Claims for Patent: 9,758,541

Summary for Patent: 9,758,541

Title:	Metallocene derivatives with anticancer activity
Abstract:	The present invention relates to a compound of the following formula (I) or a pharmaceutically acceptable salt or solvate thereof, a stereoisomer or a mixture of stereoisomers in any ratio, or a water-soluble derivative, as well as to methods for preparing same and to the use thereof, in particular in the treatment of cancer. ##STR00001##
Inventor(s):	Jaouen; Gerard (Cachan, FR), Pigeon; Pascal (Paris, FR), Top; Siden (Lisses, FR)
Assignee:	PARIS SCIENCES ET LETTRES--QUARTIER LATIN (FR)
Application Number:	15/032,877
Patent Claims:	1. A compound of the following formula (I): ##STR00061## or a pharmaceutically acceptable salt or solvate thereof, a stereoisomer or a mixture of stereoisomers in any ratio, or a water-soluble derivative, in which: M is Fe, Ru or Os, n is an integer comprised between 1 and 8, R1 and R2 are, independently from each other, H, CF.sub.3, CN, OR.sup.4 or NR.sup.5R.sup.6, and R3 is CO.sub.2R.sup.7, OR.sup.8 or NR.sup.9R.sup.10, wherein: R.sup.4 is H, (C.sub.1-C.sub.6)alkyl, --CO--(C.sub.1-C.sub.6)alkyl or --(CH.sub.2).sub.mNR.sup.11R.sup.12, R.sup.5, R.sup.6, R.sup.11 and R.sup.12 are, independently from one another, H, (C.sub.1-C.sub.6)alkyl or --CO--(C.sub.1-C.sub.6)alkyl, R.sup.7 is H or (C.sub.1-C.sub.6)alkyl, R.sup.8 is H, (C.sub.1-C.sub.6)alkyl or --CO--(C.sub.1-C.sub.6)alkyl, R.sup.9 and R.sup.10 are, independently from one another, H, (C.sub.1-C.sub.6)alkyl or --CO--(C.sub.1-C.sub.6)alkyl, or R.sup.9 and R.sup.10 form together with the nitrogen atom bearing them a cycle of the following formula: ##STR00062## in which: represents a single or double bond, X1 and X2 are, independently from one another, C.dbd.O, SO.sub.2, CH--OR.sup.19, CH--SR.sup.20, CH--NR.sup.21R.sup.22 or CH--NHC(O)R.sup.23, R.sup.13 and R.sup.14 are, independently from one another, H or (C.sub.1-C.sub.6)alkyl, or R.sup.13 and R.sup.14 form together with the carbon atoms bearing them a 5- or 6-membered hydrocarbon cycle, R.sup.19, R.sup.20, R.sup.21 and R.sup.22 are, independently from one another, H or (C.sub.1-C.sub.6)alkyl, and R.sup.23 is a (C.sub.1-C.sub.6)alkyl group, and m is an integer comprised between 1 and 8. 2. The compound according to claim 1, wherein n is an integer comprised between 2 and 6. 3. The compound according to claim 1, wherein it has the following formula (Ia): ##STR00063## 4. The compound according to claim 1, wherein M is Fe. 5. The compound according to claim 1, wherein R1 and R2 are, independently from each other, H, OR.sup.4 or NR.sup.5R.sup.6. 6. The compound according to claim 1, wherein one of R1 and R2 is OR.sup.4 and the other is H or OR.sup.4. 7. The compound according to claim 1, wherein R3 is CO.sub.2R.sup.7, OR.sup.8 or NR.sup.9R.sup.10 with: R.sup.7 being a --(C.sub.1-C.sub.6)alkyl group, R.sup.8 being H, and at least one of R.sup.9 and R.sup.10 being, independently from one another, --CO--(C.sub.1-C.sub.6)alkyl, or R.sup.9 and R.sup.10 forming together with the nitrogen atom bearing them a cycle of the following formula: ##STR00064## in which , R.sup.13 and R.sup.14 are as defined in claim 1, and at least one of X1 and X2 is C.dbd.O. 8. The compound according to claim 1, selected from the following compounds: ##STR00065## ##STR00066## ##STR00067## ##STR00068## ##STR00069## ##STR00070## and pharmaceutically acceptable salts and solvates thereof. 9. A pharmaceutical composition comprising at least one compound according to claim 1, in combination with at least one pharmaceutically acceptable vehicle. 10. The pharmaceutical composition according to claim 9, further comprising at least one additional active ingredient. 