hydrogens;  
 “amido” is the group —C(O)NR h R i ′, where R h  and R i ′ may independently be hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl whereas these generic groups have meanings being identical with definitions of the corresponding groups as defined in this legend;  
 “carboxyl” is the group —C(O)OR j  where R j  is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;  
 “carbamino” is the group —NHCOR k  where R k  may be hydrogen, alkyl, substituted alkyl, heterocycle, aryl, substituted aryl, heteroaryl and substituted heteroaryl whereas these generic groups have meanings being identical with definitions of the corresponding groups as defined in this legend;  
 “aryl” is an aromatic carbocyclic group having from 6 to 18 carbon atoms and being composed of at least one aromatic or multiple condensed rings in which at least one of which being aromatic;  
 “substituted aryl” is an aromatic carbocyclic group having from 6 to 18 carbon atoms and being composed of at least one aromatic ring or of multiple condensed rings at least one of which being aromatic; The ring(s) are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, hydroxyl, carbylmercapto, alkylamino, carbyloxy, amino, amido, carboxyl, nitro, mercapto or sulpho;  
 “heterocycle” is a heterocyclic group having from 4 to 9 carbon atoms and at least one heteroatom selected from the group consisting of N, O or S;  
 “heteroaryl” is a heterocyclic group having from 4 to 9 carbon atoms and at least one heteroatom selected from the group consisting of N, O or S with at least one ring of this group being aromatic;  
 “substituted heteroaryl” is a heterocyclic group having from 4 to 9 carbon atoms and at least one heteroatom selected from the group consisting of N, O or S with at least one ring of this group being aromatic and this group being substituted with one or more substituents selected from the group consisting of halogen, alkyl, carbyloxy, carbylmercapto, alkylamino, amido, carboxyl, hydroxyl, nitro, mercapto or sulpho;  
 “arylalkyl” is the group —R 1 —Ar wherein R 1  is: 
 a) a branched or unbranched alkyl group having 1-6 carbon atoms,  
 b) a branched or unbranched alkenyl group having 2-6 carbon atoms,  
 c) a branched or unbranched alkinyl group having 2-6 carbon atoms;  
 
 “Ar” is an aromatic carbocyclic group having from 6-18 carbon atoms and being composed of at least one aromatic ring or of multiple condensed rings at least one of which being aromatic and the group being optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, hydroxyl, carbylmercapto, alkylamino, carbyloxy, amino, amido, carboxyl, nitro, mercapto or sulpho;  
 “heteroalkyl” is the group -R m -L wherein R m  is: 
 a) a branched or unbranched alkyl group having 1-6 carbon atoms,  
 b) a branched or unbranched alkenyl group having 2-6 carbon atoms,  
 c) a branched or unbranched alkinyl group having 2-6 carbon atoms,  
 d) a branched or unbranched alkyl, alkenyl or alkinyl group having 1-6 carbon atoms and being substituted by one or more substituents selected from the group consisting of hydroxyl, mercapto, carbylmercapto, halogen, carbyloxy, amino, amido, carboxyl, cycloalkyl, sulpho or acyl; and  
 
 L is a heterocyclic group having from 4 to 9 carbon atoms and at least one heteroatom selected from the group consisting of N, O or S and the group being unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, alkylmercapto, alkylamino, amido, carboxyl, hydroxy, nitro, mercapto or sulpho;  
 “heteroarylalkyl” is the group -R n -G wherein R n  is 
 a) a branched or unbranched alkyl group having 1-6 carbon atoms,  
 b) a branched or unbranched alkenyl group having 2-6 carbon atoms,  
 c) a branched or unbranched alkinyl group having 2-6 carbon atoms,  
 d) a branched or unbranched alkyl, alkenyl or alkinyl group having 1-6 carbon atoms and being substituted by one or more substituents selected from the group consisting of hydroxyl, mercapto, carbylmercapto, halogen, carbyloxy, amino, amido, carboxyl, cycloalkyl, sulpho or acyl; and  
 
