摘要 |
The present invention relates to pyrrolobenzodiazepines (PBDs) and in particular to PBD monomers with a 4-(1-methyl-1H-pyrrol-3-yl)phenyl based amino acid residue containing substituent and methods of synthesising PBD monomers. The inventors have found that cytoxiticy and DNA binding of prior art PBD conjugates can be improved by the incorporation of a single 4-(1-methyl-1H-pyrrol-3-yl)phenyl based amino acid residue in combination with a single heteroaryl based amino acid residue in a PBD conjugate. This results in highly effective compounds for the treatment of proliferative diseases. The present invention therefore provides a PBD compound of formula (I) or a salt or solvate thereof, wherein: the dotted double bond indicates the presence of a single or double bond between C2 and C3; R2 is selected from -H, -OH, =O, =CH2, -CN, -R, OR, halo, dihalo, =CHR, =CHRR’, -O-SO2-R, CO2R and COR; R7 is 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 C1-7 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; R10 and R11 either together form a double bond, or are selected from H and QRQ respectively, where Q is selected from O, S and NH and RQ is H or C1-7 alkyl or H and SOxM, where x is 2 or 3, and M is a monovalent pharmaceutically acceptable cation; A is either (A1) or (A2) where X and Y are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S; B is either a single bond or (B1) where X and Y are as defined above; and R1 is C1-4 alkyl. |