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Treatment of brain cancer

a brain cancer and tumor technology, applied in the field of brain cancer treatment, can solve the problems of brain metastases, a leading cause of death in erbb2+ breast cancer patients, and a serious unmet medical need

Inactive Publication Date: 2015-04-23
ARRAY BIOPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009]Another aspect provides a method of treating brain cancer in a mammal comprising administering a therapeutically effective amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol to the mammal.
[0010]Another aspect provides a method of treating brain cancer in a patient having brain cancer comprising administering a therapeutically effective amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol to the patient.
[0011]Another aspect provides a method of treating or preventing brain cancer in a mammal in need of such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine or (2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)amino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol.

Problems solved by technology

In breast cancer patients, brain metastases are a leading cause of death in ErbB2+ breast cancer patients and a serious unmet medical need.

Method used

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Examples

Experimental program
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Effect test

example 1

Growth of NCI-N87 Gastric Carcinoma in Nude Mice Implanted Intracranially

[0221]Tumor cells (NCI-N87 gastric carcinoma cells, NCI, Bethesda, Md.) were implanted in nude BALB / c female mice (Charles River Laboratories International, Inc.) via intracranial injection directly into the brain. The mice were separated into four groups (N=5) and were injected with vehicle (saline), 1×105 tumor cells, 2.5×105 tumor cells, or 5×105 tumor cells. The results are shown in FIG. 1. Brain tumor cell burden was associated with decreased survival in the NCI-N87 model.

[0222]In a pilot study using 14C albumin as the tracer and mannitol as the positive control for blood brain barrier (BBB) disruption, it was confirmed that the intracranial inoculation procedure did not mechanically disrupt the blood brain barrier.

example 2

Inhibition of NCI-N87 Gastric Carcinoma Xenograft Growth in Mice Implanted Intracranially

[0223]Anesthetized nude BALB / c female mice (Taconic Laboritories Inc., Germantown, N.Y.) were inoculated with human tumor cells (NCI-N87 gastric carcinoma cells, NCI, Bethesda, Md.) intracranially at lamba suture. 5×105 cells in saline were implanted via intracranial injection. The mice were separated into three groups (N=12); vehicle (acidified 30% Captisol®, pH about 4.5), 50 mg / kg lapatanib PO BID (30% Captisol®), and 75 mg / kg N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine PO BID (acidified 30% Captisol®, pH about 4.5). Dosing began two days after implantation. The dose may have been reduced as necessary if drug-related weight loss (approximately 5%) was observed. The mice were monitored twice daily for general health and behavioral / neurological effects, and body weights (BW) were determined twice weekly. At first ...

example 3

Brain Pharmacokinetic (PK) Study in Mice

[0224]Nude female BALB / c mice were administered a single PO dose (dose volume 10 mL / kg) of lapatanib (50 mg / kg, 30% Captisol®) and N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine (75 mg / kg, 30% Captisol, weigh out compound and add 30% Captisol® to give 7.5 mg / mL solution, then add 5 N HCl in 200 μL increments until it forms a clear, yellow solution). The mice were separated into groups and their PK was studied at 4 time points (0.5, 1, 2 and 4 hours, 4 mice per group per timepoint). The animals were euthanized by CO2 inhalation at the time points. Whole blood was drawn (300 μL) by cardiac puncture and placed in an eppendorf tube containing ethylenediaminetetraacetic acid (“EDTA”) (37.5 μL, 1.5%). The samples were centrifuged, and the plasma was decanted and frozen at −20 ° C. until delivered to analytical chemistry. The brains were collected. The animals were perfuse...

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Abstract

Compounds for the treatment of brain cancer are provided herein. Pharmaceutical compositions comprised of those compounds for the treatment of brain cancer are also provided herein.

Description

BACKGROUND OF THE INVENTION[0001]1. Field of the Invention[0002]N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine for the treatment of brain cancer is provided herein.[0003]2. Description of the State of the Art[0004]N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine (also called “ARRY-380”), which has the structure:is a selective ErbB2 (HER2) inhibitor described in WO 2007 / 059257, which is incorporated by reference in its entirety. N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine has been tested in human clinical trials for hyperproliferative diseases, particularly cancer, and more particularly metastatic breast cancer, colorectal cancer, and salivary gland cancer (see Koch, Kevin. “ARRY-380: A Selective, Oral HER2 Inhibitor for the Treatment of Solid Tumors...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/517A61K45/06
CPCA61K45/06A61K31/517A61K31/337A61K31/7068A61P35/04A61P35/00A61K2300/00A61K31/437A61K39/395A61K9/2027A61K9/2054A61K2039/505
Inventor LEE, PATRICE A.WINSKI, SHANNON L.KOCH, KEVIN
Owner ARRAY BIOPHARMA
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