Unsymmetrical pyrrolobenzodiazepine-dimers for treatment of proliferative diseases

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-C1-3alkylene;
• 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+, wherein the proliferative disease is selected from leukemias and ovarian cancer.