Claims for Patent: 9,321,778

Summary for Patent: 9,321,778

Title:	Piperazinyl derivatives for the treatment of cancer
Abstract:	The present invention relates to piperazinyl derivatives of formula (I) and the use thereof as a drug, particularly for the treatment of cancer, the pharmaceutical compositions containing said derivatives, and the method for synthesising same. ##STR00001##
Inventor(s):	Carniato; Denis (Marcoussis, FR), Briand; Jean-Francois (Saclay, FR), Gutmann; Mathieu (Vaugrigneuse, FR), Busnel; Olivier (Allennes les Marais, FR), Bougeret; Cecile (Nevers, FR), Deprez; Benoit (Lille, FR), Jaillardon; Karine (Saint Michel s/Orge, FR)
Assignee:	Pitty; Marc Henry (Boulogne-Billancourt, FR)
Application Number:	14/369,407
Patent Claims:	1. A compound of following general formula (I): ##STR00062## or a pharmaceutically acceptable salt thereof, a stereoisomer or a mixture of stereoisomers in any proportion, where: X is a (C.sub.1-C.sub.6)alkyl, phenyl, benzyl, C(O)OR5 or C(O)NHR5 group; R1 is a hydrogen atom or a C(O)H, C(O)R6 or C(O)OR6 group; R2 is a hydrogen atom or a (C.sub.1-C.sub.6)alkyl group; or R2 together with R1 or X forms a saturated hydrocarbon chain to form a 5- or 6-membered ring; R3 is a hydrogen or halogen atom or a (C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)alkoxy group; R4 is a hydrogen or halogen atom, CN, NO.sub.2, or a (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, aryloxy, benzyloxy or heteroaryloxy group, the said group optionally being substituted by one or more halogen atoms; Ar is a thiophenyl group or a phenyl group optionally substituted by one or more halogen atoms; and R5 and R6 independently of one another are a (C.sub.1-C.sub.6)alkyl, aryl-(C.sub.1-C.sub.6)alkyl or aryl group, the said group optionally being substituted by one or more halogen atoms. 2. The compound according to claim 1, having the following formula (I-bis): ##STR00063## 3. The compound according to claim 1, wherein Ar is a thiophenyl group or a phenyl group substituted by one or more fluorine atoms. 4. The compound according to claim 3, wherein Ar is a thiophenyl group or a 4-fluoro-phenyl group. 5. The compound according to claim 1, wherein R4 is a hydrogen or halogen atom or a (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy or aryloxy group, the said group optionally being substituted by one or more halogen atoms. 6. The compound according to claim 1, wherein R3 is a hydrogen atom or a (C.sub.1-C.sub.6)alkyl group. 7. The compound according to claim 1, wherein X is a (C.sub.1-C.sub.6)alkyl, phenyl or benzyl group; R1 and R2 are a hydrogen atom; R3 is a hydrogen atom or a (C.sub.1-C.sub.6)alkyl group; R4 is a halogen atom or a (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, aryloxy or benzyloxy group, the said group optionally being substituted by one or more halogen atoms; Ar is a thiophenyl group or a phenyl group optionally substituted by a fluorine atom; and R5 and R6 independently of one another are a (C.sub.1-C.sub.6)alkyl, aryl-(C.sub.1-C.sub.6)alkyl or aryl group, the said group optionally being substituted by one or more fluorine atoms. 8. The compound according to claim 1, selected from among: ##STR00064## ##STR00065## ##STR00066## ##STR00067## ##STR00068## ##STR00069## ##STR00070## ##STR00071## ##STR00072## ##STR00073## ##STR00074## ##STR00075## ##STR00076## ##STR00077## ##STR00078## ##STR00079## ##STR00080## ##STR00081## ##STR00082## ##STR00083## ##STR00084## ##STR00085## ##STR00086## ##STR00087## ##STR00088## ##STR00089## ##STR00090## ##STR00091## ##STR00092## ##STR00093## 9. A method for the treatment of a cancer, the method comprising the administration to a person in need thereof of an effective amount of the compound of general formula (I) according to claim 1, wherein the cancer is selected from the group consisting of breast cancer, leukaemia, colon cancer, pancreatic cancer, and ovarian cancer. 10. The method according to claim 9, wherein the cancer is a chemotherapy-resistant cancer. 