Chemical derivatives and their application as antitelomerase agent

Abstract

The present invention relates to cancer therapy and to novel anticancer agents 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  A compound corresponding to the following general formula: 
       nitrogen-containing aromatic ring —(NR 3 )p—(CO)n-distribution agent —(CO)m—(NR′ 3 )q—aromatic or non-aromatic ring wherein    n, m, p and q are identical or different and are integers 0 or 1; and    wherein 
 the nitrogen-containing aromatic ring is: 
 a quinoline optionally substituted with at least 
 one group N(Ra)(Rb) in which Ra and Rb, are identical or different, and are independently of each other hydrogen or a C1-C4 alkyl; or  
 one C1-C4 alkyl or alkoxy;  
 
 a quinoline possessing a nitrogen atom in quaternary form; or  
 a pyridine;  
 
 the aromatic or non-aromatic ring is: 
 a quinoline optionally substituted with at least 
 one group N(Ra)(Rb) in which Ra and Rb, are identical or different, and are independently hydrogen or a C1-C4 alkyl; or  
 one C1-C4 alkyl or alkoxy;  
 
 a quinoline possessing a nitrogen atom in quaternary form;  
 a pyridine;  
 a phenyl optionally substituted with halogen, C1-C4 alkoxy, cyano, carbonylamino optionally substituted with one or more C1-C4 alkyl, guanyl, C1-C4 alkylthio, amino, C1-C4 alkylamino, C1-C4 dialkylamino, nitro, C1-C4 alkyleneamino or C2-C4 alkenyleneamino; or  
 a mono-, bi- or tricyclic aromatic or non-aromatic heterocyclic nucleus containing 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, C1-C4 alkylene or C2-C4 alkenylene;  
 
 R 3  and R′ 3 , which are identical or different, represent independently of each other hydrogen or C1-C4 alkyl;  
 the distribution agent is: 
 —NH-phenyl-NH—, —NH-phenyl-CH2-NH—, —NH—CH2-phenyl-CH2-NH—, —NH—CH2-phenyl-NH—, —CH2-phenyl-CH2-, —CH2-phenyl, -phenyl-CH2-, —CH2- pyridinyl- or —CH═CH—; and wherein —NH-phenyl-NH—, —NH-phenyl-CH2-NH—, —NH—CH2-phenyl-CH2-NH—, —NH—CH2-phenyl-NH—, —CH2-phenyl-CH2-, —CH2-phenyl, -phenyl-CH2-, —CH2-pyridinyl-, and —CH═CH— are optionally substituted with one or more radicals chosen from halogen, C1-C4 alkyl, and thio, oxy or amino which are themselves optionally substituted with one or more C1-C4 alkyl;  
 or an isomer, an enantiomer, a diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.  
 
   
   
   
       2  The compound according to  claim 1  which binds the G-quadruplex structure of telomeres.  
   
   
       3  The compound according to  claim 1  wherein the distribution agent is chosen from -NH-phenyl-NH—, —NH-phenyl-CH2-NH—, —CH2-phenyl-CH2-, —CH2-pyridinyl- and —CH═CH—.  
   
   
       4  The compound according to  claim 1  wherein the distribution agent is chosen from —NH-1,3-phenyl-NH—, —NH-1,4-phenyl-NH—, —NH-1,4-phenyl-CH2-NH—, —CH2-1,4-phenyl-CH2-, —CH2-2,5-pyridinyl and —CH═CH—.  
   