 G is a heterocyclic group having from 4 to 9 carbon atoms and at least one heteroatom selected from the group consisting of N, O or S with at least one ring of which being aromatic and the group being optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, carbyloxy, carbylmercapto, alkylamino, amido, carboxyl, hydroxyl, nitro, mercapto or sulpho;  
 “cycloalkyl” is a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms;  
 “substituted cycloalkyl” is a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms and being substituted by one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulpho;  
 “heterocycloalkyl” is a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms which at least one ring carbon atom of its cyclic structure being replaced with a heteroatom selected from the group consisting of N, O, S or P;  
 “substituted heterocycloalkyl” is a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms which at least one ring carbon atom of its cyclic structure being replaced with a heteroatom selected from the group consisting of N, O, S or P and the group is containing one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulpho;  
 “cycloalkyl alkyl” is the group -R o -J where R o  is: 
 a) a branched or unbranched alkyl group having 1-6 carbon atoms,  
 b) a branched or unbranched alkenyl group having 2-6 carbon atoms,  
 c) a branched or unbranched alkinyl group having 2-6 carbon atoms,  
 d) a branched or unbranched alkyl, alkenyl or alkinyl group having 1-6 carbon atoms and being substituted by one or more substituents selected from the group consisting of hydroxyl, mercapto, carbylmercapto, halogen, carbyloxy, amino, amido, carboxyl, cycloalkyl, sulpho or acyl, whereas these generic substituent group have meanings being identical with definitions of the corresponding groups as defined in this legend; and  
 
 J is: 
 a) a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms; and  
 b) a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms which contains one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulpho;  
 
 “heterocycloalkylalkyl” is the group -R p V where R p  is: 
 a) a branched or unbranched alkyl group having 1-6 carbon atoms,  
 b) a branched or unbranched alkenyl group having 2-6 carbon atoms,  
 c) a branched or unbranched alkinyl group having 2-6 carbon atoms, and  
 d) a branched or unbranched alkyl, alkenyl or alkinyl group having 1-6 carbon atoms and being substituted by one or more substituents selected from the group consisting of hydroxyl, mercapto, carbylmercapto, halogen, carbyloxy, amino, amido, carboxyl, cycloalkyl, sulpho or acyl; and  
 
 V is: 
 a) a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms with at least one being replaced with a heteroatom selected from the group consisting of N, O, S or P; and  
 b) a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms with at least one being replaced with a heteroatom selected from the group consisting of N, O, S or P and the group contains one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulpho.  
 
 
     
     
         2 . Substituted nitrogen heterocyclic derivatives of the formula I according to  claim 1 , wherein R6═H.  
     
     
         3 . Substituted nitrogen heterocyclic derivatives of the formula I according to  claim 1 , wherein R2═H and R6, R8 and R9 are as defined in  claim 1 .  
     
     
         4 . Substituted nitrogen heterocyclic derivatives according to  claim 1 , of the formula Ib,  
       
         
           
           
               
               
           
         
       
       wherein R2, R6, R8 and R9 are as defined in  claim 1 .  
     
     
         5 . Substituted nitrogen heterocyclic derivatives of the formula Ib according to  claim 4 , wherein R6═H and R2, R8 and R9 are defined as in  claim 1 .  
     
     
         6 . Substituted nitrogen heterocyclic derivatives of the formula Ib according to  claim 4 , wherein R2═H and R6, R8 and R9 are as defined in  claim 1 .  
     
