PYRROLOBENZODIAZEPINES AND CONJUGATES THEREOF

• US 20130266595A1
• Filed: 10/12/2012
• Published: 10/10/2013
• Est. Priority Date: 10/14/2011
• Status: Active Grant

• Current Assignee: MedImmune Ltd. (Astrazeneca PLC), Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG), Spirogen Developments SARL
• Inventors: Flygare, John A., Howard, Philip Wilson, Masterson, Luke, Gunzner-Toste, Janet L., Pillow, Thomas
• Granted Patent: US 11,135,303 B2
• Time in Patent Office: Days
• US Class Current: 424/181.1
• CPC Class Codes: A61K 47/6803 Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• 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

Abstract

A conjugate of formula (A):

where Y is selected from a single bond, and a group of formulae A1 or A2:

where N shows where the group binds to the N10 of the PBD moiety;

• • R^L1 and R^L2 are independently selected from H and methyl, or together with the carbon atom to which they are bound form a cyclopropylene group;
  • CBA represents a cell binding agent;
  • Q is independently selected from O, S and NH;
  • R¹¹ is either H, or R or, where Q is O, SO₃M, where M is a metal cation.

Claims

1. A conjugate of formula (A):

2. The conjugate according to claim 1, wherein R^L1 and R^L2 are both H.

3. The conjugate according to claim 1, wherein R^L1 and R^L2 are both methyl.

4. The conjugate according to claim 1, wherein one of R^L1 and R^L2 is H and the other is methyl.

5. The conjugate according to claim 1, wherein Y is a single bond.

6. The conjugate according to claim 1, wherein Y is:

7. The conjugate according to claim 1, wherein Y is:

8. The conjugate according to claim 1, wherein R⁹ and R¹⁹ are H.

9. The conjugate according to claim 1, wherein R⁶ and R¹⁶ are H.

10. The conjugate according to claim 1, wherein R⁷ are R¹⁷ are both OR^7A, where R^7A is optionally substituted C_1-4 alkyl.

11. The conjugate of claim 10, wherein R^7A is Me.

12. The conjugate according to claim 1, wherein X is O.

13. The conjugate according to claim 1, wherein R¹¹ is H.

14. The conjugate according to claim 1, wherein there is a double bond between C2 and C3 in each monomer unit.

15. The conjugate according to claim 14, wherein R² and R¹² are independently selected from H and R.

16. The conjugate according to claim 15, wherein R² and R¹² are independently R.

17. The conjugate according to claim 16, wherein R² and R¹² are independently optionally substituted C_5-20 aryl.

18. The conjugate according to claim 1, wherein R² and R¹² are independently selected from ═

O, ═

CH₂, ═

CH—

R^D, and ═

C(R^D)₂.

19. The conjugate according to claim 18, wherein R² and R¹² are ═

CH₂.

20. The conjugate according to claim 1, wherein R″

is a C₃ alkylene group or a C₅ alkylene group.

21. The conjugate according to claim 1, wherein the cell binding agent is an antibody or an active fragment thereof.

22. The conjugate according to claim 21, wherein the antibody or antibody fragment is an antibody or antibody fragment for a tumour-associated antigen.

23. The conjugate of claim 21 wherein the antibody or antibody fragment is an antibody which binds to one or more tumor-associated antigens or cell-surface receptors selected from (1)-(36):

(1) BMPR1B (bone morphogenetic protein receptor-type IB);

(2) E16 (LAT1, SLC7A5);

(3) STEAP1 (six transmembrane epithelial antigen of prostate);

(4) 0772P (CA125, MUC16);

(5) MPF (MPF, MSLN, SMR, megakaryocyte potentiating factor, mesothelin);

(6) Napi3b (NAPI-3B, NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate), member 2, type II sodium-dependent phosphate transporter 3b);

(7) Sema5b (FLJ10372, KIAA1445, Mm.42015, SEMA5B, SEMAG, Semaphorin 5b Hlog, seine domain, seven thrombospondin repeats (type 1 and type 1-like), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 5B);

