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Aldh-2 inhibitors in treatment of addiction

An R20, compound technology, applied in the field of new ALDH-2 inhibitors, can solve the problem of no proof and so on

Inactive Publication Date: 2010-12-22
GILEAD PALO ALTO +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Attempts have been made to treat tobacco addiction by convincing patients to voluntarily stop using tobacco (behavioral therapy), but this approach has not proven to be very successful

Method used

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  • Aldh-2 inhibitors in treatment of addiction

Examples

Experimental program
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Effect test

preparation example Construction

[0348] Preparation of the compound of step 1-chemical formula (2)

[0349] Usually, make the compound of chemical formula I (wherein R 1 is benzonitrile), dibutyltin oxide, and azidotrimethylsilane were subjected to microwaves. The reaction is carried out at a temperature of about 150°C for about 10-30 minutes. When the reaction is substantially complete, the product of formula (2) is isolated by conventional means, for example by chromatography on silica gel.

[0350] Step 2 - Preparation of Compounds of Formula I

[0351] The purified product of formula (2) is suspended in an aqueous solvent such as acetonitrile / water and a catalytic amount of a strong acid such as trifluoroacetic acid is added. The solvent is removed to provide a compound of formula I, wherein R 1 is phenyl substituted by tetrazol-5-yl.

[0352] Similarly, where R 1 Is the compound of formula I of [1,2,4]-oxadiazol-3-yl substituted by benzonitrile at the 5-position into wherein R 1 is a compound ...

Embodiment 1

[0466] Preparation of compounds of formula R1WX

[0467] A. Preparation of compounds of formula (4), wherein R is phenyl

[0468]

[0469] A 50 mL round bottom flask equipped with a condenser was charged with benzamide (compound of formula (b), 363.4 mg, 3.0 mmol) and 1.3-dichloroacetone (457.1 mg, 3.6 mmol, 1.2 equiv). The mixture was heated at 130° C. for 1 hour under nitrogen atmosphere. After cooling to room temperature, the resulting mixture was purified by recrystallization from acetonitrile (6 mL). The suspension was heated under reflux reaction conditions for 5 minutes and then cooled to ambient temperature. The resulting solid was filtered through a glass filter, and the crystals on the filter were washed with acetonitrile (2 mL). The desired product, 4-(chloromethyl)-2-phenyl-1,3-oxazole, was obtained as a colorless powder.

[0470] b. Preparation of other compounds of formula (4a), wherein R is phenyl

[0471] Similarly, following the procedure of Exam...

Embodiment 2

[0501] The preparation of the compound of chemical formula (5)

[0502]

[0503] step 1- The preparation of the compound of chemical formula (9)

[0504] 1-(2-Hydroxy-4-methoxyphenyl)ethan-1-one (20 g, 120 mmol) and N,N-dimethylformamide dimethyl acetal (23 g, 181 mmol) were stirred at 90°C mixture for 2 hours. After cooling to room temperature, the reaction mixture afforded a yellow precipitate which was washed with ethyl acetate (3 x 30ml), water (2 x 50ml) and then dried under reduced pressure to give 3-(Dimethylamino)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (9); MS 222.1 (M+H).

[0505] Step 2- The preparation of the compound of chemical formula (5)

[0506] 3-(Dimethylamino)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (20.0 g, 90.37 mmol) was dissolved in anhydrous chloroform ( To a solution in 100 ml) was added N-iodosuccinimide (23.5 g, 99.22 mmol) and silica gel (40 g). The reaction mixture was stirred at 0°C for 60 minutes, then the insoluble mater...

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Abstract

Disclosed are novel isoflavone derivatives having the structure of Formula I which are useful as ALDH-2 inhibitors for treating mammals for dependence upon drugs of addiction, for example addiction to dopamine-producing agent such as cocaine, morphine, amphetamines, nicotine, and alcohol.

Description

[0001] This application is a continuation-in-part of U.S. Patent Application Serial No. 11 / 829,836, filed July 27, 2007, which claims U.S. Provisional Patent Application Serial No. 60 / 834,083, filed July 27, 2006 and filed in 2006 Priority to US Provisional Patent Application Serial No. 60 / 846,428, filed September 21, the entire contents of which are incorporated herein by reference. technical field [0002] The present invention relates to novel ALDH-2 inhibitors and their use in the treatment of drug addiction in mammals, for example, addiction to dopamine producing agents such as cocaine, opiates, amphetamines, nicotine, and alcohol. ALDH-2 inhibitors have also been shown to be effective in treating obesity. The invention also relates to processes for the preparation of such compounds, as well as pharmaceutical compositions comprising them. Background technique [0003] Today, dependence on addictive drugs causes major health problems worldwide. For example, alcohol abu...

Claims

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Application Information

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IPC IPC(8): C07D311/36C07D405/04C07D405/14C07D413/12C07D413/14C07D417/12A61K31/353A61P25/32
CPCC07D311/36C07D413/14C07D405/14C07D405/04C07D417/12C07D413/12A61P25/30A61P25/32A61P25/34A61P25/36A61P43/00
Inventor 雅罗斯拉夫·比洛金埃尔法蒂赫·埃尔扎因杰夫·扎布沃茨基迈克尔·奥根陶佩里小林徹也马修·阿贝尔曼拉奥·卡拉范培东伊万·戴蒙德罗伯特·江马里亚·皮亚·阿罗尔福李小芬姚丽娜江湛姜永明陶国新
Owner GILEAD PALO ALTO
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