Treatment of cancer with dihydropyrazino-pyrazines

Patent metadata

Field	Value
Publication number	US-9505764-B2
Application number	US-201414254015-A
Country	US
Kind code	B2
Filing date	Apr 16, 2014
Priority date	Apr 17, 2013
Publication date	Nov 29, 2016
Grant date	Nov 29, 2016

Abstract

Provided herein are methods for treating or preventing chronic lymphocytic leukemia, comprising administering an effective amount of a Dihydropyrazino-Pyrazine Compound to a patient having chronic lymphocytic leukemia.

First claim

What is claimed is:

1. A method for treating CLL or T-PLL, comprising administering an effective amount of 1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof to a patient having CLL or T-PLL.

2. The method of claim 1 , wherein the CLL or T-PLL is characterized by one or more of deletion of all or part of chromosome 11q, loss or mutation of the gene encoding ATM, loss of ATM expression or function, mutation of IgVH, wild type IgVH, wild type p53/ATM, mutation of p53, dysfunctional p53 or Zap-70 positivity.

3. The method of claim 1 , wherein CLL or T-PLL is that in which the PI3K/mTOR pathway is activated.

4. The method of claim 1 , wherein the CLL or T-PLL is characterized by deletion of all or part of chromosome 11q or loss or mutation of the gene encoding ATM.

5. The method of claim 1 , wherein the CLL is SLL.

6. A method for achieving an International Workshop on Chronic Lymphocytic Leukemia (IWCLL) response definition of complete response, complete response with incomplete marrow recovery, partial response or stable disease in a patient having CLL or T-PLL, comprising administering an effective amount of 1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof to said patient.

7. A method for achieving a National Cancer Institute-sponsored Working Group on Chronic Lymphocytic Leukemia (NCI-WG CLL) response definition of complete response, complete response with incomplete marrow recovery, partial response or stable disease in a patient having CLL or T-PLL, comprising administering an effective amount of 1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof to said patient.

8. A method for treating CLL or T-PLL, comprising administering an effective amount of 1 ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof to a patient having CLL or T-PLL, wherein the treatment results in one or more of inhibition of disease progression, increased Time To Progression (TTP), increased Overall Survival (OS), increased Progression-free Survival (PFS), increased Event-free Survival, increased Disease-free Survival, increased Response Duration, increased Lymphoma-specific survival, and/or increased Time To Next Treatment.

9. The method of claim 6 , 7 or 8 , wherein the CLL or T-PLL is characterized by deletion of all or part of chromosome 11q, loss or mutation of the gene encoding ATM, loss of ATM expression or function, mutation of IgVH, wild type IgVH, wild type p53/ATM, mutation of p53, dysfunctional p53 or Zap-70 positivity.

10. The method of claim 6 , 7 or 8 , wherein the CLL or T-PLL is that in which the PI3K/mTOR pathway is activated.

11. The method of claim 6 , 7 or 8 , wherein the CLL or T-PLL is characterized by deletion of all or part of chromosome 11q or loss or mutation of the gene encoding ATM.

12. The method of claim 6 , 7 or 8 , wherein the CLL is SLL.

13. A method for inhibiting phosphorylation of S6RP, 4E-BP1 and/or AKT in a biological sample of a patient having CLL or T-PLL, comprising administering an effective amount of 1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof to said patient and comparing the amount of phosphorylated S6RP, 4E-BP1 and/or AKT in a biological sample of said patient obtained prior to and after administration of 1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein less phosphorylated S6RP, 4E-BP1 and/or AKT in said biological sample obtained after administration of 1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof relative to the amount of phosphorylated S6RP, 4E-BP1 and/or AKT in said biological sample obtained prior to administration of 1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

14. The method of claim 13 , wherein the CLL or T-PLL is characterized by deletion of all or part of chromosome 11q, loss or mutation of the gene encoding ATM, loss of ATM expression or function, mutation of IgVH, wild type IgVH, wild type p53/ATM, mutation of p53, dysfunctional p53 or Zap-70 positivity.

15. The method of claim 13 , wherein the CLL or T-PLL is that in which the PI3K/mTOR pathway is activated.

16. The method of claim 13 , wherein the CLL or T-PLL is characterized by deletion of all or part of chromosome 11q or loss or mutation of the gene encoding ATM.

17. The method of claim 13 , wherein the CLL is SLL.

18. A method for inhibiting DNA-PK activity in a skin sample of a patient having CLL or T-PLL, comprising administering an effective amount of 1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof to said patient and comparing the amount of phosphorylated DNA-PK in a biological sample of said patient obtained prior to and after administration of 1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein less phosphorylated DNA-PK in said biological sample obtained after administration of 1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof relative to the amount of phosphorylated DNA-PK in said biological sample obtained prior to administration of 1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof indicates inhibition.

19. The method of claim 18 , wherein the CLL or T-PLL is characterized by deletion of all or part of chromosome 11q, loss or mutation of the gene encoding ATM, loss of ATM expression or function, mutation of IgVH, wild type IgVH, wild type p53/ATM, mutation of p53, dysfunctional p53 or Zap-70 positivity.

20. The method of claim 18 , wherein the CLL or T-PLL is that in which the PI3K/mTOR pathway is activated.

21. The method of claim 18 , wherein the CLL or T-PLL is characterized by deletion of all or part of chromosome 11q or loss or mutation of the gene encoding ATM.

22. The method of claim 18 , wherein the CLL is SLL.

23. A method for measuring inhibition of phosphorylation of S6RP, 4E-BP1 or AKT in a patient having CLL or T-PLL, comprising administering an effective amount of 1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof to said patient, measuring the amount of phosphorylated S6RP, 4E-BP1 or AKT in said patient, and comparing said amount of phosphory

Assignees

• Signal Pharm Llc

Inventors

• Raymon Heather
• Xu Shuichan
• Lopez-Girona Antonia
• Tsuji Toshiya
• Hege Kristen Mae

Classifications

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

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

• A61K31/4985 Primary

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title