Unsymmetrical pyrrolobenzodiazepine-dimers for treatment of proliferative diseases

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, NHR N wherein R N is selected from the group consisting of H and 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 —, where 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;

where 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 aromatic rings selected from benzene or pyridine;

Y and/or Y′ are independently selected from the group consisting of 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 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 Ca 2+ and Mg 2+ , wherein the proliferative disease is selected from leukemias and ovarian cancer.

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 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 OH, SH, or 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 and 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:

18. A method according to claim 1 , wherein the compound of formula I is: