Methods for Treating Cancer Using Pyrimidine and Pyridine Compounds with BTK Inhibitory Activity

a technology which is applied in the field of pyrimidine and pyridine compounds, can solve the problems of difficult to develop a reversible inhibitor that selectively inhibits a desired (la, target) kinase, difficult to maintain inhibition over extended periods of time, and high dosages

Inactive Publication Date: 2017-05-04
MERCK PATENT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Given the structure of the ATP-binding sites are highly conserved among kinases, it has been difficult to develop a reversible inhibitor that selectively inhibits a desired (La, target) kinase.
Moreover, given that many reversible kinase inhibitors readily dissociate fro...

Method used

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  • Methods for Treating Cancer Using Pyrimidine and Pyridine Compounds with BTK Inhibitory Activity
  • Methods for Treating Cancer Using Pyrimidine and Pyridine Compounds with BTK Inhibitory Activity
  • Methods for Treating Cancer Using Pyrimidine and Pyridine Compounds with BTK Inhibitory Activity

Examples

Experimental program
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Effect test

example 1

Mosaic Spot Assay (CLL Patient Samples)

[0175]The Mosaic Spot Assay was conducted in accordance with Mosaic Laboratories' SOPs. The CLL blood and bone marrow mononuclear cells were evaluated for viability and cell count prior to plating in Mosaic Spot Media (X-Vivo 10 Media [Lonza, Fisher Scientific, Carlsbad, Calif.]+10% FBS [Life Technologies, Carlsbad, Calif.]) in a 96-well cytophobic plate in the presence of compounds and two controls: 1) a cytotoxic dose of cisplatin serving as a positive control; and 2) no drug treatment serving as a reference and negative control. Tumor cells were placed in a humidified 37° C. incubator with 5% CO2 for 4 days. At the end of the incubation, cells were removed and cytocentrifuged onto positive charged glass slides (Superfrost+, VWR, Radnor, Pa.). Slides were stained with Wright Giemsa in accordance with Mosaic Laboratories SOPs. Cell growth was measured by a hematopathologist. The results are provided in FIG. 1.

example 2

MCL / ABC-DLBCL Cell Lines

[0176]Cell lines that were preserved in liquid nitrogen were thawed and expanded in growth media containing full serum. Once cells reached expected doubling times, screening began. Cells were seeded in growth media in black 384-well tissue culture treated plates. Cells were equilibrated in assay plates via centrifugation and placed in incubators (attached to the Dosing Modules) at 37° C. for twenty-four hours before treatment. At the time of treatment, a set of assay plates (which do not receive treatment) were collected and ATP levels were measured by adding ATPLite (Perkin Elmer). These Tzero (T0) plates were read using ultra-sensitive luminescence on Envision plate readers. Assay plates were incubated with compound for seventy-two hours and were analyzed using ATPLite. All data points were collected via automated processes and were subject to quality control and analyzed using Horizon's proprietary software. Assay plates were accepted if they passed the ...

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Abstract

The present invention provides methods of treating cancer using pyrimidine and pyridine compounds which are inhibitors of Bruton's tyrosine kinase (BTK).

Description

RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional applications U.S. Ser. No. 62 / 250,575, filed on Nov. 4, 2015, U.S. Ser. No. 62 / 296,143, filed on Feb. 17, 2016, and U.S. Ser. No. 62 / 341,189, filed on May 25, 2016, the contents of which are incorporated herein by reference, in their entireties.FIELD OF THE INVENTION[0002]The invention relates to a series of pyrimidine and pyridine compounds that are useful as therapeutics in the treatment of cancer in mammals. More particularly, embodiments of the present invention describe irreversible kinase inhibitors including, but not limited to, inhibitors of Bruton's tyrosine kinase (hereinafter referred to as: “BTK”). Methods for the preparation of the aforementioned compounds are disclosed in addition to the incorporation of these compounds into pharmaceutical compositions that include the same.BACKGROUND[0003]Protein kinases constitute a large family of structurally related enzymes that are responsible for t...

Claims

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Application Information

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IPC IPC(8): A61K31/506A61K31/55A61K31/5377A61K31/505A61K31/69
CPCA61K31/506A61K31/505A61K31/55A61K31/5377A61K31/69A61P35/00C07D401/12
Inventor HUCK, BAYARD R.GOODSTAL, SAMANTHA M.GIMMI-MCKIM, CLAUDE
Owner MERCK PATENT GMBH
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