Claims for Patent: 8,519,188

Summary for Patent: 8,519,188

Title:	Compounds which can be used for the treatment of cancers
Abstract:	The present invention relates to a compound of general formula (I): and also to the pharmaceutically acceptable salts thereof, to the isomers or isomer mixtures thereof in all proportions, in particular to an enantiomer mixture, and especially to a racemic mixture. The present invention also relates to the use of these compounds as a medicament, and in particular for the treatment of cancer, and also to the compositions containing them. ##STR00001##
Inventor(s):	Carniato; Denis (Marcoussis, FR), Jaillardon; Karine (Saint Michel S/orge, FR), Busnel; Olivier (Lille, FR), Gutmann; Mathieu (Vaugrigneuse, FR), Briand; Jean-Francois (Orsay, FR), Deprez; Benoit (Lille, FR), Thomas; Dominique (Gif S/yvette, FR), Bougeret; Cecile (Le Vesinet, FR)
Assignee:	Marc-Henry Pitty (Boulogne, FR)
Application Number:	12/997,764
Patent Claims:	1. A pharmaceutical composition comprising at least one compound of formula (I): ##STR00063## or a pharmaceutically acceptable salt thereof, an isomer or isomer mixture thereof in all proportions, for which: R1 represents a hydrogen atom or a (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.10)cycloalkyl, (C.sub.3-C.sub.10)cycloalkenyl, aryl, heteroaryl, aryl-(C.sub.1-C.sub.6)alkyl, heteroaryl-(C.sub.1-C.sub.6)alkyl group, said group being optionally substituted by one or more groups selected from a halogen atom, (C.sub.1-C.sub.6)alkoxy, --NH.sub.2, --COOH, --CN, --OH, --NR.sup.7R.sup.8, --O--(C.sub.1-C.sub.6)alkyl-NR.sup.7R.sup.8, benzyloxy, aryloxy, --C(O)O--(C.sub.1-C.sub.6)alkyl, --NH--C(O)O--(C.sub.1-C.sub.6)alkyl, --C(O)NH.sub.2, --C(O)NR.sup.9R.sup.10, --S--(C.sub.1-C.sub.6)alkyl, --S(O)--(C.sub.1-C.sub.6)alkyl, --SO.sub.2--(C.sub.1-C.sub.6)alkyl, --SO.sub.2NH.sub.2, --SO.sub.2NR.sup.11R.sup.12, NR.sup.13SO.sub.2R.sup.14 and a (C.sub.1-C.sub.6)alkyl group optionally substituted by one or more halogen atoms, R2 represents a hydrogen atom or a (C.sub.1-C.sub.6)alkyl, or R1 and R2 together form, with the nitrogen atom carrying them: a heteroaryl optionally substituted by one or more groups selected from a halogen atom, a --CN, --NH.sub.2, --NR.sup.40R.sup.41, NO.sub.2, OH, (C.sub.1-C.sub.6)alkoxy, aryloxy, benzyloxy, --O(C.sub.1-C.sub.6)alkyl-NR.sup.42R.sup.43, --C(O)O--(C.sub.1-C.sub.6)alkyl, --NHC(O)O--(C.sub.1-C.sub.6)alkyl, --C(O)NH.sub.2, --C(O)NR.sup.44R.sup.45, --SO.sub.2NH.sub.2, --SO.sub.2NR.sup.46R.sup.47 and --NR.sup.48SO.sub.2R.sup.49 group, or a 3 to 7-membered heterocycle optionally substituted by one or more groups selected from a halogen atom, a (C.sub.3-C.sub.10)cycloalkyl, (C.sub.3-C.sub.10)cycloalkenyl, aryl, heteroaryl, aryl-(C.sub.1-C.sub.6)alkyl, heteroaryl-(C.sub.1-C.sub.6)alkyl, heterocycloalkyl-(C.sub.1-C.sub.6)alkyl, --OH, --NH.sub.2, --C(O)OH, --C(O)NH.sub.2, --C(S)NH.sub.2, --OR.sup.50, --OC(O)R.sup.51, --C(O)R.sup.52, --C(O)OR.sup.53, --NHC(O)R.sup.54, --NHC(O)OR.sup.55, --SO.sub.2R.sup.56--(C.sub.1-C.sub.6)alkyl-C(O)OR.sup.57, --NR.sup.58R.sup.59, --C(O)NR.sup.60R.sup.61, --C(O)N(R.sup.62)(aryl), C(O)N(R.sup.63)(heteroaryl), --C(O)NHNR.sup.64R.sup.65, --C(S)NR.sup.66R.sup.67, --C(S)N(R.sup.68)(aryl), --C(S)N(R.sup.69)(heteroaryl), --C(S)NHNR.sup.70R.sup.71, --OC(O)--NR.sup.72R.sup.73--(C.sub.1-C.sub.6)alkyl-C(O)--NR.sup.74R.sup.7- 5, --(C.sub.1-C.sub.6)alkyl-NR.sup.103--C(O)--OR.sup.104, --(C.sub.1-C.sub.6)alkyl-NR.sup.76R.sup.77, --C(NOR.sup.78)-aryl radical, and a (C.sub.1-C.sub.6)alkyl group optionally substituted by one or more halogen atoms, the aryl and heteroaryl unit of said radical, when present, being optionally substituted by one or more groups selected from a halogen atom, a --CN, --OH, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, --NR.sup.79R.sup.80, --(C.sub.1-C.sub.6)alkyl-NR.sup.81R.sup.82 and --O--(C.sub.1-C.sub.6)alkyl-NR.sup.83R.sup.84 group, R3 represents a hydrogen atom or a (C.sub.1-C.sub.6)alkyl, or --(C.sub.1-C.sub.4)alkyl-NR.sup.15R.sup.16 group, R4 represents a (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.10)cycloalkyl, aryl, or heteroaryl group, said group being optionally substituted by one or more groups selected from a halogen atom, a --(CF.sub.3).sub.2OH, --CN, --NH.sub.2, --OPO.sub.3H.sub.2, --NR.sup.17R.sup.18, --NO.sub.2, --COOH, --OH, --O(C.sub.1-C.sub.6)alkyl-OPO.sub.3H.sub.2, --O--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl, --O(C.sub.1-C.sub.6)alkyl-NR.sup.19R.sup.20, --NR.sup.81 (C.sub.1-C.sub.6)alkyl-NR.sup.85R.sup.86, benzyloxy, --C(O)O--(C.sub.1-C.sub.6)alkyl, --NHC(O)O--(C.sub.1-C.sub.6)alkyl, --C(O)NH.sub.2, --C(O)NR.sup.21R.sup.22, --S--(C.sub.1-C.sub.6)alkyl, --S(O)--(C.sub.1-C.sub.6)alkyl, --SO.sub.2--(C.sub.1-C.sub.6)alkyl, --SO.sub.2NH.sub.2, --SO.sub.2NR.sup.23R.sup.24, --NR.sup.25SO.sub.2R.sup.26, 3 to 7-membered heterocycloalkyl, aryloxy radical, a (C.sub.1-C.sub.6)alkyl group optionally substituted by one or more halogen atoms and a (C.sub.1-C.sub.6)alkoxy optionally substituted by one or more fluorine atoms, and the aryl and heteroaryl unit of said radical, when present, being optionally fused to a 5 or 6-membered heterocycle, or R3 and R4 form with the carbon carrying them a ring selected from a (C.sub.3-C.sub.10)cycloalkyl and a 3 to 7-membered heterocycloalkyl, said ring being optionally substituted by a (C.sub.1-C.sub.6)alkyl, --C(O)--(C.sub.1-C.sub.6)alkyl, --C(O)O--(C.sub.1-C.sub.6)alkyl group, R5 represents a (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.10)cycloalkyl, (C.sub.3-C.sub.10)cycloalkenyl, aryl, heteroaryl, aryl-(C.sub.1-C.sub.6)alkyl, heteroaryl-(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.10)cycloalkyl-(C.sub.1-C.sub.6)alkyl, (3 to 7-membered heterocycloalkyl)-(C.sub.1-C.sub.6)alkyl group, said group being optionally substituted by one or more groups selected from a halogen atom, a --NH.sub.2, --COOH, --CN, --OH, --NO.sub.2, --B(OH).sub.2, (C.sub.1-C.sub.6)alkoxy, --O--(C.sub.1-C.sub.6)alkyl-NR.sup.27R.sup.28, --O--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl, aryloxy, --C(O)O--(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkynyl, --NR.sup.29R.sup.30, --NHC(O)O--(C.sub.1-C.sub.6)alkyl, --C(O)NH.sub.2, --C(O)NR.sup.31R.sup.32, --S--(C.sub.1-C.sub.6)alkyl, --S(O)-- (C.sub.1-C.sub.6)alkyl, --SO.sub.2--(C.sub.1-C.sub.6)alkyl, --SO.sub.2NH.sub.2, --SO.sub.2NR.sup.33R.sup.34, --NR.sup.35SO.sub.2R.sup.36, aryl, heteroaryl, (C.sub.1-C.sub.6)alkylheteroaryl, 3 to 7-membered heterocycloalkyl, (3 to 7-membered heterocycloalkyl)-(C.sub.1-C.sub.6)alkoxy radical and a (C.sub.1-C.sub.6)alkyl group optionally substituted by one or more halogen atoms, the aryl or heteroaryl unit of said radical, when present, being optionally fused to a 5 or 6-membered heterocycle, and R6 represents --CHR.sup.37Hal, with Hal representing a halogen atom, wherein: R.sup.7 to R.sup.13, R.sup.15 to R.sup.18, R.sup.21 to R.sup.25, R.sup.27 to R.sup.35, R.sup.37, R.sup.40 to R.sup.48, R.sup.58 to R.sup.84, R.sup.89 to R.sup.102 represent, independently of one another, a hydrogen atom or a (C.sub.1-C.sub.6)alkyl group, or, if two groups are carried by the same nitrogen, the two groups form with the nitrogen atom carrying them a 3 to 7-membered heterocycloalkyl, R.sup.14, R.sup.26, R.sup.36 and R.sup.49 represent, independently of one another, a (C.sub.1-C.sub.6)alkyl group, R.sup.50 to R.sup.57, R.sup.87 and R.sup.88 represent, independently of one another, a (C.sub.1-C.sub.6)alkyl, aryl, heteroaryl, aryl-(C.sub.1-C.sub.6)alkyl, heteroaryl-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyl-aryl or (C.sub.1-C.sub.6)alkyl-heteroaryl group, and R.sup.19, R.sup.20, R.sup.85 et R.sup.86 represent, independently of one another, a (C.sub.1-C.sub.6)alkyl group, or (R.sup.19 and R.sup.20) and/or (R.sup.85 and R.sup.86) together form, with the nitrogen atom carrying them, a 3 to 7-membered heterocycloalkyl optionally substituted by one or more groups selected from a halogen atom, a (C.sub.3-C.sub.10)cycloalkyl, aryl, heteroaryl, aryl-(C.sub.1-C.sub.6)alkyl, heteroaryl-(C.sub.1-C.sub.6)alkyl, --C(O)OR.sup.87, --SO.sub.2R.sup.88, --OH, (C.sub.1-C.sub.6)alkoxy, --OC(O)--(C.sub.1-C.sub.6)alkyl, --OC(O)--NR.sup.89R.sup.90, --NHC(O)O--(C.sub.1-C.sub.6)alkyl, --C(O)NH.sub.2, --C(O)NR.sup.91R.sup.92, --C(S)NR.sup.93R.sup.94, --C(O)NHNR.sup.95R.sup.96, --C(S)NHNR.sup.97R.sup.98 radical and a (C.sub.1-C.sub.6)alkyl group optionally substituted by one or more halogen atoms, the aryl and heteroaryl unit of said radical, when present, being optionally substituted by one or more groups, selected from a halogen atom and a (C.sub.1-C.sub.6)alkyl, --CN, --OH, NR.sup.99R.sup.100, (C.sub.1-C.sub.6)-alkoxy, --O--(C.sub.1-C.sub.6)alkyl-NR.sup.101R.sup.102 group, in association with one or more pharmaceutically acceptable excipients. 