2-arylamide substituted thiophene imide ester compound and its preparation method and use

A technology of compounds and compositions, applied in the field of medicine, capable of solving problems such as undisclosed synthesis methods

Active Publication Date: 2022-05-20
INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

WO2014 / 190199 A1 disclosed the compound represented by formula (IV) on November 27, 2014 for the treatment of drug-resistant and persistent tuberculosis, but the patent does not show the relevant synthesis method of the compound represented by formula (IV)

Method used

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  • 2-arylamide substituted thiophene imide ester compound and its preparation method and use
  • 2-arylamide substituted thiophene imide ester compound and its preparation method and use
  • 2-arylamide substituted thiophene imide ester compound and its preparation method and use

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specific Embodiment approach

[0104] The present invention can be described in detail by the following examples, but it does not imply any adverse limitation on the present invention. The present invention has been described in detail herein, and its specific embodiments are also disclosed. For those skilled in the art, it is necessary to make various changes and improvements to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. Obvious.

[0105] For all of the following examples, standard manipulations and purification methods known to those skilled in the art can be used. All temperatures are in °C (degrees Celsius) unless otherwise indicated. Compound structures were determined by nuclear magnetic resonance spectroscopy (NMR) and / or mass spectroscopy (MS). Melting points (Mp) are given in °C, uncorrected for temperature.

[0106] Preparation of the Example section

[0107] The structure of the compound was obtained by H NMR spect...

preparation example 1

[0125] Preparation of (2-aminothiophene-3-carbonyl)methyl carbamate (intermediate A-1)

[0126]

[0127] The first step: the preparation of methyl (2-cyanoacetyl) carbamate 2a

[0128] Under the protection of Ar, compound 1a (15.0g, 176.35mmol), 90mL toluene, methyl carbamate (13.24g, 176.35mmol), and 5.4mL DMF were placed in a 250mL round-bottomed flask in turn, and POCl was slowly added dropwise at 0°C. 3 (8.22mL, 88.18mmol), after the addition, the reaction temperature was raised to 80°C and reacted for 3h, TLC detected that the reaction was complete, the reaction solution was poured out, and the remaining tan solid was added to 500mL of water, beating, suction filtration, and drying with an infrared lamp. Intermediate 2a was obtained, white solid 14.64g, yield 58.6%. 1 H NMR (400MHz, DMSO-d 6 )δ: 11.04(br s,1H), 4.11(s,2H), 3.67(s,3H).

[0129] The second step: the preparation of methyl 2-(2-aminothiophene-3-carbonyl)carbamate A-1

[0130] Under the protection of Ar...

preparation example 2

[0132] Preparation of (2-aminothiophene-3-carbonyl) ethyl carbamate (intermediate A-2)

[0133]

[0134] The first step: preparation of (2-cyanoacetyl) ethyl carbamate 3a

[0135] Using 1a (15g, 176.35mmol) as the raw material, the intermediate 3a was obtained as a light yellow solid, 17.4g, with a yield of 63.2%. 1 H NMR (400MHz, DMSO-d 6 )δ:10.98 (br s,1H),4.15-4.10(m,2H),4.09(s,2H),1.21(t,J=6.8Hz,3H).

[0136] The second step: the preparation of methyl 2-(2-aminothiophene-3-carbonyl)carbamate A-2

[0137] Using 3a (16.3 g, 104.4 mmol) as the raw material, the intermediate A-2 was obtained as a light yellow solid of 17.5 g, with a yield of 78.3%, using the similar operation steps in the second step of Preparation Example 1. 1 H NMR (400MHz, DMSO-d 6 )δ: 10.02(br s,1H),7.65(br s,2H),7.25(d,J=6.0Hz,1H),6.22(d,J=6.0Hz,1H), 4.16-4.10(m,2H ),1.23(t,J=7.6Hz,3H).MS(ESI):m / z 215.05(M+H) + .

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Abstract

The invention discloses 2-arylamide substituted thiophene imide ester compounds, their preparation method and use, their synthesis method and their use as antibacterial agents in infectious diseases caused by bacteria, especially those caused by mycobacteria. Application in tuberculosis (Tuberculosis, TB). Specifically, the present invention relates to compounds of formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising the compounds of the present invention, wherein R 1 , R 2 , R 3 , R 4 , R 5 and Y are as described in the specification. The present invention aims to prepare new compounds with anti-mycobacterial activity, which can be used as potential new drugs for the treatment or prevention of infectious diseases caused by bacteria, especially tuberculosis (TB) diseases caused by Mycobacterium tuberculosis sexual therapy and can be used to overcome problems related to drug resistance.

Description

technical field [0001] The invention belongs to the technical field of medicine. Particularly relate to the thiophene imide ester compound that substituted 2-arylamide group shown in general formula (I), its preparation method, the pharmaceutical composition that takes this compound as active ingredient, and they are used in the treatment and / or prevention of tuberculosis Application in infectious diseases caused by mycobacteria. Background technique [0002] Tuberculosis (TB) is a chronic fatal disease caused by Mycobacterium tuberculosis. It is a major infectious disease that endangers human health and causes human death. Like AIDS, tuberculosis has become one of the leading causes of death in the world. According to World Health Organization (WHO) estimates (Global tuberculosis report 2017), the number of new tuberculosis cases worldwide in 2016 was approximately 10.4 million, of which 90% were adults, 65% were men, and 10% of new tuberculosis cases were HIV-positive in...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D333/38C07D491/113C07D409/12A61K31/551A61K31/4025A61K31/5377A61K31/4535A61K31/381A61K31/541A61K31/397A61P31/06
CPCC07D333/38C07D491/113C07D409/12A61P31/06Y02A50/30
Inventor 黄海洪李刚王鹏旭
Owner INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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