Pyrrolobenzodiazepines and conjugates thereof

Abstract

A conjugate of formula (A): the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and C3; R2 is independently selected from H, OH, =0, =CH2, CN, R, OR, =CH-RD, =C(RD)2, 0-S02-R, C02R and COR, and optionally further selected from halo or dihalo; where RD is independently selected from R, C02R, COR, CHO, C02H, and halo; R6 and R9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR', NO2, Me3Sn and halo; R7 is independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR', N02, Me3Sn and halo; Y is selected from a single bond, and a group of formulae A1 or A2: where N shows where the group binds to the N10 of the PBD moiety; RL1 and RL2 are independently selected from H and methyl, or together with the carbon atom to which they are bound form a cyclopropylene group; CBA represents a cell binding agent; Q is independently selected from O, S and NH; R11 is either H, or R or, where Q is O, S03M, where M is a metal cation; R and R' are each independently selected from optionally substituted C1-12alkyl, C3-20 heterocyclyl and C5-20aryl groups, and optionally in relation to the group NRR', R and R' together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-; 6- or 7-metfibered heteracyciie ring; wherein R12 R16, R19 and R17 are as defined for R2, R6, R9 and R7 respectively: wherein R" is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms, e.g. O, S, N(H}; NMe and / or aromatic rings, e.g. benzene or pyridine, which rings are optional y substituted; X and X' are independently selected from O, S and N(H).

Description

technical field [0001] The present invention relates to pyrrolobenzodiazepines (PBDs), in particular pyrrolobenzodiazepines with a labile N10 protecting group in the form of a cell binding agent linker. Background technique [0002] Pyrrolobenzodiazepines [0003] Some pyrrolobenzodiazepines (PBDs) have the ability to recognize and bind specific DNA sequences; the preferred sequence is PuGPu. The first PBD antitumor antibiotic, anthranilidine, was discovered in 1965 (Leimgruber et al., J.Am.Chem.Soc., 87, 5793-5795 (1965); Leimgruber et al., J.Am.Chem.Soc. ., 87, 5791-5793 (1965)). Since then, a large number of naturally occurring PBDs have been reported, and more than 10 synthetic routes have been developed for various analogs (Thurston et al., Chem. Rev. 1994, 433-465 (1994); Antonow, D. and Thurston, D.E., Chem. Rev. 2011111(4), 2815-2864). Family members include abbeymycin (Hochlowski et al, J. Antibiotics, 40, 145-148 (1987)), chikamycin (Konishi et al, J. Antibioti...

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Problems solved by technology

Some cytotoxic drugs tend to be inactive or less active when conjugated to larger antibodies or protein receptor ligands

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