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A kind of n-aryldithiopyrrolone-pyrone hybrid derivative and its preparation method and application

A technology of aryl dithiopyrrolone and its derivatives, which is applied in the fields of pharmaceutical formulations, medical preparations containing active ingredients, organic chemistry, etc.

Active Publication Date: 2020-06-12
SHENZHEN HEPALINK PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But so far, there are no literature and patent reports that N-aryl dithiopyrrolidone-pyrone hybrid derivatives have bacterial RNA polymerase inhibitory activity

Method used

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  • A kind of n-aryldithiopyrrolone-pyrone hybrid derivative and its preparation method and application
  • A kind of n-aryldithiopyrrolone-pyrone hybrid derivative and its preparation method and application
  • A kind of n-aryldithiopyrrolone-pyrone hybrid derivative and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Embodiment 1: the preparation of following formula compound 1-3,14-18

[0043]

[0044]

[0045]

[0046] Compound 6-amino-4-(2,4-dimethoxyphenyl)-[1,2]dithio[4,3-b]pyrrol-5(4H)-one hydrochloride (III, 2g , 5.8mmol) was dissolved in tetrahydrofuran (40mL), triethylamine (1.76g, 17.39mmol) and phenyl chloroformate (1.17g, 7.54mmol) were added respectively, reacted at room temperature for 8h, tetrahydrofuran was distilled off under reduced pressure, and distilled water was added (50mL), extracted with dichloromethane (3×30mL), combined the organic phases, washed the organic phase with saturated NaCl solution (30mL), dried over anhydrous magnesium sulfate, filtered, evaporated the solvent under reduced pressure, petroleum ether / ethyl acetate As the eluent, compound 17 was obtained by column chromatography (the next reaction can also be carried out directly without purification).

[0047] Dissolve compound 17 (1.0g, 2.3mmol) in tetrahydrofuran (20mL), add N-methyl-2...

Embodiment 2

[0056] Embodiment 2: the preparation of compound 4-6,19

[0057]

[0058]

[0059] Compound 17 (3.50mmol) was dissolved in tetrahydrofuran (30mL), ethanolamine (12.26mmol) was added, reacted at room temperature for 7h, tetrahydrofuran was evaporated under reduced pressure, distilled water (60mL) was added, extracted with dichloromethane (3×30mL), The organic phases were combined, washed with saturated NaCl solution (30 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure with petroleum ether / ethyl acetate as the eluent. Compound 19 was obtained by column chromatography. 1 H NMR (400MHz, DMSO-d 6 )δ8.52(s,1H),7.27(d,J=8.6Hz,1H),6.88(t,J=5.6Hz,1H),6.80(d,J=2.5Hz,1H),6.70(s, 1H), 6.68(dd, J=8.7, 2.6Hz, 1H), 3.88(s, 3H), 3.79(s, 3H), 3.48(t, J=5.6Hz, 2H), 3.21-3.18(m, 2H ).

[0060] Compound 14-16 (0.79mmol) was dissolved in toluene (2mL), oxalyl chloride (2.36mmol) was added dropwise at 0°C, and stirred for 1h (TLC ...

Embodiment 3

[0064] Embodiment 3: the preparation of compound 7-9,20

[0065]

[0066]

[0067] Dissolve triphosgene (1.45mmol) in ultra-dry THF (12.5mL), seal the flip plug, and add 6-amino-4-(2,4-dimethoxyphenyl)- [1,2]dithio[4,3-b]pyrrol-5(4H)-one hydrochloride (III, 1.45mmol), triethylamine (15.2mmol) and ultra-dry THF (50mL) mixed solution, ice After reacting in the bath for 2-3h, an ultra-dry THF solution (25 mL) of ethylene glycol (4.35 mmol) was quickly added dropwise. After the dropwise addition was completed, react at room temperature for 12 h. After the reaction, evaporate the solvent under reduced pressure, add 50 mL of water, extract with dichloromethane (3 × 30 mL), combine the organic phases, and wash the organic phases with saturated NaCl solution (30 mL). Magnesium sulfate water was dried, filtered, and the solvent was evaporated under reduced pressure, and chloroform / methanol (50:1) was the eluent, and column chromatography obtained compound 20, R f (CHCl 3 / MeOH...

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Abstract

The invention discloses an N-aryl dithiopyrrolidone-pyrone heterozygous derivative as well as a preparation method and application thereof, and provides derivatives of which structural formulas are asshown in formulas (I) and (II) which are shown in the description. In the formulas, Ar is selected from C6 to C10 aryl or heterocyclic rings containing 1 to 3 heteroatoms which are respectively and independently selected from N, O or S, X is selected from one of NH, NCH3 and O, and n is independently selected from 2, 3, 4, 5, 6 and 7. During preparation, different N-aryl dithiopyrrolidone compounds are selected as raw materials to hybridize with a pyrone carboxylic acid derivative through acylation reaction, so that a target derivative is obtained. The prepared derivative, pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is a bacteria RNA (Ribonucleic Acid) polymerase inhibitor and is used for development of antibacterial agents.

Description

technical field [0001] The invention belongs to the field of new drug design and synthesis, in particular to an N-aryl dithiopyrrolidone-pyrone hybrid derivative and its preparation method and application. Background technique [0002] With the widespread use and even abuse of antibiotics, bacterial resistance continues to increase, making new antibiotics occupy an important position in the field of medicine. The abuse of antibiotics not only leads to the occurrence of adverse drug events and drug-induced diseases, but also leads to the emergence of drug resistance. At present, important drug-resistant bacteria have been found to be vancomycin-resistant Staphylococcus aureus (VRSA); Mycobacterium tuberculosis resistance can be single-drug resistance to ramifen or rifampin, or to rifampicin, ramifen, ethylamine Butanol and other multidrug resistance at the same time. Therefore, the development of new antibacterial drugs has become a top priority. [0003] Bacterial RNA pol...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D495/04A61P31/04A61K31/407
CPCA61P31/04C07D495/04
Inventor 谭相端段小群刘文涛周异欢彭彥芬黄默涵蒙杰雲吕玉彬
Owner SHENZHEN HEPALINK PHARMA GRP CO LTD
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