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Naphthalene derivative and application thereof in drugs

A drug and pharmaceutical technology, applied in the treatment of central nervous system dysfunction, in the field of naphthalene compounds of melatonin receptor agonists, can solve problems such as shortening sleep latency

Inactive Publication Date: 2015-01-21
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The melatonin receptor agonist ramelteon (ramelteon), which was first listed in the United States in 2005, is used for the treatment of insomnia, which can shorten the sleep latency, improve sleep efficiency and sleep maintenance. Compared with traditional drugs, this drug does not damage the Cognitive activities on the next day, no withdrawal symptoms; but this drug has mild side effects, such as headache, fatigue, lethargy, etc. (Arendt J, Van Someren E J, Appleton R, et a1., Clinical update: melatonin and sleep disorders. Clin Med , 2008, 8(4): 381-383)

Method used

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  • Naphthalene derivative and application thereof in drugs
  • Naphthalene derivative and application thereof in drugs
  • Naphthalene derivative and application thereof in drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0219] Embodiment 1N-((1-(naphthalene-1-yl) cyclopropyl) methyl) acetamide

[0220]

[0221] Step 1) Synthesis of 1-(naphthalene-1-yl)cyclopropanecarbonitrile

[0222] At -30°C, 2-(naphthalene-1-yl)acetonitrile (500mg, 2.99mmol) and sodium hydride (60%, 598mg, 14.95mmol) were added to 10mL of anhydrous DMF, and after stirring for 1h, slowly drop Add 1,2-dibromoethane (0.52 mL, 5.98 mmol, dissolved in 10 mL DMF), slowly raise the temperature to 25°C, and react for 1 hour. The reaction was stopped, quenched by adding 30 mL of saturated brine, extracted with ethyl acetate (30 mL×3), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was spin-dried under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate (v / v)=50 / 1) to obtain the title compound as a white solid (325 mg, 56.2%).

[0223] MS(ESI,pos.ion)m / z:194.2[M+1] + ;

[0224] 1 H NMR (400MHz, CDCl 3 )δ8.41(d, J=8.4Hz, 1H), 7....

Embodiment 2

[0234] Embodiment 2N-((1-(7-methoxynaphthalene-1-yl)cyclopropyl)methyl)acetamide

[0235]

[0236] Step 1) Synthesis of 1-(7-methoxynaphthalene-1-yl)cyclopropanecarbonitrile

[0237] The title compound of this step was prepared by referring to the method described in Step 1 of Example 1, that is, 2-(7-methoxynaphthalene-1-yl)acetonitrile (1.0g, 5.07mmol), sodium hydride (60%, 1.01g, 25.35 mmol) and 1,2-dibromoethane (0.88mL, 10.14mmol, dissolved in 10mL DMF) were prepared by reacting in anhydrous DMF (10mL), and the crude product was subjected to silica gel column chromatography (petroleum ether / ethyl acetate (v / v)=50 / 1), concentrated and dried to obtain the title compound as a white solid (615 mg, 54.4%).

[0238] MS(ESI,pos.ion)m / z:224.1[M+1] + ;

[0239] 1 H NMR (400MHz, CDCl 3 )δ7.79 (t, J = 9.2Hz, 2H), 7.64 (d, J = 2.0Hz, 1H), 7.46 (dd, J = 6.8, 0.8Hz, 1H), 7.28 (dd, J = 7.2, 8.0 Hz, 1H), 7.24 (dd, J = 8.8, 2.4Hz, 1H), 4.02 (s, 3H), 1.84 (q, J = 4.8Hz, 2H), ...

Embodiment 3

[0248] Embodiment 3N-((1-(7-fluoronaphthalene-1-yl)cyclopropyl)methyl)acetamide

[0249]

[0250] Step 1) Synthesis of 1-(7-fluoronaphthalen-1-yl)cyclopropanecarbonitrile

[0251] The title compound of this step was prepared by referring to the method described in Step 1 of Example 1, that is, 2-(7-fluoronaphthalen-1-yl)acetonitrile (700mg, 3.78mmol), sodium hydride (60%, 756mg, 18.90mmol) and 1,2-Dibromoethane (0.65mL, 7.56mmol, dissolved in 10mL DMF) was prepared by reaction in anhydrous DMF (10mL), and the crude product was subjected to silica gel column chromatography (petroleum ether / ethyl acetate (v / v) =50 / 1), concentrated and dried to give the title compound as a white solid (520 mg, 65.1%).

[0252] MS(ESI,pos.ion)m / z:212.1[M+1] + ;

[0253] 1 H NMR (400MHz, CDCl 3 )δ7.98(dd, J=10.4,1.2Hz,1H),7.90(dd,J=8.8,5.6Hz,1H),7.85(d,J=8.4Hz,1H),7.53(d,J=7.2 Hz, 1H), 7.40(t, J=7.6Hz, 1H), 7.34(td, J=8.8, 2.0Hz, 1H), 1.87(q, J=4.8Hz, 2H), 1.43(q, J=4.8 Hz, 2H).

[0...

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Abstract

The invention provides a number of naphthalene derivatives or stereoisomers, tautomers, nitrogen oxides, metabolites, pharmaceutically acceptable salts or prodrugs thereof which are used for excitement of melatonin receptors. The invention also discloses pharmaceutical compositions containing such compounds and application thereof in treatment of central nervous system dysfunction of mammals, especially human.

Description

technical field [0001] The invention belongs to the field of medicines, and in particular relates to a class of novel compounds that can be used for treating central nervous system dysfunction, their preparation methods, pharmaceutical compositions containing the compounds, and the role of the compounds and their pharmaceutical compositions in treating central nervous system dysfunction. applications in obstacles. More specifically, the present invention describes naphthalene compounds that can be used as melatonin receptor agonists. Background technique [0002] Melatonin is a neuroendocrine hormone secreted by the pineal gland. Its main physiological functions are: 1. Anti-tumor effect. Melatonin can inhibit breast cancer, melanoma, prostate cancer, liver cancer, etc. The growth of cancer cells is an important physiological tumor suppressor; 2. Antioxidation, the body can produce free radicals through enzymatic and non-enzymatic reactions, such as oxygen free radicals, hy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/18C07C233/13C07C231/02A61K31/165A61P25/00A61P25/20A61P25/24A61P25/22A61P25/18A61P25/08A61P25/16A61P25/28A61P25/06A01N1/02
Inventor 张英俊金传飞聂飚徐景宏蔡少瑜
Owner SUNSHINE LAKE PHARM CO LTD
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