Inhibitors of IAP

Patent metadata

Field	Value
Publication number	US-11096982-B2
Application number	US-201916372940-A
Country	US
Kind code	B2
Filing date	Apr 2, 2019
Priority date	Jan 3, 2012
Publication date	Aug 24, 2021
Grant date	Aug 24, 2021

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.

First claim

We claim:

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:

wherein
Ph is phenyl;
R 1 is C 3-7 cycloalkyl; and
R 2 , R 3 , R 4 , R 5 , and R 6 are each independently in each occurrence H or
C 1-6 alkyl;

or a pharmaceutically acceptable salt thereof;
wherein the further therapy comprises radiation therapy and/or contacting with one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 , wherein R 2 -R 6 are each independently H or methyl.

3. The method according to claim 1 , wherein R 1 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:

wherein
Ph is phenyl;
R 1 is C 3-7 cycloalkyl; and
R 2 , R 3 , R 4 , R 5 , and R 6 are each independently in each occurrence H or
C 1-6 alkyl;

or a pharmaceutically acceptable salt thereof;
wherein the further therapy comprises radiation therapy and/or administering one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof.

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 R 2 -R 6 are each independently H or methyl.

10. The method according to claim 7 , wherein R 1 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:

wherein
Ph is phenyl;
R 1 is C 3-7 cycloalkyl; and
R 2 , R 3 , R 4 , R 5 , and R 6 are each independently in each occurrence H or
C 1-6 alkyl;

or a pharmaceutically acceptable salt thereof;
wherein the further therapy comprises radiation therapy and/or contacting with one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof.

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 R 2 -R 6 are each independently H or methyl.

16. The method according to claim 13 , wherein R 1 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:

wherein
Ph is phenyl;
R 1 is C 3-7 cycloalkyl; and
R 2 , R 3 , R 4 , R 5 , and R 6 are each independently in each occurrence H or
C 1-6 alkyl;

or a pharmaceutically acceptable salt thereof;
wherein the further therapy comprises radiation therapy and/or contacting with one or more biologically active ingredient different from the compound of formula I or a pharmaceutically acceptable salt thereof.

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 R 2 -R 6 are each independently H or methyl.

22. The method according to claim 19 , wherein R 1 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

Assignees

• Genentech Inc

Inventors

• Cohen Frederick
• Gazzard Lewis J
• Tsui Vickie Hsiao-Wei
• Flygare John A

Classifications

• C07D417/14 Primary

  containing three or more hetero rings · CPC title

• C07K5/0806

  the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07K5/08

  Tripeptides · CPC title

• C07K5/0815

  with the first amino acid being basic · CPC title