Unsymmetrical pyrrolobenzodiazepine-dimers for treatment of proliferative diseases
View Patent ↗A compound with the formula I:
1. A method of treatment of a proliferative disease, comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound of formula I:
wherein:
R 2 is of formula II:
where A is a C 5-7 aryl group, X is selected from the group consisting of: OH, SH, CO 2 H, COH, N═C═O, and NHR N , wherein R N is selected from the group consisting of H, C 1-4 alkyl, and (OC 2 H 4 ) m OCH 3 , where m is 1 to 3, and either:
(i) Q 1 is a single bond, and Q 2 is selected from the group consisting of a single bond and —Z—(CH 2 ) n —, wherein Z is selected from the group consisting of a single bond, O, S and NH and n is from 1 to 3, or
(ii) Q 1 is —CH═CH—, and Q 2 is a single bond;
R 12 is a C 5-10 aryl group, optionally substituted by one or more substituents selected from the group consisting of: halo, nitro, cyano, ether, C 1-7 alkyl, C 3-7 heterocyclyl and bis-oxy-C 1-3 alkylene;
R 6 and R 9 are independently selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo;
wherein R and R′ are independently selected from the group consisting of optionally substituted C 1-12 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups;
R 7 is selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NHRR′, nitro, Me 3 Sn and halo;
either:
(a) R 10 is H, and R 11 is OH, or OR A , where R A is C 1-4 alkyl,
(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 SO Z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;
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 by aromatic rings selected from the group consisting of benzene and pyridine;
Y and/or Y′ are independently selected from the group consisting of O, S, and NH;
R 6 ′, R 7 ′, R 9 ′ are selected from the same groups as R 6 , R 7 and R 9 , respectively, and R 10 ′ and R 11 ′ are the same as R 10 and R 11 , wherein if R 11 and R 11 ′ are SO Z M, M represents a divalent pharmaceutically acceptable cation selected from the group consisting of Ca 2+ and Mg 2+ , wherein the proliferative disease is selected from the group consisting of kidney cancers and breast carcinomas.
2. A method according to claim 1 , wherein R 7 is a C 1-4 alkyloxy group.
3. A method according to claim 1 , wherein Y is O.
4. A method according to claim 1 , wherein R″ is C 3-7 alkylene.
5. A method according to claim 1 , wherein R 9 is H, and R 6 is selected from the group consisting of H and halo.
6. A method according to claim 1 , wherein A is phenyl.
7. A method according to claim 1 , wherein X is selected from the group consisting of OH, SH, and NH 2 .
8. A method according to claim 1 , wherein Q 1 is a single bond.
9. A method according to claim 8 , wherein Q 2 is a single bond.
10. A method according to claim 8 , wherein Q 2 is —Z—(CH 2 ) n —, Z is O or S and n is 1 or 2.
11. A method according to claim 1 , wherein Q 1 is —CH═CH—.
12. A method according to claim 1 , wherein R 12 is a C 5-7 aryl group.
13. A method according to claim 12 , wherein R 12 is phenyl.
14. A method according to claim 1 , wherein R 12 is a C 8-10 aryl group.
15. A method according to claim 1 , wherein R 10 and R 11 form a nitrogen-carbon double bond.
16. A method according to claim 1 , wherein R 6 ′, R 7 ′, R 9 ′, R 10 ′, R 11 ′ and Y′ are the same as R 6 , R 7 , R 9 , R 10 , R 11 and Y respectively.
17. A method according to claim 1 , wherein the compound of formula I is: