Indole derivatives and use thereof in medicine

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

Active Publication Date: 2015-04-08
GUANGZHOU ANYANREN PHARMA TECH 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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  • Indole derivatives and use thereof in medicine
  • Indole derivatives and use thereof in medicine
  • Indole derivatives and use thereof in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0188] Example 1: 1-(6-methoxy-4,4-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)propane Synthesis of yl-1-ones

[0189]

[0190] Step 1) Synthesis of tert-butyl-3-(cyanomethyl)-5-methoxyl-1H-indole-1-carboxylate

[0191] 2-(5-methoxy-1H-indol-3-yl)acetonitrile (5.59g, 30.0mmol), 4-dimethylaminopyridine (0.37g, 3.0mmol), anhydrous dichloromethane (30mL) Sequentially added to a 250mL eggplant-shaped bottle, slowly added di-tert-butyl dicarbonate (8.51g, 39.0mmol) diluted with anhydrous dichloromethane (50mL) dropwise under stirring, and the reaction was continued at room temperature for 4 hours after the drop was completed. Stop the reaction, add water to separate the layers, extract the aqueous phase with dichloromethane (3×50mL), combine the organic phases, wash with tap water (3×50mL) and saturated brine (30mL) successively, evaporate the organic phase to dryness under reduced pressure, and carry out silica gel Separation and purification by column chromatograph...

Embodiment 2

[0217] Example 2: 1-(6-methoxy-4,4-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)butane Synthesis of yl-1-ones

[0218]

[0219] Step 1) 1-(6-Methoxy-4,4-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]indol-2(9H)-yl)butyl Synthesis of -1-one

[0220] 6-Methoxy-4,4-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (127mg, 0.55mmol), anhydrous N, N-dimethylformamide (15 mL), N,N-diisopropylethylamine (0.39 mL, 2.2 mmol) and 2-(7-azobenzotriazole)-N,N,N' ,N'-Tetramethyluronium hexafluorophosphate (323mg, 0.82mmol) was successively added into a 100mL eggplant-shaped flask, and at -10°C, anhydrous N,N-dimethylformamide (5mL ) dissolved n-butyric acid (0.06mL, 0.66mmol), after the dropwise reaction was continued for 20 minutes, it was transferred to room temperature and reacted for 10 hours. Stop the reaction, add water to separate the layers, extract the aqueous phase with dichloromethane (3×30mL), combine the organic phases, wash with tap water (3×50mL) and saturated brine (30...

Embodiment 3

[0224] Embodiment 3: the synthesis of N-((1-(5-methoxy-1H-indol-3-yl) cyclopropyl) methyl) propanamide

[0225]

[0226] Step 1) Synthesis of tert-butyl-3-(1-cyanocyclopropyl)-5-methoxy-1H-indole-1-carboxylate

[0227] The title compound of this step was prepared by referring to the method described in step 2 of Example 1, that is, tert-butyl-3-(cyanomethyl)-5-methoxy-1H-indole-1-carboxylate (5g, 17.46mmol), 1,2-dibromoethane (2.28mL, 26.9mmol), 60% sodium hydride (1.75g, 43.8mmol) were prepared by reacting in anhydrous dimethyl sulfoxide (45mL), and the crude product was purified by silica gel Separation and purification by column chromatography (petroleum ether / ethyl acetate (v / v)=100 / 1) gave the title compound (light yellow liquid, 1.66 g, 30.4%).

[0228] MS(ESI,pos.ion)m / z:313.3[M+H] + ;

[0229] 1 H NMR (600MHz, CDCl 3 )δ (ppm): 7.98 (s, 1H), 7.43 (s, 1H), 7.20 (d, J = 2.4Hz, 1H), 6.96 (dd, J = 9.0, 2.4Hz, 1H), 3.89 (s, 3H), 1.67~1.65(m, 2H), 1.64(s, 9H), 1.33...

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Abstract

The invention provides a series of indole derivatives or stereoisomers, tautomers, nitrogen oxides, metabolic products and pharmaceutically acceptable salts or prodrugs thereof. The indole derivatives can be taken as melatonin receptor stimulants. The invention also discloses a pharmaceutical composition containing the compounds, and a use of the compounds or the pharmaceutical composition of the compounds in treating the functional disorder of the central nervous system of mammal and in particular 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 indole compounds that can be used as melatonin receptor agonists. Background technique [0002] At present, drug therapy is one of the main methods for treating insomnia. The sedative and hypnotics used clinically include: barbiturates, benzodiazepines drugs, non-benzodiazepines Drugs, antidepressants, melatonin and traditional Chinese medicine, etc. Barbiturates are derivatives of barbituric acid (malonylurea), which selectively inhibit the ascending reticular activation system of the thalamus, thereby blocki...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D209/14A61K31/437A61K31/4045A61P25/00A61P25/20A61P25/24A61P25/22A61P25/18A61P25/08A61P25/16A61P25/28A61P25/06
CPCC07D209/14C07D471/04C07D471/10
Inventor 张英俊金传飞高金恒
Owner GUANGZHOU ANYANREN PHARMA TECH CO LTD
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