CYTOTOXIC AGENTS UNDERSTANDING NEW TOMAIMYCIN DERIVATIVES.

摘要

Compounds of formula (I): where: ---- represents an optional single bond; ---- represents either a single bond or a double bond; with the proviso that when ---- represents a single bond, U and U ', the same or different, independently represent H and W and W, the same or different, are independently selected from the group consisting of OH, -OR, -OCOR, -OCOOR, -OCONRR', a cyclic carbamate such that N10 and C11 are a part of the cycle, -NRCONRR ', -OCSNHR, a cyclic thiocarbamate such that N10 and C11 are a part of the cycle, -SH, -SR, -SOR, -SOOR, 10-SO3, -OSO3, -NRSOOR, -NRR' , optionally cyclic amine such that N10 and C11 are a part of the cycle, - NROR ', -NRCOR, -N3, a cyano, a halo, a triarylphosphonium trialkyl; and when it represents a double bond, U and U' are absent and W and W 'represent H; R1, R2, R1 ', R2' are the same or different and are independently selected from a Halide or Alkyl optionally substituted with one or more Hal, CN, NRR ', CF3, OR, Aryl, Het, S (O) qR, or R1 and R2 and R1 'and R2' together form a group containing a double bond = B and = B 'respectively.B and B' are the same or different and are independently selected from alkyl optionally substituted with one or more of Hal, CN, NRR ', CF3, OR, S (O) qR, Aryl, Het; - A and A 'are the same or different and are independently selected from Alkyl or Alkenyl each being optionally substituted with one or more of Hal, CN, NRR', CF3, OR, S (O) qR, Aryl, Het, Alkyl, Alkenyl - Y and Y 'are the same or different and are independently chosen from H, OR; - q is 0, 1 or 2; n, n', same or different, are 0 or 1; R and R 'are the same or different and are independently selected from H, Alkyl, Aryl, each being optionally substituted with Hal, CN, NRR ', CF3, OR, Aryl, Het; - T is -NR- or an aryl or heteroaryl of 4 to 10 members, each being optionally substituted with one or more Hal, CN, NRR ', CF3, OR, S (O) q R, alkyl and substituted with one or more substituent (s) containing thiol-, sulfuro-odisulfide of formula: - (CR13R14) t (CR15R16) u (OCH2CH2) ySZ ';-( CR13R14) t (CR17 = CR18) (CR15R16) and (OCH2CH2) ySZ' ;-( CR13R14) t (NT19CO) (CR15R18) u (OCH2CH2) ySZ ';-( CR13R14) t (OCO) (R15R16) u (OCH2CH2) ySZ ';-( CR13R14) t (CO) (CR15R16) u (OCH2CH2) ySZ' :-( CR13R14) t (CONR19) (CR15R16) u (OCH2CH2) ySZ ';-( CR13R14) t-phenyl-CO (CR15R16) uSZ'; - (CR13R14) t-furyl-CO (CR15R16) uSZ ';-( CR13R14) t-oxazolyl-CO (CR15R16) uSZ'; - (CR13R14) t-thiazolyl-CO (CR15R16) uSZ ';-( CR13R14) t-thienyl-CO (CR15R16) uSZ' ;-( CR13R14) t-imidazolyl-CO (CR15R16) uSZ ', E0629015403-01- 46 - (CR13R14) t-morpholino-CO (CR15R16) uSZ ';-( CR13R14) t-piperazino-CO (CR15R16) uSZ' ;-( CR13R14) tN-methyl-piperazino-CO (CR15R16) uSZ ';-( CR13R14 ) t-phenyl-QSZ ';-( CR13R14) t-furyl-QSZ'; - (CR13R14) t-oxazolyl-QSZ ';-( CR13R14) t-thiazolyl-QSZ' ;-( CR13R14) t-thienyl-QSZ ';-( CR13R14) t-imidazolyl-QSZ' ;-( CR13R14) t- morpholino-QSZ '; - (CR13R14) t-piperazino-QSZ ';-( CR13R14) tN-methylpiperazino-QSZ'; - O (CR13R14) t (CR15R16) or (OCH2CH2) and SZ '; - O (CR13R14) t-NR19CO) (CR15R16) u (OCH2CH2) and SZ '; - O (CR13R14) t (CR17 = CR18) (CR15R16) t (OCH2CH2) and SZ'; 10-O-phenyl-OSZ '; - O-furil-QSZ'; -O-oxazolyl-QSZ '; -O-thiazolyl-QSZ '; -O-thienyl-QSZ '; - O-imidazolyl-QSZ'; - O-morpholino-QSZ '; - O-piperazino-QSZ'; - ON-methylpiperazino-QSZ '; - OCO- (CR13R14) t (CR17 = CR18) (CR15R16) u (OCH2CH2) ySZ '; - OCONR12 (CR13R14) t (CR15R16) u (OCH2CH2) ySZ'; 15-OCO-phenyl-QSZ '; -OCO-furil-QSZ '; -OCO-oxazolyl-QSZ '; - OCO-thiazolyl-QSZ'; - OCO-thienyl-QSZ '; - OCO-imidazolyl-QSZ'; - OCO-morpholino-QSZ '; -OCO-piperazino-QSZ'; -OCO-N-methylpiperazino-QSZ '; - CO (CR13R14) t (CR15R16) u (OCH2CH2) and SZ'; - CO- (CR13R14) t (CR17 = CR18) (CR15R16) u (OCH2CH2) and SZ '; - CONR12 (CR13R14) tCR15R16) or (OCH2CH2) and SZ '; - CO-phenyl-QSZ'; -CO-furil-QSZ '; -CO-oxazolyl-QSZ '; -CO-thiazolyl-QSZ '; -CO-thienyl-QSZ '; -CO-imidazolyl-QSZ '; -CO-morpholino-QSZ '; -CO-piperazino-QSZ '; - CO-piperidino-QSZ'; - CO-N-methylpiperazino-QSZ '; - NR19 (CR13R14) t (CR15R16) or (OCH2CH2) and SZ'; - NR19CO (CR13R14) t (CR15R16 ) u (OCH2CH2) ySZ '; - NR19 (CR13R14) t (CR17 = CR18) (CR15R16) t (OCH2CH2) and SZ'; - NR19CO (CR13R14) t (CR17 = CR18) (CR15R16) t (OCH2CH2) and SZ '; -NR19CONR12 (CR13R14) t (CR15R16) or (OCH2CH2) and SZ '; - NR19CONR12 (CR13R14) t (CR17 = CR18) (CR15R16) t (OCH2CH2) and SZ'; 30-NR19CO-phenyl-QSZ '; -NR19CO-furil-OSZ '; -NR19CO-oxazolyl-QSZ '; - NR19CO-thiazolyl-QSZ'; -NR19CO-thianyl-QSZ '; -NR19CO-imidazolyl-QSZ '; - NR19CO-morpholino-QSZ'; -NR19CO-piperazino-QSZ '; - NR19CO-piperidino-QSZ'; -NR19CO-N-methylpiperazino-QSZ '; - NR19-phenyl-QSZ'; -NR19-furil-QSZ '; -NR19-oxazolyl-QSZ '; -NR19-thiazolyl-QSZ '; - NR19-thienyl-QSZ'; -NR19-imidazolyl-QSZ '; -NR19-morpholino-QSZ '; - NR19-piperazino-QSZ'; -NR19-piperidino-QSZ '; -NR19-N-methylpiperazino-QSZ '; -NR19CO-NR12-phenyl-QSZ '; -NR19CO-NR12-oxazolyl-QSZ '; - NR19CO-NR12-thiazolyl-QSZ'; - NR19CO-NR12-thienyl-QSZ '; - NR19CO-NR12-piperidino-QSZ'; - S (O) q (CR13R14) t (CR15R16) u (OCH2CH2) ySZ '; - S (O) q (CR13R14) t (CR17 = CR18) (CR15R16) t (OCH2CH2) and SZ'; 5-SCONR12 (CR13R14) t (CR15R16) u (OCH2CH2) ySZ '; -SCO-morpholino-QSZ'; -SCO-piperazino-QSZ '; - SCO-piperidino-QSZ'; -SCO-N-methylpiperazino-QSZ'd where: * Z 'is H, Ac, R19' or SR19 '; * Q is a direct bond or a linear alkyl or branched alkyl having 1-10 carbon atoms or a spacer polyethylene glycol with 2 to 20 ethyleneoxy repeating units; * R19 'and R12 are the same or different and are linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms or single or substituted aryl or heterocycle and R12 may also be H; * R13, R14, R15 and R16 are the same or different and are H or a linear or branched alkyl having 1 to 4 carbon atoms, * R17, R18 and R19 are H or alkyl; * u is an integer of 1 to 10 and can also be 0, * t is an integer from 1 to 10 and can also be 0, * and is an integer from 1 to 20 and can also be 0 or its pharmaceutically acceptable salts, hydrates or hydrated salts or the polymorphic crystalline structures of these compounds or their optical isomers, racemates, diastereomers or enantiomers