CYTOTOXIC PEPTIDES AND ANTIBODY DRUG CONJUGATES THEREOF

• US 20130129753A1
• Filed: 11/07/2012
• Published: 05/23/2013
• Est. Priority Date: 11/17/2011
• Status: Active Grant

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: MADERNA, Andreas, STROP, Pavel, DOROSKI, Matthew David, O'DONNELL, Christopher John, SUBRAMANYAM, Chakrapani, VETELINO, Beth, DUSHIN, Russell George, GRAZIANI, Edmund Idris
• Granted Patent: US 8,828,401 B2
• Time in Patent Office: Days
• US Class Current: 424/179.1
• CPC Class Codes: A61K 38/06 Tripeptides
• CPC Class Codes: A61K 38/07 Tetrapeptides
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 47/68031 the drug being an auristatin
• CPC Class Codes: A61K 47/6811 the drug being a protein or peptide, e.g. transferrin or bleomycin
• CPC Class Codes: A61K 47/6851 the antibody targeting a determinant of a tumour cell
• CPC Class Codes: A61K 47/6855 the tumour determinant being from breast cancer cell
• CPC Class Codes: A61K 47/6863 the tumour determinant being from stomach or intestines cancer cell
• CPC Class Codes: A61K 47/6889 Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/00 Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C07K 5/0205 containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
• CPC Class Codes: C07K 5/0808 the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• CPC Class Codes: C07K 7/02 Linear peptides containing at least one abnormal peptide link
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids

Abstract

The present invention is directed to cytotoxic pentapeptides, to antibody drug conjugates thereof, and to methods for using the same to treat cancer.

Claims

1. A compound of formula I:

10. The compound, salt or solvate of claim 1, wherein

W is

11. The compound, salt or solvate of claim 1, wherein R¹ is hydrogen, C₁-C₈ alkyl or C₁-C₈ haloalkyl.

14. The compound, salt or solvate of claim 1, wherein R^3A is hydrogen, C₁-C₈ alkyl, C₁-C₈ haloalkyl, C₃-C₈ carbocyclyl, C₁-C₁₀ heterocyclyl, aryl, heteroaralkyl or aralkyl;

and R^3B is C₁-C₈ alkyl, C₁-C₈ haloalkyl, C₃-C₈ carbocyclyl, C₁-C₁₀ heterocyclyl, aryl, heteroaralkyl, aralkyl or halogen.

15. The compound, salt or solvate of claim 1, wherein R^3A and R^3B taken together are C₂-C₈ alkylene or C₁-C₈ heteroalkylene.

16. The compound, salt or solvate of claim 1, wherein R^4A is hydrogen, C₁-C₈ alkyl, C₁-C₈ haloalkyl, C₃-C₈ carbocyclyl, C₁-C₁₀ heterocyclyl, aryl, heteroaralkyl or aralkyl;

and R^4B is C₁-C₈ alkyl, C₁-C₈ haloalkyl, C₃-C₈ carbocyclyl, C₁-C₁₀ heterocyclyl, aryl, heteroaralkyl or aralkyl;

or R^4A and R^4B taken together are C₂-C₈ alkylene or C₁-C₈ heteroalkylene.

19. The compound, salt or solvate of claim 1 , wherein R⁵ is

26. An antibody drug conjugate comprising a radical of a compound of any of claims 1, 2, or 3.

2. A compound of formula IIa:

12. The compound, salt or solvate of claim 2 wherein R¹ is

21. The compound, salt or solvate of claim 2, wherein Y is —

C₂-C₂₀ alkylene-, —

C₂-C₂₀ heteroalkylene-, —

C₃-C₈ carbocyclo-, -arylene-, —

C₃-C₈heterocyclo-, —

C₁-C₁₀alkylene-arylene-, -arylene-C₁-C₁₀alkylene-, —

C₁-C₁₀alkylene-(C₃-C₈-carbocyclo)-, —

(C₃-C₈-carbocyclo)-C₁-C₁₀alkylene-, —

C₁-C₁₀alkylene-(C₃-C₈heterocyclo)-, or —

(C₃-C₈ heterocyclo)-C₁-C₁₀alkylene-;

3. A compound of formula IIIa:

20. The compound, salt or solvate of claim 3, wherein R⁵ is

4. A compound of formula IIb:

13. The compound, salt or solvate of claim 4 wherein R¹ is

29. A pharmaceutical composition comprising a compound of claim 4, or a pharmaceutically acceptable salt or solvate thereof, and pharmaceutically acceptable excipient.

30. A method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 4.

5. A compound of formula IIIb:

22. The compound, salt or solvate of claim 5, wherein antibody is selected from trastuzumab, oregovomab, edrecolomab, cetuximab, a humanized monoclonal antibody to the vitronectin receptor (α

_vβ

₃);

alemtuzumab;

a humanized anti-HLA-DR antibody for the treatment of non-Hodgkin'"'"'s lymphoma;

131I Lym-1, a murine anti-HLA-Dr10 antibody for the treatment of non-Hodgkin'"'"'s lymphoma;

a humanized anti-CD2 mAb for the treatment of Hodgkin'"'"'s Disease or non-Hodgkin'"'"'s lymphoma;

labetuzumab;

bevacizumab;

ibritumomab tiuxetan;

ofatumumab;

panitumumab;

rituximab;

tositumomab;

ipilimumab;

gemtuzumab;

an anti-IL13 antibody; and

an anti-Notch antibody.

6. A compound of formula IIc:

17. The compound, salt or solvate of claim 6, wherein R^3A′

and R^3B′

are defined as either of the following;

(i) R^3A′

is hydrogen, C₁-C₈ alkyl, C₁-C₈ haloalkyl, C₃-C₈ carbocyclyl, C₁-C₁₀ heterocyclyl, aryl, heteroaralkyl, aralkyl or halogen; and

R^3B′

is C₁-C₈ alkyl, C₁-C₈ haloalkyl, C₃-C₈ carbocyclyl, C₁-C₁₀ heterocyclyl, aryl, heteroaralkyl, halogen or aralkyl, or R^3B′

is C₂-C₄ alkylene and forms 5-7 member ring as indicated by ;

or

(ii) R^3A′

and R^3B′

taken together are C₂-C₈ alkylene or C₁-C₈ heteroalkylene;

18. The compound, salt or solvate of claim 6, wherein R^4A′

and R^4B′

are defined as either of the following;

(i) R^4A′

is hydrogen, C₁-C₈ alkyl, C₁-C₈ haloalkyl, C₃-C₈ carbocyclyl, C₁-C₁₀ heterocyclyl, aryl, heteroaralkyl or aralkyl; and

R^4B′

is hydrogen, C₁-C₈ alkyl, C₁-C₈ haloalkyl, C₃-C₈ carbocyclyl, C₁-C₁₀ heterocyclyl, aryl, heteroaralkyl or aralkyl;

or

(ii) R^4A′

and R^4B′

taken together are C₂-C₈ alkylene or C₁-C₈ heteroalkylene;

7. A compound of formula IIIc:

8. A compound of formula lid:

9. A compound of formula IIId:

23. A compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:

25. A payload-linker or an antibody-drug-conjugate comprising a radical of a compound of claim 23 or 24.

28. An antibody-drug-conjugate comprising a radical of a compound of any one of claims 23, 24, 25, 26, or 27.

24. A compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:

27. A compound, or a pharmaceutically acceptable salt or solvate thereof, selected from: