BENZODIAZEPINES AND CONJUGATES THEREOF

• US 20150209444A1
• Filed: 11/20/2014
• Published: 07/30/2015
• Est. Priority Date: 05/25/2012
• Status: Active Grant

• Current Assignee: ImmunoGen Incorporated (Abbvie Incorporated)
• Original Assignee: ImmunoGen Incorporated (Abbvie Incorporated)
• Inventors: Chari, Ravi V.J., Miller, Michael Louis
• Granted Patent: US 9,555,125 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 47/68035 the drug being a pyrrolobenzodiazepine
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 519/00 Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
• CPC Class Codes: C07K 16/30 from tumour cells
• CPC Class Codes: C07K 19/00 Hybrid peptides , i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes

Abstract

Conjugates and compounds for making conjugates which are PBD molecules linked via the N10 position are disclosed, along with the use of the conjugates for treating proliferative diseases, including cancer.

Claims

1. A conjugate comprising a cell-binding agent (CBA) covalently linked to a dimer compound, or a salt or solvate of the dimer, wherein the dimer compound comprises:

i) a monomer of formula (I);

8. The conjugate of claim 1, wherein the conjugate is represented by a structural formula selected from:

9. The conjugate of claim 8, wherein X′

is —

O—

.

10. The conjugate of claim 8, wherein R^3″

is a C₃ alkylene group, a C₄ alkylene group, or a C₅ alkylene group.

11. The conjugate of claim 1, wherein R^5b is a group:

12. The conjugate of claim 11, wherein L¹ comprises a contiguous sequence of amino acids.

13. The conjugate of claim 11, wherein L¹ comprises a dipeptide —

X₁—

X₂—

, and wherein the dipeptide in L¹ as represented by —

NH—

X₁—

X₂—

CO—

is selected from;

-Phe-Lys-, -Val-Ala-, -Val-Lys-, -Ala-Lys-, -Val-Cit-, -Phe-Cit-, -Leu-Cit-, -Ile-Cit-, -Phe-Arg-, -Trp-Cit-, Lys-Lys, Phe-Ala, Phe-N⁹-tosyl-Arg, Phe-N⁹-nitro-Arg, Val-Arg, Arg-Val, Arg-Arg, Val-D-Cit, Val-D-Lys, Val-D-Arg, D-Val-Cit, D-Val-Lys, D-Val-Arg, D-Val-D-Cit, D-Val-D-Lys, D-Val-D-Arg, and D-Arg-D-Arg, where Cit is citrulline;

or L¹ comprises a tripeptide —

X₁—

X₂—

X₃— and

wherein the tripeptide in L¹ as represented by —

NH—

X₁—

X₂—

X₃—

CO—

is selected from Gly-Gly-Gly, Phe-Phe-Lys, D-Phe-Phe-Lys, Gly-Phe-Lys, Leu-Ala-Leu, Ile-Ala-Leu and Val-Ala-Val;

or L¹ comprises a tetrapeptide —

X₁—

X₂—

X₃—

X₄— and

wherein the tetrapeptide in L¹ as represented by —

NH—

X₁—

X₂—

X₃—

X₄—

CO—

is selected from Ala-Leu-Ala-Leu, β

-Ala-Leu-Ala-Leu and Gly-Phe-Leu-Gly.

14. The conjugate of claim 13, wherein —

C(═

O)O— and

L² together form the group;

16. The conjugate of claim 11, wherein A is:

20. The conjugate of claim 1, wherein R^5a in formula (I) is H or an amine protecting group, and R^4b is selected from —

H, —

OR^6′

, —

OCOR^4′

, —

SR⁶, —

NR^4′

R^5′

, an optionally substituted 5- or 6-membered nitrogen-containing heterocycle, —

SO₃M, —

SO₂M and a sulfate —

OSO₃M.

21. The conjugate of claim 20, wherein R^4b is selected from —

SO₃M, —

OH, —

OMe, —

OEt or —

NHOH.

26. The conjugate of claim 8, wherein R⁶, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are all —

H and R⁸ is —

OMe.

27. A pharmaceutical composition comprising the conjugate of claim 1, and a pharmaceutically acceptable diluent, carrier or excipient.

29. A method of treating a proliferative disease, comprising administering to a patient the pharmaceutical composition of claim 27.

58. A method of preparing a conjugate of claim 1, or salts and solvates thereof, the method comprising reacting a cell binding agent with a dimer compound, or a salt or solvate of the dimer, comprising:

i) a monomer of formula (I);

59. An article of manufacture comprising a pharmaceutical composition of claim 27;

a container; and

a package insert or label indicating that the pharmaceutical composition can be used to treat cancer.

2-7. -7. (canceled)

15. (canceled)

17-19. -19. (canceled)

22-25. -25. (canceled)

28. (canceled)

30-31. -31. (canceled)

32. A dimer compound, or a salt or solvate of the dimer, comprising:

i) a monomer of formula (I);

33-57. -57. (canceled)