Pyrrolobenzodiazepines
View Patent ↗Compounds of formula (I): formula (I) and salts, solvates, chemically protected forms, and prodrugs thereof, are disclosed wherein R 2 is selected from: an optionally substituted napthyl group; an optionally substituted thiophenyl or furanyl group; and a phenyl group substituted by: one or more chloro or fluoro groups; an ethyl or propyl group; a 4-t-butyl group; a 2-methyl group; or two methyl groups in the 2- and 6-positions.
1. A compound of formula (I):
or pharmaceutically acceptable salts, or solvates thereof, wherein: R 6 , R 7 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 C 1-7 alkyl, heterocyclyl having 3 to 20 ring atoms of which 1 to 10 are ring heteroatoms independently selected from the group consisting N, O and S and aryl or heteroaryl having 5 to 20 ring atoms, the heteroaryl groups having one or more heteratoms independently selected from the group consisting of N, O and S; R 8 is selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo, or the compound is a dimer with each monomer being of formula (I), where the R 8 groups of each monomers form together a dimer bridge having the formula —X—R″—X— linking the monomers,
where R″ is a C 3-12 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 the group consisting of benzene and pyridine, and each X is independently selected from O, S, or NH;
or any pair of adjacent groups from R 6 to R 9 together form a group —O—(CH 2 ) p —O —, where p is 1 or 2; and
R 2 is a napthyl group, optionally substituted by one or more substituents selected from the group consisting of halo, C 1-7 alkyl, C 1-7 alkoxy, heterocyclyl having 3 to 20 ring atoms of which 1 to 10 are ring heteroatoms independently selected from the group consisting N, O and S and aryl or heteroaryl having 5 to 20 ring atoms, the heteroaryl groups having one or more heteratoms independently selected from the group consisting of N, O and S.
2. A compound according to claim 1 , wherein R 9 is H.
3. A compound according to claim 1 , wherein R 6 is H.
4. A compound according to claim 1 , wherein R 7 and R 8 (when the compound is not a dimer) are selected from OMe and OCH 2 Ph.
5. A pharmaceutical composition containing a compound of claim 1 , and a pharmaceutically acceptable carrier or diluent.
6. A method of treatment of melanomas, or breast, renal, or lung cancer, comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound of claim 1 .
7. A compound of formula (II)
wherein
R 2 is a napthyl group, optionally substituted by one or more substituents selected from the group consisting of halo, C 1-7 alkyl, C 1-7 alkoxy, heterocyclyl having 3 to 20 ring atoms of which 1 to 10 are ring heteroatoms independently selected from the group consisting N, O and S and aryl or heteroaryl having 5 to 20 ring atoms, the heteroaryl groups having one or more heteratoms independently selected from the group consisting of N, O and S;
R 6 , R 7 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo;
R 8 is selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo, or the compound is a dimer with each monomer being of formula (II), where the R 8 groups of each monomers form together a dimer bridge having the formula —X—R″—X— linking the monomers, where R″ is a C 3-12 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 the group consisting of benzene and pyridine, and each X is independently selected from O, S, or NH;
or any pair of adjacent groups from R 6 to R 9 together form a group —O—(CH 2 ) p —O—, where p is 1 or 2;
R 10 is selected from:
(a) 4—NO 2 —C 6 H 4 —CH 2 —;
(b) 2—NO 2 —, 4,5-diMeO—C 6 H 4 —CH 2 ;
(c) C 6 H 5 —CH 2 —; and
(d) Me—SO 2 —C 2 H 4 —;
R 11 is selected from OH, OR or SR; and
R and R′ are independently selected from C 1-7 alkyl, heterocyclyl having 3 to 20 ring atoms of which 1 to 10 are ring heteroatoms independently selected from the group consisting N, O and S and aryl or heteroaryl having 5 to 20 ring atoms, the heteroaryl groups having one or more heteratoms independently selected from the group consisting of N, O and S.