(8) PSCA hlg (2700050C12Rik, C530008O16Rik, RIKEN cDNA 2700050C12, RIKEN cDNA 2700050C12 gene);

(9) ETBR (Endothelin type B receptor);

(10) MSG783 (RNF124, hypothetical protein FLJ20315);

(11) STEAP2 (HGNC_—

8639, IPDA-1, PCANAP1, STAMP1, STEAP2, STMP, prostate cancer associated gene 1, prostate cancer associated protein 1, six transmembrane epithelial antigen of prostate 2, six transmembrane prostate protein);

(12) TrpM4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel, subfamily M, member

     4);

(13) CRIPTO (CR, CR1, CRGF, CRIPTO, TDGF1, teratocarcinoma-derived growth factor);

(14) CD21 (CR2 (Complement receptor

     2) or C3DR (C3d/Epstein Barr virus receptor) or Hs

     73792);

(15) CD79b (CD79B, CD79β

, IGb (immunoglobulin-associated beta), B29);

(16) FcRH2 (IFGP4, IRTA4, SPAP1A (SH2 domain containing phosphatase anchor protein 1a), SPAP1B, SPAP1C);

(17) HER2;

(18) NCA;

(19) MDP;

(20) IL20Rα

;

(21) Brevican;

(22) EphB2R;

(23) ASLG659;

(24) PSCA;

(25) GEDA;

(26) BAFF-R (B cell-activating factor receptor, BLyS receptor 3, BR3);

(27) CD22 (B-cell receptor CD22-B isoform);

(28) CD79a (CD79A, CD79a, immunoglobulin-associated alpha);

(29) CXCR5 (Burkitt'"'"'s lymphoma receptor

     1);

(30) HLA-DOB (Beta subunit of MHC class II molecule (Ia antigen));

(31) P2X5 (Purinergic receptor P2X ligand-gated ion channel

     5);

(32) CD72 (B-cell differentiation antigen CD72, Lyb-2);

(33) LY64 (Lymphocyte antigen 64 (RP105), type I membrane protein of the leucine rich repeat (LRR) family);

(34) FcRH1 (Fc receptor-like protein

     1);

(35) IRTA2 (Immunoglobulin superfamily receptor translocation associated

     2); and

(36) TENB2 (putative transmembrane proteoglycan).

24. The conjugate of claim 21 wherein the antibody or antibody fragment is a cysteine-engineered antibody.

25. The conjugate of claim 21 wherein the antibody or antibody fragment is an antibody which binds to an ErbB receptor.

26. The conjugate of claim 25 wherein the antibody is trastuzumab.

27. The conjugate of claim 21 wherein Ab is an anti-HER2, an anti-Steap1, or an anti-CD22 antibody.

28. The conjugate according to claim 21 wherein the drug loading (p) of drugs (D) to antibody (Ab) is an integer from 1 to about 8.

29. The conjugate according to claim 28, wherein p is 1, 2, 3, or 4.

30. The conjugate according to claim 28 comprising a mixture of the antibody-drug conjugate compounds, wherein the average drug loading per antibody in the mixture of antibody-drug conjugate compounds is about 2 to about 5.

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

32. The pharmaceutical composition of claim 31 further comprising a therapeutically effective amount of a chemotherapeutic agent.

33. A method of treating cancer comprising administering to a patient the pharmaceutical composition of claim 31.

34. The method of claim 33 wherein the patient is administered a chemotherapeutic agent, in combination with the conjugate.

35. Use of a conjugate according to any claim 1 to provide a compound of formula (B) at a target location:

36. The use according to claim 35, wherein the target location is a proliferative cell population.

37. Use of a conjugate according to claim 1 to provide a compound of formula (C) at a target location:

38. A compound of formula (E):

39. The compound of claim 38, which is:

40. The compound of claim 38, which is:

41. A method of preparing a conjugate according to claim 1, the method comprising the step of reacting a cell binding agent with compound (D) as defined in claim 38.

42. An article of manufacture comprising a pharmaceutical composition of claim 31;

a container; and

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