Cytotoxic agents comprising new tomaymycin derivatives

A compound of formula (I)

• wherein
• represents an optional single bond;
• represents either a single bond or a double bond;
• provided 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′, —NRCONRR′, —OCSNHR, —SH, —SR, —SOR, —SOOR, —SO3, —OSO3, —NRSOOR, N3, a cyano, a halo, a trialkyl and triarylphosphonium;
• and when 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 independently chosen from halide and alkyl optionally substituted by one or more Hal, CN, NRR′, CF3, OR, Aryl, Het, S(O)qR;
• or R1 and R2 and R1′ and R2′ form together a double bond containing group ═B and ═B′ respectively;
• B and B′ are the same or different and independently represent alkenyl being optionally substituted by one or more Hal, CN, R, CF3, OR, Aryl, HetS(O)qR;
• or B and B′ represent an oxygen atom;
• X and X′ are the same or different and independently chosen from one or more —O—, —NR—, —(C═O)—, and —S(O)q—;
• A and A′ are the same or different and independently represent alkyl or alkenyl optionally containing an oxygen, a nitrogen or a sulfur atom and each being optionally substituted by one or more Hal, CN, NRR′, CF3, OR, S(O)qR, Aryl, Het, Alkyl, or Alkenyl;
• Y and Y′ are the same or different and independently chosen from H and OR;
• T is —NR—, or a 4 to 10-membered aryl, cycloalkyl, heterocyclic or heteroaryl, each being optionally substituted by one or more Hal, CN, NRR′, CF3, R, OR, S(O)qR, or alkyl, and substituted by one more linkers;
• n, n′, equal or different are 0 or 1;
• q is 0, 1 or 2;
• R and R′ are equal or different and independently chosen from H, Alkyl, Aryl, each being optionally substituted by Hal, CN, NRR′, CF3, R, OR, S(O)qR, Aryl, or Het;
• wherein said one or more linkers is chosen from:
• —(CR13R14)t(CR15R16)u(OCH2CH2)ySZ′, —(CR13R14)t(CR17═CR18)(CR15R16)y(OCH2CH2)ySZ′, —(CR13R14)t(NR19CO)(CR15R16)u(OCH2CH2)y SZ′, —(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′, —(CR13R14)t-morpholino-CO(CR15R16)uSZ′, —(CR13R14)t-piperazino-CO(CR15R16)uSZ′, —(CR13R14)t-N-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)t-N-methylpiperazino-QSZ′, or
• —O(CR13R14)t(CR15R16)u(OCH2CH2)ySZ′, —O(CR13R14)t(NR19CO)(CR15R16)u(OCH2CH2)ySZ′, —O(CR13R14)t (CR17═CR18)(CR15R16)t (OCH2CH2)ySZ′, —O-phenyl-QSZ′, —O-furyl-QSZ′, —O-oxazolyl-QSZ′, —O-thiazolyl-QSZ′, —O-thienyl-QSZ′, —O-imidazolyl-QSZ′, —O-morpholino-QSZ′, —O-piperazino-QSZ′, —O-N-methylpiperazino-QSZ′,
• —OCO—(CR13R14)t (CR17═CR18)(CR15R16)u(OCH2CH2)ySZ′, —OCONR12(CR13R14)t(CR15R16)u (OCH2CH2)ySZ′, —OCO-phenyl-QSZ′, —OCO-furyl-QSZ′, —OCO-oxazolyl-QSZ′, —OCO-thiazolyl-QSZ′, —OCO-thienyl-QSZ′, —OCO-imidazolyl-QSZ′, —OCO-morpholino-QSZ′, —OCO-piperazino-QSZ′, —OCO—N-methylpiperazino-QSZ′, or
• —CO(CR13R14)t(CR15R16)u (OCH2CH2)y SZ′, —CO—(CR13R14)t (CR17═CR18)(CR15R16)u(OCH2CH2)ySZ′, —CONR12(CR13R14)t(CR15R16)u (OCH2CH2)ySZ′, —CO-phenyl-QSZ′, —CO-furyl-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)u(OCH2CH2)ySZ′, —NR19CO(CR13R14)t(CR15R16)u(OCH2CH2)ySZ′, —NR19(CR13R14)t (CR 17═CR18)(CR15R16)t (OCH2CH2)ySZ′, —NR19CO(CR13R14)t (CR17═CR18)(CR15R16)t (OCH2CH2)ySZ′, —NR19CONR12(CR13R14)t(CR15R16)u (OCH2CH2)ySZ′, —NR19CO NR12(CR13R14)t (CR17═CR18)(CR15R16)t (OCH2CH2)ySZ′, —NR19CO-phenyl-QSZ′, —NR19CO-furyl-QSZ′, —NR19CO-oxazolyl-QSZ′, —NR19CO-thiazolyl-QSZ′, —NR19CO-thienyl-QSZ′, —NR19CO-imidazolyl-QSZ′, —NR19CO-morpholino-QSZ′, —NR19CO-piperazino-QSZ′, —NR19CO-piperidino-QSZ′, —NR19CO—N-methylpiperazino-QSZ′, —NR19-phenyl-QSZ′, —NR19-furyl-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)ySZ′,
• —SCONR12(CR13R14)t(CR15R16)u (OCH2CH2)ySZ′,
• —SCO-morpholino-QSZ′, —SCO-piperazino-QSZ′, —SCO-piperidino-QSZ′, and —SCO—N-methylpiperazino-QSZ′, wherein:
• Z′ is H, a thiol protective group, R20′ or SR20′ wherein R20′ represents alkyl, aryl, heterocyclic or heteroaryl,
• wherein Q is a direct link or a linear alkyl or branched alkyl having from 1-10 carbon atoms or a polyethylene glycol spacer with 2 to 20 repeating ethylene oxy units;
• R19 and R12 are the same or different and are linear alkyl, branched alkyl or cyclic alkyl having from 1 to 10 carbon atoms, or simple or substituted aryl or heterocyclic, and R12 can in addition be H,
• R13, R14, R15 and R16 are the same or different and are H or a linear or branched alkyl having from 1 to 4 carbon atoms,
• R17 and R18 are H or alkyl,
• u is an integer from 1 to 10 and can also be 0,
• t is an integer from 1 to 10 and can also be 0,
• y is an integer from 1 to 20 and can also be 0;
• or
• a pharmaceutically acceptable salt thereof.