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Substituted aryl heteroaryl compound and application thereof

A compound and halogenated alkyl technology, applied in the direction of medical preparations containing active ingredients, organic chemistry, drug combinations, etc., can solve the problems of safety refusal to approve, and achieve high safety, promote side effects, and good drug efficacy

Active Publication Date: 2017-05-17
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, currently the only drug related to orexin receptors on the market is Suvorexant, an anti-insomnia drug developed by Merck of the United States, which is an orexin receptor antagonist. was rejected by the US FDA

Method used

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  • Substituted aryl heteroaryl compound and application thereof
  • Substituted aryl heteroaryl compound and application thereof
  • Substituted aryl heteroaryl compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0197] Example 1: N-(2-(5-(4-fluorophenyl)pyrimidin-2-yl)ethyl)-2-(2H-1,2,3-triazol-2-yl)benzyl Amide synthesis

[0198]

[0199] Step 1) Synthesis of 2-(5-bromopyrimidin-2-yl)-2-cyanoacetic acid tert-butyl ester

[0200] 5-Bromo-2-chloropyrimidine (5.80g, 30.00mmol), potassium carbonate (12.60g, 90.25mmol) and N-methylpyrrolidone (25mL) were sequentially added to a 100mL reaction flask, followed by slowly adding tert-cyanoacetic acid After the addition of butyl ester (6.50 mL, 45.00 mmol), the reaction temperature was raised to 80° C. for 3 hours. Stop the reaction, pour the reaction solution into water (400mL), adjust the solution to pH=5 with dilute hydrochloric acid, filter with suction, collect the solid, and the crude product is directly separated and purified by silica gel column chromatography (petroleum ether / dichloromethane (v / v) =1 / 5) to obtain the title compound (yellow solid, 3.19 g, 35.72%). MS(ESI,pos.ion)m / z:298.14[M+H] + ;

[0201] 1 H NMR (CDCl 3 ...

Embodiment 2

[0230] Example 2: N-ethyl-N-(2-(5-(4-fluorophenyl)pyrimidin-2-yl)ethyl)-2-(2H-1,2,3-triazole-2 -Synthesis of benzamide

[0231]

[0232] N-(2-(5-(4-fluorophenyl)pyrimidin-2-yl)ethyl)-2-(2H-1,2,3-triazol-2-yl)benzamide (0.20 g, 0.51mmol) and anhydrous DMF (5mL) were added to a 50mL reaction flask in turn, followed by sodium hydride (0.02g, 0.82mmol), stirred at 0°C for 5 minutes, and bromoethane (0.07g, 0.62mmol ), reacted at room temperature for 2 hours. The reaction was stopped, the reaction solution was diluted with water, extracted with ethyl acetate, the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the obtained crude product was directly separated and purified by column chromatography (petroleum ether / acetone ( v / v)=5 / 1) to obtain the title compound (pale yellow oil, 0.10 g, 47%).

[0233] MS(ESI,pos.ion)m / z:417.20[M+H] + ;

[0234] HPLC: 95.05%.

Embodiment 3

[0235] Example 3: N-(2-(5-(4-fluorophenyl)pyrimidin-2-yl)ethyl)-5-methyl-2-(2H-1,2,3-triazole-2 -Synthesis of benzamide

[0236]

[0237] Step 1) Synthesis of 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid

[0238] The title compound of this step was prepared by referring to the method described in step 6 of Example 1, namely 1,2,3-triazole (3.45g, 50mmol), 2-iodo-5-methylbenzoic acid (5.24g, 20mmol) , cesium carbonate (11.72g, 36mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (0.51g, 3.6mmol) and cuprous iodide (0.38g, 2mmol) in N , N-dimethylformamide (30mL) was prepared by reacting under nitrogen protection at 100°C for 4 hours, and the crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v)=50 / 1) to obtain the title compound ( Yellow solid, 2.76 g, 68%).

[0239] MS(ESI,neg.ion)m / z:202.1[M-H] - ;

[0240] 1 H NMR (CD 3 OD,600MHz)δ(ppm):7.88(s,2H),7.66(d,1H),7.59(d,J=8.2Hz,1H),7.50~7.48(dd,J=8.1Hz,1.1Hz,1H ...

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PUM

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Abstract

The invention relates to a substituted aryl heteroaryl compound and application thereof, and further relates to a pharmaceutical composition containing the substituted aryl heteroaryl compound and application thereof. The compound or the pharmaceutical composition can be used for an antagonistic orexin receptor. The invention further relates to a method for preparing the compound and the pharmaceutical composition, and application of the compound and the pharmaceutical composition to preparation of drugs for treating or preventing nervous and psychogenic disorders and diseases of central nervous systems of mammals, especially human beings.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to a compound, a composition, a preparation method and an application thereof which can be used for treating or preventing neurological and mental disorders and diseases of the central nervous system. More specifically, the present invention describes aryl heteroaryl compounds that can be used as orexin receptor antagonists. Background technique [0002] Orexin, also known as hypocretin and orexin, includes orexin A and orexin B (or hypocretin-1 and hypocretin-2), which are secreted by the hypothalamus A neuroendocrine hormone that acts in the central nervous system. Its main physiological functions are: 1. Regulate food intake. Orexin can obviously promote food intake, and it responds in a dose-dependent manner, and activates neurons that regulate food intake; 2. Participating in the regulation of energy metabolism, orexin can significantly increase the metabolic rat...

Claims

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Application Information

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IPC IPC(8): C07D403/12A61K31/506A61P25/00A61P25/22A61P25/24A61P25/18A61P25/30A61P25/32A61P25/20A61P25/08A61P25/16A61P25/28A61P25/06
CPCC07D403/12
Inventor 金传飞韦德活薛亚萍张英俊
Owner SUNSHINE LAKE PHARM CO LTD
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