2. The pharmaceutical composition according to claim 1, wherein the isomer mixture is an enantiomer mixture. 3. The pharmaceutical composition according to claim 2, wherein the enantiomer mixture is a racemic mixture. 4. The pharmaceutical composition according to claim 1, wherein R.sup.2 represents a hydrogen atom, and R.sup.1 represents a (C.sub.3-C.sub.10)cycloalkyl or aryl-(C.sub.1-C.sub.6)alkyl group, said group being optionally substituted by one or more groups selected from a halogen atom, a (C.sub.1-C.sub.6)alkoxy, --NH.sub.2, --COOH, --CN, --OH, --NR.sup.7R.sup.8, --O--(C.sub.1-C.sub.6)alkyl-NR.sup.7R.sup.8, benzyloxy, aryloxy, --C(O)O--(C.sub.1-C.sub.6)alkyl, --NH--C(O)O--(C.sub.1-C.sub.6)alkyl, --C(O)NH.sub.2, --C(O)NR.sup.9R.sup.10, --S--(C.sub.1-C.sub.6)alkyl, --S(O)--(C.sub.1-C.sub.6)alkyl, --SO.sub.2--(C.sub.1-C.sub.6)alkyl, --SO.sub.2NH.sub.2, --SO.sub.2NR.sup.11R.sup.12, --NR.sup.13SO.sub.2R.sup.14 radical and a (C.sub.1-C.sub.6)alkyl group optionally substituted by one or more halogen atoms. 5. The pharmaceutical composition according to claim 4, wherein R.sup.1 represents a cyclohexyl, cyclopentyl or benzyl group, said group being optionally substituted by one or more groups selected from a halogen atom, a (C.sub.1-C.sub.6)alkoxy, --NH.sub.2, --COOH, --CN, --OH, --NR.sup.7R.sup.8, --O--(C.sub.1-C.sub.6)alkyl-NR.sup.7R.sup.8, benzyloxy, aryloxy, --C(O)O--(C.sub.1-C.sub.6)alkyl, --NH--C(O)O--(C.sub.1-C.sub.6)alkyl, --C(O)NH.sub.2, --C(O)NR.sup.9R.sup.10, --S--(C.sub.1-C.sub.6)alkyl, --S(O)--(C.sub.1-C.sub.6)alkyl, --SO.sub.2--(C.sub.1-C.sub.6)alkyl, --SO.sub.2NH.sub.2, --SO.sub.2NR.sup.11R.sup.12, --NR.sup.13SO.sub.2R.sup.14 radical and a (C.sub.1-C.sub.6)alkyl group optionally substituted by one or more halogen atoms. 6. The pharmaceutical composition according to claim 5, wherein R.sup.1 represents a cyclohexyl, cyclopentyl or benzyl group, said group being optionally substituted by one or more groups selected from a halogen atom and a (C.sub.1-C.sub.6)alkoxy, --NH.sub.2, --COOH, benzyloxy, aryloxy, --C(O)O((C.sub.1-C.sub.6)alkyl), --NHC(O)O((C.sub.1-C.sub.6)alkyl) group. 7. The pharmaceutical composition according to claim 1, wherein --NR1R2 represents the following piperazine ring: ##STR00064## R.sup.104 representing a hydrogen atom, a (C.sub.3-C.sub.10)cycloalkyl, (C.sub.3-C.sub.10)cycloalkenyl, aryl, heteroaryl, aryl-(C.sub.1-C.sub.6)alkyl, heteroaryl-(C.sub.1-C.sub.6)alkyl, heterocycloalkyl-(C.sub.1-C.sub.6)alkyl, --C(O)R.sup.52, --C(O)OR.sup.53, --C(O)OH, --C(O)NH.sub.2, --C(S)NH.sub.2, --C(O)NR.sup.60R.sup.61, --C(S)NR.sup.66R.sup.67, --SO.sub.2R.sup.56, --C(O)NHNR.sup.64R.sup.65, --C(S)NHNR.sup.70R.sup.71 radical, and a (C.sub.1-C.sub.6)alkyl group optionally substituted by one or more halogen atoms, the aryl and heteroaryl unit of said radical, when present, being optionally substituted by one or more groups selected from a halogen atom, a --CN, --OH, (C.sub.1-C.sub.6)alkoxy, --NR.sup.79R.sup.80, and --O--(C.sub.1-C.sub.6)alkyl-NR.sup.83R.sup.84 group. 8. The pharmaceutical composition according to claim 1, wherein R4 represents a (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.10)cycloalkyl, phenyl, or thiophenyl group, said group being optionally substituted by one or more groups selected from a halogen atom, a --(CF.sub.3).sub.2OH, --CN, --NH.sub.2, --OPO.sub.3H.sub.2, --NR.sup.17R.sup.18, --NO.sub.2, --COOH, --OH, --O(C.sub.1-C.sub.6)alkyl-OPO.sub.3H.sub.2, --O-- (C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl, --O(C.sub.1-C.sub.6)alkyl-NR.sup.19R.sup.20, --NR.sup.81(C.sub.1-C.sub.6)alkyl-NR.sup.85R.sup.86, benzyloxy, --C(O)O--(C.sub.1-C.sub.6)alkyl, --NHC(O)O--(C.sub.1-C.sub.6)alkyl, --C(O)NH.sub.2, --C(O)NR.sup.21R.sup.22, --S--(C.sub.1-C.sub.6)alkyl, --S(O)--(C.sub.1-C.sub.6)alkyl, --SO.sub.2--(C.sub.1-C.sub.6)alkyl, --SO.sub.2NH.sub.2, --SO.sub.2NR.sup.23R.sup.24, --NR.sup.25SO.sub.2R.sup.26, 3 to 7-membered heterocycloalkyl, aryloxy radical, a (C.sub.1-C.sub.6)alkyl group optionally substituted by one or more halogen atoms and a (C.sub.1-C.sub.6)alkoxy optionally substituted by one or more fluorine atoms, and the aryl and heteroaryl unit of said radical, when present, being optionally fused to a 5 or 6-membered heterocycle. 