Benzodiazepine derivatives

摘要

The invention relates to novel benzodiazepine derivatives with antiproliferative activity and more specifically to novel benzodiazepines of formula (I) and (II), in which the diazepine ring (B) is fused with a heterocyclic ring (CD), wherein the heterocyclic ring is bicyclic or a compound of formula (III), in which the diazepine ring (B) is fused with a heterocyclic ring (C), wherein the heterocyclic ring is monocyclic. The invention provides cytotoxic dimers of these compounds. The invention also provides conjugates of the monomers and the dimers. The invention further provides compositions and methods useful for inhibiting abnormal cell growth or treating a proliferative disorder in a mammal using the compounds or conjugates of the invention. The invention further relates to methods of using the compounds or conjugates for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or associated pathological conditions.

主权项

1. A compound represented by formula (VI): or a pharmaceutically acceptable salt, optical isomer, racemate, diastereomer, or enantiomer thereof, wherein: the double line between N and C represents a single bond or a double bond, provided that when it is a double bond X is absent and Y is H, and when it is a single bond, X is H; Y is selected from —OR, —OCOR′, —OCOOR′, —OCONR′R″, —NR′R″, —NRCOR′, —NRCOP, wherein P is an amino acid or a polypeptide containing between 2 to 20 amino acid units, —SR′, —SOR′, —SO2R′, —SO3, —OSO3, a halogen, cyano, and an azido, wherein R, R′ and R″ are the same or different and are selected from H, optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, (—OCH2CH2)n, wherein n is an integer from 1 to 2000, a 5- or 6-membered heteroaryl ring containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5 to 18 membered fused ring system, wherein at least one of the rings is aromatic, containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur, an aryl having from 6 to 18 carbon atoms, a 3 to 18-membered heterocyclic ring having 1 to 6 heteroatoms selected from O, S, N and P, wherein the optional substituent is selected from halogen, OR7, NR8R9, NO2, NRCOR′, SR10, SOR′, —SO2R′, —SO3, —OSO3, SO2NRR′, cyano, an azido, —COR11, —OCOR11 or —OCONR11R12, wherein R7, R8, R9, R10, R11 and R12 are each independently selected from H, linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, (—OCH2CH2)n, wherein n is an integer from 1 to 2000, a 5- or 6-membered heteroaryl ring containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5 to 18 membered fused ring system, wherein at least one of the rings is aromatic, containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur, an aryl having from 6 to 18 carbon atoms, a 3 to 18-membered heterocyclic ring having 1 to 6 heteroatoms selected from O, S, N and P, and R10 is optionally SR13 or COR13, wherein R13 is selected from linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, a 5- or 6-membered heteroaryl ring containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5 to 18 membered fused ring system, wherein at least one of the rings is aromatic, containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur, an aryl having from 6 to 18 carbon atoms, a 3 to 18-membered heterocyclic ring having 1 to 6 heteroatoms selected from O, S, N and P, optionally R11 is OR14, wherein R14 has the same definition as R, optionally R″ is OH; W is C═O; R6 is OR, SR or NRR′, wherein R and R′ have the same definition as given above, optionally R6 is a linking group; X′ is selected from CH2; Y′ is O; Z′ is CH2; A and A′ are the same or different and are O, —CRR′O, S, —CRR′S, —NR15 or CRR′NHR15, wherein R and R′ have the same definition as given above and wherein R15 has the same definition as R; D and D′ are same or different and independently selected from linear, branched or cyclic alkyl, alkenyl or alkynyl having 1 to 10 carbon atoms, each of which can be optionally substituted with any one of halogen, OR7, NR8R9, NO2, NRCOR′, SR10, SOR′, —SO2R′, —SO3, —OSO3, SO2NRR′, cyano, an azido, —COR11, OCOR11 or OCONR11R12, wherein the definitions of R7, R8, R9, R10, R11 and R12 are as defined above, or (—OCH2CH2)n, wherein n is an integer from 1 to 2000; L is absent, an optionally substituted phenyl group, or a 3 to 18-membered heterocyclic ring having 1 to 6 heteroatoms selected from O, S, N and P that is optionally substituted, wherein the optional substituent is a linking group that enables linkage to a cell binding agent via a covalent bond, or the optional substituent is selected from linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, optionally substituted with any one of halogen, OR7, NR8R9, NO2, NRCOR′, SR10, SOR′, —SO2R′, —SO3, —OSO3, SO2NRR′, cyano, an azido, —COR11, OCOR11 or OCONR11R12, wherein R7, R8, R9, R10, R11 and R12 are as defined above, or (—OCH2CH2)n, wherein n is an integer from 1 to 2000; optionally, L itself is a linking group that enables linkage to a cell binding agent via a covalent bond; provided that the compound has no more than one linking group that enables linkage to a cell binding agent via a covalent bond.