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Aldh-2 inhibitors in the treatment of addiction

A technology of R20 and compounds, applied in the field of novel ALDH-2 inhibitors

Inactive Publication Date: 2010-01-13
GILEAD PALO ALTO +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Attempts have also been made to treat tobacco addiction by persuading patients to voluntarily stop using tobacco (behavioral therapy), but this approach has not been shown to be very effective

Method used

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  • Aldh-2 inhibitors in the treatment of addiction
  • Aldh-2 inhibitors in the treatment of addiction
  • Aldh-2 inhibitors in the treatment of addiction

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0341] Step 1-Preparation of the compound of formula (2)

[0342] Usually, where R 1 The mixture of the compound of formula I which is benzonitrile (or benzonitrile), dibutyltin oxide, and trimethyl azide is subjected to microwave treatment. 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 separated by conventional means, such as by chromatography (or chromatography) on silica gel.

[0343] Step 2-Preparation of Compound of Formula I

[0344] 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. Removal of solvent provides where R 1 The compound of formula I which is a phenyl substituted by tetrazol-5-yl.

[0345] Similarly, where R 1 The compound of formula I which is [1,2,4]-oxadiazol-3-yl substituted by benzonitrile at position 5 is converted t...

Embodiment 1

[0454] Preparation of the compound of formula (4)

[0455] A. Preparation of compounds of formula (4) where R is phenyl

[0456]

[0457] A 50 mL round bottom flask equipped with a condenser was filled with benzamide (compound of formula (b), 363.4 mg, 3.0 mmol) and 1,3-dichloroacetone (457.1 mg, 3.6 mmol, 1.2 equivalents). The mixture was heated at 130°C for 1 hour under nitrogen. After cooling to room temperature, the resulting mixture was purified from acetonitrile (6 mL) by recrystallization. The suspension was heated for 5 minutes under reflux reaction conditions and cooled to ambient temperature. The obtained solid was filtered through a glass filter, and the crystals on the filter were rinsed with acetonitrile (2 mL). The desired product, 4-(chloromethyl)-2-phenyl-1,3-oxazole (285.8 mg, 1.48 mmol, 49%) was obtained as a colorless powder.

[0458] B. Preparation of other compounds of formula (4a) where R is phenyl

[0459] Similarly, following the procedure of Example IA,...

Embodiment 2

[0489] Preparation of the compound of formula (5)

[0490]

[0491] step 1- Preparation of the compound of formula (9)

[0492] A mixture of 1-(2-hydroxy-4-methoxyphenyl)ethan-1-ol (20g, 120mmol) and N,N-dimethylformamide dimethyl acetal (23g, 181mmol) Stir at 90°C for 2 hours. After cooling to room temperature, the reaction mixture was provided with a yellow precipitate, which was washed with ethyl acetate (3x30ml), water (2x50ml), and dried under reduced pressure to produce 3-(dimethylamino) as the trans isomer -1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (9); MS 222.1(M+H)

[0493] Step 2- Preparation of the compound of formula (5)

[0494] To 3-(dimethylamino)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (20.0g, 100ml) in anhydrous chloroform (100ml) at 0°C 90.37mmol) was added N-iodosuccinimide (23.5g, 99.22mmol) and silica gel (40g). The reaction mixture was stirred at 0°C for 60 minutes, and then insoluble materials were filtered off. The filtrate was rinsed with aqueo...

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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 claims the priority of U.S. Provisional Patent Application Serial No. 60 / 834,083 filed on July 27, 2006 and U.S. Provisional Patent Application Serial No. 60 / 846,428 filed on September 21, 2006. All content is incorporated into this article by reference. Technical field [0002] The present invention relates to novel ALDH-2 inhibitors, and to their application in the treatment of mammalian dependence on drugs, such as dopamine-producing agents such as cocaine, opiates, amphetamines, Nicotine, and alcohol addiction. ALDH-2 inhibitors have also been shown to be effective in treating obesity. The invention also relates to methods for preparing such compounds, as well as to pharmaceutical compositions containing them. Background technique [0003] Nowadays, dependence on drug addiction causes major health problems worldwide. For example, alcohol abuse and alcohol dependence can cause liver, pancreas and kidney diseases, heart diseases, including dilated card...

Claims

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Application Information

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IPC IPC(8): C07D311/36C07D413/10C07D413/14A61K31/352
Inventor 杰夫·扎布沃茨基马修·阿贝尔曼迈克尔·奥根伊万·戴蒙德马里亚·皮亚·阿罗尔福姚丽娜范培东埃尔法蒂赫·埃尔扎因拉奥·卡拉陶佩里小林徹也李晓芬雅罗斯拉夫·比洛金姜永明陶国新蒋海波
Owner GILEAD PALO ALTO
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