Inhibitors of IAP

• US 11,096,982 B2
• Filed: 04/02/2019
• Issued: 08/24/2021
• Est. Priority Date: 01/03/2012
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Cohen, Frederick, Gazzard, Lewis J., Tsui, Vickie Hsiao-Wei, Flygare, John A.
• Primary Examiner(s): Alstrum-Acevedo, James H
• Assistant Examiner(s): Sabila, Mercy H
• Application Number:
  US16/372,940
• Publication Number:
  US 20190224269A1
• Time in Patent Office: 875 Days
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/06 Tripeptides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 5/08 Tripeptides
• CPC Class Codes: C07K 5/0804 and aliphatic
• CPC Class Codes: C07K 5/0806 the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• CPC Class Codes: C07K 5/0812 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/0815 with the first amino acid being basic

Abstract

Novel inhibitors of IAP that are useful as therapeutic agents for treating malignancies and have the general formula I:

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as described herein.

Claims

1. A method for inhibiting the binding of an inhibitor of apoptosis (IAP) protein to a caspase protein comprising a combination therapy of contacting said IAP protein with a compound according to formula I and applying a further therapy to the IAP protein:

2. The method according to claim 1, wherein R²-R⁶ are each independently H or methyl.

3. The method according to claim 1, wherein R¹ is cyclohexyl.

4. The method according to claim 1, wherein said compound according to formula (I) is (S)-1-[(S)-2-cyclohexyl-2-((S)-2-methylamino-propionylamino)-acetyl]-pyrrolidine-2-carboxylic acid (2-oxazol-2-yl-4-phenyl-thiazol-5-yl)-amide or a pharmaceutically acceptable salt thereof.

5. The method according to claim 1, wherein said further therapy is radiation therapy.

6. The method according to claim 1, wherein said further therapy is contacting the IAP protein with one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof, wherein the biologically active ingredient comprises:

a cytostatic compound;

an antineoplastic compound;

a chemotherapy compound;

a compound which sensitizes or induces apoptosis by binding to death receptors;

an agent that modulates a protein kinase; and

/or an agent that modulates non-kinase biological targets or processes.

7. A method for treating a disease or condition associated with the overexpression of an inhibitor of apoptosis (IAP) in a mammal, comprising a combination therapy of administering to said mammal an effective amount of a compound according to formula I and applying a further therapy to said mammal:

8. The method according to claim 7, wherein said compound according to formula (I) is (S)-1-[(S)-2-cyclohexyl-2-((S)-2-methylamino-propionylamino)-acetyl]-pyrrolidine-2-carboxylic acid (2-oxazol-2-yl-4-phenyl-thiazol-5-yl)-amide or a pharmaceutically acceptable salt thereof.

9. The method according to claim 7, wherein R²-R⁶ are each independently H or methyl.

10. The method according to claim 7, wherein R¹ is cyclohexyl.

11. The method according to claim 7, wherein said further therapy is radiation therapy.

12. The method according to claim 7, wherein said further therapy is administering one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof, wherein the biologically active ingredient comprises:

a cytostatic compound;

an antineoplastic compound;

a chemotherapy compound;

a compound which sensitizes or induces apoptosis by binding to death receptors;

an agent that modulates a protein kinase; and

/or an agent that modulates non-kinase biological targets or processes.

13. A method of inducing apoptosis in a cell comprising a combination therapy of introducing into said cell a compound according to formula I and applying a further therapy to said cell:

14. The method according to claim 13, wherein said compound according to formula (I) is (S)-1-[(S)-2-cyclohexyl-2-((S)-2-methylamino-propionylamino)-acetyl]-pyrrolidine-2-carboxylic acid (2-oxazol-2-yl-4-phenyl-thiazol-5-yl)-amide or a pharmaceutically acceptable salt thereof.

15. The method according to claim 13, wherein R²-R⁶ are each independently H or methyl.

16. The method according to claim 13, wherein R¹ is cyclohexyl.

17. The method according to claim 13, wherein said further therapy is radiation therapy.

18. The method according to claim 13, wherein said further therapy is contacting the cell with one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof, wherein the biologically active ingredient comprises:

a cytostatic compound;

an antineoplastic compound;

a chemotherapy compound;

a compound which sensitizes or induces apoptosis by binding to death receptors;

an agent that modulates a protein kinase; and

/or an agent that modulates non-kinase biological targets or processes.

19. A method of sensitizing a cell to an apoptotic signal comprising a combination therapy of introducing into said cell a compound according to formula I and applying a further therapy to said cell:

20. The method according to claim 19, wherein said compound according to formula (I) is (S)-1-[(S)-2-cyclohexyl-2-((S)-2-methylamino-propionylamino)-acetyl]-pyrrolidine-2-carboxylic acid (2-oxazol-2-yl-4-phenyl-thiazol-5-yl)-amide or a pharmaceutically acceptable salt thereof.

21. The method according to claim 19, wherein R²-R⁶ are each independently H or methyl.

22. The method according to claim 19, wherein R¹ is cyclohexyl.

23. The method according to claim 19, wherein said further therapy is radiation therapy.

24. The method according to claim 19, wherein said further therapy is contacting the cell with one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof, wherein the biologically active ingredient comprises:

a cytostatic compound;

an antineoplastic compound;

a chemotherapy compound;

a compound which sensitizes or induces apoptosis by binding to death receptors;

an agent that modulates a protein kinase; and

/or an agent that modulates non-kinase biological targets or processes.

25. A method for treating cancer in a mammal, comprising a combination therapy of administering to said mammal an effective amount of a compound according to formula I and applying a further therapy to said mammal:

26. The method according to claim 25, wherein said compound according to formula (I) is (S)-1-[(S)-2-cyclohexyl-2-((S)-2-methylamino-propionylamino)-acetyl]-pyrrolidine-2-carboxylic acid (2-oxazol-2-yl-4-phenyl-thiazol-5-yl)-amide or a pharmaceutically acceptable salt thereof.

27. The method according to claim 25, wherein R²-R⁶ are each independently H or methyl.

28. The method according to claim 25, wherein R¹ is cyclohexyl.

29. The method according to claim 25, wherein said further therapy is radiation therapy.

30. The method according to claim 25, wherein said further therapy is administering one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof, wherein the biologically active ingredient comprises:

a cytostatic compound;

an antineoplastic compound;

a chemotherapy compound;

a compound which sensitizes or induces apoptosis by binding to death receptors;

an agent that modulates a protein kinase; and

/or an agent that modulates non-kinase biological targets or processes.