11. A pharmaceutical composition comprising at least one compound of general formula (I) according to claim 1, in association with one or more pharmaceutically acceptable excipients. 12. The pharmaceutical composition according to claim 11, comprising at least one other active ingredient. 13. The pharmaceutical composition according to claim 12, wherein the at least one other active ingredient is an anticancer agent. 14. The pharmaceutical composition according to claim 13, wherein the at least one other active ingredient is chosen from among cisplatin and its derivatives; taxanes, paclitaxel and docetaxel; vinca alkaloids; purine analogues s; topoisomerase I inhibitors; topoisomerase II inhibitors; anti-tumour nucleoside derivatives; alkylating agents; derivatives of anti-tumour anthracyclines; molecules targeting the IGF-I receptor; tetracarcin derivatives; corticosteroids; antibodies; antagonists or selective modulators of oestrogen receptors; aromatase inhibitors; differentiating agents; DNA methyl-transferase inhibitors; antifolates; antibiotics; antimetabolites; apoptosis-inducing agents and anti-angiogenic agents of Bcl-2 inhibitors; agents binding to tubulin; kinase inhibitors; farnesyl transferase inhibitors; histone-deacetylase inhibitors; inhibitors of the ubiquitin-proteasome system; and telomerase inhibitors. 15. The pharmaceutical composition according to claim 14, wherein the cisplatin derivatives are chosen among carboplatin and oxalyplatin; the taxanes are chosen among taxol, taxotere, paclitaxel and docetaxel; the vinca alkaloids are chosen among vinblastine, vincristine and vinorelbine; the purine analogues are chosen among mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine; the topoisomerase I inhibitors are chosen among camptothecin compounds; the topoisomerase II inhibitors are chosen among epipodophyllotoxin, podophyllotoxin and the derivatives thereof; the anti-tumour nucleoside derivatives are chosen among 5-fluorouracil, leucovorin, gemcitabine and capecitabine; the alkylating agents are chosen among nitrogen mustards, nitroso-ureas, alkylsulfonates, ethylenimines, methylmelamines and tetrazines; the derivatives of anti-tumour anthracyclines are chosen among daunorubicin, adriamycin, doxil, idarubicin and mitoxantrone; the molecule targeting the IGF-I receptor is picropodophyllin; the tetracarcin derivative is tetrocarcin A; the corticosteroid is prednisone; the antibodies are chosen among trastuzumab (anti-HER2 antibody), rituximab (anti-CD20 antibody), gemtuzamab, cetuximab, pertuzumab and bevacizumab; the antagonists or selective modulators of oestrogen receptors are chosen among tamoxifen, fulvestrant, toremifene, droloxifene, faslodex and raloxifene; the aromatase inhibitors are chosen among exemestane, anastrozole, letrozole and vorozole; the differentiating agents are chosen among retinoids and agents blocking the metabolism of retinoic acid; the DNA methyl-transferase inhibitors are chosen among azacytidine and decitabine; the antifolate is permetrexed disodium; the antibiotics are chosen among antinomycin D, bleomycin, mitomycin C, actinomycin D, carminomycin, daunomycin and plicamycin; the antimetabolites are chosen among chlofarabine, aminopterin, cytosine arabinoside, floxuridine and methotrexate; the apoptosis-inducing agents and anti-angiogenic agents of Bcl-2 inhibitors are chosen among YC 137, BH 312, ABT 737, gossypol, HA 14-1, TW 37 and decanoic acid; the agents binding to tubulin are chosen among combrestatin, colchicine derivatives and nocodazole; the kinase inhibitors are chosen among flavoperidol, imatinib mesylate, erlotinib and gefitinib; the farnesyl transferase inhibitor is tipifarnib; the histone-deacetylase inhibitors are chosen among sodium butyrate, suberoylanilide hydroxamic acid, depsipeptide, NVP-LAQ824, R306465, JNJ-26481585 and trichostatin A; the inhibitors of the ubiquitin-proteasome system are chosen among MLN 0.41, bortezomib and yondelis; and the telomerase inhibitor is telomestatin. 