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Anti-inflammatory drug and use thereof

A pharmacy and compound technology, applied in the field of preparing anti-inflammatory drugs and heterocyclic lactone compounds, can solve the problem of low side effects

Active Publication Date: 2019-06-21
CHENGDU SHIBEIKANG BIOLOGICAL MEDICINE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Therefore, new anti-inflammatory drugs with good therapeutic effect and low side effects are still an unmet clinical need.

Method used

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  • Anti-inflammatory drug and use thereof
  • Anti-inflammatory drug and use thereof
  • Anti-inflammatory drug and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Compound 1: (S)-2-((3aS,7aS)-1-ethyl-7a-hydroxy-2-oxooctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)- 3,3,3-Methyl trifluoropropionate and compound 2: (S)-2-((3aR,7aR)-1-ethyl-7a-hydroxy-2-oxooctahydro-5H-pyrrolo[ Synthesis of 3,2-c]pyridin-5-yl)-3,3,3-trifluoropropionic acid methyl ester

[0048]

[0049] Synthesis of Step 1IM1:

[0050]

[0051] At room temperature, slowly drop 50 mL of anhydrous THF suspension dissolved with 4.8 g of sodium hydride into 400 mL of anhydrous THF dissolved with 40.0 g of SM1, stir at room temperature for 30 min, and slowly add dropwise of anhydrous THF solution with 47.0 g of SM2 94 mL of THF solution was stirred at room temperature for 2 h, and the reaction was monitored by TLC iodine display. After the reaction was completed, 500 mL of saturated brine was added, and the product was extracted with 1000 mL of DCM. Organic layer with Na 2 SO 4 After drying, the solvent was removed by evaporation under reduced pressure. The residue w...

Embodiment 2

[0073] Compound 7: (S)-2-((S)-1-ethyl-7a-hydroxy-2-oxo-1,2,4,6,7,7a-hexahydro-5H-pyrrolo[3, 2-c]pyridin-5-yl)-3,3,3-trifluoropropionic acid methyl ester and compound 8: (S)-2-((R)-1-ethyl-7a-hydroxy-2-oxo Synthesis of Di-1,2,4,6,7,7a-hexahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-3,3,3-trifluoropropionic acid methyl ester

[0074]

[0075] Synthesis of Step 1IM1:

[0076]

[0077] At room temperature, slowly drop 96 mL of anhydrous THF suspension dissolved with 9.6 g of sodium hydride into 800 mL of anhydrous THF dissolved with 80.0 g of SM1, stir at room temperature for 30 min, and slowly add dropwise of anhydrous THF suspension with 94.1 g of SM2 dissolved therein 188 mL of THF solution was stirred at room temperature for 2 h, and the reaction was monitored by TLC iodine display. After the reaction was completed, 1000L saturated brine was added, and the product was extracted with 2000mL DCM. Organic layer with Na 2 SO 4 After drying, the solvent was removed by evaporati...

Embodiment 3

[0104] Compound 22: (S)-2-(2-chlorophenyl)-2-((3aS,7aR)-7a-hydroxyl-2-oxohexahydrofuro[3,2-c]pyridine-5(4H )-base) Synthesis of methyl acetate

[0105]

[0106] Synthesis of Step 1IM1:

[0107]

[0108] At room temperature, slowly drop 81 mL of anhydrous THF suspension with 8.1 g of sodium hydride into 673 mL of anhydrous THF dissolved with 67.3 g of SM1, stir for 30 min, and then slowly drop into anhydrous THF solution of 84.3 g of SM2 85mL and stirred at room temperature for 12h, TLC iodine display to monitor the reaction. After the reaction was completed, 700 mL of saturated brine was added and extracted with 1500 mL of DCM. Organic layer with Na 2 SO 4 After drying, the solvent was removed by evaporation under reduced pressure. The residue was purified on a basic alumina column to obtain 23.6 g (yield 27.1%) of IM1 as a colorless oily liquid (DCM / MeOH=20 / 1 to 5 / 1). LC-MS(ESI)[M+H+] + =258.4(M+H + ) is consistent with the structure.

[0109] Synthesis of step...

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PUM

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Abstract

The invention discloses an anti-inflammatory drug and use thereof. The drug comprises a chiral compound of formula I, or a pharmaceutically acceptable salt, solvate or deuterate thereof; W and Z are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, monocyclic aryl, monocyclic aryloxy or monocyclic heteroaryl; the substitution means that the substance is substituted by one or more groups selected from halogen, C1-C6 alkyl, nitro, amino or hydroxyl; ring A is selected from monocyclic or bicyclic heteroaryl, C3-C6 lactonic ring, C3-C6 lactam ring and C3-C6 thiolactone ring; and alpha and beta are two chiral sites in the compound, and an absolute configuration of alpha and beta are each independently selected froman S or R configuration. The compound disclosed by the invention has remarkable anti-inflammatory effects and is expected to become a new type of non-steroidal anti-inflammatory drugs.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to an unsaturated pyrrolidone compound and a similar heterocyclic lactone compound, and the use of the compound in preparing anti-inflammatory drugs. Background technique [0002] As an excellent clinical drug, non-steroidal anti-inflammatory drugs (NSAIDs) have been developed for more than 100 years, during which they have been used as first-line treatment drugs for various anti-inflammation and pain. The pharmacodynamic mechanism of NSAIDs was first proposed by Vane.JR et al. in 1971. NSAIDs inhibit the biological activity of cyclooxygenase (COX) to block the synthesis of inflammatory mediators from arachidonic acid—prostaglandin (PG), and then play a role in detoxification. Heat, analgesic, anti-inflammatory effects. Unfortunately, these drugs all exhibit severe gastrointestinal irritation and nephrotoxicity, which limits their clinical application. Therefore, pharmaceutical...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D491/048C07D495/04A61K31/4355A61K31/4365A61K31/437A61P29/00A61P19/02A61P1/04A61P7/02A61P9/10A61P19/08
Inventor 周杨苏龙文
Owner CHENGDU SHIBEIKANG BIOLOGICAL MEDICINE TECH CO LTD
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