Pyrrolobenzodiazepines

摘要

A compound with the formula (I), wherein: R2 is of formula (II), where X is selected from the group comprising: OH, SH, CO2H, COH, N═C═O, NHNH2, CONHNH2, formula (A), formula (B), NHRN, wherein RN is selected from the group comprising H and C1-4 alkyl; RC1, RC2 and RC3 are independently selected from H and unsubstituted C1-2 alkyl; and either: R12 is selected from the group consisting of: (ia) C5-10 aryl group, optionally substituted by one or more substituents selected from the group comprising: halo, nitro, cyano, ether, C1-7 alkyl, C3-7 heterocyclyl and bis-oxy-C1-3 alkylene; (ib) C1-5 saturated aliphatic alkyl; (ic) C3-6 saturated cycloalkyl; (id) formula (C), wherein each of R21, R22 and R23 are independently selected from H, C1-3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R12 group is no more than 5; (ie) formula (D), wherein one of R25a and R25b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and (if) formula (E), where R24 is selected from: H; C1-3 saturated alkyl; C2-3 alkenyl; C2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; R6 and R9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, nitro, Me3Sn and halo; where R and R′ are independently selected from optionally substituted C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; R7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NHRR′, nitro, Me3Sn and halo; either: (a) R10 is H, and R11 is OH, ORA, where RA is C1-4 alkyl; (b) R10 and R11 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound; or (c) R10 is H and R11 is SOzM, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation; R″ is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms, and/or aromatic rings; Y and Y′ are selected from O, S, or NH; R6′, R7′, R9′ are selected from the same groups as R6, R7 and R9 respectively and R10′ and R11′ are the same as R10 and R11, wherein if R11 and R11′ are SOzM, M may represent a divalent pharmaceutically acceptable cation.;

主权项

1. A compound of formula I: wherein: R2 is of formula II: wherein X is selected from the group consisting of: OH, SH, CO2H, COH, N═C═O, NHNH2, CONHNH2, and NHRN, wherein RN is selected from the group consisting of H and C1-4 alkyl; RC1, RC2 and RC3 are independently selected from the group consisting of H and unsubstituted C1-2 alkyl; R12 is selected from the group consisting of:
(ia) phenyl, naphthyl, and C5-10 heteroaryl group, optionally substituted by one or more substituents selected from the group consisting of: halo, nitro, cyano, C1-7 alkyloxy, C1-7 alkyl, C3-7 heterocyclyl and bis-oxy-C1-3 alkylene;(ib) C1-5 saturated aliphatic alkyl;(ic) C3-6 saturated cycloalkyl;(id) wherein each of R21, R22 and R23 are independently selected from the group consisting of H, C1-3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, wherein the total number of carbon atoms in the R12 group is no more than 5;(ie) wherein one of R25a and R25b is H and the other is selected from the group consisting of: pyridyl, thiophenyl and phenyl, which phenyl is optionally substituted by a substituent selected from the group consisting of halo, methyl, and methoxy; and(if) wherein R24 is selected from the group consisting of: H C1-3 saturated alkyl C2-3 alkenyl C2-3 alkynyl cyclopropyl pyridyl, thiophenyl and phenyl, which phenyl is optionally substituted by a substituent selected from the group consisting of halo, methyl, and methoxy; R6 and R9 are H; R7 is a C1-4 alkoxy group, optionally substituted by a C5 heteroaryl or phenyl group; either:
(a) R10 is H, and R11 is OH, ORA, wherein RA is C1-4 alkyl;(b) R10 and R11 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound or(c) R10 is H and R11 is SOzM, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation; R″ is a C3-12 alkylene group, optionally interrupted by one or more aromatic rings; Y and Y′ are selected from the group consisting of O, S, and NH; R6′, R7′, R9′ are selected from the same groups as R6, R7 and R9 respectively and R10′ and R11′ are the same as R10 and R11, respectively, wherein if R11 and R11′ are SOzM, each M is a monovalent pharmaceutically acceptable cation or together represent a divalent pharmaceutically acceptable cation, wherein the term C3-7 heterocyclyl refers to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compounds which has from 3 to 7 ring atoms of which 1 to 4 are ring heteroatoms selected from the group consisting of N, O and S, wherein the term C5-10 heteroaryl refers to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heteroaromatic compound which has from 5 to 10 ring atoms of which 1 to 4 are ring heteroatoms selected from the group consisting of N, O and S.