16. The pharmaceutical composition according to claim 15, wherein the camptothecin compounds are chosen among irinotecan and topotecan; the podophyllotoxin derivatives are chosen among etoposide and teniposide; the nitrogen mustards are chosen among cyclophosphamide, mechlorethamine, chlorambucil and melphalan; the nitroso-ureas are chosen among carmustin, lomustin and streptozocin; the alkylsulfonate is busulfan; the ethylenimines and methylmelamines are chosen among thiotepa and hexamethylmelamine; the tetrazine is dacarbazine; the retinoids are chosen among retinoic acid and vitamin D; and the agent blocking the metabolism of retinoic acid is Accutane. 17. A pharmaceutical composition comprising: (i) at least one formula (I) compound according to claim 1; and (ii) at least one other active ingredient, as combination products for simultaneous, separate or time-staggered use thereof. 18. The pharmaceutical composition according to claim 17, wherein the at least one other active ingredient is an anticancer agent. 19. The pharmaceutical composition according to claim 17, wherein the at least one other active ingredient is selected from among cisplatin and the derivatives thereof; taxanes; vinca alkaloids; purine analogues; topoisomerase I inhibitors; topoisomerase II inhibitors; anti-tumour nucleoside derivatives; alkylating agents; derivatives of anti-tumour anthracyclines; molecules targeting the IGF-I receptor; tetracarcin derivatives; corticosteroids; antibodies; antagonists or selective modulators of oestrogen receptors; aromatase inhibitors; differentiating agents; DNA methyl-transferase inhibitors; antifolates; antibiotics; antimetabolites; apoptosis-inducing agents and anti-angiogenic agents of Bcl-2 inhibitors; agents binding to tubulin; kinase inhibitors; farnesyl transferase inhibitors; histone-deacetylase inhibitors; inhibitors of the ubiquitin-proteasome system s; and telomerase inhibitors. 20. The pharmaceutical composition according to claim 19, wherein the cisplatin derivatives are chosen among carboplatin and oxalyplatin; the taxanes are chosen among taxol, taxotere, paclitaxel and docetaxel; the vinca alkaloids are chosen among vinblastine, vincristine and vinorelbine; the purine analogues are chosen among mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine; the topoisomerase I inhibitors are chosen among camptothecin compounds; the topoisomerase II inhibitors are chosen among epipodophyllotoxin, podophyllotoxin and the derivatives thereof; the anti-tumour nucleoside derivatives are chosen among 5-fluorouracil, leucovorin, gemcitabine and capecitabine; the alkylating agents are chosen among nitrogen mustards, nitroso-ureas, alkylsulfonates, ethylenimines, methylmelamines and tetrazines; the derivatives of anti-tumour anthracyclines are chosen among daunorubicin, adriamycin, doxil, idarubicin and mitoxantrone; the molecule targeting the IGF-I receptor is picropodophyllin; the tetracarcin derivative is tetrocarcin A; the corticosteroid is prednisone; the antibodies are chosen among trastuzumab (anti-HER2antibody), rituximab (anti-CD20 antibody), gemtuzamab, cetuximab, pertuzumab and bevacizumab; the antagonists or selective modulators of oestrogen receptors are chosen among tamoxifen, fulvestrant, toremifene, droloxifene, faslodex and raloxifene; the aromatase inhibitors are chosen among exemestane, anastrozole, letrozole and vorozole; the differentiating agents are chosen among retinoids and agents blocking the metabolism of retinoic acid; the DNA methyl-transferase inhibitors are chosen among azacytidine and decitabine; the antifolate is permetrexed disodium; the antibiotics are chosen among antinomycin D, bleomycin, mitomycin C, actinomycin D, carminomycin, daunomycin and plicamycin; the antimetabolites are chosen among chlofarabine, aminopterin, cytosine arabinoside, floxuridine and methotrexate; the apoptosis-inducing agents and anti-angiogenic agents of Bcl-2 inhibitors are chosen among YC 137, BH 312, ABT 737, gossypol, HA 14-1, TW 37 and decanoic acid; the agents binding to tubulin are chosen among combrestatin, colchicine derivatives and nocodazole; the kinase inhibitors are chosen among flavoperidol, imatinib mesylate, erlotinib and gefitinib; the farnesyl transferase inhibitor is tipifarnib; the histone-deacetylase inhibitors are chosen among sodium butyrate, suberoylanilide hydroxamic acid, depsipeptide, NVP-LAQ824, R306465, JNJ-26481585 and trichostatin A; the inhibitors of the ubiquitin-proteasome system are chosen among MLN 0.41, bortezomib and yondelis; and the telomerase inhibitor is telomestatin. 