9. The pharmaceutical composition according to claim 1, wherein R.sup.3 represents a hydrogen atom and R.sup.4 represents an aryl or heteroaryl group said group being optionally substituted by one or more groups selected from a halogen atom, a --CF.sub.3, --B(OH).sub.2, --CN, --OH, --NR.sup.17R.sup.18, --NO.sub.2, --COOH, 3 to 7-membered heterocycloalkyl, (C.sub.1-C.sub.6)alkyl, --S-- (C.sub.1-C.sub.6)alkyl, aryloxy, --O(C.sub.1-C.sub.6)alkyl-NR.sup.19R.sup.20 radical and a (C.sub.1-C.sub.6)alkoxy optionally substituted by one or more fluorine atoms, and said group being optionally fused to a 5 or 6-membered heterocycle. 10. The pharmaceutical composition according to claim 9, wherein R4 represents a phenyl or thiophenyl group said group being optionally substituted by one or more groups selected from a halogen atom, a --CF.sub.3, --B(OH).sub.2, --CN, --OH, --NR.sup.17R.sup.18, --NO.sub.2, --COOH, 3 to 7-membered heterocycloalkyl, (C.sub.1-C.sub.6)alkyl, --S-- (C.sub.1-C.sub.6)alkyl, aryloxy, --O(C.sub.1-C.sub.6)alkyl-NR.sup.19R.sup.20 radical and a (C.sub.1-C.sub.6)alkoxy optionally substituted by one or more fluorine atoms, and said group being optionally fused to a 5 or 6-membered heterocycle. 11. The pharmaceutical composition according to claim 1, wherein R5 represents a (C.sub.1-C.sub.6)alkyl, heteroaryl, (C.sub.3-C.sub.10)cyclo alkyl-(C.sub.1-C.sub.6)alkyl, aryl-(C.sub.1-C.sub.6)alkyl or aryl group, the aryl core of the aryl or aryl-(C.sub.1-C.sub.6)alkyl group being optionally fused to a 5 or 6-membered heterocycle, and being optionally substituted by one or more groups selected from a halogen atom, a --CF.sub.3, --CN, --NR.sup.29R.sup.30, --NO.sub.2, --C(CF.sub.3).sub.2OH, (C.sub.1-C.sub.6)alkoxy, aryloxy, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkynyl, aryl and 5 or 6-membered heterocycloalkyl group. 12. The pharmaceutical composition according to claim 11, wherein the 5 or 6-membered heterocycle comprises two oxygen atoms. 13. The pharmaceutical composition according to claim 1, wherein the compound of formula (I) is selected from: ##STR00065## ##STR00066## ##STR00067## ##STR00068## ##STR00069## ##STR00070## ##STR00071## ##STR00072## ##STR00073## ##STR00074## ##STR00075## ##STR00076## ##STR00077## ##STR00078## ##STR00079## 14. The pharmaceutical composition according to claim 1, further comprising at least one other active principle. 15. A pharmaceutical composition comprising: (i) at least one compound of formula (I) as defined in claim 1, and (ii) at least one other active principle, as combination products for use simultaneously, separately or spread over time. 16. The pharmaceutical composition according to claim 14, wherein the at least one active principle is selected from cisplatin and the derivatives thereof; vinca alkaloids; purine analogues; topoisomerase I inhibitors; topoisomerase II inhibitors; antitumoural nucleoside derivatives; alkylating agents; antitumoural anthracycline derivatives; molecules targeting the IGF-I receptor; tetracarcin derivatives; corticosteroids; antibodies; selective oestrogen receptor antagonists or modulators; aromatase inhibitors; differentiating agents; DNA methyltransferase inhibitors; antifolates; antibiotics; antimetabolites; apoptosis inducing agents and Bcl-2 inhibitor antiangiogenic agents; agents binding to tubulin; kinase inhibitors; farnesyltransferase inhibitors; histone deacetylase inhibitors; inhibitors of the ubiquitin proteasome system; and telomerase inhibitors. 17. The pharmaceutical composition according to claim 15, wherein the at least one active principle is selected from cisplatin and the derivatives thereof; vinca alkaloids; purine analogues; topoisomerase I inhibitors; topoisomerase II inhibitors; antitumoural nucleoside derivatives; alkylating agents; antitumoural anthracycline derivatives; molecules targeting the IGF-I receptor; tetracarcin derivatives; corticosteroids; antibodies; selective oestrogen receptor antagonists or modulators; aromatase inhibitors; differentiating agents; DNA methyltransferase inhibitors; antifolates; antibiotics; antimetabolites; apoptosis inducing agents and Bcl-2 inhibitor antiangiogenic agents; agents binding to tubulin; kinase inhibitors; farnesyltransferase inhibitors; histone deacetylase inhibitors; inhibitors of the ubiquitin proteasome system; and telomerase inhibitors. 