Unsymmetrical pyrrolobenzodiazepine-dimers for treatment of proliferative diseases

Patent metadata

Field	Value
Publication number	US-9624227-B2
Application number	US-201414579094-A
Country	US
Kind code	B2
Filing date	Dec 22, 2014
Priority date	Oct 17, 2008
Publication date	Apr 18, 2017
Grant date	Apr 18, 2017

Abstract

A compound with the formula I:

First claim

The invention claimed is:

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:

Assignees

• Medimmune Ltd

Inventors

• Howard Philip Wilson
• Gregson Stephen John
• Masterson Luke

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D519/06

  containing at least one condensed beta-lactam ring system, provided for by groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00, e.g. a penem or a cepham system · CPC title