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Novel compounds as histamine H3 receptor ligands

A compound, the technology of acetamide, applied in the field of new compounds as histamine H3 receptor ligands, can solve the problem of not launching compounds

Active Publication Date: 2013-12-11
SUVEN LIFE SCI LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although some histamine H3 receptor ligands have been disclosed, so far no compounds have been released on the market in this field of research, and the discovery of novel chemical structures for the treatment of diseases affected by the histamine H3 receptor There is still a need and scope for new drugs

Method used

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  • Novel compounds as histamine H3 receptor ligands
  • Novel compounds as histamine H3 receptor ligands
  • Novel compounds as histamine H3 receptor ligands

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0159] Example 1: Preparation of N-[4-(1-cyclobutylpiperidin-4-yloxy)phenyl]-2-(morpholin-4-yl)-acetamide dihydrochloride

[0160] Step (i): Preparation of 2-chloro-N-[4-(1-cyclobutylpiperidin-4-yloxy)phenyl]acetamide

[0161] To a solution of 4-[(1-cyclobutyl-4-piperidinyl)oxy]aniline (81 g, 0.329 mol, obtained in preparation 1) in dichloromethane (1L) under a nitrogen atmosphere at 0°C Add triethylamine (66.5g, 0.658 mol). The resulting material was then treated dropwise with a solution of chloroacetyl chloride (44.6 g, 0.395 mol) in dichloromethane (1 L) at 0°C and stirred at 0°C for 1 hour. The reaction mixture was washed with water, dried over sodium sulfate and concentrated under vacuum, and the crude compound thus obtained was purified by flash chromatography (methanol:chloroform, 2:8) to obtain 76.1 g of the title compound (yield: 72%).

[0162] 1 H-NMR (δppm): 1.55-1.99 (12H, m), 2.49-2.67 (3H, m), 4.19 (2H, s), 4.26-4.28 (1H, m), 6.88-6.90 (2H, d, J =8.9Hz), 7.44-7.46 (2...

Embodiment 2

[0173] HPLC: 99.54%; MP: 249.2-251.5°C; salt content: 16.09% (dihydrochloride); Example 2: 2-[4-(1-cyclobutylpiperidin-4-yloxy)benzene Preparation of 1-(morpholin-4-yl)ethanone hydrochloride

[0174] Step (i): Preparation of 2-[4-(1-cyclobutylpiperidin-4-yloxy)phenylamino]-1-(morpholin-4-yl)ethanone

[0175] Stir 4-(1-cyclobutylpiperidin-4-yloxy)aniline (0.5g, 0.002mol), 2-chloro-1-(morpholin-4-yl)ethanone (0.5g) at reflux temperature , 0.003) and potassium carbonate (0.56g, 0.004mol) in dimethylformamide (25ml). After the reaction was completed, the mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (250 mL) and water (250 mL). The combined organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude compound was purified by flash chromatography (chloroform:triethylamine, 9.5:0.5) to obtain 0.3 g of the title compound (yield: 40%).

[0176] Step (ii): Preparation of 2...

Embodiment 3

[0180] Example 3: Preparation of N-[4-(1-cyclobutylpiperidin-4-yloxy)-2-fluorophenyl]-2-(morpholin-4-yl)acetamide dihydrochloride

[0181] Step (i): Preparation of tert-butyl 4-[3-fluoro-4-(2-(morpholin-4-yl)acetylamino)phenoxy]piperidine-1-carboxylate

[0182] At reflux temperature 4-[4-(2-chloroacetylamino)-3-fluorophenoxy]piperidine-1-carboxylic acid tert-butyl ester (3.31g, 0.0085mol, obtained in Preparation 3), A mixture of morpholine (0.89 g, 0.01 mol) and potassium carbonate (1.75 g, 0.012 mol) in acetonitrile (30 mL) was stirred for 5 hours. The mixture was concentrated under reduced pressure, and the residue thus obtained was partitioned between ethyl acetate (50 mL) and water (50 mL). The resulting aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with brine solution, dried over sodium sulfate and concentrated. The crude compound was purified by flash chromatography (ethyl acetate:hexane, 3:7) to obtain 3.1 g of the title ...

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Abstract

The present invention relates to novel compounds of formula (I), and their pharmaceutically acceptable salts and compositions containing them. The present invention also relates to a process for the preparation of above said novel compounds, and their pharmaceutically acceptable salts. The compounds of formula (I) are useful in the treatment of various disorders that are related to Histamine H3 receptors.

Description

Technical field [0001] The present invention relates to treatments involving histamine H 3 The novel compounds of formula (I) and their pharmaceutically acceptable salts and compositions containing them for various diseases of the recipient. [0002] Background technique [0003] The histamine H3 receptor is a G protein coupled receptor (GPCR) and is one of four histamine receptor families. The histamine H3 receptor was identified in 1983, and its cloning and characterization were completed in 1999. Histamine H 3 The receptor is expressed to a higher degree in the central nervous system and to a lower degree in the peripheral nervous system. [0004] Literature evidence shows that histamine H3 receptor can be used to treat cognitive disorder (British Journal of Pharmacology, 2008, 154(6), 1166-1181), dementia (Drug News Perspective, 2010, 23(2) ,99-103), attention deficit hyperactivity disorder, epilepsy, sleep disorder, sleep apnea, obesity (Indian Journal of Pharmacology,2001,3...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D405/12C07D413/12A61K31/5355A61P25/00
CPCC07D401/12C07D405/12C07D413/12C07D401/14C07D211/46A61P25/00A61P25/04A61P25/08A61P25/18A61P25/20A61P25/28A61P3/04A61P43/00
Inventor 罗摩克里希纳·尼罗吉阿尼尔·卡巴里·欣德拉马萨斯特里·坎布汉帕蒂阿莫·迪纳卡尔·德什潘德阿迪·雷迪·德瓦拉姆普迪纳拉辛哈雷迪·甘加达萨里桑格拉姆·凯沙里·萨拉夫维什沃塔姆·纳加拉杰·孔迪凯雷普拉迪普·贾亚拉扬伊什蒂雅克·艾哈迈德穆罕默德·阿卜杜勒哈米德·穆拉文卡特斯瓦卢·贾斯蒂
Owner SUVEN LIFE SCI LTD
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