   
       5  The compound according to  claim 1  wherein the distribution agent is —CH═CH— or -CH2-pyridinyl.  
   
   
       6  The compound according to  claim 1  wherein p and q are 1.  
   
   
       7  The compound according to  claim 1  having the following formula (IA):  
     
       
         
         
             
             
         
       
     
     wherein 
 n, m, p and q are identical or different and are integers 0 or 1; 
 A represents: 
 —NH-phenyl-NH—, —NH-phenyl-CH2-NH—, —NH—CH2-phenyl-CH2-NH—, —NH—CH2-phenyl-NH—, —CH2-phenyl-CH2-, —CH2-phenyl, -phenyl-CH2-, —CH2-pyridinyl- or —CH═CH—;  
 and wherein —NH-phenyl-NH—, —NH-phenyl-CH2-NH—, —NH—CH2-phenyl-CH2-NH—, —NH—CH2-phenyl-NH—, —CH2-phenyl-CH2-, —CH2-phenyl, -phenyl-CH2-, —CH2-pyridinyl- or —CH═CH—; are optionally substituted with one or more radicals chosen from halogen, C1-C4 alkyl, and thio, oxy or amino which are themselves optionally substituted with one or more C1-C4 alkyl;  
 
 R 3  and R′ 3 , which are identical or different, represent independently of each other hydrogen or C1-C4 alkyl;  
 Ar 1  and Ar 2 , which are identical or different, and are independently of each other selected from: 
 a quinoline optionally substituted with at least 
 a group N(Ra)(Rb) in which Ra and Rb are identical or different, and are independently of each other hydrogen or a C1-C4 alkyl; or  
 a C1-C4 alkyl or alkoxy;  
 
 a quinoline possessing a nitrogen atom in quaternary form;  
 a pyridine optionally attached at the 4-position or fused with an aryl or heteroaryl group, optionally substituted with a C1-C4 alkyl;  
 a phenyl optionally substituted with halogen, C1-C4 alkoxy, cyano, carbonylamino optionally substituted with one or more C1-C4 alkyl, guanyl, C1-C4 alkylthio, amino, C1-C4 alkylamino, C1-C4 dialkylamino, nitro, C1-C4 alkyleneamino or C2-C4 alkenyleneamino; or  
 a mono- or bi- or tricyclic aromatic or non-aromatic heterocyclic ring containing 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, C1-C4 alkylene or C2-C4 alkenylene;  
 or an isomer, an enantiomer, a diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.  
 
 
 
   
   
       8  The compound according to  claim 7  wherein A is chosen from —NH-phenyl-NH—, —NH-phenyl-CH2-NH—, —CH2-phenyl-CH2-, —CH2-pyridinyl- and —CH═CH—.  
   
   
       9  The compound according to  claim 7  wherein A is chosen from —NH-1,3-phenyl-NH—, —NH-1,4-phenyl-NH—, —NH-1,4-phenyl-CH2-NH— and —CH2-1,4-phenyl-CH2-.  
   
   
       10  The compound according to  claim 1  having the following formula (I):  
     
       
         
         
             
             
         
       
     
     wherein 
 n and m are identical or different and are integers 0 or 1; 
 A represents: 
 —NH-phenyl-NH—, —NH-phenyl-CH2-NH— or —CH2-phenyl-CH2-, —CH2-pyridinyl-, CH2-, —CH2-pyridinyl-, and —CH═CH—; and wherein —NH-phenyl-NH—, —NH-phenyl-CH2-NH—, —CH2-phenyl-CH2- and —CH2-pyridinyl-are optionally substituted with one or more radicals chosen from halogen, C1-C4 alkyl, and thio, oxy or amino which are themselves optionally substituted with one or more C1-C4 alkyl;  
 
 R 3  and R′ 3 , which are identical or different, represent independently of each other hydrogen or C1-C4 alkyl;  
 Ar 1  and Ar 2 , which are identical or different, and are independently of each other selected from: 
 a quinoline optionally substituted with at least 
 a group N(Ra)(Rb) in which Ra and Rb are identical or different, and are independently of each other hydrogen or a C1-C4 alkyl; or  
 
