Claims for Patent: 6,995,175

Summary for Patent: 6,995,175

Title:	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.
Inventor(s):	Bouchard; Herve (Thiais, FR), Hittinger; Augustin (Igny, FR)
Assignee:	Aventis Pharma S.A. (Antony, FR)
Application Number:	10/721,210
Patent Claims:	1. A compound corresponding to the following formula: nitrogen-containing aromatic ring --(NR.sub.3)p-(CO)n- distribution agent --(CO)m-(NR'.sub.3)q- aromatic or non-aromatic ring wherein n, m, p and q are 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 quinoilne 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 quino line possessing a nitrogen atom in quaternary form; a pyridine; or 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; R.sub.3 and R'.sub.3, which are identical or different, represent independently of each other hydrogen or C1 C4 alkyl; the distribution agent is: a triazine group 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; a 5- or 6-membered heterocyclic radical containing a sulfur, oxygen or nitrogen atom; a phenyl; or a diazine group; and wherein the heterocyclic, phenyl and diazine are optionally substituted with the same groups as the triazine; or an isomer, an enantiomer, a diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof; with the proviso that: when the distribution agent is 2,5-pyridyl, 2,6-pyridyl, 2,5-furanyl or phenyl unsubstituted or substituted with NH.sub.2 or 2-chloro, and R.sub.3 and R'.sub.3 are hydrogen, then the nitrogen-containing aromatic ring and the aromatic ring are not both quinoline which is unsubstituted or substituted with C1 C4 alkyl. 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 the heterocyclic group, phenyl, and diazine. 4. The compound according to claim 1 wherein the distribution agent is thienyl or pyridyl. 5. The compound according to claim 1 wherein the distribution agent is chosen from thienyl, pyridyl, phenyl, and diazine. 6. The compound according to claim 1 wherein the diazine group is a pyrimidine. 7. The compound according to claim 1 having the following formula (IA): ##STR00033## wherein n, m, p and q are 1; A represents: a 5- to 6-membered heterocyclic radical containing a sulfur, oxygen or nitrogen atom; a phenyl or a diazine group; and wherein the heterocyclic, phenyl and diazine 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.sub.3 and R'.sub.3, which are identical or different, represent independently of each other hydrogen or C1 C4 alkyl; Ar.sub.1 and Ar.sub.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 C4alkyl; or 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 an isomer, an enantiomer, a diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof; with the proviso that: when A is 2,5-pyridyl, 2,6-pyridyl, 2,5-furanyl or phenyl unsubstituted or substituted with NH.sub.2 or 2-chloro, and when R.sub.3 and R'.sub.3 are hydrogen, then Ar.sub.1 and Ar.sub.2 are not both quinoline which is unsubstituted or substituted with C1 C4 alkyl. 8. The compound according to claim 11 wherein A is chosen from heterocyclic group, phenyl and pyrimidine. 9. The compound according to claim 7 wherein the diazine group which A may represent is pyrimidine. 10. The compound according to claim 1 having the following formula (I): ##STR00034## wherein n and m are 1; A represents: a 5- to 6-membered heterocyclic radical containing a sulfur, oxygen or nitrogen atom; a phenyl; or a diazine group; and wherein the heterocyclic, phenyl and diazine 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.sub.3 and R'.sub.3, which are identical or different, represent independently of each other hydrogen or C1 C4 alkyl; Ar.sub.1 and Ar.sub.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; or 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 an isomer, an enantiomer, a diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof; with the proviso that: when A is 2,5-pyridyl, 2,6-pyridyl, 2,5-furanyl or phenyl unsubstituted or substituted with NH.sub.2 or 2-chloro, and when R.sub.3 and R.sub.3' are hydrogen, then Ar.sub.1 and Ar.sub.2 are not both quinoline which is unsubstituted or substituted with C1 C4 alkyl. 11. The compound according to claim 10 wherein A is chosen from thienyl, pyridyl, phenyl and pyrimidine. 12. The compound according to claim 10 wherein Ar.sub.1 and Ar.sub.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.sub.1 and Ar.sub.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 according to claim 10 wherein A is optionally substituted with methylthio or halogen. 16. The compound of formula (IA) according to claim 11 wherein: A represents: thienyl or pyridyl; pheny; or pyrimidyl optionally substituted with one or more radicals chosen from halogen or C1 C4 alkylthio; R.sub.3 and R'.sub.3, which are identical or different, represent independently of each other hydrogen or C1 C4 alkyl; Ar.sub.1 and Ar.sub.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; or a pyridyl; or an isomer, an enantiomer, a diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof. 17. The compound of formula (IA) according to claim 7 wherein: A represents: thienyl or pyridyl; phenyl; or pyrimidyl optionally substituted with one or more radicals chosen from halogen or C1 C4 alkylthio; R.sub.3 and R'.sub.3, which are identical or different, represent independently of each other hydrogen or C1 C4 alkyl; Ar.sub.1 and Ar.sub.