Claims for Patent: 8,426,462

Summary for Patent: 8,426,462

Title:	Ferrocene derivatives with anticancer activity
Abstract:	The present invention relates to compounds of the following formula (I): ##STR00001## and to the pharmaceutically acceptable salts thereof, to the isomers and the mixtures of isomers thereof and to the water-soluble derivatives thereof, as well as to the method for preparing same and to the use thereof, particularly in the treatment of cancer.
Inventor(s):	Jaouen; Gerard (Cachan, FR), Vessieres-Jaouen; Anne (Cachan, FR), Plazuk; Damian (Garbatma Letnisko, PL)
Assignee:	Centre National de la Recherche Scientifique (CNRS) (Paris, FR)
Application Number:	13/002,177
Patent Claims:	1. A compound of the following formula (I): ##STR00024## or a pharmaceutically acceptable salt thereof, wherein: A1 and A2, independently from each other, are either a bond between the cyclopentadienyl and the carbon of the double bond, or a linear alkyl chain comprising n1 and n2 carbon atoms, respectively, optionally substituted with one or more group(s) selected from halogen; phenyl optionally substituted with OH; (C.sub.1-C.sub.6)alkyl optionally substituted with one or more halogen(s); and (C.sub.3-C.sub.6)cycloalkyl optionally substituted with one or more halogen(s), wherein n1 and n2 are, independently from each other, an integer comprised between 1 and 4, with the proviso that A1 and A2 are not simultaneously a bond and that the A1-C-A2 chain contains at least 3 carbon atoms, R1 and R2 each represent hydrogen or together form a linear alkyl chain connecting the two cyclopentadienyl groups and having 3 to 5 carbon atoms, wherein said chain is optionally substituted with one or more group(s) selected from halogen; phenyl optionally substituted with OH; (C.sub.1-C.sub.6)alkyl optionally substituted with one or more halogen(s); and (C.sub.3-C.sub.6)cycloalkyl optionally substituted with one or more halogen(s), and R3 and R4, independently from each other, are hydrogen or a CF.sub.3, CN, OR.sup.5 or NR.sup.6R.sup.7 group, wherein: R.sup.5 is hydrogen or a --CO--(C.sub.1-C.sub.20)alkyl or --(CH.sub.2).sub.mNR.sup.8R.sup.9 group, R.sup.6, R.sup.7, R.sup.8 and R.sup.9 are, independently from one another, hydrogen or a (C.sub.1-C.sub.6)alkyl or acyl group, and m is an integer comprised between 2 and 8. 2. The compound according to claim 1, wherein R3 and/or R4 independently from each other, are OR.sup.5. 3. The compound according to claim 1, wherein R3 and/or R4 are located in the para-position on the phenyl ring. 4. The compound according to claim 1, wherein R1 and R2 each represent hydrogen. 5. The compound according to claim 1, wherein A1 or A2 represents a bond. 6. The compound according to claim 1 selected from the compounds of the following formulae 4 to 11: ##STR00025## ##STR00026## 7. A pharmaceutical composition comprising at least one compound according to claim 1, in combination with a pharmaceutically acceptable vehicle. 8. The pharmaceutical composition according to claim 7, further comprising at least one additional active ingredient. 9. A pharmaceutical composition comprising: (i) at least one compound according to claim 1, (ii) at least one additional active ingredient, as combination products to be administered simultaneously, separately or sequentially. 10. The composition according to claim 8, wherein the at least one additional active ingredient is selected from 6-mercaptopurin, fludarabin, cladribin, pentostatin, cytarabin, 5-fluorouracil, gemcitabine, 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. 11. The composition according to claim 9, wherein the at least one additional active ingredient is selected from 6-mercaptopurine, fludarabin, cladribin, pentostatin, cytarabin, 5-fluorouracil, gemcitabine, 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 the formula (Ia) or (Ib) according to claim 1 comprising the following steps: (i) McMurry coupling of a compound of the following formula (II): ##STR00027## wherein R1, R2, A1 and A2 are as defined in claim 1, with a compound of the following formula (III): ##STR00028## wherein R3 and R4 are as defined in claim 1, to form the compound of the formula (Ia) or (Ib), and (ii) recovering the compound of the formula (Ia) or (Ib), obtained in step (i) above. 13. The compound according to claim 1, wherein A1 and A2, independently from each other, are either a bond between the cyclopentadienyl and the carbon of the double bond, or a linear alkyl chain comprising n1 and n2 carbon atoms, respectively, optionally substituted with one or more group(s) selected from halogen; phenyl optionally substituted with OH; (C.sub.1-C.sub.6)alkyl optionally substituted with one or more halogen(s); and (C.sub.3-C.sub.6)cycloalkyl optionally substituted with one or more halogen(s), wherein n1 and n2 are, independently from each other, an integer comprised between 1 and 4, with the proviso that A1 and A2 are not simultaneously a bond and that the A1-C-A2 chain contains 3, 4 or 5 carbon atoms. 14. The compound according to claim 2, wherein R3 and R4 independently from each other, are OR.sup.5, wherein R.sup.5 is hydrogen or a --CO--(C.sub.1-C.sub.20)alkyl or --(CH.sub.2).sub.mNR.sup.8R.sup.9 group. 15. The compound according to claim 2, wherein R3 and/or R4 independently from each other, are OH. 16. The compound according to claim 2, wherein R3 and R4 are OH. 17. The compound according to claim 3, wherein R3 and R4 are located in the para-position on the phenyl ring.

Details for Patent 8,426,462

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2028-07-03