     
         7 . Substituted nitrogen heterocyclic derivatives of the formula I according to  claim 1 , selected from the group consisting of 
 a) 2-(l-hydroxymethylpropylamino)-6-benzylamino-8-Q-9-isopropylpurine;    b) 2-(2-aminopropylamino)-6-benzylamino-8-Q-9-isopropylpurine;    c) 2-(2-hydroxypropylamino)-6-benzylamino-8-Q-9-isopropylpurine;    d) 2-diethylamino-6-(4-methoxybenzylamino)-8-Q-9-isopropylpurine;    e) 2-(2-hydroxypropylamino)-6-(3-chloro-4-carboxyanilino)-8-Q-9-isopropylpurine;    f) 2-(R)-(2-hydroxypyrrolidin-1-yl)-6-benzylamino-8-Q-9-isopropylpurine;    g) 2-(R)-(l-isopropyl-2-hydroxyethylamino)-6(3-chloro-4-carboxyanilino)-8-Q-9-isopropylpurine;    h) 2-(R)-(1-isopropyl-2-hydroxyethylamino)-6-benzylamino-8-Q-9-isopropylpurine;    i) 2-(R)-(1-isopropyl-2-hydroxyethylamino)-6-(3-chloroanilino)-8-Q-9-isopropylpurine;    j) 2-alkylamino-6-dimethylamino-8-Q -9-(R)-(2-phosphonomethoxypropyl)purine;    k) 2-alkylamino-6-diethylamino-8-Q-9(R)-(2-phosphonomethoxypropyl)purine;    l) 2-alkylamino-6 -butylamino-8-Q-9-(R)-(2-phosphonomethoxypropyl) purine;    m) 2-alkylamino-6-(2-butylamino)-8-Q-9-(R)-(2-phosphonomethoxypropyl)purine;    n) 2-alkylamino6-cyclopropylamino-8-Q-9-(R)-(2-phosphonomethoxypropyl)purine;    o) 2-amino-6-cyclohexylamino-8-Q-9-(R)-(2-phosphonomethoxypropyl)purine;    p) 2-alkylamino-6-(pyrrolidin-1-yl)-8-Q-9-(R)-(2-phosphonomethoxypropyl)purine;    q) 2-alkylamino-6-(morpholin-1-yl)-8-Q-9-(R)-(2-phosphonomethoxypropyl)purine;    wherein Q is chloro, hydroxy, bromo, fluoro, amino, amido, carboxy, cyano, methylamino, thio, methylthio, ω-hydroxyalkylamino, ω-hydroxyalkyloxy, ω-carboxyalkylamino, ω-aminoalkylamino, ω-fosfonoalkylamino, ω-fosfonoalkyloxy, or propinyl.    
     
     
         8 . Substituted nitrogen heterocyclic derivatives of the formula I according to  claim 1 , selected from the group consisting of: 
 2-(2-hydroxypropylamino)-6-(3-chloroanilino)-8-S-9-isopropylpurine;    wherein S is chloro, hydroxy, bromo, amino, C 1 -C 6  alkyl, methyl, ethyl, propyl, isopropyl, vinyl, allyl, propargyl.    
     
     
         9 . A method for preparing substituted nitrogen heterocyclic derivatives of formula I according to  claim 1 , wherein R2, R6, R8 and R9 are as defined in  claim 1 , A is a group of formula  
       
         
           
           
               
               
           
         
       
       and Z is N, characterized in that a trisubstituted derivative of formula XI,  
       
         
           
           
               
               
           
         
       
       wherein R2, R6 and R9 are as defined in  claim 1 , is brominated by using a brominating system selected from a group consisting of bromine/acetic acid, bromine/chloroform, bromine/acetate buffer, bromine/water, N-bromosuccinimide/dimethylformamide and bromoacetamide/dimethylformamide to obtain a derivative of formula XIa,  
       
         
           
           
               
               
           
         
       
       wherein R2, R6 and R9 are as defined in  claim 1 , and a bromine atom in position 8 of the derivative of formula XIa is then optionally subjected to a substitution in order to replace said bromine atom by another substituent R8 as defined in  claim 1 .  
     
     
         10 . A method for preparing substituted nitrogen heterocyclic derivatives of the formula I according to  claim 1 , wherein R2, R6, R8 and R9 are as defined in  claim 1 , A is a group of formula  
       
         
           
           
               
               
           
         
       
       and Z is N, characterized in that a trisubstituted derivative of formula XIb,  
       
         
           
           
               
               
           
         
       
       wherein R6 and R9 are as defined in  claim 1 , is brominated by using a brominating system selected from a group consisting of bromine/acetic acid, bromine/chloroform, bromine/acetate buffer, bromine/water, N-bromosuccinimide/dimethylformamide and bromoacetamide/dimethylformamide to obtain a derivative of formula XIc,  
       
         
           
           
               
               
           
         
       
       wherein R6 and R9 are as defined in  claim 1 , and a chlorine atom in position 2 and a bromine atom in position 8 of the derivative of formula XIc are optionally, either progressively or simultaneously, subjected to a nucleophilic substitution in order to replace said chlorine and bromine atoms by other substituents R2 and R8 as defined in  claim 1 .  
     
