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Novel sodium channel blockers

A general formula, selected technology, applied in the preparation of organic compounds, medical preparations containing active ingredients, preparation of isocyanate derivatives, etc., can solve the problem of unclear intracellular mechanism of cancer cell morphology

Inactive Publication Date: 2005-08-24
UNIV OF VIRGINIA ALUMNI PATENTS FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But so far, the intracellular mechanism by which Na+ channel activity regulates cancer cell morphology is unclear, although ion channels have been implicated in several types of cellular behaviors that may be related to different stages of metastasis

Method used

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  • Novel sodium channel blockers

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Experimental program
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Embodiment approach

[0047] According to one embodiment, the present invention provides a sodium channel blocker, wherein the blocker has the general formula:

[0048] or

[0049] where R is selected from C 1 -C 12 Alkyl, C 2 -C 8 Alkenyl, C 2 -C 8 Alkynyl, -(CH 2 ) n C 3 -C 6 Cycloalkyl,

[0050]

[0051] and

[0052] where n is an integer from 0-4. R 2 is H or C 1 -C 4 Alkyl, R 4 and R 5 independently selected from H, halogen, C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, -COR 10 and (C 1 -C 4 ) alkoxy, and R 6 selected from H, halogen, C 1 -C 8 Alkyl, amino, hydroxyl, C 1 -C 8 alkoxy and

[0053] and

[0054] where R 7 and R 8 independently selected from H, C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl and C 2 -C 4 Alkynyl, and R 9 is H, or R 8 and R 9 together with the atoms to which they are attached form an optionally substituted heterocyclic ring, and R 10 Choose from H, C 1 -C 4 Alkyl, NH 2 and OH.

[0055] In one embodiment, the pres...

Embodiment 1

[0116] Organic synthesis of the mentioned compounds

[0117] compound R 3 1 3-Cl2 4-Cl3 2-Cl4 4-OCH35 H9 4-F1

[0118] Hydroxyamide compounds 1-5 were synthesized according to literature procedures and as outlined in Scheme 1. Typically, the corresponding nitrile is converted to the ketone by Grignard addition, followed by conversion of the ketone to the TMS ether using TMSCN. TMS ethers were cleaved to cyanohydrins with 1% HCl, followed by hydrolysis of the corresponding cyanohydrins to the final products using concentrated HCl / HCl gas. Hydantoin analogs 44 and 66 were prepared from commercially available ketones by Bucherer-Berg reactions.

[0119] Process I

[0120]

[0121] Enantioselective synthesis of hydroxyamides using a Sharpless dihydroxylation strategy.

[0122] Since most existing compounds are chiral, it would be expected that it would be desirable to prepare several grams of each enantiomer of the active analog. To this end,...

Embodiment 2

[0149] Effects of synthesized compounds on the binding of 3H-BTX-B

[0150] One assay for screening compounds that are modulators of sodium channel activity is based on the use of the radioligand 3[H]-BTX-B assay. BTX binds to position 2 on the channel protein, thus those compounds that can compete with or inhibit BTX binding to sodium channels are potential sodium channel inhibitors. This assay represents a flexible tool to pre-screen for sodium channel binding prior to more rigorous functional assays such as evaluating compounds by electrophysiology. Compounds 2 and 44 showed potent inhibition of 3H-BTX-B binding compared to phenytoin (see Table 1).

[0151] Table 1 3H-BTX-B inhibition data

[0152] Compound 3H-BTX-B(μM)

[0153] 5 9±2

[0154] 44 5±1

[0155] Phenytoin 40

[0156]

[0157] name

[0158] name

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Abstract

The present invention is directed to novel phenytoin derivative compounds and the use of such compounds as sodium channel blockers. Such compositions have utility as anti-cancer agents and can be used to limit or prevent PCa growth and / or metastasis.

Description

[0001] related application [0002] Pursuant to 35 USC § 199(e), this application claims priority to U.S. Provisional Application Serial Nos. 60 / 373,440, filed April 18, 2002, and 60 / 373,784, filed April 19, 2002, the contents of which are This is incorporated by reference. field of invention [0003] The present invention relates to novel compounds and the use of these compounds as sodium channel blockers. These compositions have utility in the treatment of diseases associated with inappropriate sodium channel activity, as well as the use of these compounds as anticancer agents. Background of the invention [0004] The ability of a cell to change its morphology and migrate is inherent in cancer cell metastasis. Although the precise biological mechanisms of cell morphogenesis during metastasis have not been elucidated, it is known that these changes involve cell-matrix interactions and cytoskeletal components. Na+ channels involved in cell morphogenesis have been describe...

Claims

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Application Information

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IPC IPC(8): A61K31/16A61K31/4015A61K31/4166A61K31/421A61K45/00A61P35/00A61P43/00C07C219/08C07C235/02C07C235/06C07C235/34C07C237/04C07C237/06C07C237/20C07C275/22C07D233/74C07D233/76C07D233/78C07D235/02
CPCC07D233/78C07C235/34A61K31/421A61K31/4166C07D235/02A61K31/4015C07C237/04C07D233/76C07D233/74A61P35/00A61P43/00
Inventor M·L·布朗
Owner UNIV OF VIRGINIA ALUMNI PATENTS FOUND
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