ALDH-2 inhibitors in the treatment of addiction

一种化合物、苯基的技术，应用在成瘾治疗中的ALDH-2抑制剂领域，能够解决没有证明等问题

Inactive Publication Date: 2014-04-30
GILEAD SCI INC
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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 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

Embodiment 1

[0219] Preparation of compounds of formula (2)

[0220] a. prepared where R 3 is a compound of formula (2) that is hydrogen

[0221]

[0222] To 7-hydroxy-3-(4-nitrophenyl)-4H-chromen-4-one (7-hydroxy-3-(4-nitrophenyl)-4H-chromen-4-one) (commercially available, (10 g, 48.3 mmol)) in dichloromethane (100 mL), added pyridine (15.6 mL, 193.2 mmol), and cooled the mixture in an ice bath. To this solution was slowly added trifluoromethanesulfonic anhydride (16.3 mL, 96.6 mmol) at 0 °C, and then the solution was warmed to room temperature and stirred for 1 hour until the reaction was complete. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was heated in acetonitrile and the solid was filtered off to give 3-(4-nitrophenyl)-4-oxo-4H-chromen-7-yl trifluoromethanesulfonate (3-(4-nitrophenyl )-4-oxo-4H-chromen-7-yltrifluoromethanesulfonat...

Embodiment 2

[0224] Preparation of compounds of formula (3)

[0225] a. prepared where R 3 is a compound of formula (3) where hydrogen

[0226]

[0227] To a suspension of 3-(4-nitrophenyl)-4-oxo-4H-chromen-7-yl trifluoromethanesulfonate (5.0 g, 14.75 mmol) in tetrahydrofuran (20 mL) was added fresh A solution of sodium dithionite (5.13 g in 20 mL) was prepared. The mixture was stirred at room temperature for 2 hours, and then additional sodium dithionite (2.57 g) was added in two portions. The reaction mixture was stirred at room temperature for 24 hours, after which time the reaction was complete. The organic solvent was evaporated under reduced pressure, and then water (10 mL) was added to the suspension. The solid in the suspension was filtered off and dried under high vacuum. The product was heated with acetonitrile and stirred until room temperature was reached. The solid was filtered off to afford 3-(4-aminophenyl)-4-oxo-4H-chromen-7-yl trifluoromethanesulfonate (4.1 ...

Embodiment 3

[0229] Preparation of compounds of formula (4)

[0230] a. prepared where R 2 is methyl and R 3 is a compound of formula (4) where hydrogen

[0231]

[0232] 3-(4-Aminophenyl)-4-oxo-4H-chromen-7-yl trifluoromethanesulfonate (2.2 g, 7.12 mmol) in pyridine (10 mL) was dissolved within 5 min at 0 °C Methanesulfonyl chloride (1.1 mL, 14.24 mmol) was added to the suspension, and then allowed to warm to room temperature with stirring. After 2 hours, the reaction was complete and water was added in portions with vigorous stirring. The organic phase was then separated and concentrated, and the resulting solid was filtered and dried under high vacuum. The solid was heated in acetonitrile and stirred until room temperature was reached, then filtered off to give 3-(4-(methylsulfonylamino)phenyl)-4-oxo-4H-chromen-7-yltrifluoromethanesulfonic acid Esters (2.49g). 1 H NMR (DMSO, 400MHz) 9.87(s, 1H); 8.60(s, 1H); 8.31(d, J=8.0Hz, 1H); 8.09(s, 1H); 7.65(d, J=8.0Hz, 1H ); 7.5...

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PUM

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Abstract

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

Description

[0001] References to related applications [0002] Pursuant to 35 U.S.C. § 119(e) this application claims the benefit of U.S. Provisional Patent Application Serial No. US61 / 529164, filed August 30, 2011, which is adopted in its entirety by incorporated herein by reference. technical field [0003] The present invention relates to novel ALDH-2 inhibitors and their use in the treatment of addictive drug and substance dependence in patients in need thereof, for example, on 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 pharmaceutical compositions comprising the compounds of the invention. Background technique [0004] Today, dependence on addictive drugs causes major health problems worldwide. For example, alcohol abuse and dependence can cause liver, pancreatic, and kidney disease, heart disease, including dilated car...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/36C07D405/06A61K31/352A61K31/397A61K31/4178
CPCC07D405/06C07D311/36C07D405/10C07D407/06A61P25/30A61P25/32A61P25/34A61P25/36A61P3/04A61P43/00
Inventor 迈克尔·格劳普钱德拉塞卡·文卡塔拉马尼杰夫·扎布沃茨基
Owner GILEAD SCI INC
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