11. The pharmaceutical composition according to claim 10, wherein the at least one additional active ingredient is selected from 6-mercaptopurin, fludarabin, cladribin, pentostatin, cytarabin, 5-fluorouracil, gemcitabin, methotrexate, raltitrexed, irinotecan, topotecan, etoposide, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, mitoxantrone, chlormethin, cyclophosphamide, ifosfamide, melphalan, chlorambucil, busulfan, carmustin, fotemustin, streptozocin, carboplatin, cisplatin, oxaliplatin, procarbazin, dacarbazin, bleomycin, vinblastin, vincristin, vindesin, vinorelbin, paclitaxel, docetaxel, L-asparaginase, flutamide, nilutamide, bicalutamide, cyproterone acetate, triptorelin, leuprorelin, goserelin, buserelin, formestane, aminoglutethimide, anastrazole, letrozole, tamoxifen, octreotide and lanreotide. 12. A process for preparing a compound of formula (I) according to claim 1, in which R3 is CO.sub.2--(C.sub.1-C.sub.6)alkyl or OR.sup.8 with R.sup.8H, comprising the following steps: (i) McMurry coupling between a compound of the following formula (II): ##STR00071## wherein M and n are as defined in claim 1 and R3 is as defined above, and a compound of the following formula (III): ##STR00072## wherein R1 and R2 are as defined in claim 1, to give a compound of formula (I) as defined above, and (ii) optionally salification or solvatation of the compound of formula (I) obtained in step (i) to give a pharmaceutically acceptable salt or solvate thereof. 13. A process for preparing a compound of formula (I) according claim 1, in which R3 is OR.sup.8, comprising the following steps: (a) reduction of a compound of the following formula (lb): ##STR00073## wherein M, n, R1 and R2 are as defined in claim 1 and Alk is (C.sub.1-C.sub.6)alkyl, to give a compound of formula (I) in which R3 is OH, (b) optionally substitution of the compound obtained in step (a) to give a compound of formula (I) in which R3 is OR.sup.8 with R.sup.8H, and (c) optionally salification or solvatation of the compound of formula (I) obtained in step (a) or (b) to give a pharmaceutically acceptable salt or solvate thereof. 14. A process for preparing a compound of formula (I) according to claim 1, in which R3 is COOH, comprising the following steps: (1) saponification of a compound of the following formula (Ic): ##STR00074## wherein M, n, R1 and R2 are as defined in claim 1 and Alk is (C.sub.1-C.sub.6)alkyl, to give a compound of formula (I) in which R3 is COOH, and (2) optionally salification or solvatation of the compound of formula (I) obtained in step (1) to give a pharmaceutically acceptable salt or solvate thereof. 15. A process for preparing a compound of formula (I) according to claim 1, in which R3 is NR.sup.9R.sup.10, comprising the following steps: (A) reaction of a compound of the following formula (Id): ##STR00075## wherein M, n, R1 and R2 are as defined in claim 1 and Hal is a halogen atom, with a compound of formula HNR.sup.9R.sup.10, to give a compound of formula (I) in which R3 is NR.sup.9R.sup.10, and (B) optionally salification or solvatation of the compound of formula (I) obtained in step (A) to give a pharmaceutically acceptable salt or solvate thereof. 16. A method for the treatment of cancer comprising administering to a patient in need thereof an effective amount of a compound according to claim 1. 17. The method according to claim 16, wherein the compound is used alone or in combination, simultaneously, separately or sequentially, with ionizing or non-ionizing radiations or with at least one additional active ingredient. 18. The method according to claim 17, wherein the at least one additional active ingredient is selected from 6-mercaptopurin, fludarabin, cladribin, pentostatin, cytarabin, 5-fluorouracil, gemcitabin, methotrexate, raltitrexed, irinotecan, topotecan, etoposide, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, mitoxantrone, chlormethin, cyclophosphamide, ifosfamide, melphalan, chlorambucil, busulfan, carmustin, fotemustin, streptozocin, carboplatin, cisplatin, oxaliplatin, procarbazin, dacarbazin, bleomycin, vinblastin, vincristin, vindesin, vinorelbin, paclitaxel, docetaxel, L-asparaginase, flutamide, nilutamide, bicalutamide, cyproterone acetate, triptorelin, leuprorelin, goserelin, buserelin, formestane, aminoglutethimide, anastrazole, letrozole, tamoxifen, octreotide and lanreotide.

Details for Patent 9,758,541

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2033-10-30