Inhibitors of IAP

Patent metadata

Field	Value
Publication number	US-9238675-B2
Application number	US-201414269739-A
Country	US
Kind code	B2
Filing date	May 5, 2014
Priority date	Jan 3, 2012
Publication date	Jan 19, 2016
Grant date	Jan 19, 2016

Abstract

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

wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as described herein.

First claim

We claim:

1. A method for inhibiting the binding of an IAP protein to a caspase protein comprising contacting said IAP protein with a compound according to formula I

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 11-6 alkyl;

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 2 wherein R 1 is cyclohexyl.

5. The method according to claim 2 , wherein one of R 2 and R 3 is H and the other is methyl; or R 4 is methyl; or R 5 and R 6 are each H.

6. The method according to claim 1 , wherein said compound 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.

7. A method for treating a disease or condition associated with the overexpression of an IAP in a mammal, comprising administering to said mammal an effective amount of a compound according to formula I

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.

8. The method according to claim 7 , wherein said compound 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. A method of inducing apoptosis in a cell comprising introducing into said cell a compound according to formula I

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.

10. The method according to claim 9 , wherein said compound is S)- 1-[(S)-2-cyclohexyl-2- ((S)-2-methylamino-propionylamino)-acetyl]-pyrrolidine-2-carboxylic acid (2-oxazol-2-yl-4-phenyl-thiazol-5yl)-amide or a pharmaceutically acceptable salt thereof of.

11. A method of sensitizing a cell to an apoptotic signal comprising introducing into said cell a compound according to formula I

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 11-6 alkyl;

or a pharmaceutically acceptable salt thereof.

12. The method of claim 11 , wherein said apoptotic signal is induced by contacting said cell with a compound selected from the group consisting of cytarabine, fludarabine, 5-fluoro-2′-deoxyuiridine, gemcitabine, methotrexate, bleomycin, cisplatin, cyclophosphamide, adriamycin (doxorubicin), mitoxantrone, camptothecin, topotecan, colcemid, colchicine, paclitaxel, vinblastine, vincristine, tamoxifen, finasteride, docetaxel and mitomycin C.

13. The method of claim 11 , wherein said apoptotic signal is induced by contacting said cell with Apo2L/TRAIL.

14. The method according to claim 11 , wherein said compound 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 of claim 14 , wherein said apoptotic signal is induced by contacting said cell with a compound selected from the group consisting of cytarabine, fludarabine, 5-fluoro-2′-deoxyuiridine, gemcitabine, methotrexate, bleomycin, cisplatin, cyclophosphamide, adriamycin (doxorubicin), mitoxantrone, camptothecin, topotecan, colcemid, colchicine, paclitaxel, vinblastine, vincristine, tamoxifen, finasteride, docetaxel and mitomycin C.

16. The method of claim 14 , wherein said apoptotic signal is induced by contacting said cell with Apo2L/TRAIL.

17. A method for treating cancer, comprising administering to said mammal an effective amount of a compound according to formula I

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 11-6 alkyl;

or a pharmaceutically acceptable salt thereof.

18. The method according to claim 17 , wherein said compound 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.

Assignees

• Genentech Inc

Inventors

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

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07K5/0806

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

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title