Chemical derivatives and their application as antitelomerase agent

Abstract

The present invention relates to cancer therapy and to novel anticancer agent having a mechanism of action which is quite specific. It also relates to novel chemical compounds as well as their therapeutic application in humans.

1 . Compounds which bind the G-quadruplex structure of telomers, characterized in that they correspond to the following general formula:  
       nitrogen-containing aromatic ring-NR3-distribution agent-NR′3-aromatic ring  in which 
 the nitrogen-containing aromatic ring represents: 
 a quinoline optionally substituted with at least one group N(Ra)(Rb) in which Ra and Rb, which are identical or different, represent hydrogen or a short-chain C1-C4 alkyl and/or alkoxy radical and/or  
 a quinoline possessing a nitrogen atom in quaternary form or  
 a benzamidine or  
 a pyridine  
 
 the aromatic ring represents 
 a quinoline optionally substituted with at least one group N(Ra)(Rb) in which Ra and Rb, which are identical or different, represent hydrogen or a short-chain C1-C4 alkyl and/or alkoxy radical and/or  
 a quinoline possessing a nitrogen atom in quaternary form or  
 a benzamidine or  
 a pyridine or  
 a phenyl ring optionally substituted at the meta or para position with a halogen group, C1-C4 alkoxy group, cyano group, carbonylamino group optionally substituted with one or more C1-C4 alkyl groups, guanyl groups, C1-C4 alkylthio groups, amino groups, C1-C4 alkylamino groups, C1-C4 dialkylamino groups for each alkyl group, nitro group, alkyleneamino group or alkenyleneamino group or  
 a mono- or bi- or tricyclic heterocyclic ring comprising 0 to 2 heteroatoms per ring provided that at least one heteroatom is present in at least one ring optionally substituted with one or more C1-C4 alkyl groups or with alkylene or alkenylene groups  
 
 R3 and R′3, which are identical or different, represent independently of one another hydrogen or a C1-C4 alkyl radical  
 the distribution agent represents: 
 a triazine group optionally substituted with an alkyl radical having 1 to 4 carbon atoms, a thio, oxy or amino radical which are themselves optionally substituted with one or more short-chain alkyl chains containing 1 to 4 carbon atoms or a halogen atom or  
 a carbonyl group or  
 a group C(═NH)—NH—C(═NH) or  
 an alkyldiyl group containing 3 to 7 carbon atoms or  
 a diazine group optionally substituted with the same groups as the triazine or one of its salts.  
 
   
     
     
         2 . Compounds according to  claim 1 , characterized in that the distribution agent is chosen from the triazine or diazine groups.  
     
     
         3 . Compounds according to  claim 2 , characterized in that the diazine groups are pyrimidines.  
     
     
         4 . Compounds according to  claim 1 , characterized in that they correspond to formula (I) below:  
       
         
           
           
               
               
           
         
         in which: 
 A represents 
 an amino group of formula NR1R2 in which R1 and R2, which are identical or different, represent hydrogen or a straight or branched alkyl group containing 1 to 4 carbon atoms or  
 
 a group OR1 or SR1 in which R1 has the same meaning as above or  
 an alkyl group containing 1 to 4 carbon atoms or a trifluoromethyl group or  
 a hydrogen atom or  
 a halogen atom chosen from fluorine, chlorine, bromine or iodine  
 
         R3 and R′3, which are identical or different, represent independently of one another hydrogen or a C1-C4 alkyl group  
         Ar 1  and Ar 2 , which are identical or different, represent  
         1. when Ar 1  and Ar 2  are identical: 
 a quinoline motif optionally substituted with at least one group N(Ra)(Rb) in which Ra and Rb, which are identical or different, represent hydrogen or a short-chain alkyl and/or alkoxy radical containing 1 to 4 carbon atoms or  
 a quinoline possessing a nitrogen atom in quaternary form or  
 a benzamidine or  
 a pyridine attached at the 4-position or fused with an aryl or heteroaryl group optionally substituted with a C1-C4 alkyl group  
 
         2. when Ar 1  and Ar 2  are different 
 Ar 1  and Ar 2  both represent one of the possibilities mentioned above for Ar 1  and Ar 2  or  
 Ar 1  represents one of the above possibilities and Ar 2  represents 
 a phenyl ring optionally substituted at the meta or para position with a halogen group, C1-C4 alkoxy group, cyano group, carbonylamino group optionally substituted with one or more C1-C4 alkyl groups, guanyl groups, C1-C4 alkylthio groups, amino groups, C1-C4 alkylamino groups, C1-C4 dialkylamino groups for each alkyl group, nitro group, alkyleneamino group or alkenyleneamino group  
 a mono- or bi- or tricyclic heterocyclic ring comprising 0 to 2 heteroatoms per ring provided that at least one heteroatom is present in at least one ring optionally substituted with one or more C1-C4 alkyl groups or with alkylene or alkenylene groups or one of its salts.  
 
