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Melatonin (MT1/MT2) receptor stimulant, and preparation method and application thereof

A halogen and optical isomer technology, applied in the field of medicinal chemistry, pharmacology, and pharmacology, can solve the problems of weak experimental activity, weak clinical effect, and insufficient distribution

Inactive Publication Date: 2020-02-21
NANJING CHANGAO PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Many opinions put forward by EMEA, such as the clinical effect of the 16mg group of ramelteon is weaker than that of the 8mg group, the lack of hypnotic activity in the long-term experiment, and the uniformity of the effect of the placebo group, etc., these problems all point to ramelteon The main contradiction is that the in vivo experimental activity is not strong
[0014] In view of the above situation, there is an urgent need to develop a class of novel MT1 / MT2 receptor agonists in this area. This class of agonists will overcome the above-mentioned defects of ramelteon. Insufficient exposure and other issues to improve

Method used

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  • Melatonin (MT1/MT2) receptor stimulant, and preparation method and application thereof
  • Melatonin (MT1/MT2) receptor stimulant, and preparation method and application thereof
  • Melatonin (MT1/MT2) receptor stimulant, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0182] (S)-3-(4,5-difluoro-1,2,7,8-tetrahydrobenzo[1,2-b:4,3-b']difuran-1-yl)-N- The preparation of methyl propionamide (formula 1 compound)

[0183]

[0184] Step (1) Synthesis of 2,3-difluorophenyl-2-chloroacetate (compound of formula 1-2).

[0185] The compound of formula 1-1 (2.6g, 0.02mol) was dissolved in dry dichloromethane, ice bathed, triethylamine (2.63g, 0.026mol) was added, and chloroacetyl chloride (2.94g, 0.026mol, 1.3eq), dropwise, naturally warming up to room temperature overnight, thin-layer chromatography detection, the reaction is completed, poured into ice water to quench, dichloromethane extraction, organic phase washed with saturated brine, dried over anhydrous sodium sulfate, filtered, reduced The solvent was evaporated under pressure to obtain a brown liquid (4.13 g, 100%), namely the compound of formula 1-2, which was directly put into the next reaction.

[0186] Step (2) Synthesis of 2-chloro-1-(3,4-difluoro-2-hydroxyphenyl)ethan-1-one (compound ...

Embodiment 2

[0227] (S)-3-(4,5-difluoro-1,2,7,8-tetrahydrobenzo[1,2-b:4,3-b']difuran-1-yl)-N- The preparation of propyl propionamide (formula 2 compound)

[0228]

[0229] (S)-3-(4,5-difluoro-1,2,7,8-tetrahydrobenzo[1,2-b:4,3-b']difuran-1-yl)-N- Synthesis of Propylpropionamide (Compound of Formula 2). .

[0230] The compound of formula 1-15 (55 mg, 0.2 mmol) was dissolved in dry dichloromethane (5 mL), and HOBT (42 mg, 0.3 mmol), HATU (117 mg, 0.3 mmol), diisopropylethylamine (35 mg, 0.5mmol), n-propylamine (18mg, 0.3mmol), room temperature reaction overnight, thin-layer chromatographic detection, after the reaction was completed, the solvent was evaporated under reduced pressure, and column chromatography (EA) gave a white solid (28mg, 45%) formula 2 compound .

[0231] Formula 2 compound: 1 H NMR (400MHz, Chloroform-d)δ5.38(s,1H),4.73–4.55(m,3H),4.33(dd,J=9.0,5.2Hz,1H),3.59–3.46(m,1H), 3.15(dddtd,J=18.0,15.3,12.9,7.7,5.7Hz,4H),2.20–2.02(m,3H),1.98–1.84(m,1H),1.47(d,J=7.3Hz,2H), ...

Embodiment 3

[0233] (S)-3-(4,5-difluoro-1,2,7,8-tetrahydrobenzo[1,2-b:4,3-b']difuran-1-yl)-N- The preparation of isopropyl propionamide (formula 3 compound)

[0234]

[0235] (S)-3-(4,5-difluoro-1,2,7,8-tetrahydrobenzo[1,2-b:4,3-b']difuran-1-yl)-N- Synthesis of isopropylpropionamide (compound of formula 3). .

[0236] The compound of formula 1-15 (41 mg, 0.15 mmol) was dissolved in dry dichloromethane (5 mL), and HOBT (32 mg, 0.225 mmol), HATU (88 mg, 0.225 mmol), diisopropylethylamine (26 mg, 0.375mmol), isopropylamine (14mg, 0.225mmol), react overnight at room temperature, thin-layer chromatography detects, after the reaction is completed, the solvent is evaporated under reduced pressure, and column chromatography (EA) obtains a white solid (20mg, 42%), the formula 3 compounds.

[0237] Formula 3 compound: 1 H NMR (400MHz, Chloroform-d) δ5.21(s,1H),4.72–4.52(m,3H),4.32(dd,J=9.0,5.2Hz,1H),3.99(dp,J=7.7,6.5 Hz,1H),3.50(dd,J=8.6,4.5Hz,1H),3.29–3.16(m,1H),3.09(dddd,J=15.3,9.2,6.9,1....

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Abstract

The invention relates to a melatonin (MT1 / MT2) receptor stimulant, and a preparation method and an application thereof. Specifically, the invention provides a novel melatonin (MT1 / MT2) receptor stimulant and a preparation method thereof, and an application of the novel melatonin (MT1 / MT2) receptor stimulant in preparation of medicines used for treating diseases or symptoms related to melatonin (MT1 / MT2) receptors. The melatonin (MT1 / MT2) receptor stimulant provided by the invention has good biological activity.

Description

technical field [0001] The invention belongs to the fields of pharmacy, medicinal chemistry and pharmacology, and more specifically relates to a new type of melatonin (MT1 / MT2) receptor agonist and a preparation method thereof, and the use of this type of compound for the treatment of melatonin and melatonin Application in drugs for hormone (MT1 / MT2) receptor-related insomnia, anxiety, depression and other diseases or conditions. Background technique [0002] Insomnia is a clinical common disease, and the incidence rate is very high. According to reports, in the United States in the past 20 years, the prevalence of insomnia was about 30% to 35%, of which 10% to 15% of patients reached a severe level; the results of the British and Australian surveys were similar. In my country, there are currently about 300 million adult patients with insomnia symptoms such as difficulty falling asleep, frequent dreams and easy waking, difficulty falling asleep after waking up, and waking u...

Claims

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Application Information

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IPC IPC(8): C07D493/04C07D307/77A61K31/343A61P25/20A61P25/22A61P25/24
CPCA61P25/20A61P25/22A61P25/24C07B2200/07C07D307/77C07D493/04
Inventor 吴建睿刘亦斌王伟赵传生宋海峰
Owner NANJING CHANGAO PHARMA SCI & TECH CO LTD
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