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N-(2-(substituted-naphth-1-yl)ethyl)-substituted amide compounds, and preparation thereof and application thereof

A compound, the technology of acetamide, which is applied in the field of N-(2-(substituted-naphthalen-1-yl)ethyl) substituted amide compounds, its preparation and application, can solve individual differences and poor oral bioavailability And other issues

Inactive Publication Date: 2019-01-22
BEIJING GREATWAY PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Poor oral bioavailability also leads to significant interindividual variability

Method used

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  • N-(2-(substituted-naphth-1-yl)ethyl)-substituted amide compounds, and preparation thereof and application thereof
  • N-(2-(substituted-naphth-1-yl)ethyl)-substituted amide compounds, and preparation thereof and application thereof
  • N-(2-(substituted-naphth-1-yl)ethyl)-substituted amide compounds, and preparation thereof and application thereof

Examples

Experimental program
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preparation example Construction

[0123] In one embodiment of the present invention, the synthetic method of the present invention also comprises:

[0124] The above-mentioned acetamide / propionamide compound is dissolved in toluene and reacted with anhydrous aluminum chloride to obtain naphthol; and

[0125] Reaction of the naphthol with deuterated iodomethane yields a deuterated acetamide / propionamide compound.

[0126] In one embodiment of the present invention, the synthetic method of the present invention also comprises:

[0127] The acetamide / propionamide compound or deuterated acetamide / propionamide compound described above is reacted with an acid to form a salt.

[0128] For specific operations, for example, reference may be made to the description of the embodiments.

[0129] According to the detailed teaching of the present invention and the existing general knowledge of synthesis, those skilled in the art can easily synthesize the compound of formula I of the present invention.

[0130] Another as...

Embodiment 1 and Embodiment 2、8

[0141] The synthesis of embodiment 1 and embodiment 2,8:

[0142] The reaction scheme is as above, and the specific synthesis operation is as follows:

[0143] Intermediate 1:

[0144]

[0145] 3-liter three-necked bottle, with a condenser tube on the shelf. Add 328 grams (2.46 mol) of aluminum trichloride into 1.7 liters of dichloromethane under an ice bath, and stir to dissolve it completely. Add 156.8 g (138 mL, 1.10 mol) of o-chloroanisole at one time, and then add 123 g (1.23 mol) of succinic anhydride in batches, the system will generate heat and gas, and spontaneous reflux will occur. After the spontaneous reflux is over, start heating to reflux. After refluxing for 2 hours, the progress of the reaction was monitored by TLC, and the reaction was terminated when the starting material disappeared. After natural cooling, pour into 5 liters of ice water. Under stirring, it was acidified with 300 ml of concentrated hydrochloric acid, and a large amount of solids ap...

Embodiment 1

[0171] Example 1: N-(2-(6-Chloro-7-deuteromethoxy-naphthalen-1-yl)ethyl)acetamide

[0172]

[0173] 17.3 grams of intermediate 7 were dissolved in 1 liter of acetone, 27.2 grams of potassium carbonate, 1.3 grams of potassium iodide, 12.4 grams (5.31 milliliters) of deuterated methyl iodide were added thereto, after 24 hours of reaction at room temperature, TLC monitored the reaction to be complete, filtered, and the filtrate was spin-dried , add 400 milliliters of ethyl acetate to the residue, then wash with 200 milliliters of water and saturated aqueous sodium chloride successively, filter the organic phase after drying with anhydrous sodium sulfate, add 2 grams of gacs to the filtrate and boil for 30 minutes, then filter, Spin-dried and treated with cyclohexane / ethyl acetate to obtain a white powdery solid. Yield 81.4%, melting point: 148-151°C

[0174] 1 H-NMR (400MHz, DMSO-d6), δ: 1.83 (s, 3H), 3.11-3.20 (m, 2H), 3.29-3.35 (m, 2H), 7.30-7.36 (m, 2H), 7.70-7.72 (dd,...

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Abstract

The invention relates to N-(2-(substituted-naphth-1-yl)ethyl)-substituted amide compounds, and application of the same as melatonin receptor agonists and 5-HT2c receptor antagonists. Specifically, theinvention relates to the compounds as shown in a formula I which is described in the specification, or pharmaceutically acceptable salts or solvates thereof, or mixtures of the compounds, the salts and the solvates, and pharmaceutical compositions of the compounds, the salts, the solvates or the mixtures. X, R1, R2 in the formula I are as defined in the specification. The compounds as shown in the formula I of the invention can be used as melatonin receptor agonists and 5-HT2c receptor antagonists and is applicable to the preparation of drugs used for treating and / or preventing melatonin system diseases, stress, anxiety, seasonal affective disorders, cardiovascular diseases, digestive diseases, schizophrenia, phobias, depression, major depression, sleep disorders, sleep disturbance, insomnia or fatigue caused by jet lag, weight disorders and other diseases and illnesses.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to N-(2-(substituted-naphthalene-1-yl)ethyl) substituted amide compounds and their preparation methods, pharmaceutical compositions and the prevention / treatment of melatoninergic system diseases, tension, Anxiety, Seasonal Affective Disorder, Cardiovascular Disease, Digestive Disease, Schizophrenia, Phobia, Depression, Major Depression, Sleep Disorder, Sleep Disorder, Jet Lag Insomnia or Fatigue, Weight Disorder, etc. the use of. Background technique [0002] Melatonin receptor (MT) agonists are a new class of compounds with antidepressant, anxiolytic, circadian cycle and body weight regulation effects. Compared with currently commonly used selective serotonin (5-HT) reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) antidepressants, melatonin receptor agonism Drug-based compounds have multiple advantages in application, mainly less adv...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/18A61K31/165A61K45/06C07C231/12C07C231/00A61P25/22A61P25/18A61P25/00A61P9/00A61P1/00A61P25/20A61P25/24A61P3/00
CPCC07C233/18A61K31/165A61K45/06A61P1/00A61P3/00A61P9/00A61P25/00A61P25/18A61P25/20A61P25/22A61P25/24C07C231/00C07C231/12C07B59/001A61K9/2009A61K9/2013A61K9/2018A61K9/2027A61K9/2059C07B2200/05C07C231/14
Inventor 陶宏
Owner BEIJING GREATWAY PHARMA TECH CO LTD
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