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Last Updated: March 29, 2024

Claims for Patent: 8,614,339


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Summary for Patent: 8,614,339
Title:Dimeric derivatives of artemisinin and application in anti-cancer therapy
Abstract: The present invention relates to dimeric derivatives of 10-trifluoromethylated artemisinin of formula (I) below: Formula (I) and the pharmaceutically acceptable salts thereof, and also to the preparation method thereof and to the uses thereof, especially in the treatment of cancer. ##STR00001##
Inventor(s): Begue; Jean-Pierre (Paris, FR), Bonnet-Delpon; Daniele (Paris, FR), Crousse; Beno t (Igny, FR), Fournial; Anais (Renaze, FR), Mordant; Celine (Saint Julien en Genevois, FR), Fahy; Jacques (Labruguiere, FR)
Assignee: Pierre Fabre Medicament (Boulogne-Billancourt, FR) Centre National de la Recherche Scientifique (CNRS) (Paris, FR) Universite Paris-Sud 11 (Orsay, FR)
Application Number:13/054,321
Patent Claims:1. A dimeric derivative of 10-trifluoromethylated artemisinin of formula (I): ##STR00065## or a pharmaceutically acceptable salt thereof, wherein: a and b represent 2, A represents: a heteroatom selected from an atom of nitrogen, oxygen and sulphur, the nitrogen atom being optionally substituted by a radical R1 selected from a hydrogen atom and the following groups: (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.3-C.sub.8)cycloalkyl, aryl-(C.sub.1-C.sub.6)alkyl, heteroaryl-(C.sub.1-C.sub.6)alkyl, heterocycle-(C.sub.1-C.sub.6)alkyl, optionally substituted aryl, optionally substituted heteroaryl, --COR2, --CO.sub.2R2, --C(O)NR2R2a, --SO.sub.2R2, --CH.sub.2C(O)OR2 and --CH.sub.2C(O)NR2R2a, with R2 representing a hydrogen atom or one of the following groups: (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, optionally substituted polyamine, (C.sub.3-C.sub.8)cycloalkyl, aryl-(C.sub.1-C.sub.6)alkyl, heteroaryl-(C.sub.1-C.sub.6)alkyl, optionally substituted aryl or optionally substituted heteroaryl, and R2a representing a hydrogen atom or a (C.sub.1-C.sub.6)alkyl group, or a saturated heterocycle comprising one or more heteroatoms selected from atoms of oxygen, sulphur and nitrogen, of which at least one nitrogen atom is linked to carbon 10, represents a single bond when A represents an atom of oxygen or sulphur or a heterocycle, or represents a single bond or a double bond when A represents a nitrogen atom, the aforesaid nitrogen atom being substituted by a radical R1 as defined above when represents a single bond, B represents a --CH.sub.2--Y--, --C(.dbd.O)--Y-- or --CH(OR3)-group, with Y representing O, S, N--R1 or a heterocycle, with R1 as defined above, and R3 representing a hydrogen atom or a (C.sub.1-C.sub.6)alkyl or aryl group, and X represents: when represents a double bond: a .dbd.C(X1)-(O--X2).sub.c-group with X1 and X2 representing, independently of each other, a (C.sub.1-C.sub.6)alkyl or (C.sub.2-C.sub.6)alkenyl group and c representing 0 or 1, or when represents a single bond: one of the following groups: (C.sub.1-C.sub.6)alkyl optionally substituted by one or more OH groups; (C.sub.2-C.sub.6)alkenyl; (C.sub.2-C.sub.6)alkynyl; [(C.sub.1-C.sub.6)alkyl].sub.n-(C.sub.3-C.sub.8)cycloalkyl-[(C.sub.1-C.su- b.6)alkyl].sub.p; [(C.sub.1-C.sub.6)alkyl].sub.n-heterocycle[(C.sub.1-C.sub.6)alkyl].sub.p; [(C.sub.1-C.sub.6)alkyl].sub.n-aryl-[(C.sub.1-C.sub.6)alkyl].sub.p; [(C.sub.1-C.sub.6)alkyl].sub.n-heteroaryl-[(C.sub.1-C.sub.6)alkyl].sub.p; with n and p representing, independently of each other, 0 or 1, a --CO--(CH.sub.2).sub.q-- or --CO--(CH.sub.2).sub.q--CO-- group for which q represents an integer equal to 1, 2, 3 or 4, or a --CO.sub.r--(CH.sub.2).sub.s--Z--(CH.sub.2).sub.t--CO.sub.u-- group for which r and u represent, independently of each other, an integer equal to 0 or 1, s and t represent, independently of each other, an integer equal to 0, 1, 2, 3 or 4, and Z represents an --S--, --S--S--, --SO--, --SO.sub.2--, --Se--Se--, --O--P(O)(OR3)-O--, --NR1-, (C.sub.3-C.sub.8)-cycloalkyl, aryl or heteroaryl group, with R1 and R3 as defined above.

2. The dimeric derivative of claim 1, wherein A represents an oxygen or nitrogen atom.

3. The dimeric derivative of claim 1, wherein B represents a --CH.sub.2O--, --CH.sub.2NR1-, --C(.dbd.O)NR1-, --CH(OR3)- or --CH.sub.2-(heterocycle)-group, with R1 and R3 as defined in claim 1.

4. The dimeric derivative of claim 1, wherein represents a single bond and X represents a (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.1-C.sub.6)alkyl-heteroaryl-(C.sub.1-C.sub.6)alkyl, --(CH.sub.2).sub.q--NR1- or --CO--(CH.sub.2).sub.q-- group, with q as defined in claim 1.

5. The dimeric derivative of claim 1 selected from the following compounds: ##STR00066## ##STR00067## ##STR00068## ##STR00069## ##STR00070## ##STR00071## ##STR00072##

6. A pharmaceutical composition comprising at least one dimeric derivative according to claim 1 and at least one pharmaceutically acceptable carrier.

7. The pharmaceutical composition of claim 6 further comprising at least one other active ingredient.

8. A pharmaceutical composition comprising: (i) at least one compound according to claim 1, and (ii) at least one other active ingredient, as combination products for a simultaneous, separated or sequential use.

9. The composition of claim 8, wherein the at least one other active ingredient is selected from anticancer agents.

10. The pharmaceutical composition according to claim 9, wherein the anticancer agent is selected from 6-mercaptopurine, fludarabine, cladribine, pentostatin, cytarabine, 5-fluorouracil, gemcitabine, methotrexate, raltitrexed, irinotecan, topotecan, etoposide, daunorubicin, doxorubicin, epirubicin, idarubicin, pirarubicin, mitoxantrone, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, busulfan, carmustine, fotemustine, streptozocin, carboplatin, cisplatin, oxaliplatin, procarbazine, dacarbazine, bleomycin, vinblastine, vincristine, vindesine, vinorelbine, paclitaxel, docetaxel, L-asparaginase, flutamide, nilutamide, bicalutamide, cyproterone acetate, triptorelin, leuprorelin, goserelin, buserelin, formestane, aminoglutethimide, anastrozole, letrozole, tamoxifen, octreotide and lanreotide.

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