 a C1-C4 alkyl or alkoxy;  
 a quinoline possessing a nitrogen atom in quaternary form;  
 a pyridine optionally attached at the 4-position or fused with an aryl or heteroaryl group, optionally substituted with a C1-C4 alkyl;  
 a phenyl optionally substituted with halogen, C1-C4 alkoxy, cyano, carbonylamino optionally substituted with one or more C1-C4 alkyl, guanyl, C1-C4 alkylthio, amino, C1-C4 alkylamino, C1-C4 dialkylamino, nitro, C1-C4 alkyleneamino or C2-C4 alkenyleneamino; or  
 a mono- or bi- or tricyclic aromatic or non-aromatic heterocyclic ring containing 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, C1-C4 alkylene or C2-C4 alkenylene;  
 or an isomer, an enantiomer, a diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.  
 
 
 
   
   
       11  The compound according to  claim 10  wherein n is 0 or 1 and m is 1.  
   
   
       12  The compound according to  claim 10  wherein Ar 1  and Ar 2  represent: 
 a quinoline optionally substituted with at least 
 a group N(Ra)(Rb) in which Ra and Rb are identical or different, and are independently of each other hydrogen or C1-C4 alkyl; or  
 a C1-C4 alkyl or alkoxy;  
   a quinoline possessing a nitrogen atom in quaternary form; or    pyridine.    
   
   
       13  The compound according to  claim 10  wherein Ar 1  and Ar 2  are chosen from the following groups: 4-amino-, 4-methylamino-, 4-dimethylamino- or 4-alkoxy-quinolyl or -quinolinium in which the quinolinium is optionally substituted with one or two methyl groups.  
   
   
       14  The compound according to  claim 10  wherein A is optionally substituted with one or more radicals chosen from halogen, C1-C4 thioalkyl, amino, C1-C4 alkylamino or C1-C4 dialkylamino.  
   
   
       15  The compound of formula (IA) according to  claim 7  wherein: 
 n, m, p and q are identical or different and are integers 0 or 1; 
 A represents: 
 —NH-1,3-phenyl-NH—, —NH-1,4-phenyl-NH—, —NH-1,4-phenyl-CH2-NH—, —CH2-1,4-phenyl-CH2-, —CH2-2,5-pyridinyl- or —CH═CH—; or  
 
 R 3  and R′ 3 , which are identical or different, represent independently of each other hydrogen or C1-C4 alkyl;  
 Ar 1  and Ar 2 , which are identical or different, and are independently of each other selected from: 
 a quinoline optionally substituted with at least 
 a group N(Ra)(Rb) in which Ra and Rb are identical or different, and are independently of each other hydrogen or C1-C4 alkyl; or  
 a C1-C4 alkyl or alkoxy;  
 
 a quinoline possessing a nitrogen atom in quaternary form;  
 a pyridyl; or  
 a mono- or bi- or tricyclic aromatic or non-aromatic heterocyclic ring containing 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, C1-C4 alkylene or C2-C4 alkenylene;  
 or an isomer, an enantiomer, a diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.  
 
   
   
   
       16  The compound according to  claim 15  wherein Ar 1  and Ar 2 , which are identical or different, and are independently of each other chosen from the 4-amino-, 4-methylamino-, 4-dimethylamino- or 4-alkoxy-quinolyl or -quinolinium groups in which the quinolinium is optionally substituted with one or two methyl groups.  
   
   
       17  The compound according to  claim 15  wherein R 3  and R 3 ′ represent hydrogen.  
   
   
       18  The compound according to  claim 15  wherein: 
 1. Ar 1  represents: 
 a quinoline substituted with at least 
 one group N(Ra)(Rb) in which Ra and Rb are identical or different, and are independently of each other hydrogen or C1-C4 alkyl; or  
 a C1-C4 alkyl or alkoxy;  
 
 a quinoline possessing a nitrogen atom in quaternary form; and  
   2. Ar 2  represents 
 a quinoline substituted with at least 
 one group N(Ra)(Rb) in which Ra and Rb are identical or different, and are independently of each other hydrogen or C1-C4 alkyl; or  
 a C1-C4alkyloralkoxy;  
 
 a quinoline possessing a nitrogen atom in quaternary form;  
 a pyridyl;  
 quinoline, benzimidazole, indole, benzothiophene, benzofuran, benzothiazole, benzoxazole, carbazole, quinazoline, quinoxaline, piperidyl, piperazinyl, morpholino, azepine and diaza-azepine, which are optionally substituted by one or more C1-C4 alkyl, C1-C4 alkylene or C2-C4 alkenylene;  
 or an isomer, an enantiomer, a diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.  
   