18. The pharmaceutical composition according to claim 16, wherein the cisplatin derivatives are selected from carboplatin and oxaliplatin; the taxanes are selected from taxol, taxotere, paclitaxel and docetaxel; the vinca alkaloids are selected from vinblastine, vincristine and vinorelbine; the purine analogues are selected from mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine; the topoisomerase I inhibitors are selected from compounds of camptothecin; the topoisomerase II inhibitors are selected from epipodophyllotoxin, podophyllotoxin and the derivatives thereof; thz antitumoural nucleoside derivatives are selected from 5-fluorouracil, leucovorin, gemcitabine and capecitabine; the alkylating agents are selected from nitrogen mustards, nitrosoureas, alkyl sulphonates, ethyleneimines, methylmelamines, and tetrazines; the antitumoural anthracycline derivatives are selected from daunorubicin, adriamycin, doxil, idarubicin and mitoxantrone; the molecule targeting the IGF-I receptor is picropodophyllin; the tetracarcin derivatives is tetrocarcin A; the corticosteroid is prednisone; the antibodies are selected from trastuzumab (anti-HER2 antibody), rituximab (anti-CD20 antibody), gemtuzamab, cetuximab, pertuzumab and bevacizumab; the selective oestrogen receptor antagonists or modulators are selected from tamoxifen, fulvestrant, toremifene, droloxifene, faslodex and raloxifene; the aromatase inhibitors are selected from exemestane, anastrozole, letrozole and vorozole; the differentiating agents are selected from retinoids and retinoic acid metabolism blocking agents; the DNA methyltransferase inhibitors are selected from azacytidine and decitabine; the antifolate is disodium permetrexed; the antibiotics are selected from antinomycin D, bleomycin, mitomycin C, actinomycin D, caminomycin, daunomycin and plicamycin; the antimetabolites are selected from chlofarabine, aminopterin, cytosine arabinoside, floxuridine and methotrexate; the apoptosis inducing agents and Bcl-2 inhibitor antiangiogenic agents are selected from YC 137, BH 312, ABT 737, gossypol, HA 14-1, TW 37 and decanoic acid; the agents binding to tubulin are selected from combrestatin, colchicine derivatives and nocodazole; the kinase inhibitors are selected from flavoperidol, imatinib mesylate, erlotinib and gefitinib; the farnesyltransferase inhibitor is tipifarnib; the histone deacetylase inhibitors are selected from sodium butyrate, suberoylanilide hydroxamic acid, depsipeptide, NVP-LAQ824, R306465, JNJ-26481585 and trichostatin A; the inhibitors of the ubiquitin proteasome system are selected from MLN 0.41, bortezomib and yondelis; and the telomerase inhibitor is telomestatin. 19. The pharmaceutical composition according to claim 17, wherein the cisplatin derivatives are selected from carboplatin and oxaliplatin; the taxanes are selected from taxol, taxotere, paclitaxel and docetaxel; the vinca alkaloids are selected from vinblastine, vincristine and vinorelbine; the purine analogues are selected from mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine; the topoisomerase I inhibitors are selected from compounds of camptothecin; the topoisomerase II inhibitors are selected from epipodophyllotoxin, podophyllotoxin and the derivatives thereof; thz antitumoural nucleoside derivatives are selected from 5-fluorouracil, leucovorin, gemcitabine and capecitabine; the alkylating agents are selected from nitrogen mustards, nitrosoureas, alkyl sulphonates, ethyleneimines, methylmelamines, and tetrazines; the antitumoural anthracycline derivatives are selected from daunorubicin, adriamycin, doxil, idarubicin and mitoxantrone; the molecule targeting the IGF-I receptor is picropodophyllin; the tetracarcin derivatives is tetrocarcin A; the corticosteroid is prednisone; the antibodies are selected from trastuzumab (anti-HER2 antibody), rituximab (anti-CD20 antibody), gemtuzamab, cetuximab, pertuzumab and bevacizumab; the selective oestrogen receptor antagonists or modulators are selected from tamoxifen, fulvestrant, toremifene, droloxifene, faslodex and raloxifene; the aromatase inhibitors are selected from exemestane, anastrozole, letrozole and vorozole; the differentiating agents are selected from retinoids and retinoic acid metabolism blocking agents; the DNA methyltransferase inhibitors are selected