Diamino heterocyclic carboxamide compound

Patent metadata

Field	Value
Publication number	US-9487491-B2
Application number	US-201414472959-A
Country	US
Kind code	B2
Filing date	Aug 29, 2014
Priority date	May 8, 2009
Publication date	Nov 8, 2016
Grant date	Nov 8, 2016

Abstract

Provided is a compound useful as an inhibitor against the kinase activity of EML4-ALK fusion protein. As a result of intensive and extensive studies on compounds having inhibitory activity against the kinase activity of EML4-ALK fusion protein, the present inventors found that the diamino heterocyclic carboxamide compounds of the present invention had inhibitory activity against the kinase activity of EML4-ALK fusion protein. By this finding, the present invention was completed. The compounds of the present invention can be used as a pharmaceutical composition for preventing and/or treating cancer, such as lung cancer, non-small cell lung cancer, and small cell lung cancer.

First claim

The invention claimed is:

1. A method for treating non-small cell lung cancer, which comprises administering to a patient in need thereof an effective amount of a 6-ethyl-3-({3-methoxy-4-[4-(4methylpiperazin-1-yl)piperidin-1 -yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide or a salt thereof.

2. The method according to claim 1 , which comprises administering a fumaric acid salt of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino) pyrazine-2-carboxamide.

3. The method according to claim 1 , which comprises administering 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1 - yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate (HFM).

4. The method according to claim 1 , wherein said administration is oral administration.

5. The method according to claim 4 , wherein said 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5 -(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide or salt thereof is administered in a daily amount of 0.01 to 10 mg/kg of body weight of said patient.

6. The method according to claim 2 , wherein said administration is oral administration.

7. The method according to claim 6 , wherein said fumaric acid salt of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1 -yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide or salt thereof is administered in a daily amount of 0.01 to 10 mg/kg of body weight of said patient.

8. The method according to claim 3 , wherein said administration is oral administration.

9. The method according to claim 8 , wherein said 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5 -(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate (HFM) is administered in a daily amount of 0.01 to 10 mg/kg of body weight of said patient.

10. A method for treating acute myelocytic leukemia or atypical chronic myelocytic leukemia, which comprises administering to a patient in need thereof an effective amount of 6-ethyl-3-({3 -methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide or a salt thereof.

11. The method of claim 10 , wherein said acute myelocytic leukemia is mutant FLT3 polynucleotide-positive acute myelocytic leukemia, FLT3 internal tandem duplication (ITD) positive acute myelocytic leukemia, or acute myelocytic leukemia with FLT3 point mutation.

12. The method of claim 10 , wherein said atypical chronic myelocytic leukemia is FLT3 fusion polynucleotide-positive atypical chronic myelocytic leukemia.

13. The method according to claim 10 , which comprises administering a fumaric acid salt of 6-ethyl-3-({3-methoxy-4-[4-(4 -methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4 -ylamino)pyrazine-2-carboxamide.

14. The method according to claim 10 , which comprises administering 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1 -yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate (HFM).

15. The method according to claim 10 , wherein said administration is oral administration.

16. The method according to claim 15 , wherein said 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide or salt thereof is administered in a daily amount of 0.01 to 10 mg/kg of body weight of said patient.

17. The method according to claim 13 , wherein said administration is oral administration.

18. The method according to claim 17 , wherein said fumaric acid salt of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide or salt thereof is administered in a daily amount of 0.01 to 10 mg/kg of body weight of said patient.

19. The method according to claim 14 , wherein said administration is oral administration.

20. The method according to claim 19 , wherein said 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate (HFM) is administered in a daily amount of 0.01 to 10 mg/kg of body weight of said patient.

21. The method according to claim 11 , which comprises administering a fumaric acid salt of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide.

22. The method according to claim 11 , which comprises administering 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate (HFM).

23. The method according to claim 21 , wherein said administration is oral administration.

24. The method according to claim 23 , wherein said fumaric acid salt of 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide is administered in a daily amount of 0.01 to 10 mg/kg of body weight of said patient.

25. The method according to claim 22 , wherein said administration is oral administration.

26. The method according to claim 25 , wherein said 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide hemifumarate (HFM) is administered in a daily amount of 0.01 to 10 mg/kg of body weight of said patient.

Assignees

• Astellas Pharma Inc
• Kotobuki Pharmaceutical Co Ltd

Inventors

• Shimada Itsuro
• Kurosawa Kazuo
• Matsuya Takahiro
• Iikubo Kazuhiko
• Kondoh Yutaka
• Kamikawa Akio
• Tomiyama Hiroshi
• Iwai Yoshinori

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P35/02

  specific for leukemia · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D239/48 Primary

  Two nitrogen atoms · CPC title