Pyrrolobenzodiazepines as antiproliferative agents

Patent metadata

Field	Value
Publication number	US-9376440-B2
Application number	US-201314397842-A
Country	US
Kind code	B2
Filing date	Apr 30, 2013
Priority date	Apr 30, 2012
Publication date	Jun 28, 2016
Grant date	Jun 28, 2016

Abstract

Novel pyrrolobenzodiazepines (PBDs) having a (1-methyl-1H-pyrrol-3-yl)phenyl based amino acid residue and use thereof as antiproliferative agents are disclosed herein.

First claim

The invention claimed is:

1. A compound of formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein:
the dotted double bond indicates the presence of a single or double bond between C2 and C3;
R 2 is selected from —H, —OH, ═O, ═CH 2 , —CN, —R, OR, halo, dihalo, ═CHR, ═CRR′, —O—SO 2 —R, CO 2 R and COR;
R 7 is 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 optionally substituted C 1-7 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups;
R 10 and R 11 either together form a double bond, or are selected from H and QR Q respectively,
where Q is selected from O, S and NH and R Q is H or C 1-7 alkyl or H and SO x M, where x is 2 or 3, and M is a monovalent pharmaceutically acceptable cation;
A is either:

where X and Y are selected from: CH and NMe; C—OH and NMe; CH and S; N and NMe; N and S;
B is either a single bond or:

Where X and Y are as defined above; and
R 1 is C 1-4 alkyl.

2. A compound according to claim 1 , where in group A, X and Y are selected from CH and NMe; and N and NMe.

3. A compound according to claim 1 , wherein B is a single bond.

4. A compound according to claim 1 , where B is B1 and in group B1, X and Y are selected from CH and NMe; and N and NMe.

5. A compound according to claim 1 , wherein R 7 is selected from H and OR.

6. A compound according to claim 5 , wherein R 7 is OR 7A , where R 7A is optionally substituted C 1-7 alkyl.

7. A compound according to claim 6 , wherein R 7A is selected from Me, CH 2 Ph and allyl.

8. A compound according to claim 1 , wherein R 10 and R 11 form a double bond together.

9. A compound according to claim 1 , wherein R 1 is methyl.

10. A compound according to claim 1 , wherein R 2 is selected from —H, ═CH 2 , —R, ═CHR, and ═CRR′.

11. A compound according to claim 1 , wherein R 2 is of the configuration C1:

12. A compound according to claim 1 , wherein R 2 is selected from optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridyl, optionally substituted quinolinyl, optionally substituted thienyl, optionally substituted furanyl, or isoquinolinyl.

13. A compound according to claim 12 , wherein R 2 group bears one to three substituent groups.

14. A compound according to claim 12 , wherein the optional substituents are selected from methoxy, ethoxy, fluoro, chloro, cyano, bis-oxy-methylene, methyl-piperazinyl, morpholino and methyl-thienyl.

15. A compound according to claim 12 , wherein R 2 is selected from 4-methoxy-phenyl, 3-methoxyphenyl, 4-ethoxy-phenyl, 3-ethoxy-phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 3,4-bisoxymethylene-phenyl, 4-methylthienyl, 4-cyanophenyl, 4-phenoxyphenyl, quinolin-3-yl and quinolin-6-yl, isoquinolin-3-yl and isoquinolin-6-yl, 2-thienyl, 2-furanyl, methoxynaphthyl, and naphthyl.

16. A compound according to claim 1 , wherein R 2 is selected from:
(a) C 1-5 saturated aliphatic alkyl;
(b) C 3-6 saturated cycloalkyl;
(c)

wherein each of R 21 , R 22 and R 23 are 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;
(d)

wherein one of R 25a and R 25b 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
(e)

where R 24 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.

17. A compound according to claim 1 , wherein if R 2 is selected from ═O, ═CH 2 , ═CHR, ═CRR′, there is a single bond between C2 and C3.

18. A compound according to claim 1 , wherein there is no double bond between C2 and C3 and R 2 is H.

19. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable carrier or diluent.

20. A method of treatment of a patient suffering from a proliferative disease, comprising administering to said patient a therapeutically acceptable amount of a compound according to claim 1 , wherein the proliferative disease is selected from epidermoid cancer, lung cancer, ovarian cancer, breast cancer, chronic lymphocytic leukemia, and pancreatic cancer.

Assignees

• Medimmune Ltd

Inventors

• Howard Philip Wilson
• Thurston David Edwin
• Rahman Khondaker Mirazur

Classifications

• A61K31/5517

  condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title