Patent WO-2014096368-A1 (WO)
Title: Pyrrolobenzodiazepines and conjugates thereof
Inventor: HOWARD PHILIP WILSON
IPC: A61P35/00
Filed: 2013-12-20
Abstract: A compound with the formula (I) and salts and solvates thereof, wherein: when there is a double bond present between C2 and C3, R 2  is selected from the group consisting of: (ia) C 5-10  aryl group, optionally substituted by one or more substituents selected from the group comprising: halo, nitro, cyano, ether, C 1-7  alkyl, C 3-7  heterocyclyl and bis-oxy-C 1-3  alkylene; (ib) C 1-5  saturated aliphatic alkyl; (ic) C 3-6  saturated cycloalkyl; (id) (Formula (S)), wherein each of R 11 , R 12  and R 13  are independently selected from H, C 1-3  saturated alkyl, C 2-3  alkenyl, C 2-3  alkynyl and cyclopropyl, where the total number of carbon atoms in the R 2  group is no more than 5; (ie) (Formula (T)), wherein one of R 15a  and R 15b  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 (U)), where R 14  is selected from: H; C 1-3  saturated alkyl; C 2-3  alkenyl; C 2-3  alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; when there is a single bond present between C2 and C3, R 2  is (Formula (V)), where R 16a  and R 16b  are independently selected from H, F, C 1-4  saturated alkyl, C 2-3  alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C 1-4  alkyl amido and C 1-4  alkyl ester; or, when one of R 16a  and R 16b  is H, the other is selected from nitrile and a C 1-4  alkyl ester; when there is a double bond present between C2' and C3', R 12  is selected from the group consisting of: (ia) C 5-10  aryl group, optionally substituted by one or more substituents selected from the group comprising: halo, nitro, cyano, ether, carboxy, ester, C 1-7  alkyl, C 3-7  heterocyclyl and bis-oxy-C 1-3  alkylene; (ib) C 1-5  saturated aliphatic alkyl; (ic) C 3-6  saturated cycloalkyl; (id) (Formula (W)), wherein each of R 21 , R 22  and R 23  are independently selected from H, C 1-3  saturated alkyl, C 2-3  alkenyl, C 2-3  alkynyl and cyclopropyl, where the total number of carbon atoms in the R 12  group is no more than 5; (ie) (Formula (X)), wherein one of R 25a  and R 25b  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 (Y)), where R 24  is selected from: H; C 1-3  saturated alkyl; C 2-3  alkenyl; C 2-3  alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; when there is a single bond present between C2' and C3', R 12  is (Formula (Z)), where R 26a  and R 26b  are independently selected from H, F, C 1-4  saturated alkyl, C 2-3  alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C 1-4  alkyl amido and C 1-4  alkyl ester; or, when one of R 26a  and R 26b  is H, the other is selected from nitrile and a C 1-4  alkyl ester; R 6  and R 9  are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', nitro, Me 3 Sn and halo; where R and R' are independently selected from optionally substituted C 1-12  alkyl, C 3-20  heterocyclyl and C 5-20  aryl groups; R 7  is selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NHRR', nitro, Me 3 Sn and halo; R" is a C 3-12  alkylene group, which chain may be interrupted by one or more heteroatoms, e.g. O, S, NR N2  (where R N2  is H or C 1-4  alkyl), and/or aromatic rings, e.g. benzene or pyridine; Y and Y' are selected from O, S, or NH; R 6' , R 7' , R 9'  are selected from the same groups as R 6 , R 7  and R 9  respectively; R 20  is H or Me and R 21a  and R 21 b are both H or together form =O; R L  is a linker for connection to a cell binding agent; R 11b  is selected from OH, OR A , where R A  is C 1-4  alkyl, and SO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation.