New 2-(hetero)aryl-tetrahydroquinoline derivatives and 1,2,3,4-tetrahydro-1,5-naphthyridine derivatives are mitotic motor protein Eg5 inhibitors used as anticancer agents for treating carcinoma or leukemia

摘要

2-(Hetero)aryl-substituted 1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydro-1,5-naphthyridine derivatives (I) (including tricyclic analogs, e.g. pyrano-quinolines), are new. 2-(Hetero)aryl-substituted 1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydro-1,5-naphthyridine derivatives of formula (I) and their derivatives, solvates, tautomers, salts and stereoisomers (including mixtures in all proportions) are new. W = CH or N; R 1 - R 3 = H, R, A, Ar, halo, (CY 2) n-Q 1, cycloalkyl, SMe, SCN, CF 3, OCF 3, OA, SCF 3, SF 5, SiMe 3, CO-(CY 2) n-Me, CH(CH 2) n-Q 2, NCO, NCOOR, N(CH 2) nOH, CHNH 2, C(OH)R, CHNCOR, N(CH 2) nCOOR, N(CH 2) nCONR 2, XCONR(CH 2) nNR 2, N((CH 2) nXCOOR)-CO(CH 2) nAr, N((CH 2) nXR)-Q 3, N((CH 2) nNRCOOR)CO(CH 2) nAr, N((CH 2) nNR 2)-Q 4, O(CH 2) nNR 2, X(CH 2) nNR 2 or NCO(CH 2) nNR 2, or R 1 + R 2 = -N-C(CF 3)=N-, -N-CR=N- or -N-N=N-; Q 1 = SA, SCF 3, SCN, CF 3, OCF 3, OH, COOR, CN, halo, NR 2, OA, OCOA, CONR 2, NHCOA, NHSO 2A or N-pyrrolidone; Q 2 = NRCOOR, COOR, OH, NR 2, Ar, R 1 or X(CH 2) nAr; Q 3 = CO(CH 2) nAr, CO(CH 2) nXAr or SO 2(CH 2) nAr; Q 4 = CO(CH 2) nAr, CO(CH 2) nNRAr or SO 2(CH 2) nAr; Ar = aryl or heteroaryl; Y = H, A or halo; A = alkyl or cycloalkyl (both os by one or more halo); R = H or A, or geminal groups R = (CH 2) 5, (CH 2) 4, (CH 2) 2X(CH 2) 2 or (CH 2) 2Z(CH 2) 2; (MK#12) R 4, R 5 = H, N-pyrrolidone residue (optionally substituted by one or more of OR, NO 2, halo, CF 3, OCF 3, CN, NR 2, SR or Ar), -X(CH 2) 2OR, -XCO(CH 2) nMe, -X(CH 2) 2NR 2, R 1, arylthio, aryloxy or CH 2SiMe 3, or R 4 + R 5 = X(CR 2) 2, X(CR 2) 3, X(CHCH 2OR)(CH 2) 2, X(CHCH 2NR 2)(CH 2) 2, X(CH 2) 2NR 2, (CR 2) 3, X(CR 2) 4, CR=CR-CR=CR, XCHQ(CR 2) 2, XCHQCR 2, R-N-(C=X)-N-R or XC((CH 2) nOR) 2CH 2CH 2; X = O, S or NR; Q = halomethyl, CHO, COR a, CH 2R a, CH 2OCOR a, CH 2NCOR 1, CH 2N(R 1) 2, CH 2OR 1, CH 2OCON(R 1) 2, CH 2OCOOR 1, CH 2NHCON(R 1) 2 or -CH 2NHCOOR 1; R a = -(CH 2) n-(X(CH 2) n) m-Q 5, 4-(CH 2CH(CONH 2)-COO-(CH 2) nQ 6)-1H-imidazol-1-yl, 2-oxa-3-oxo-4,7,7-tri-(R)-bicyclo-(2,2,1)-heptan-ylcarbonyloxy, OR, NHR 2, NR 2, NR(CH 2) n-aryl, NR(CH 2) n-OR, COOR, N-pyrrolidone, OCOR, NR(CH 2) n-NR 2, N((CH 2) nNR 2)CO(CH 2) nQ 7, N((CH 2) nNHCOOR)-CO-aryl, R 1, N(CH 2(CH 2) nOR) 2, NR(CH 2) nNCOOR, X(CH 2) nX(CH 2) nXR, X(CH 2) nX(CH 2) nOH, NR(CH 2) nO(CH 2) nOH, (CH 2) nCOOR, OCONR(CH 2) nOR, OCONR(CH 2) nNR 2, NR(CH 2) nNR 2, N((CH 2) nXR)CO(CH 2) nAr, N(R)(CH2) nN(R)COOR, XCOO(CH 2) nNR 2, OSO 2A, OSO 2CF 3, OSO 2-aryl, OCONR 2 or OCH 2(CH 2) nNR 2; Q 5 = 2- or 3-oxo-piperidino, 3,3,5,5- or 2,2,6,6-tetra-(R)-cyclohexyl or 3,3,5,5-tetra-(R)-piperidino, all having CH 2 in the 4-position replaced by Z, or R 1-substituted 2-oxo-pyrrolidino, cyclopentyl, pyrrolidino (optionally substituted by NR 2 or in the 3-position by NA 2), R 1-substituted 2-thienyl, 1H-imidazol-1-yl or 1H-1,2,4-tetrazol-1-yl; Q 6 = Ar or R 1; Q 7 = CO(CH 2) nAr; Z = CH 2, X, CHCONH 2, CH(CH 2) n-Q 2, NCO, NCOOR, N(CH 2) nOH, CHNH 2, C(OH)R, CHNCOR, N(CH 2) nCOOR, N(CH 2) nCONR 2, XCONR(CH 2) nNR 2, N((CH 2)XCOOR)-CO(CH 2) nAr, N((CH 2) nXR)-Q 3, N((CH 2) nNRCOOR)CO(CH 2) nAr, N((CH 2) nNR 2)-Q 4, O(CH 2) nNR 2, X(CH 2) nNR 2 or NCO(CH 2) nNR 2; R 6 = Ar (optionally substituted by one or more of Ar (optionally substituted by halo, NO 2, CN, A, OR, OCOR, COR, NR 2, CF 3 , OCF 3 or OCH(CF 3) 2), halo, NO 2, CN, OR, A, (CY 2) nOR, OCOR, (CY 2) n-COOR, (CY 2) n-CN, NCOR, COR or (CY 2) n-NR 2)); R 7 = COR, CONR 2, COOR, H or A; m = 0-2, and n = 0-7. Independent claims are also included for: (1) the preparation of (I); and (2) mixtures of compounds (I) with each other or with bis-aromatic compounds of formula (V) (specifically pentamidine or its salt) or their analogs or metabolites. Y', Z' = O or N; R 9, R 10 = H, OH, halo, 1-10C alkoxy, OCF 3, NO 2 or NH 2; n = 2-6, and R 8, R 11 (in m- or p-position) = -C(NH 2)=NH, -C(NH 2)=NOH, imidazolin-2-yl, 1-methyl-imidazolin-2-yl or tetrazol-5-yl. [Image] ACTIVITY : Cytostatic. MECHANISM OF ACTION : Mitotic motor protein inhibitor; Mitotic motor protein regulator; Mitotic motor protein modulator. In a test, 3,4-tetrahydropyrano-fused 6-tert. butyl-2-(3-thienyl)-1,2,3,4-tetrahydroquinoline derivative (Ia) inhibited the cell cycle of HCT cells, typically in presence of 0.4 mu M the cells were in 7% G1, 7% S and 86% G2/M phase, compared with 36% G1, 43% S and 21% G2/M in the absence of (Ia).