Combination treatment of solid cancers with antimetabolites and tyrosine kinase inhibitors

摘要

A 2-aminoarylthiazole or 2-aminoaryloxazole of formula II: ** Formula ** wherein the substituents Z and R1-R3 in Formula II are defined as follows: Z is oxygen or sulfur, R1 and R2 are selected from: i) hydrogen, F, Cl, Br, I, ii) an alkyl group 1 defined as a linear, branched or cycloalkyl group containing 1 to 10 carbon atoms and optionally substituted with one or more heteroatoms selected from F, Cl, Br, I , oxygen, and nitrogen, the latter optionally in the form of a pending basic nitrogen functionality; as well as trifluoromethyl, carboxyl, cyano, nitro, formyl; as well as CO-R, COO-R, CONH-R, SO2-R, and SO2NH-R where R is a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with at least one selected heteroatom F, Cl, Br, I, oxygen, and nitrogen, the latter optionally in the form of a pending basic nitrogen functionality; as well as a cycloalkyl or aryl1 or heteroaryl1 group optionally substituted by a pendant basic nitrogen functionality, or iii) an aryl1 group defined as phenyl or a substituted variant thereof bearing any combination, at any ring position, of one or more substituents selected from: I, F, Cl, or Br; an alkyl1 group; a cycloalkyl, aryl, or heteroaryl group optionally substituted by a pending basic nitrogen functionality; trifluoromethyl, O-alkyl1, carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl, N (alkyl1) (alkyl1), and amino, the latter nitrogen substituents optionally in the form of a basic nitrogen functionality; NHCO-R or NHCOO-R or NHCONH-R or NHSO2-R or NHSO2NH-R or CO-R or COO-R or CONH-R or SO2-R or SO2NH25 R or C (NOH) NH2, C (N) NH2 wherein R corresponds to hydrogen, alkyl1, aryl or heteroaryl, or iv) a heteroaryl1 group defined as a pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyrrolyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl group. , indolyl, benzimidazole, benzoxazole, benzothiazole, quinolinyl group, which may additionally carry any combination, at any position in the ring, of one or more substituents selected from F, Cl, Br, I; an alkyl1 group; a cycloalkyl, aryl or heteroaryl group optionally substituted by a pending basic nitrogen functionality; trifluoromethyl, O-alkyl1, carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl1, N (alkyl1) (alkyl1) and amino, the latter nitrogen substituents optionally in the form of a basic nitrogen functionality; NHCO-R or NHCOO-R or NHCONH-R or NHSO2-R or NHSO2NH-R or CO-R or COO-R or CONH-R or SO2-R or SO2NHR where R corresponds to hydrogen, alkyl1, or v) a group O-aryl1, or NH-aryl1, or O-heteroaryl1 or NH-heteroaryl1 vi) trifluoromethyl, O-alkyl1, carboxyl, cyano, nitro, formyl, hydroxy, NH-alkyl1, N (alkyl1) (alkyl1) and amino, these last nitrogen substituents optionally in the form of a basic nitrogen functionality, or vii) NHCO-R or NHCOO-R or NHCONH-R or NHSO2-R or NHSO2NH-R or CO-R or COO-R or CONH-R or SO2 -R or SO2NH-R where R corresponds to hydrogen, alkyl1, aryl1 or heteroaryl1 R3 is selected from hydrogen, F, Cl, Br, I, a linear or branched alkyl group containing from 1 to 10 carbon atoms and optionally substituted with one or more heteroatoms selected from F, Cl, Br, I, oxygen, and nitrogen, the latter optionally in the form of a pending basic nitrogen functionality; as well as trifluoromethyl, C1-6 alkyloxy, amino, C1-6 alkylamino, di (C1-6alkyl) amino, carboxyl, cyano, nitro, formyl, hydroxy, and COR, COO-R, CONHR, SO2-R, and SO2NH -R where R corresponds to hydrogen, alkyl1, aryl or heteroaryl, and at least one antineoplastic agent selected from the group comprising gemcitabine, docetaxel, paclitaxel, irinotecan, doxorubicin, 5-fluorouracil, vincristine, etoposide, lomustine, dacarbazine, cisplatin and carboplatin, for use in the treatment of a solid cancer resistant to said at least one antineoplastic agent, in patients in need of such treatment.