from azacytidine and decitabine; the antifolate is disodium permetrexed; the antibiotics are selected from antinomycin D, bleomycin, mitomycin C, actinomycin D, caminomycin, daunomycin and plicamycin; the antimetabolites are selected from chlofarabine, aminopterin, cytosine arabinoside, floxuridine and methotrexate; the apoptosis inducing agents and Bcl-2 inhibitor antiangiogenic agents are selected from YC 137, BH 312, ABT 737, gossypol, HA 14-1, TW 37 and decanoic acid; the agents binding to tubulin are selected from combrestatin, colchicine derivatives and nocodazole; the kinase inhibitors are selected from flavoperidol, imatinib mesylate, erlotinib and gefitinib; the farnesyltransferase inhibitor is tipifarnib; the histone deacetylase inhibitors are selected from sodium butyrate, suberoylanilide hydroxamic acid, depsipeptide, NVP-LAQ824, R306465, JNJ-26481585 and trichostatin A; the inhibitors of the ubiquitin proteasome system are selected from MLN 0.41, bortezomib and yondelis; and the telomerase inhibitor is telomestatin. 20. The pharmaceutical composition according to claim 19, wherein the compounds of camptothecin are selected from irinotecan and topotecan; the podophyllotoxin derivatives are selected from etoposide and teniposide; the nitrogen mustards are selected from cyclophosphamide, mechlorethamine, chlorambucil and melphalan; the nitrosoureas are selected from carmustine, lomustine and streptozocin; the alkyl sulphonate is busulphan; the ethyleneimines and methylmelamines are selected from thiotepa and hexamethylmelamine; the tetrazine is dacarbazine; the retinoids are selected from retinoic acid and vitamin D; and the retinoic acid metabolism blocking agent is accutane. 21. The pharmaceutical composition according to claim 19, wherein the compounds of camptothecin are selected from irinotecan and topotecan; the podophyllotoxin derivatives are selected from etoposide and teniposide; the nitrogen mustards are selected from cyclophosphamide, mechlorethamine, chlorambucil and melphalan; the nitrosoureas are selected from carmustine, lomustine and streptozocin; the alkyl sulphonate is busulphan; the ethyleneimines and methylmelamines are selected from thiotepa and hexamethylmelamine; the tetrazine is dacarbazine; the retinoids are selected from retinoic acid and vitamin D; and the retinoic acid metabolism blocking agent is accutane. 22. A method for treating a cancer comprising administering to a person in need thereof of an effective amount of a compound of formula (I) as defined in claim 1, wherein the cancer is selected from the group consisting of breast cancer, myeloma, and leukaemia. 23. The method according to claim 22, wherein the cancer is a cancer resistant to chemotherapy. 24. A compound of general formula (I): ##STR00080## wherein R1, R2, R3, R4, R5 and R6 are as defined in claim 1, provided that: if R1 represents a hydrogen atom, a tert-butyl, sec-butyl, cyclohexyl, hexyl, ethyl or methyl group, or a phenyl group, optionally substituted by one or more groups selected from F, ethoxy and CF.sub.3, R2 represents a hydrogen atom or a methyl group, or R1 and R2 together form, with the nitrogen atom carrying them, a morpholine or piperidine group, R3 represents a hydrogen atom, and R4 represents a methyl or ethyl group or a phenyl group optionally substituted with one or more groups selected from Cl, OH, methoxy, NO.sub.2 or NMe.sub.2, or R3 and R4 together form, with the carbon atom carrying them, a cyclopentane or cyclohexane, and R6 represents a --CH.sub.2Cl group, then R5 does not represent a prop-2-yne, (C.sub.1-C.sub.8)alkyl, furylmethyl, tetrahydropyrane, thiopyrane or 1,3-benzodioxolyl-methyl group; or a benzyl group optionally substituted by a chlorine atom or NO.sub.2; or a phenyl group optionally substituted by one or more Br, ethyl or methyl groups. 25. The compound according to claim 24, selected from: ##STR00081## ##STR00082## ##STR00083## ##STR00084## ##STR00085## ##STR00086## ##STR00087## ##STR00088## ##STR00089## ##STR00090## ##STR00091## ##STR00092## ##STR00093## ##STR00094## ##STR00095## 26. The method according to claim 23, wherein the cancer is resistant to adriamycin or doxorubicin. 