Substituted 1,3-miscellaneous azole compound, preparation method thereof, pharmaceutical composition containing substituted 1,3-miscellaneous azole compound and purpose thereof

A compound and drug technology, applied in the direction of medical preparations containing active ingredients, organic chemistry, antibacterial drugs, etc., can solve the problems of high treatment costs, patients can not follow the doctor's treatment guidelines well, and achieve good selectivity Effect

Active Publication Date: 2016-08-03
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Second-line anti-tuberculosis drugs (such as: amikacin, kanamycin, capreomycin, etc.) are used to treat multidrug-resistant tuberculosis, and the course of treatment is generally 2 to 4 years, requiring relatively high treatment costs
As a result, patients do not follow doctors' treatment guidelines well, which in turn leads to the emergence of extensively drug-resistant tuberculosis (XDR-TB)

Method used

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  • Substituted 1,3-miscellaneous azole compound, preparation method thereof, pharmaceutical composition containing substituted 1,3-miscellaneous azole compound and purpose thereof
  • Substituted 1,3-miscellaneous azole compound, preparation method thereof, pharmaceutical composition containing substituted 1,3-miscellaneous azole compound and purpose thereof
  • Substituted 1,3-miscellaneous azole compound, preparation method thereof, pharmaceutical composition containing substituted 1,3-miscellaneous azole compound and purpose thereof

Examples

Experimental program
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preparation example Construction

[0054] The present invention also relates to the preparation method of the compound of the present invention, it comprises the following steps:

[0055] a) make formula compound and formula The compound undergoes acylation reaction in dry tetrahydrofuran solution to generate the formula compound of;

[0056]

[0057] or

[0058] b) make formula compound and formula The compound is condensed in DMF in the presence of HATU and DIPEA to obtain the formula compound of,

[0059] where R 1 , R 2 , R 3 and X are as defined above.

[0060] In a preferred embodiment, the formula The compound is synthesized by the following synthetic route:

[0061] When R 3 When is hydrogen and X is S, the formula The compound is synthesized by the following synthetic route:

[0062]

[0063] a) make formula The compound reacts with liquid bromine in dichloromethane compounds; and

[0064] b) make formula The compound of the formula is prepared by reacting with thiou...

Embodiment 1

[0118] Embodiment 1: Synthesis of 3-(methoxycarbonylhydrazone)-ethyl butyrate

[0119]

[0120] Take 7.28g (0.055mol) of ethyl acetoacetate in a 100mL three-neck flask, add 35mL of ethanol to dissolve, and add dropwise 15mL of an ethanol solution of 5.02g (0.055mol) of methyl carbazate at room temperature. After the addition was completed, the mixture was stirred at room temperature for 6 hours, and the solvent was evaporated under reduced pressure to obtain the title compound as a light yellow thick oily liquid, which turned into yellow crystals upon standing and cooling, 10.51 g, yield 94.5%.

Embodiment 2

[0121] Example 2: Synthesis of ethyl 4-methyl-1,2,3-thiadiazole-5-carboxylate

[0122]

[0123] Add 13 mL (0.18 mol) of thionyl chloride to a 100 mL three-neck flask equipped with a drying tube and an exhaust gas absorption device, and slowly add 11.80 g of 3-(methoxycarbonylhydrazone)-butyric acid ethyl ester dropwise under ice-salt bath conditions (0.06mol) of dichloromethane solution 50mL. After 24 hours of reaction, excess thionyl chloride and dichloromethane were distilled off under reduced pressure to obtain a brown solid. Column separation, eluting with petroleum ether-ethyl acetate: 10:1 (V / V), gave the title compound as a yellow oil, 6.72 g, yield 65.1%.

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Abstract

The invention relates to a substituted 1,3-miscellaneous azole compound, a preparation method thereof, a pharmaceutical composition containing the substituted 1,3-miscellaneous azole compound and a purpose thereof. The invention relates to the compound in a formula I, or its pharmaceutically acceptable salt, a stereisomer or a solvate, wherein R1, R2, R3 and X are defined as a specification; and the invention also relates to the preparation method, the pharmaceutical composition containing the substituted 1,3-miscellaneous azole compound and the purpose thereof. The compound of the present invention is the novel antituberculous compound, is effective to mycobacterium tuberculosis-susceptible strains, also possesses activity on strains with tolerance on traditional first-line antituberculous drugs such as isoniazide and rifampicin, and has good selectivity to mycobacterium tuberculosis.

Description

technical field [0001] The present invention relates to a substituted 1,3-heteroazole compound, and also relates to a preparation method of the compound, a pharmaceutical composition containing it and use thereof. Background technique [0002] Tuberculosis (Tuberculosis, TB) is a chronic infectious disease common to humans, livestock and poultry, which is caused by Mycobacterium tuberculosis (Mtb) infection. Mycobacterium tuberculosis may invade various organs of the human body, but mainly invades the lungs, which is called pulmonary tuberculosis. Tuberculosis, also known as tuberculosis and "white plague", is an ancient infectious disease, and tuberculosis has existed since human beings existed. So far, it is still the second largest killer threatening human health. Statistics from the World Health Organization show that in 2012 alone, there were approximately 8,600,000 new infections of Mycobacterium tuberculosis, and 1,300,000 people died of tuberculosis (320,000 of who...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/14C07D417/12C07D413/14A61K31/4439A61K31/433A61P31/06
Inventor 司书毅李东升朱宁屿姜威林媛李妍高娜娜蒋建东游雪甫
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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