PYRROLOBENZODIAZEPINES AND CONJUGATES THEREOF

• US 20130028917A1
• Filed: 04/15/2011
• Published: 01/31/2013
• Est. Priority Date: 04/15/2010
• Status: Abandoned Application

• Current Assignee: MedImmune Ltd. (Astrazeneca PLC)
• Original Assignee: Spirogen Developments SARL (Astrazeneca PLC)
• Inventors: Howard, Philip Wilson, Masterson, Luke, Tiberghien, Arnaud, Flygare, John A., Gunzner, Janet L., Polakis, Paul, Polson, Andrew, Raab, Helga E., Spencer, Susan D.
• Application Number:
  US13/641,198
• Publication Number:
  US 20130028917A1
• Time in Patent Office: Days
• US Class Current: 424/178.1
• CPC Class Codes: A61K 47/6849 the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
• CPC Class Codes: A61K 47/6855 the tumour determinant being from breast cancer cell
• CPC Class Codes: A61K 47/6869 the tumour determinant being from a cell of the reproductive system: ovaria, uterus, testes, prostate
• 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: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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 of formula (A):

2. The conjugate of claim 1, wherein R¹⁰ is removable from the N10 position to leave an N10-C11 imine bond.

3. The conjugate of any one of claim 1 or claim 2, wherein R¹⁰ is a group:

4. The conjugate of claim 5, wherein L¹ is enzyme cleavable.

5. The conjugate of claim 3 or claim 4, wherein L¹ comprises a contiguous sequence of amino acids.

6. The conjugate of claim 5, wherein L¹ comprises a dipeptide and the group —

X₁—

X₂—

in dipeptide, —

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-.

7. The conjugate according to claim 6, wherein the group —

X₁—

X₂—

in dipeptide, —

NH—

X₁—

X₂—

CO—

, is selected from;

-Phe-Lys-,

-Val-Ala-,

-Val-Lys-,

-Ala-Lys-,

-Val-Cit-.

8. The conjugate according to claim 7, wherein the group —

X₁—

X₂—

in dipeptide, —

NH—

X₁—

X₂—

CO—

, is -Phe-Lys-, -Val-Ala- or -Val-Cit-.

9. The conjugate according to any one of claims 6 to 8, wherein the group X₂—

CO—

is connected to L².

10. The conjugate according to any one of claims 6 to 9, wherein the group NH—

X₁—

is connected to A.

11. The conjugate according to any one of claims 6 to 10, wherein L² together with OC(═

O) forms a self-immolative linker.

12. The conjugate according to claim 11, wherein C(═

O)O and L² together form the group;

13. The conjugate according to claim 12, wherein Y is NH.

14. The conjugate according to claim 12 or claim 13, wherein n is 0.

15. The conjugate according to claim 3, wherein L¹ and L² together with —

OC(═

O)—

comprise a group selected from;

16. The conjugate according to claim 15, wherein the wavy line indicates the point of attachment to A.

17. The conjugate according to any one of claims 3 to 16, wherein A is:

18. The conjugate according to any one of claims 3 to 17, wherein the cell binding agent is connected to A through a thioether bond formed from a cysteine thiol residue of the cell binding agent and a malemide group of A.

19. The conjugate according to any one of the preceding claims, wherein the cell binding agent of R¹⁰ is an antibody or an active fragment thereof.

20. The conjugate according to claim 19, wherein the antibody or antibody fragment is an antibody or antibody fragment for a tumour-associated antigen.

21. The conjugate according to any one of the preceding claims, wherein R⁹ is independently H.

22. The conjugate according to any one of the preceding claims, wherein R⁶ is independently H.

23. The conjugate according to any one of the preceding claims, wherein R⁷ is independently OR^7A, where R^7A is independently optionally substituted C_1-4 alkyl.

24. The conjugate of claim 23, wherein R^7A is Me.

25. The conjugate according to any one of the preceding claims, wherein X is O.

26. The conjugate according to any one of the preceding claims, wherein R¹¹ is H.

27. The conjugate according to any one of the preceding claims, wherein the dotted lines indicate the optional presence of a double bond between C2 and C3.

28. The conjugate according to any one of the preceding claims, wherein R² is independently selected from H, ═

O, ═

CH₂, R, ═

CH—

R^D, and ═

C(R^D)₂.

29. The conjugate according to any one of the preceding claim 28, wherein R² is independently ═

CH₂.

30. The conjugate according to any one of the preceding claim 28, wherein R² is independently R.

31. The conjugate according to any one of the preceding claim 30, wherein R² is independently optionally substituted C_5-20 aryl.

32. The conjugate according to any one of the preceding claims, wherein the conjugate is a dimer, and R⁸ groups of each monomer form together the dimer bridge.

33. The conjugate according to claim 32, wherein R″

is a C₃ alkylene group or a C₅ alkylene group.

34. The conjugate according to claim 32 or claim 33, wherein the conjugate is a dimer with one monomer being of formula (A) and the other being of formula (B), and the compound having the structure shown below:

35. The conjugate according to claim 32 or claim 33, wherein the conjugate is a dimer with each monomer being of formula (A), and the compound having the structure shown below:

36. The conjugate according to claim 32 or claim 33, wherein the conjugate is a dimer with each monomer being of formula (A), and the compound having the structure shown below:

37. The conjugate according to claim 36, wherein R^C is removable from the N10 position to leave an N10-C11 imine bond.

38. The conjugate according to claim 37, wherein R^C is a carbamate protecting group selected from:

Alloc

Fmoc

Boc

Troc

Teoc

Psec

Cbz

PNZ.

39. The conjugate according to claim 37, wherein R^C is a group:

40. The conjugate according to claim 39, wherein L³ is a cleavable linker L¹, and is defined in any one of claims 4 to 9.

41. The conjugate according to claim 39 or claim 40, wherein L² together with OC(═

O) forms a self-immolative linker, and the self-immolative linker is as defined in any one of claims 12 to 14.

42. The conjugate according to any one of claims 39 to 41, wherein G² is Ac or Moc, or is a carbamate protecting group selected from:

Alloc

Fmoc

Boc

Troc

Teoc

Psec

Cbz

PNZ.

43. The conjugate according to any one of the preceding claims for use in therapy.

44. The conjugate according to any one of claims 1 to 42, for use in the treatment of a proliferative disease in a subject.

45. The conjugate according to claim 44, wherein the disease is cancer.

46. The conjugate according to according to any one of the preceding claims, having the formula:

Ab-(L-D)_p

where Ab is an antibody attached by a linker moiety (L) to the formula (A) PBD drug moiety (D), and p is an integer from 1 to about 8.

47. The conjugate of claim 46 wherein Ab 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) Sema 5b (FLJ10372, KIAA1445, Mm.42015, SEMA5B, SEMAG, Semaphorin 5b Hlog, sema 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, IPCA-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).

48. The conjugate of claim 46 wherein Ab is a cysteine-engineered antibody.

49. The conjugate of either claim 46 or claim 47 wherein Ab is an antibody which binds to an ErbB receptor.

50. The conjugate of claim 49 wherein Ab is trastuzumab.

51. The conjugate of either claim 46 or claim 47 wherein Ab is an anti-HER2, an anti-Steap1, or an anti-CD22 antibody.

52. The conjugate of any one of claims 46 to 51 wherein p is 1, 2, 3, or 4.

53. The conjugate of any one of claims 46 to 52 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.

54. The conjugate of any one of claims 46 to 53 having a formula selected from:

55. The conjugate of claim 54, where n is an integer from 1 to 12.

56. The conjugate of claim 55, where n is 4 or 8.

57. A pharmaceutical composition comprising the conjugate of any one of claims 1 to 56 a pharmaceutically acceptable diluent, carrier or excipient.

58. The pharmaceutical composition of claim 57 further comprising a therapeutically effective amount of a chemotherapeutic agent.

59. Use of a conjugate according to any one of claims 1 to 56 in the preparation of a medicament for use in the treatment of a proliferative disease in a subject.

60. A method of treating cancer comprising administering to a patient the pharmaceutical composition of claim 57.

61. The method of claim 60 wherein the patient is administered a chemotherapeutic agent, in combination with the conjugate.

62. Use of a conjugate according to any one of claims 1 to 56 to provide a compound of formula (C) at a target location:

63. The use according to claim 62, wherein the target location is a proliferative cell population.

64. Use of a conjugate according to any one of claims 1 to 56 to provide a compound of formula (D) at a target location:

76. A method of preparing a conjugate according to any of claims 1 to 56, the method comprising the step of reacting a cell binding agent with the compound (E) as defined in any one of claims 65 to 75.

77. An article of manufacture comprising a pharmaceutical composition of claim 57;

a container; and

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

65. A compound of formula (E):

66. The compound of claim 65 having the structure:

67. The compound of claim 66, where n is an integer from 1 to 12.

68. The compound of claim 67 where n is 4 or 8.

69. The compound of claim 65 having the structure:

70. The compound of claim 69 where n is an integer from 1 to 12.

71. The compound of claim 70 where n is 4 or 8.

72. The compound of claim 65 having the structure:

73. The compound of claim 72 where n is an integer from 1 to 12.

74. The compound of claim 73 where n is 4 or 8.

75. The compound of claim 65, which is selected from: