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Last Updated: March 28, 2024

Claims for Patent: 6,645,964


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Summary for Patent: 6,645,964
Title: 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.
Inventor(s): Mailliet; Patrick (Fontenay Sous Bois, FR), Riou; Jean-Fran.cedilla.ois (Paris, FR), Mergny; Jean-Louis (Villejuif, FR), Laoui; Abdelazize (Nogent sur Marne, FR), Lavelle; Fran.cedilla.ois (Paris, FR), Petitgenet; Odile (Paris, FR)
Assignee: Aventis Pharma S.A. (Atony, FR)
Application Number:09/722,361
Patent Claims:1. Compounds which bind the G-quadruplex structure of the telomers, characterized in that they correspond to the following general formula:

in which nitrogen-containing aromatic ring represents: a quinoline optionally substituted with at least one group in which Ra and Rb, which are identical or different, represent a short-chain C1-C4 alkyl, alkoxy radical, a quinoline possessing a nitrogen atom in quaternary form, 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, a short-chain C1-C4 alkyl, alkoxy radical, a quinoline possessing a nitrogen atom quaternary form, a benzamidine, a pyridine, 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, alkylene-amino group or alkenyleneamino group, or a mono- or bi- or tricyclic hetero-cyclic 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 one of its salts

with the proviso that the compound is not (a) benzenecarboximidamide,4-[4-chloro-6-(phenylamino)-1,3,5-triazin-2-yl]amin o, or (b) 1,3,5-triazine-2,4,6-triamine,N,N'-bis(4-amino-2-methyl-6-quinolinyl)-trih ydrochloride.

2. Compounds according to claim 1, characterized in that they correspond to formula (I) below: ##STR45##

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.sub.1 and Ar.sub.2, which are identical or different, represent

1. when Ar.sub.1 and Ar.sub.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.sub.1 and Ar.sub.2 are different Ar.sub.1 and Ar.sub.2 both represent one of the possibilities mentioned above for Ar.sub.1 and Ar.sub.2 or Ar.sub.1 represents one of the above possibilities and Ar.sub.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 hetero-cyclic 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.

3. Compounds according to claim 2, characterized in that Ar.sub.1 and Ar.sub.2 represent a group chosen from the following groups: 4-amino- or 4-methyamino- or 4-dimethylamino-quinolyl or -quinolinium in which the quinolinium ring is optionally substituted with a methyl group.

4. Compounds according to claim 2, 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.

5. Compounds according to claim 2, characterized in that A represents a methylthio group.

6. Compounds corresponding to the following formula (I): ##STR46##

in which: A represents an amino group of formula NR1 R2 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, a group OR1 or SR1 in which R1 has the same meaning as above, an alkyl group containing 1 to 4 carbon atoms or a trifluoromethyl group, 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.sub.1 and Ar.sub.2, which are identical or different, represent

1. when Art and Ar.sub.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, alkoxy radical containing 1 to 4 carbon atoms, a quinoline possessing a nitrogen atom in quaternary form, 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 optionally substituted with a C1-C4 alkyl group

2. when Ar.sub.1 and Ar.sub.2 are different Ar.sub.1 and Ar.sub.2 both represent one of the possibilities mentioned above for Ar.sub.1 and Ar.sub.2 or Ar.sub.1 represents one of the above possibilities and Ar.sub.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 hetero-cyclic 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 or 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; and

with the proviso that the compound is not (a) benzenecarboximidamide,4-[4-chloro-6-(phenylamino)-1,3,5-triazin-2-yl]amin o, or (b) 1,3,5-triazine-2,4,6-triamine,N,N'-bis(4-amino-2-methyl-6- quinolinyl)-trihydrochloride.

7. Compounds according to claim 6, characterized in that when Ar.sub.1 and Ar.sub.2 are identical, Ar.sub.1 and Ar.sub.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.

8. Compounds according to claim 6, characterized in that R1 and R2 represent hydrogen.

9. Compounds according to claim 6, characterized in that A represents a methylthio group.

10. Compounds according to claim 6, characterized in that when Ar.sub.1 and Ar.sub.2 are different 1. Ar.sub.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.sub.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, carbonyl-amino, 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.

11. Compounds according to claim 6, 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'-methyl-4'-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'-methyl4'-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'-quinaidinyl)amino]triazine hydrate.

12. Compounds according to claim 11 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-[1,3,5]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-methyl-quinoline-4,6-diamine N6-[4-(4-methoxy-2-methylquinolin-6-ylamino)-6-methylsulphanyl-[1,3,5]triaz in-2-yl]-4-methoxy-2-methylquinolin-6-amine.

13. A pharmaceutical composition comprising one or more compounds of claim 6, and a pharmaceutically acceptable carrier.

14. Therapeutic combinations consisting of a compound according to claim 1 and another anticancer compound.

15. Combinations according to claim 14, 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.

16. Therapeutic combination consisting of the administration of a compound according to claim 1 and the administration of radiation.

17. Combinations according to any one of claims 14 to 16, characterized in that each of the compounds or treatments is administered simultaneously, separately or sequentially.

18. A method of inhibiting telomerase activity, comprising administering a therapeutically effective amount of one or more compounds of claim 1 to a patient, wherein the level of telomerase activity in the patient following the administration is reduced relative to the level of telomerase activity existing prior to the administration.

19. A method of treating a cancer, comprising administering a therapeutically effective amount of one or more compounds of claim 1 to a patient in need of such a treatment, wherein the level of telomerase activity following the administration is reduced relative to the level of telomerase activity existing prior to the administration.

Details for Patent 6,645,964

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Recordati Rare Diseases, Inc. ELSPAR asparaginase For Injection 101063 01/10/1978 ⤷  Try a Trial 2019-11-29
Genentech, Inc. HERCEPTIN trastuzumab For Injection 103792 09/25/1998 ⤷  Try a Trial 2019-11-29
Genentech, Inc. HERCEPTIN trastuzumab For Injection 103792 02/10/2017 ⤷  Try a Trial 2019-11-29
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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