   
   
       19  The compound of formula (IA) according to  claim 7  chosen from: 
 1-(4-methoxy-2-methylquinolin-6-yl)-3-{3-[3-(4-methoxy-2-methylquinolin-6-yl)ureido]phenyl}urea;    1-(4-dimethylamino-2-methylquinolin-6-yl)-3-{4-[3-(4-dimethylamino-2-methylquinolin-6-yl)ureido]phenyl}urea;    1-(4-dimethylamino-2-methylquinolin-6-yl)-3-{3-[3-(4-dimethylamino-2-methylquinolin-6-yl)ureido]phenyl}urea    1-(4-dimethylamino-2-methylquinolin-6-yl)-3-{4-[3-(4-dimethylamino-2-methylquinolin-6-yl)ureido]tolyl}urea    N,N′-bis(4-dimethylamino-2-methylquinolin-6-yl)-but-2-enediamide;    N,N′-bis(4-dimethylamino-2-methylquinolin-6-yl)-1,4-phenylenediacetamide; and    [(4-dimethylamino-2-methylquinolin-6-yl)-amido]-5-[(4-dimethylamino-2-methylquinolin-6-ylamino)methyl]pyridine-2-carboxylic acid;    [(4-dimethylamino-2-methylquinolin-6-yl)-amido]-5-[(4-dimethylamino-2-methylquinolin-6-ylamino)methyl]pyridine-2-carboxylic acid hydrochloride;    or an isomer, an enantiomer, a diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.    
   
   
       20  The compound according to  claim 19  chosen from: 
 1-(4-methoxy-2-methylquinolin-6-yl)-3-{3-[3-(4-methoxy-2-methylquinolin-6-yl)ureido]phenyl}urea;    1-(4-dimethylamino-2-methylquinolin-6-yl)-3-{4-[3-(4-dimethylamino-2-methyl-quinolin-6-yl)ureido]phenyl}urea;    N,N′-bis(4-dimethylamino-2-methylquinolin-6-yl)-but-2-enediamide;    N,N′-bis(4-dimethylamino-2-methylquinolin-6-yl)-1,4-phenylenediacetamide; and    [(4-dimethylamino-2-methylquinolin-6-yl)-amido]-5-[(4-dimethylamino-2-methylquinolin-6-ylamino)methyl]pyridine-2-carboxylic acid hydrochloride;    or an isomer, an enantiomer, a diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.    
   
   
       21  A pharmaceutical composition comprising therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically acceptable carrier;  
     
       
         
         
             
             
         
       
     
     wherein 
 n and m are identical or different and are integers 0 or 1; 
 A represents: 
 —NH-phenyl-NH—, —NH-phenyl-CH2-NH— or —CH2-phenyl-CH2-, —CH2-pyridinyl- and —CH═CH—;  
 and wherein  
 
 NH-phenyl-NH—, —NH-phenyl-CH2-NH—, —CH2-phenyl-CH2-, and —CH2-pyridinyl- are optionally substituted with one or more radicals chosen from halogen, C1-C4 alkyl, and thio, oxy or amino which are themselves optionally substituted with one or more C1-C4 alkyl;  
 
