Spiro-oxindole compounds and their use as therapeutic agents

a technology of spiro-oxindole and compound, which is applied in the direction of biocide, cardiovascular disorder, drug composition, etc., can solve the problems of major pathophysiological conditions, major changes, and insufficient potency and therapeutic index of spiro-oxindole, so as to increase the potency of existing or future drug therapy and reduce adverse events

Inactive Publication Date: 2010-04-22
XENON PHARMACEUTICALS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0048]In another aspect, the invention provides pharmaceutical therapy in combination with one or more other compounds of the invention or one or more other accepted therapies or as any combination thereof to increase the potency of an existing or future drug therapy or to decrease the adverse events associated with the accepted therapy. In one embodiment, the present invention relates to a pharmaceutical composition combining compounds of the present invention with established or future therapies for the indications listed in the invention.

Problems solved by technology

Research in this area has identified variants of the alpha subunits that result in major changes in channel function and activities, which can ultimately lead to major pathophysiological conditions.
However, the potency and therapeutic index of these blockers is not optimal and have limited the usefulness of these compounds in a variety of therapeutic areas where a sodium channel blocker would be ideally suited.
Opioids also lack anti-inflammatory activity.
Inhibition of COX-1, which is found in platelets, GI tract, kidneys and most other human tissues, is thought to be associated with adverse effects such as gastrointestinal bleeding.
However, evidence now suggests that chronic use of certain selective COX-2 inhibitors can result in an increased risk of stroke occurrence.
All opioid analgesics have a risk of causing respiratory depression, liver failure, addiction and dependency, and as such are not ideal for long-term or chronic pain management.
Well known local analgesics such as lidocaine and xylocalne are non-selective ion channel blockers which can be fatal when administered systemically.
Such TTX-S agents suffer from dose-limiting side effects, including dizziness, ataxia and somnolence, primarily due to action at TTX-S channels in the brain.
Damage to peripheral nerves following trauma or disease can result in changes to sodium channel activity and the development of abnormal afferent activity including ectopic discharges from axotomised afferents and spontaneous activity of sensitized intact nociceptors.
These changes can produce long-lasting abnormal hypersensitivity to normally innocuous stimuli, or allodynia.
However, pharmacotherapy for neuropathic pain has generally had limited success with little response to commonly used pain reducing drugs, such as NSAIDS and opiates.
There remains a limited number of potent effective sodium channel blockers with a minimum of adverse events in the clinic.

Method used

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  • Spiro-oxindole compounds and their use as therapeutic agents
  • Spiro-oxindole compounds and their use as therapeutic agents
  • Spiro-oxindole compounds and their use as therapeutic agents

Examples

Experimental program
Comparison scheme
Effect test

preparation 1

Synthesis of 3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one

A. Synthesis of 3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one

[0455]To a stirred solution of 3-(benzyloxy)phenol (8.7 g, 43.5 mmol) in tetrahydrofuran (100 mL) was added iso-propylmagnesium chloride (22.7 mL, 2 M tetrahydrofuran solution, 45.4 mmol) slowly at 0° C. The mixture was allowed to stir at 0° C. for 30 min, and concentrated in vacuo to dryness. Dichloromethane (100 mL) was added, followed by the addition of a solution of 1-(diphenylmethyl)-1H-indole-2,3-dione (12.4 g, 39.5 mmol) in dichloromethane (50 mL) at 0° C. The mixture was stirred at ambient temperature for 16 h, and quenched with saturated ammonium chloride solution. The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The obtained solid was recrystallized from ethyl acetate / hexanes to afford 3-[4-(benzyl...

preparation 2

Synthesis of 3-(4-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one

A. Synthesis of 3-(4-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one

[0457]To a stirred solution of 3-bromophenol (11.9 g, 69.2 mmol) in dichloromethane (160.0 mL) at 0° C. was added isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 38.0 mL, 76.1 mmol). The solution was stirred at 0° C. for 30 min, then 1-benzhydrylindoline-2,3-dione (10.0 g, 34.6 mmol) was added. The reaction was stirred at ambient temperature for 16 h, then concentrated in vacuo to dryness. The residue obtained was dissolved in ethyl acetate (400.0 mL) and washed with saturated ammonium chloride solution (3×100.0 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to dryness. Purification by flash chromatography with 30% ethyl acetate in hexanes afforded 3-(4-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one (11.7 g, 70%) as a ...

preparation 3

Synthesis of 6-(benzyloxy)-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one

[0459]To a stirred solution of 3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one (7.4 g, 14.8 mmol), chloroiodomethane (2.7 mL, 37.0 mmol) in anhydrous tetrahydrofuran (200 mL) was added cesium carbonate (15.4 g, 47.4 mmol) under argon. The mixture was stirred at ambient temperature for 16 h, then filtered through a pad of celite. The filtrate was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / hexanes, 1 / 5) followed by the treatment with diethyl ether / hexanes to afford 6-(benzyloxy)-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (4.1 g, 55%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.42-7.25 (m, 15H), 7.16-7.09 (m, 1H), 7.07-6.90 (m, 3H), 6.62-6.38 (m, 4H), 5.03-4.90 (m, 3H), 4.73 (d, J=9.0 Hz, 1H); MS (ES+) m / z 510.1 (M+1).

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Abstract

This invention is directed to spiro-oxindole compounds, as stereoisomers, enantiomers, tautomers thereof or mixtures thereof; or pharmaceutically acceptable salts, solvates or prodrugs thereof, for the treatment and / or prevention of sodium channel-mediated diseases or conditions, such as pain.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application claims the benefit under 37 U.S.C. §119(e) of U.S. Provisional Patent Application No. 61 / 106,410, filed Oct. 17, 2008, which application is incorporated herein by reference in its entirety.FIELD OF THE INVENTION[0002]The present invention is directed to spiro-oxindole compounds and pharmaceutical compositions comprising the compounds and methods of using the compounds and the pharmaceutical compositions in treating sodium channel-mediated diseases or conditions, such as pain, as well as other diseases and conditions associated with the mediation of sodium channels.BACKGROUND OF THE INVENTION[0003]Voltage-gated sodium channels, transmembrane proteins that initiate action potentials in nerve, muscle and other electrically excitable cells, are a necessary component of normal sensation, emotions, thoughts and movements (Catterall, W. A., Nature (2001), Vol. 409, pp. 988-990). These channels consist of a highly processed alpha ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/407C07D491/107C07D491/20A61P25/00A61P9/00A61P11/00
CPCC07D491/20C07D491/107A61P9/00A61P11/00A61P25/00A61P29/00A61P35/00
Inventor CHAFEEV, MIKHAILCHOWDHURY, SULTANFRASER, LAURENFU, JIANMINLANGILLE, JONATHANLIU, SHIFENGSUN, JIANYUSUN, SHAOYISVIRIDOV, SERGUEIWOOD, MARKZENOVA, ALLA
Owner XENON PHARMACEUTICALS INC
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