UNSYMMETRICAL PYRROLOBENZODIAZEPINE-DIMERS FOR TREATMENT OF PROLIFERATIVE DISEASES

摘要

A compound with the formula I:;wherein:R2 is of formula II:;where A is a C5-7 aryl group, X is selected from the group comprising: OH, SH, CO2H, COH, N═C═O, NHRN, wherein RN is selected from the group comprising H and C1-4 alkyl, and (OC2H4)mOCH3, where m is 1 to 3, and either:(i) Q1 is a single bond, and Q2 is selected from a single bond and —Z—(CH2)n—, where Z is selected from a single bond, O, S and NH and is from 1 to 3; or(ii) Q1 is —CH═CH—, and Q2 is a single bond;R12 is a 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;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, e.g. O, S, NH, and/or aromatic rings, e.g. benzene or pyridine;Y is 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 method of treatment of a proliferative disease, comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound of formula I: wherein: R2 is of formula II: where A is a C5-7 aryl group, X is selected from the group consisting of: OH, SH, CO2H, COH, N═C═O, NHRN, wherein RN is selected from the group consisting of H and C1-4 alkyl, and (OC2H4)mOCH3, where m is 1 to 3, and either: (i) Q1 is a single bond, and Q2 is selected from the group consisting of a single bond and —Z—(CH2)n—, where Z is selected from the group consisting of a single bond, O, S and NH and n is from 1 to 3; or (ii) Q1 is —CH═CH—, and Q2 is a single bond; R12 is a C5-10 aryl group, optionally substituted by one or more substituents selected from the group consisting of: halo, nitro, cyano, ether, C1-7 alkyl, C3-7 heterocyclyl and bis-oxy-C1-3 alkylene; R6 and R9 are independently selected from the group consisting of H, R, OH, OR, SH, SR, NH2, NHR, NRR′, nitro, Me3Sn and halo; where R and R′ are independently selected from the group consisting of optionally substituted C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; R7 is selected from the group consisting of H, R, OH, OR, SH, SR, NH2, NHR, NHRR′, nitro, Me3Sn and halo; either: (a) R10 is H, and R11 is OH, or 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 selected from the group consisting of O, S, and NH, and/or aromatic rings selected from benzene or pyridine; Y and/or Y′ are independently selected from the group consisting of 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 represents a divalent pharmaceutically acceptable cation selected from Ca2+ and Mg2+.