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Naphthalene derivatives and application of naphthalene derivatives to medicine

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

Inactive Publication Date: 2014-12-24
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 derivatives and application of naphthalene derivatives to medicine
  • Naphthalene derivatives and application of naphthalene derivatives to medicine
  • Naphthalene derivatives and application of naphthalene derivatives to medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0218] Example 1 N-(2-(4-methoxynaphthalen-1-yl)ethyl)acetamide

[0219]

[0220] Step 1) Synthesis of (E)-1-methoxy-4-(2-nitrovinyl)naphthalene

[0221] Combine 4-methoxy-1-naphthaldehyde (2.0g, 10.47mmol) and NH 4 OAc (828mg, 10.47mmol) was added to nitromethane (10mL), reacted for 12h at 120℃ in oil bath, stopped the reaction, diluted with ethyl acetate (60mL), washed with saturated brine (40mL×3), and separated The organic phase was then dried with anhydrous sodium sulfate. After filtration, the filtrate was spin-dried under reduced pressure, and purified by column chromatography (dichloromethane) to obtain the title compound as a red solid (2.20 g, 89.4%).

[0222] MS(ESI,pos.ion)m / z:230.1[M+1] + ;

[0223] 1 H NMR(CDCl 3 ,400MHz)δ8.78(d,J=13.6Hz,1H), 8.28(d,J=8.4Hz,1H), 8.26-8.20(m,2H), 8.18(d,J=8.0Hz,1H), 7.72-7.68 (m, 1H), 7.63-7.59 (m, 1H), 7.11 (d, J=8.0 Hz, 1H), 4.07 (s, 3H).

[0224] Step 2) Synthesis of 2-(4-methoxynaphthalene-1-yl)ethylamine

[0225] Add (E)-1-methoxy...

Embodiment 2

[0233] Example 2 N-(2-(4-fluoronaphthalene-1-yl)ethyl)acetamide

[0234]

[0235] Step 1) Synthesis of (E)-1-fluoro-4-(2-nitrovinyl)naphthalene

[0236] The title compound in this step was prepared by referring to the method described in step 1 of Example 1, namely 4-fluoro-1-naphthaldehyde (2.0g, 11.48mmol) and NH 4 OAc (885mg, 11.48mmol) was prepared by reaction in nitromethane (10mL). The crude product was subjected to silica gel column chromatography (dichloromethane), concentrated and dried to obtain the title compound as a grayish green solid (1.89g, 75.9%).

[0237] MS(ESI,pos.ion)m / z:218.0[M+1] + ;

[0238] 1 H NMR(400MHz,DMSO)δ8.76(d,J=13.2Hz,1H), 8.34(d,J=8.4Hz,1H), 8.21(d,J=13.2Hz,1H), 8.14-8.10(m , 2H), 7.79-7.71 (m, 2H), 7.45 (dd, J=10.4, 8.4 Hz, 1H).

[0239] Step 2) Synthesis of 2-(4-fluoronaphthalene-1-yl)ethylamine

[0240] The title compound of this step was prepared by referring to the method described in step 2 of Example 1, namely (E)-1-fluoro-4-(2-nitrovinyl)nap...

Embodiment 3

[0248] Example 3 N-(2-(4-(piperazin-1-yl)naphthalene-1-yl)ethyl)acetamide

[0249]

[0250] Step 1) Synthesis of 4-(piperazin-1-yl)-1-naphthaldehyde

[0251] 4-Fluoro-1-naphthaldehyde (10g, 57.41mmol), piperazine (14.84g, 172.24mmol) and potassium carbonate (15.85g, 114.82mmol) were added to DMF (50mL) in sequence, and the temperature was increased and refluxed for 12h . After cooling to room temperature, the solvent was removed by rotary evaporation under reduced pressure, 100 mL of dichloromethane was added, and washed with water (100 mL×3). After liquid separation, the organic phase was dried with anhydrous sodium sulfate. After filtration, the filtrate was spin-dried under reduced pressure and purified by column chromatography (DCM / MeOH(v / v)=20 / 1) to obtain the title compound as a yellow solid (13g, 94.2%).

[0252] MS(ESI,pos.ion)m / z:241.2[M+H] + ;

[0253] 1 H NMR(600MHz, CDCl 3 )δ10.23(s,1H),9.33(d,J=8.4Hz,1H), 8.19(d,J=8.4Hz,1H), 7.90(d,J=7.6Hz,1H), 7.67-7.64( m, 1H), 7.5...

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Abstract

The invention provides naphthalene derivatives or stereisomers, tautomers, nitric oxides, metabolites, pharmaceutically acceptable salts or prodrugs thereof for exciting a melatonin receptor. The invention discloses pharmaceutical compositions containing the compounds, and use of the compounds or the pharmaceutical compositions of the compound for treating central nervous system dysfunction of mammal, especially human.

Description

Technical field [0001] The present invention belongs to the field of medicine, and specifically relates to a class of new compounds that can be used to treat central nervous system dysfunction, a method for preparing them, a pharmaceutical composition containing the compound, and the compound and its pharmaceutical composition in the treatment of central nervous system function Application 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 effects 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. Antioxidant, the body can generate free radicals through enzymatic and non-enzymatic reactions, such as oxygen free radicals and hydroxyl free radi...

Claims

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Application Information

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IPC IPC(8): C07C233/13C07C233/18C07C231/02C07D295/135A61K31/495A61K31/165A61P25/20A61P25/14A61P25/24A61P25/22A61P25/18A61P25/08A61P25/16A61P25/28A61P25/06
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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