 R 3  and R′ 3 , which are identical or different, represent independently of each other hydrogen or C1-C4 alkyl; 
 Ar 1  and Ar 2 , which are identical or different, and are independently of each other selected from: 
 a quinoline optionally substituted with at least 
 a group N(Ra)(Rb) in which Ra and Rb are identical or different, and are independently of each other hydrogen or a C1-C4 alkyl; or  
 a C1-C4 alkyl or alkoxy;  
 
 a quinoline possessing a nitrogen atom in quaternary form;  
 a pyridine optionally attached at the 4-position or fused with an aryl or heteroaryl group, optionally substituted with a C1-C4 alkyl;  
 a phenyl optionally substituted with halogen, C1-C4 alkoxy, cyano, carbonylamino optionally substituted with one or more C1-C4 alkyl, guanyl, C1-C4 alkylthio, amino, C1-C4 alkylamino, C1-C4 dialkylamino, nitro, C1-C4 alkyleneamino or C2-C4 alkenyleneamino; or  
 a mono- or bi- or tricyclic aromatic or non-aromatic heterocyclic ring containing 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, C1-C4 alkylene or C2-C4 alkenylene;  
 or an isomer, an enantiomer, a diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.  
 
 
 
   
   
       22  The composition according to  claim 21  which further comprises an anticancer agent.  
   
   
       23  The composition according to  claim 22  wherein the anticancer agent is chosen from alkylating agents, platinum derivatives, antibiotic agents, antimicrotubule agents, anthracyclines, group I and II topoisomerases, fluoropyrimidines, cytidine analogues, adenosine analogues, L-asparaginase, hydroxyurea, trans-retinoic acid, suramine, irinotecan, topotecan, dexrazoxane, amifostine, herceptin, oestrogenic and androgenic hormones and antivascular agents.  
   
   
       24  The composition according to  claim 21  used in conjunction with radiation treatment.  
   
   
       25  The composition according to  claim 22  wherein each of the components is administered simultaneously, separately or sequentially.  
   
   
       26 . The composition according to  claim 24  wherein the compound and the radiation treatment are administered simultaneously, separately or sequentially.  
   
   
       27 . A method of treatment of a cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound of formula (I):  
     
       
         
         
             
             
         
       
     
     wherein 
 n and m are identical or different and are integers 0 or 1; 
 A represents: 
 —NH-phenyl-NH—, —NH-phenyl-CH2-NH— or —CH2-phenyl-CH2-, —CH2-pyridinyl- and —CH═CH—;  
 and wherein  
 
 —NH-phenyl-NH—, —NH-phenyl-CH2-NH—, —CH2-phenyl-CH2-, and —CH2-pyridinyl- are optionally substituted with one or more radicals chosen from halogen, C1-C4 alkyl, and thio, oxy or amino which are themselves optionally substituted with one or more C1-C4 alkyl;  
 
 R 3  and R′ 3 , which are identical or different, represent independently of each other hydrogen or C1-C4 alkyl; 
 Ar 1  and Ar 2 , which are identical or different, and are independently of each other selected from: 
 a quinoline optionally substituted with at least 
 a group N(Ra)(Rb) in which Ra and Rb are identical or different, and are independently of each other hydrogen or a C1-C4 alkyl; or  
 a C1-C4 alkyl or alkoxy;  
 
 a quinoline possessing a nitrogen atom in quaternary form;  
 a pyridine optionally attached at the 4-position or fused with an aryl or heteroaryl group, optionally substituted with a C1-C4 alkyl;  
 a phenyl optionally substituted with halogen, C1-C4 alkoxy, cyano, carbonylamino optionally substituted with one or more C1-C4 alkyl, guanyl, C1-C4 alkylthio, amino, C1-C4 alkylamino, C1-C4 dialkylamino, nitro, C1-C4 alkyleneamino or C2-C4 alkenyleneamino; or  
 mono- or bi- or tricyclic aromatic or non-aromatic heterocyclic ring containing 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, C1-C4 alkylene or C2-C4 alkenylene;  
 or an isomer, an enantiomer, a diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.