21. The pharmaceutical composition according to claim 20, wherein the camptothecin compounds are chosen among irinotecan and topotecan; the podophyllotoxin derivatives are chosen among etoposide and teniposide; the nitrogen mustards are chosen among cyclophosphamide, mechlorethamine, chlorambucil and melphalan; the nitroso-ureas are chosen among carmustin, lomustin and streptozocin; the alkylsulfonate is busulfan; the ethylenimines and methylmelamines are chosen among thiotepa and hexamethylmelamine; the tetrazine is dacarbazine; the retinoids are chosen among retinoic acid and vitamin D; and the agent blocking the metabolism of retinoic acid is Accutane. 22. A method for the treatment of a cancer, the method comprising the administration to a person in need thereof of an effective amount of the pharmaceutical composition according to claim 11, wherein the cancer is selected from the group consisting of breast cancer, leukaemia, colon cancer, pancreatic cancer, and ovarian cancer. 23. A method for the treatment of a cancer, the method comprising the administration to a person in need thereof of an effective amount of the pharmaceutical composition according to claim 17, wherein the cancer is selected from the group consisting of breast cancer, leukaemia, colon cancer, pancreatic cancer, and ovarian cancer. 24. A method for preparing a formula (I) compound according to claim 1 comprising the following successive steps: a) reacting an amine of following formula (II): ##STR00094## where X, R1, R2, R3, R4 and Ar are as defined in claim 1, R1 not representing a hydrogen atom, with chloroacetyl chloride in the presence of a base to give a formula (I) compound where R1.noteq.H; and b) optionally deprotecting the nitrogen atom carrying the R1.noteq.H group to give a formula (I) compound where R1=H. 25. The method according to claim 24 comprising the following successive steps: i) reacting a ketoester of following formula (V): ##STR00095## where Ar is as defined in claim 1 and R represents a (C.sub.1-C.sub.6)alkyl group; with an aniline of following formula (VI): ##STR00096## where R3 and R4 are as defined in claim 1, to give an imine of following formula (VII): ##STR00097## where R, R3, R4 and Ar are as defined in claim 1; ii) reducing the imine of formula (VII) obtained at the preceding step to give an amine of following formula (VIII): ##STR00098## where R, R3, R4 and Ar are as defined in claim 1; iii) saponifying the ester function of the formula (VIII) compound obtained at the preceding step to give an acid of following formula (IV): ##STR00099## where R3, R4 and Ar are as defined in claim 1; iv) reacting the acid of formula (IV) obtained at the preceding step with a piperazine of following formula (III): ##STR00100## where X, R1 and R2 are as defined in claim 1, R1 not representing a hydrogen atom, to give an amine of formula (II) according to claim 24; v) reacting the amine of formula (II) obtained at the preceding step with chloroacetyl chloride in the presence of a base to give a formula (I) compound where R1.noteq.H; and vi) optionally deprotecting the nitrogen atom carrying the R1.noteq.H group to give a formula (I) compound where R1=H.

Details for Patent 9,321,778

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2031-12-30
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2031-12-30
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Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2031-12-30
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	02/12/2004		2031-12-30
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	03/28/2007		2031-12-30