Patent EP-2968594-A2 (EP)
Inventor: HOWARD PHILIP WILSON
IPC: A61K47/48
Filed: 2014-03-13
Abstract: A conjugate of formula A wherein: D represents either group D1 or D2 the dotted line indicates the optional presence of a double bond between C2 and C3; 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, 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) wherein each of R 31 , R 32  and R 33  a, re 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) wherein one of R 35a  and R 35b  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) where R 34  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; (ig) halo; when there is a single bond present between C2 and C3, where R 36a  and R 36b  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; D' represents either group D'1 or D2: wherein the dotted line indicates the optional presence of a double bond between C2' and C3'; R 6  and R 9  are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', NO 2 , Me 3 Sn and halo; R 7  is independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', NO 2 , Me 3 Sn and halo; Y is selected from formulae A1, A2, A3, A4, A5 and A6. L is a linker connected to a cell binding agent; CBA is the cell binding agent; n is an integer selected in the range of 0 to 48; R A4  is a C 1-6  alkylene group; either (a) R 10  is H, and R 11  is OH, OR A , where R A  is C 1-4  alkyl; or (b) R 10  and R 11  form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound; or (c) R 10  is H and R 11  is OSO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation; R and R' are each independently selected from optionally substituted C 1-12  alkyl, C 3-20  heterocyclyl and C 5-20  aryl 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-membered heterocyclic ring; wherein R 16 , R 17 , R 19 , R 20 , R 21  and R 22  are as defined for R 6 , R 7 , R 9 , R 10 , R 11  and R 2  respectively; wherein Z is CH or N; wherein T and T' are independently selected from a single bond or a C 1-9  alkylene, which chain may be interrupted by one or more heteroatoms e.g. O, S, N(H), NMe, provided that the number of atoms in the shortest chain of atoms between X and X' is 3 to 12 atoms; and X and X' are independently selected from O, S and N(H); except that there cannot be double bonds between both C2 and C3 and C2' and C3'.