     
         11 . A method for preparing substituted nitrogen heterocyclic derivatives of the formula I according to  claim 1 , wherein R2, R6 and R8 are as defined in  claim 1 , R9 is alkyl as defined in  claim 1 , A is a group of formula  
       
         
           
           
               
               
           
         
       
       and Z is N, characterized in that, a trisubstituted derivative of formula XIIa,  
       
         
           
           
               
               
           
         
       
       wherein R6 is as defined in  claim 1 ,  
       and said derivative of formula XIIa is alkylated in position 9 by using an alkylating agent in a system selected from a group consisting of K 2 CO 3 / dimethylformamide,  
       Cs 2 CO 3 /dimethylformamide, t-BuOK/dimethylformamide, t-BuOK/dimethylsulphoxide and NaH/dimethylformamide or under conditions of Mitsunobu reaction to obtain a derivative of formula XIIb  
       
         
           
           
               
               
           
         
       
       wherein R6 and alkyl are as defined in  claim 1 , and chlorine atoms in positions 2 and 8 of the derivative of formula XIIb are optionally, either progressively or simultaneously, subjected to a substitution in order to replace said chlorine atoms by other substituents R2 and R8, as defined in  claim 1 .  
     
     
         12 . A method for preparing substituted nitrogen heterocyclic derivatives of the formula I according to  claim 1 , wherein R2, R6 and R8 are as defined in  claim 1 , R9 is alkyl as defined in  claim 1 , A is a group of formula  
       
         
           
           
               
               
           
         
       
       and Z is N, characterized in that a trisubstituted derivative of formula XIIa,  
       
         
           
           
               
               
           
         
       
       wherein R6 is as defined in  claim 1 , is protected by reacting with 2-dihydropyrane/H +  to obtain a derivative of formula XIIc,  
       
         
           
           
               
               
           
         
       
       wherein R6 is as defined in  claim 1 , and the group R6 and/or a chlorine atom in position 2 and/or a chlorine atom in position 8 are optionally converted to other substituents R2, R6 and R8, as defined in  claim 1 , and in such optionally modified derivative of formula XIIc, the 2-tetrahydropyranyl group is split off to obtain a corresponding derivative of formula XIIc wherein R9 is hydrogen, and so obtained derivative of formula XIIc is then alkylated in position 9 by using an alkylating agent in a system selected from a group consisting of K 2 CO 3 /dimethylformamide, Cs 2 CO 3 /dimethylformamide, t-BuOK/dimethylformamide, t-BuOK/dimethylsulphoxide and NaH/dimethylformamide or under conditions of Mitsunobu reaction to obtain a tetrasubstituted derivative of formula XIIc, wherein R2,R6,R8 and R9 are as defined in  claim 1 .  
     
     
         13 . A method for preparing substituted nitrogen heterocyclic derivatives of the formula I according to  claim 1 , wherein R2, R6 and R8 are as defined in  claim 1 , R9 is alkyl as defined in  claim 1 , A is a group  
       
         
           
           
               
               
           
         
       
       and Z is N, characterized in that, 2,6,8-trichloropurine is subjected to a nucleophilic substitution in position 6 in order to replace a chlorine atom in position 6 by another substituent R6 as defined in  claim 1  to obtain a derivative of formula XIIa,  
       
         
           
           
               
               
           
         
       
       wherein R6 is as defined in  claim 1 ,  
       and said derivative of formula XIIa is then alkylated in position 9 by using an alkylating agent in a system selected from a group consisting of K 2 CO 3 /dimethylformamide, Cs 2 CO 3 /dimethylformamide, t-BuOK/dimethylformamide, t-BuOK/dimethylsulphoxide and NaH/dimethylformamide or under conditions of Mitsunobu reaction to obtain a derivative of formula XIIb,  
       
         
           
           
               
               
           
         
       
       wherein R6 and alkyl are as defined in  claim 1 , and chlorine atoms in positions 2 and 8 of the derivative of formula XIIb are optionally, either progressively or simultaneously, subjected to a nucleophilic substitution in order to replace said chlorine atoms by other substituents R2 and R8 as defined in  claim 1 .  
     
     
         14 . A method for preparing substituted nitrogen heterocyclic derivatives of the formula I according to  claim 1 , wherein R2 is hydrogen, R6 and R8 are as defined in  claim 1 , R9 is alkyl as defined in  claim 1 , A is a group of formula  
       
         
           
           
               
               
           
         
       
       and Z is N, characterized in that 6,8-dichloropurine is subjected to a nucleophilic substitution in position 6 in order to replace a chlorine atom in position 6 by another substituent R6 to obtain a derivative of formula XVI,  
       
         
           
           
               
               
           
         
       
       wherein R6 is as defined in  claim 1 ,  
       and said derivative of formula XVI is alkylated in position 9 by using an alkylating agent in a system selected from a group consisting of K 2 CO 3 /dimethylformamide,  
       Cs 2 CO 3 /dimethylformamide, t-BuOK/dimethylformamide, t-BuOK/dimethylsulphoxide and NaH/dimethylformamide or under conditions of Mitsunobu reaction to obtain a derivative of formula XVIa,  
       
         
           
           
               
               
           
         
       
       wherein R6 and alkyl are as defined in  claim 1 , and a chlorine atom in position 8 of the derivative of formula XVIa is optionally subjected to a substitution in order to replace said chlorine atom by another substituent R8 as defined in  claim 1 .  
     
     
         15 . A method for preparing substituted nitrogen heterocyclic derivatives of the formula I according to  claim 1 , wherein R2, R6 and R8 are as defined in  claim 1 , R9 is alkyl as defined in  claim 1 , A is a group of formula  
       
         
           
           
               
               
           
         
       
       and Z is N, characterized in that 2,6-dichloropurine is subjected to a nucleophilic substitution in position 6 in order to replace a chlorine atom in position 6 by another substituent R6, to obtain a derivative of formula XVII,  
       
         
           
           
               
               
           
         
       
       wherein R6 is as defined in  claim 1 ,  
       and said derivative of formula XVII is alkylated in position 9 by using either methyl acrylate or acrylonitrile or oxirane to obtain a derivative of formula XVIIa  
       
         
           
           
               
               
           
         
       
       wherein R6 and alkyl are as defined in  claim 1 , and said derivative of formula XVIIa is then brominated in position 8 by using a brominating system selected from a group consisting of bromine/acetic acid, bromine/chloroform, bromine/acetate buffer, bromine/water, N-bromosuccinimide/dimethylformamide and bromoacetamide/dimethylformamide to obtain a derivative of formula XVIIb,  
       
         
           
           
               
               
           
         
       
       wherein R6 and alkyl are as defined in  claim 1;   
       and said derivative of formula XVIIb is then optionally, either progressively or simultaneously, subjected to a nucleophilic substitution in positions 2 and 8 in order to replace a chlorine atom in position 2 and a bromine atom in position 8 by other substituents R2 and R8 as defined in  claim 1 .  
     
     
         16 . A method for preparing substituted nitrogen heterocyclic derivatives of the formula I according to  claim 1 , wherein R6 is a halogen or hydrogen, R2, R8 and R9 are as defined in  claim 1 , A is a group of formula  
       
         
           
           
               
               
           
         
       
       and Z is N, characterized in that a derivative of formula XVIII,  
       
         
           
           
               
               
           
         
       
       wherein R2, R8 and R9 are defined in  claim 1 , is halogenated via diazotation by using amylnitrite/CH 2 Br 2  or amylnitratite/CHI 3 , and so an obtained derivative where R6 is halogen is optionally hydrogenolyzed by using H 2 /Pd catalyst to obtain a corresponding derivative where R6 is hydrogen.