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, which 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 a pyridyl; or an isomer, an enantiomer, a diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof. 18. The compound according to claim 17 wherein Ar.sub.1 and Ar.sub.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. 19. The compound according to claim 17 wherein R.sub.3 and R.sub.3' represent hydrogen. 20. The compound according to claim 17 wherein: 1. Ar.sub.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.sub.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 C4 alkyl or alkoxy; a quinoline possessing a nitrogen atom in quaternary form; or a pyridyl; or an isomer, an enantiomer, a diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof. 21. The compound of formula (IA) according to claim 7 chosen from: bis[(4-methoxy-2-methylquinolin-6-yl)-amido]-2,5-thiophenedicarboxylic acid; bis[(4-dimethylamino-2-methylquinolin-6-yl)-amido]-2,5-thiophenedic- arboxylic acid; bis[(4-amino-2-methylquinolin-6-yl)-amido]-2,5-thiophenedicarboxylic acid; N,N'-bis(4-amino-2-methylquinolin-6-yl)isophthalamide; N,N'-bis(4-dimethylamino-2-methylquinolin-6-yl)terephthalamide; bis[(4-amino-2-methyl-quinolin-6-yl)-amido]-2,5-pyridinedicarboxylic acid hydrochloride; bis[(4-dimethylamino-2-methyl-quinolin-6-yl)-amido]-2,5-pyridinedicarboxy- lic acid; bis[(4-dimethylamino-2-methylquinolin-6-yl)-amido]-2,4-pyridined- icarboxylic acid; bis[(4-amino-2-methyl-quinolin-6-yl)-amido]-2,6-pyridinedicarboxylic acid hydrochloride; bis[(4-amino-2-methyl-quinolin-6-yl)amido]-2,6-pyridine dicarboxylic acid; bis[(4-dimethylamino-2-methylquinolin-6-yl)amido]-2,6-pyridinedicarboxyli- c acid hydrochloride; and bis[(4-dimethylamino-2-methylquinolin-6-yl)-amido]-2,6-pyridinedicarboxyl- ic acid; or an isomer, an enantiomer, a diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof. 22. The compound according to claim 21 chosen from: bis[(4-dimethylamino-2-methylquinolin-6-yl)-amido]-2,5-thiophenedicarboxy- lic acid; N,N'-bis-(4-amino-2-methylquinolin-6-yl)isophthalamide; bis[(4-amino-2-methylquinolin-6-yl)-amido]-2,6-pyridinedicarboxylic acid hydrochloride; bis[(4-amino-2-methylquinolin-6-yl)-amido]-2,5-pyridinedicarboxylic acid; bis-[(4-dimethylamino-2-methylquinolin-6-yl)-amido]-2,5-pyridinedicarboxy- lic acid; and bis[(4-dimethylamino-2-methylquinolin-6-yl)amido]-2,4-pyridinedicarboxyli- c acid; or an isomer, an enantiomer, a diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof. 23. A pharmaceutical composition comprising therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically acceptable carrier; ##STR00035## wherein n and m are 1; A represents: a 5- to 6-membered heterocyclic radical containing a sulfur, oxygen or nitrogen atom; a phenyl; or a diazine group; and wherein the heterocyclic, phenyl and diazine 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.sub.3 and R'.sub.3, which are identical or different, represent independently of each other hydrogen or C1 C4 alkyl; Ar.sub.1 and Ar.sub.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; or 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 an isomer, an enantiomer, a diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof; with the proviso that: when A is 2,5-pyridyl, 2,6-pyridyl, 2,5-furanyl or phenyl unsubstituted or substituted with NH.sub.2 or 2-chloro, and when R.sub.3 and R.sub.3' are hydrogen, then Ar.sub.1 and Ar.sub.2 are not both quinoline which is unsubstituted or substituted with C1 C4 alkyl. 24. The composition according to claim 23 which further comprises an anticancer agent. 25. The composition according to claim 24 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, heroeptin, oestrogenic and androgenic hormones and antivascular agents. 26. The composition according to claim 23 used in conjunction with radiation treatment. 27. The composition according to claim 24 wherein each of the components is administered simultaneously, separately or sequentially. 28. The composition according to claim 26 wherein the compound and the radiation treatment are administered simultaneously, separately or sequentially. 29. 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): ##STR00036## wherein n and m are 1; A represents: a 5- to 6-membered heterocyclic radical containing a sulfur, oxygen or nitrogen atom; a pheny; or a diazine group; and wherein the heterocyclic, phenyl and diazine 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.sub.3 and R'.sub.3, which are identical or different, represent independently of each other hydrogen or C1 C4 alkyl; Ar.sub.1 and Ar.sub.2, which are identical or different, and are independently of each other selected from: a quinoilne 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; or 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 an isomer, an enantiomer, a diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof: with the proviso that: when A is 2,5-pyridyl, 2,6-pyridyl, 2,5-furanyl or phenyl unsubstituted or substituted with NH.sub.2 or 2-chloro, and when R.sub.3 and R.sub.3' are hydrogen, then Ar.sub.1 and Ar.sub.2 are not both quinoline which is unsubstituted or substituted with C1 C4 alkyl.

Details for Patent 6,995,175

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2021-05-28