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

• US 10,004,735 B2
• Filed: 07/20/2017
• Issued: 06/26/2018
• Est. Priority Date: 04/16/2014
• Status: Active Grant

• Current Assignee: Signal Pharmaceuticals, LLC (Bristol-Myers Squibb Company)
• Original Assignee: Signal Pharmaceuticals, LLC (Bristol-Myers Squibb Company)
• Inventors: Fultz, Kimberly Elizabeth, Tran, Tam Minh, Xu, Shuichan, Xu, Weiming
• Primary Examiner(s): Willis, Douglas M
• Application Number:
  US15/655,270
• Publication Number:
  US 20170312278A1
• Time in Patent Office: 341 Days
• Field of Search: 544350
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/282 Platinum compounds
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/501 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 38/14 Peptides containing saccharide radicals; Derivatives thereof , e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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.

Claims

1. A method for inhibiting target of rapamycin activity in a patient, comprising administering to the patient an effective amount of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-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

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 solid tumor.

4. The method of claim 3, wherein the solid tumor is selected from the group consisting of a relapsed solid tumor and a refractory solid tumor.

5. The method of claim 3, wherein the solid tumor is an advanced solid tumor.

6. The method of claim 3, 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.

7. 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.

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.