 
       
     
     
         5 . Compounds according to  claim 3 , characterized in that Ar 1  and Ar 2  represent a group chosen from the following groups: 4-amino- or 4-methylamino- or 4-dimethylamino-quinolyl or -quinolinium in which the quinolinium ring is optionally substituted with a methyl group.  
     
     
         6 . Compounds according to  claim 1 , characterized in that the groups R1 and R2 represent the methylthio, amino, alkylamino or dialkylamino radical, in which radicals the alkyl groups possess 1 to 4 carbon atoms.  
     
     
         7 . Compounds according to  claim 2 , characterized in that A represents a methylthio group.  
     
     
         8 . Compounds of  claim 1 , characterized in that they have a telomerase-inhibiting activity.  
     
     
         9 . Compounds according to any one of the preceding claims, characterized in that they have an anticancer activity.  
     
     
         10 . Novel compounds corresponding to the following formula (I):  
       
         
           
           
               
               
           
         
         in which: 
 A represents 
 an amino group of formula NR1R2 in which R1 and R2, which are identical or different, represent a straight or branched alkyl group containing 1 to 4 carbon atoms or  
 a group OR1 or SR1 in which R1 represents hydrogen or has the same meaning as above or  
 an alkyl group containing 1 to 4 carbon atoms or a trifluoromethyl group or  
 a hydrogen atom or  
 a halogen atom chosen from fluorine, chlorine, bromine or iodine  
 
 R3 and R′3, which are identical or different, represent independently of one another a hydrogen atom or a C1-C4 alkyl group  
 Ar 1  and Ar 2 , which are identical or different, represent  
 
         1. when Ar 1  and Ar 2  are identical: 
 a quinoline motif optionally substituted with at least one group N(Ra)(Rb) in which Ra and Rb, which are identical or different, represent hydrogen or a short-chain alkyl and/or alkoxy radical containing 1 to 4 carbon atoms and/or  
 a quinoline possessing a nitrogen atom in quaternary form or  
 a benzamidine except in the case where A represents diethylamine, hydrogen or an amine group  
 a pyridine attached at the 4-position or fused with an aryl or heteroaryl group optionally substituted with a C1-C4 alkyl group  
 
         2. when Ar 1  and Ar 2  are different 
 Ar 1  and Ar 2  both represent one of the possibilities mentioned above for Ar 1  and Ar 2  or  
 Ar 1  represents one of the above possibilities and Ar 2  represents 
 a phenyl ring optionally substituted at the meta or para position with a halogen group, C1-C4 alkoxy group, cyano group, carbonylamino group optionally substituted with one or more C1-C4 alkyl groups, guanyl groups, C1-C4 alkylthio groups, amino groups, C1-C4 alkylamino groups, C1-C4 dialkylamino groups for each alkyl group, nitro group, alkyleneamino group or alkenyleneamino group  
 a mono- or bi- or tricyclic heterocyclic ring comprising 0 to 2 heteroatoms per ring provided that at least one heteroatom is present in at least one ring optionally substituted with one or more C1-C4 alkyl groups or with alkylene or alkenylene groups  
 or one of its salts excluding 2-amino-bis-4,6-[(4′-amino-6′-quinaldinyl)amino]triazine dihydrochloride and 2-amino-bis-4,6-(p-amidinoanilino)triazine dihydrochloride.  
 
 
       
     
     
         11 . Compounds according to  claim 10 , characterized in that when Ar 1  and Ar 2  are identical, Ar 1  and Ar 2  represent a group chosen from 4-amino- or 4-methylamino- or 4-dimethylamino-quinolyl or -quinolinium groups in which the quinolinium ring is optionally substituted with a methyl group.  
     
     
         12 . Compounds according to  claim 10 , characterized in that R1 and R2 represent hydrogen.  
     
     
         13 . Compounds according to  claim 10 , characterized in that A represents a methylthio group.  
     
     
         14 . Compounds according to  claim 10 , characterized in that when Arl and Ar 2  are different 
 1. Ar 1  represents: 
 a quinoline motif substituted with at least one group N(Ra)(Rb) in which Ra and Rb, which are identical or different, represent hydrogen or a short-chain alkyl or alkoxy radical containing 1 to 4 carbon atoms and/or  
 a quinoline possessing a nitrogen atom in quaternary form or  
 a benzamidine except in the case where A represents diethylamine, hydrogen or an amine group or  
 a pyridine attached at the 4-position or fused with an aryl or heteroaryl group  
   2. Ar 2  represents 
 a ring as defined above but different or  
 a phenyl ring optionally substituted at the meta or para position with a halogen, methoxy, cyano, carbonylamino, guanyl, methylthio, amino, methylamino, dimethylamino, morpholine, alkyleneamino or alkenyleneamino group  
 a quinoline, benzimidazole, indole, benzothiophene, benzofuran, benzothiazol, benzoxazol, carbazol, quinazoline or quinoxaline ring optionally substituted with one or more C1-C4 alkyl groups or with alkylene or alkenylene groups  
 or one of its salts excluding 2-amino-bis-4,6-[(4′-amino-6′-quinaldinyl)amino]triazine dihydro-chloride and 2-amino-bis-4,6-(p-amidinoanilino)-triazine.  
   
     
     
         15 . Compounds according to  claim 10  chosen from: 
 2-amino-bis-4,6-[(1′-methyl-4′-amino-6′-quinaldinio)amino]triazine dichloride  
 2-amino-bis-4,6-[(1′-ethyl-4′-amino-6′-quinaldinio)amino]triazine dichloride  
 2-dimethylamino-bis-4,6-[(1′-methyl4′-amino-6′-quinaldinio)amino]triazine dichloride  
 2-methylamino-bis-4,6-[(4′-amino-6′-quinaldinyl)amino]triazine trihydrochloride  
 2-amino-bis-4,6-[(1′-methyl-6′-quinolinio)amino]triazine dichloride  
 2-methylamino-bis-4,6-[(4′-methylamino-6′-quinaldinyl)amino]triazine dichloride trihydrochloride  
 2-amino-bis-4,6-[(9′-amino-10′-methyl-2′-acridinio)amino]triazine dichloride hydrochloride  
 2-methylthio-bis-4,6-[(1′-methyl-4′-amino-6′-quinaldinio)amino]triazine dichloride  
 2-chloro-bis-4,6-[(4′-dimethylamino-6′-quinaldinyl)amino]triazine dihydrochloride dihydrate  
 2-methylthio-bis-4,6-[(4′-dimethylamino-6′-quinaldinyl)amino]triazine hydrate  
 N,N′-(4-amino-6-quinaldinyl)urea dihydrochloride  
 N 1 ,N 5 -bis(7-chloro-l-methyl-4-quinolinio)pentane-1,5-diamine diiodide  
 bis-2,4-[(4′-amino-6′-quinaldinyl)amino]-pyrimidine trihydrochloride pentahydrate  
 1,5-(4′-amino-6′-quinaldinyl)biguanide trihydrochloride dihydrate.  
 
     
     
         16 . Compounds according to  claim 15  chosen from: 
 2-methylthio-bis-4,6-[(4′-dimethylamino-6′-quinaldinyl)amino]triazine hydrate  
 2-chloro-bis-4,6-[(4′-dimethylamino-6′-quinaldinyl)amino]triazine dihydrochloride dihydrate  
 6-[4-(4-amino-2-methylquinolin-6-ylamino)-6-methylsulphanyl-[13,5]triazin-2-ylamino]-2-methyl quinolin-4-ol  
 N6-[4-(4-dimethylamino-2-methylquinolin-6-ylamino)-6-methylsulphanyl-[1,3,5]triazin-2-yl]-2-methylquinoline-4,6-diamine  
 N6-[4-(4-amino-2-methylquinolin-6-ylamino)-6-methylsulphanyl-[1,3,5]triazin-2-yl]-2-methylquinoline-4,6-diamine  
 N6-[4-(4-methoxy-2-methylquinolin-6-ylamino)-6-methylsulphanyl-[1,3,5]triazin-2-yl]-4-methoxy-2-methylquinolin-6-amine.  
 
     
     
         17 . Use of the compounds of  claim 10  as pharmaceutical product for human use.  
     
     
         18 . Therapeutic combinations consisting of a compound according to  claim 1  and of another anticancer compound.  
     
     
         19 . Combinations according to  claim 18 , characterized in that the anticancer compound is chosen from alkylating agents, platinum derivatives, antibiotic agents, antimicrotubule agents, anthracyclines, group I and II topoisomerases, fluoropyrimidines, cytidine analogues, adenosine analogues, various enzymes and compounds such as L-asparaginase, hydroxyurea, trans-retinoic acid, suramine, irinotecan, topotecan, dexrazoxane, amifostine, herceptin as well as oestrogenic and androgenic hormones.  
     
     
         20 . Therapeutic combination consisting of a compound according to  claim 1  and of radiation.  
     
     
         21 . Combinations according to any one of  claims 18  to  20 , characterized in that each of the compounds or treatments is administered simultaneously, separately or sequentially.