Methods for treating cancer using TOR kinase inhibitor combination therapy comprising administering substituted pyrazino[2,3-b]pyrazines

Patent metadata

Field	Value
Publication number	US-9737535-B2
Application number	US-201514686872-A
Country	US
Kind code	B2
Filing date	Apr 15, 2015
Priority date	Apr 16, 2014
Publication date	Aug 22, 2017
Grant date	Aug 22, 2017

Abstract

Provided herein are methods for treating or preventing a cancer, comprising administering an effective amount of a TOR kinase inhibitor and an effective amount a second active agent to a patient having a cancer, wherein the TOR kinase inhibitor is a compound of formula (I):

and pharmaceutically acceptable salts, clathrates, solvates, stereoisomers, tautomers, metabolites, isotopologues and prodrugs thereof.

First claim

What is claimed is:

1. A method for inhibiting target of rapamycin activity in a patient, comprising administering to the patient 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, in combination with an effective amount of a second active agent,
wherein the second active agent is selected from the group consisting of a receptor tyrosine kinase inhibitor, a phosphoinositide 3-kinase pathway inhibitor, a serine/threonine-protein kinase and mitogen-activated protein kinase/extracellular signal-regulated protein kinase kinase pathway inhibitor, a deoxyribonucleic acid damaging agent, a deoxyribonucleic acid damage response agent, a cytoskeleton perturbagen, a protein stability inhibitor, a Bruton's tyrosine kinase inhibitor and a B-cell lymphoma-2 protein family inhibitor,
wherein:
the receptor tyrosine kinase inhibitor is selected from the group consisting of

the phosphoinositide 3-kinase pathway inhibitor is selected from the group consisting of

the serine/threonine-protein kinase and mitogen-activated protein kinase/extracellular signal-regulated protein kinase kinase pathway inhibitor is selected from the group consisting of

the deoxyribonucleic acid damaging agent is selected from the group consisting of

the deoxyribonucleic acid damage response agent is selected from the group consisting of

the cytoskeleton perturbagen is selected from the group consisting of

the protein stability inhibitor is selected from the group consisting of

the Bruton's tyrosine kinase inhibitor is

and
the B-cell lymphoma-2 protein family inhibitor is selected from the group consisting of

2. The method of claim 1 , wherein the patient suffers from a cancer selected from the group consisting of head cancer, neck cancer, eye cancer, mouth cancer, throat cancer, esophagus cancer, bronchus cancer, larynx cancer, pharynx cancer, chest cancer, bone cancer, lung cancer, colon cancer, rectum cancer, stomach cancer, prostate cancer, urinary bladder cancer, uterus cancer, cervix cancer, breast cancer, ovary cancer, testicle cancer, skin cancer, thyroid cancer, blood cancer, kidney cancer, liver cancer, pancreas cancer, brain cancer, a cancer of the lymph nodes, a cancer of the reproductive organs and a cancer of the central nervous system.

3. The method of claim 1 , wherein the patient suffers from a cancer associated with the pathways involving a kinase selected from the group consisting of mammalian target of rapamycin kinase, phosphoinositide 3-kinase and protein kinase B.

4. The method of claim 1 , wherein the patient suffers from a solid tumor.

5. The method of claim 4 , wherein the solid tumor is selected from the group consisting of a neuroendocrine tumor, glioblastoma multiforme, hepatocellular carcinoma, breast cancer, colorectal cancer, salivary cancer, pancreatic cancer, adenocystic cancer, adrenal cancer, esophageal cancer, renal cancer, leiomyosarcoma, paraganglioma, head and neck squamous cell carcinoma, E-twenty six overexpressing castration-resistant prostate cancer and E-twenty six overexpressing Ewing's sarcoma.

6. The method of claim 4 , wherein the solid tumor is selected from the group consisting of a relapsed solid tumor and a refractory solid tumor.

7. The method of claim 4 , wherein the solid tumor is an advanced solid tumor.

8. The method of claim 1 , wherein the second active agent is a receptor tyrosine kinase inhibitor.

9. The method of claim 1 , wherein the second active agent is a phosphoinositide 3-kinase pathway inhibitor.

10. The method of claim 1 , wherein the second active agent is a serine/threonine-protein kinase and mitogen-activated protein kinase/extracellular signal-regulated protein kinase kinase pathway inhibitor.

11. The method of claim 1 , wherein the second active agent is a deoxyribonucleic acid damaging agent.

12. The method of claim 1 , wherein the second active agent is a deoxyribonucleic acid damage response agent.

13. The method of claim 1 , wherein the second active agent is a cytoskeleton perturbagen.

14. The method of claim 1 , wherein the second active agent is a protein stability inhibitor.

15. The method of claim 1 , wherein the second active agent is a Bruton's tyrosine kinase inhibitor.

16. The method of claim 1 , wherein the second active agent is a B-cell lymphoma-2 protein family inhibitor.

Assignees

• Signal Pharm Llc

Inventors

• Fultz Kimberly Elizabeth
• Tran Tam Minh
• Xu Shuichan
• Xu Weiming

Classifications

• A61K31/704

  attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)} · CPC title

• A61K31/69

  Boron compounds · CPC title

• A61K31/4184

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title

• A61K38/14

  Peptides containing saccharide radicals; Derivatives thereof {, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin} · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title