27. A pharmaceutical composition comprising at least one compound of formula (I): ##STR00096## or a pharmaceutically acceptable salt thereof, an isomer or isomer mixture thereof in all proportions, for which: R1 represents a hydrogen atom or a (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.10)cycloalkyl, (C.sub.3-C.sub.10)cycloalkenyl, aryl, aryl-(C.sub.1-C.sub.6)alkyl, heteroaryl-(C.sub.1-C.sub.6)alkyl group, said group being optionally substituted by one or more groups selected from a halogen atom, (C.sub.1-C.sub.6)alkoxy, --NH.sub.2, --COOH, --CN, --OH, --NR.sup.7R.sup.8, --O-- (C.sub.1-C.sub.6)alkyl-NR.sup.7R.sup.8, benzyloxy, aryloxy, --C(O)O--(C.sub.1-C.sub.6)alkyl, --NH--C(O)O--(C.sub.1-C.sub.6)alkyl, --C(O)NH.sub.2, --C(O)NR.sup.9R.sup.10, --S(C.sub.1-C.sub.6)alkyl, --S(O)--(C.sub.1-C.sub.6)alkyl, --SO.sub.2--(C.sub.1-C.sub.6)alkyl, --SO.sub.2NH.sub.2, --SO.sub.2NR.sup.11R.sup.12, --NR.sup.13SO.sub.2R.sup.14 and a (C.sub.1-C.sub.6)alkyl group optionally substituted by one or more halogen atoms, R2 represents a hydrogen atom or a (C.sub.1-C.sub.6)alkyl, or R1 and R2 together form, with the nitrogen atom carrying them: a heteroaryl optionally substituted by one or more groups selected from a halogen atom, a --CN, --NH.sub.2, --NR.sup.40R.sup.41, NO.sub.2, OH, (C.sub.1-C.sub.6)alkoxy, aryloxy, benzyloxy, --O(C.sub.1-C.sub.6)alkyl-NR.sup.42R.sup.43, --C(O)O--(C.sub.1-C.sub.6)alkyl, --NHC(O)O--(C.sub.1-C.sub.6)alkyl, --C(O)NH.sub.2, --C(O)NR.sup.44R.sup.45, --SO.sub.2NH.sub.2, --SO.sub.2NR.sup.46R.sup.47 and --NR.sup.48SO.sub.2R.sup.49 group, or a 3 to 7-membered heterocycle optionally substituted by one or more groups selected from a halogen atom, a (C.sub.3-C.sub.10)cycloalkyl, (C.sub.3-C.sub.10)cycloalkenyl, aryl, heteroaryl, aryl-(C.sub.1-C.sub.6)alkyl, hetero aryl-(C.sub.1-C.sub.6)alkyl, heterocycloalkyl-(C.sub.1-C.sub.6)alkyl, --OH, --NH.sub.2, --C(O)OH, --C(O)NH.sub.2, --C(S)NH.sub.2, --OR.sup.50, --OC(O)R.sup.51, --C(O)R.sup.52, --C(O)OR.sup.53, --NHC(O)R.sup.54, --NHC(O)OR.sup.55, --SO.sub.2R.sup.56--(C.sub.1-C.sub.6)alkyl-C(O)OR.sup.57, NR.sup.58R.sup.59, --C(O)NR.sup.60R.sup.61, --C(O)N(R.sup.62)(aryl), C(O)N(R.sup.63)(heteroaryl), --C(O)NHNR.sup.64R.sup.65, --C(S)NR.sup.66R.sup.67, --C(S)N(R.sup.68)(aryl), --C(S)N(R.sup.69)(heteroaryl), --C(S)NHNR.sup.70R.sup.71, --OC(O)--NR.sup.72R.sup.73, --(C.sub.1-C.sub.6)alkyl-C(O)--NR.sup.74R.sup.75, --(C.sub.1-C.sub.6)alkyl-NR.sup.103--C(O)--OR.sup.104, --(C.sub.1-C.sub.6)alkyl-NR.sup.76R.sup.77, --C(NOR.sup.78)-aryl radical, and a (C.sub.1-C.sub.6)alkyl group optionally substituted by one or more halogen atoms, the aryl and heteroaryl unit of said radical, when present, being optionally substituted by one or more groups selected from a halogen atom, a --CN, --OH, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, --NR.sup.79R.sup.80, --(C.sub.1-C.sub.6)alkyl-NR.sup.81R.sup.82 and --O--(C.sub.1-C.sub.6)alkyl-NR.sup.83R.sup.84 group, R3 represents a hydrogen atom or a (C.sub.1-C.sub.6)alkyl, or --(C.sub.1-C.sub.4)alkyl-NR.sup.15R.sup.16 group, R4 represents a hydrogen atom or a (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.10)cycloalkyl, aryl, or heteroaryl group, said group being optionally substituted by one or more groups selected from a halogen atom, a --(CF.sub.3).sub.2OH, --CN--NH.sub.2, --OPO.sub.3H.sub.2, --NR.sup.17R.sup.18, --NO.sub.2, --COOH, --OH, --O(C.sub.1-C.sub.6)alkyl-OPO.sub.3H.sub.2, --O--(C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl, --O(C.sub.1-C.sub.6)alkyl-NR.sup.19R.sup.20, --NR.sup.81(C.sub.1-C.sub.6)alkyl-NR.sup.85R.sup.86, benzyloxy, --C(O)O--(C.sub.1-C.sub.6)alkyl, --NHC(O)O--(C.sub.1-C.sub.6)alkyl, --C(O)NH.sub.2, --C(O)NR.sup.21R.sup.22, --S--(C.sub.1-C.sub.6)alkyl, --S(O)--(C.sub.1-C.sub.6)alkyl, --SO.sub.2--(C.sub.1-C.sub.6)alkyl, --SO.sub.2NH.sub.2, --SO.sub.2NR.sup.23R.sup.24, --NR.sup.25SO.sub.2R.sup.26, 3 to 7-membered heterocycloalkyl, aryloxy radical, a (C.sub.1-C.sub.6)alkyl group optionally substituted by one or more halogen atoms and a (C.sub.1-C.sub.6)alkoxy optionally substituted by one or more fluorine atoms, and the aryl and heteroaryl unit of said radical, when present, being optionally fused to a 5 or 6-membered heterocycle, or R3 and R4 form with the carbon carrying them a ring selected from a (C.sub.3-C.sub.10)cycloalkyl and a 3 to 7-membered heterocycloalkyl, said ring being optionally substituted by a (C.sub.1-C.sub.6)alkyl, --C(O)--(C.sub.1-C.sub.6)alkyl, --C(O)O--(C.sub.1-C.sub.6)alkyl group, R5 represents a (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.10)cycloalkyl, (C.sub.3-C.sub.10)cycloalkenyl, aryl, heteroaryl, aryl-(C.sub.1-C.sub.6)alkyl, heteroaryl-(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.10)cycloalkyl-(C.sub.1-C.sub.6)alkyl, (3 to 7-membered heterocycloalkyl)-(C.sub.1-C.sub.6)alkyl group, said group being optionally substituted by one or more groups selected from a halogen atom, a --NH.sub.2, --COOH, --CN, --OH, --NO.sub.2, --B(OH).sub.2, (C.sub.1-C.sub.6)alkoxy, --O--(C.sub.1-C.sub.6)alkyl-NR.sup.27R.sup.28, --O-- (C.sub.1-C.sub.6)alkyl-O--(C.sub.1-C.sub.6)alkyl, aryloxy, --C(O)O--(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkynyl, --NR.sup.29R.sup.30, --NHC(O)O--(C.sub.1-C.sub.6)alkyl, --C(O)NH.sub.2, --C(O)NR.sup.31R.sup.32, --S--(C.sub.1-C.sub.6)alkyl, --S(O)--(C.sub.1-C.sub.6)alkyl, --SO.sub.2--(C.sub.1-C.sub.6)alkyl, --SO.sub.2NH.sub.2, --SO.sub.2NR.sup.33R.sup.34, --NR.sup.35SO.sub.2R.sup.36, aryl, heteroaryl, (C.sub.1-C.sub.6)alkylheteroaryl, 3 to 7-membered heterocycloalkyl, (3 to 7-membered heterocycloalkyl)-(C.sub.1-C.sub.6)alkoxy radical and a (C.sub.1-C.sub.6)alkyl group optionally substituted by one or more halogen atoms, the aryl or heteroaryl unit of said radical, when present, being optionally fused to a 5 or 6-membered heterocycle, and R6 represents --C.ident.CR.sup.38, wherein: R.sup.7 to R.sup.13, R.sup.15 to R.sup.18, R.sup.21 to R.sup.25, R.sup.27 to R.sup.35, R.sup.40 to R.sup.48, R.sup.58 to R.sup.84, R.sup.89 to R.sup.102 represent, independently of one another, a hydrogen atom or a (C.sub.1-C.sub.6)alkyl group, or, if two groups are carried by the same nitrogen, the two groups form with the nitrogen atom carrying them a 3 to 7-membered heterocycloalkyl, R.sup.14, R.sup.26, R.sup.36, and R.sup.49 represent, independently of one another, a (C.sub.1-C.sub.6)alkyl group, R.sup.38 represents a hydrogen atom, a (C.sub.1-C.sub.6)alkyl group, or a phenyl group, R.sup.50 to R.sup.57, R.sup.87 and R.sup.88 represent, independently of one another, a (C.sub.1-C.sub.6)alkyl, aryl, heteroaryl, aryl-(C.sub.1-C.sub.6)alkyl, heteroaryl-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyl-aryl or (C.sub.1-C.sub.6)alkyl-heteroaryl group, and R.sup.19, R.sup.20, R.sup.85 and R.sup.86 represent, independently of one another, a (C.sub.1-C.sub.6)alkyl group, or (R.sup.19 and R.sup.20) and/or (R.sup.85 and R.sup.86) together form, with the nitrogen atom carrying them, a 3 to 7-membered heterocycloalkyl optionally substituted by one or more groups selected from a halogen atom, a (C.sub.3-C.sub.10)cycloalkyl, aryl, heteroaryl, aryl-(C.sub.1-C.sub.6)alkyl, heteroaryl-(C.sub.1-C.sub.6)alkyl, --C(O)OR.sup.87, --SO.sub.2R.sup.88, --OH, (C.sub.1-C.sub.6)alkoxy, --OC(O)-- (C.sub.1-C.sub.6)alkyl, --OC(O)--NR.sup.89R.sup.90, --NHC(O)O--(C.sub.1-C.sub.6)alkyl, --C(O)NH.sub.2, --C(O)NR.sup.91R.sup.92, --C(S)NR.sup.93R.sup.94, --C(O)NHNR.sup.95R.sup.96, --C(S)NHNR.sup.97R.sup.98 radical and a (C.sub.1-C.sub.6)alkyl group optionally substituted by one or more halogen atoms, the aryl and heteroaryl unit of said radical, when present, being optionally substituted by one or more groups, selected from a halogen atom and a (C.sub.1-C.sub.6)alkyl, --CN, --OH, NR.sup.99R.sup.100, (C.sub.1-C.sub.6)alkoxy, --O--(C.sub.1-C.sub.6)alkyl-NR.sup.101R.sup.102 group, in association with one or more pharmaceutically acceptable excipients. 28. The pharmaceutical composition according to claim 27, wherein the compound of formula (I) is selected from: ##STR00097## ##STR00098## ##STR00099## ##STR00100## ##STR00101## ##STR00102## ##STR00103## ##STR00104## ##STR00105## ##STR00106## ##STR00107## ##STR00108## ##STR00109## ##STR00110## ##STR00111## ##STR00112## ##STR00113## ##STR00114## ##STR00115## ##STR00116## ##STR00117## ##STR00118## ##STR00119## ##STR00120## ##STR00121## ##STR00122## ##STR00123## ##STR00124##

Details for Patent 8,519,188

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2028-06-13
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2028-06-13
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Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2028-06-13
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	02/12/2004		2028-06-13
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Genentech, Inc.	AVASTIN	bevacizumab	Injection	125085	02/26/2004		2028-06-13