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STING protein agonist coupled with compound

A compound, optionally a technology, applied in the fields of organic chemistry, antiviral agents, drug combinations, etc., can solve the problems of failure to observe obvious curative effect, failure to activate human STING protein, etc.

Active Publication Date: 2021-04-16
ADLAI NORTYE BIOPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the drug failed to show significant efficacy when used in combination with standard chemotherapy in a human non-small cell clinical trial
Later experiments confirmed that although the similarity between human and mouse STING proteins was as high as 81%, the former gene encoded 379 amino acids, and the latter gene encoded 378 amino acids, but DMXAA could not activate human STING protein

Method used

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  • STING protein agonist coupled with compound
  • STING protein agonist coupled with compound
  • STING protein agonist coupled with compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Compound 1

[0049] Compound 1 was prepared by the following steps:

[0050]

[0051] The first step: N-tert-butoxycarbonyl-N'-benzyloxycarbonyl-L-ornithine 1a (25g, 68mmol), triethylamine (11.5mL, 81.9mmol) were dissolved in tetrahydrofuran (100mL), in Isobutyl chloroformate (10mL, 79mmol) was added dropwise in ice bath, stirred for half an hour in ice bath, sodium borohydride (7.8g, 205mmol), water (3mL, slowly added dropwise) were added successively, and the mixture was continued under ice bath Stir for 2 hours. LC-MS monitored the completion of the reaction, added water (150mL) to quench, extracted the aqueous phase (150mL*3) with ethyl acetate, combined the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 1b (20g) as a colorless oil Liquid, 83% yield. ESI-MS(m / z):353.6[M+H] + ; 1 H NMR (500MHz, DMSO-d6) δppm 7.39-7.25 (m, 5H), 7.19 (t, J = 5.2Hz, 1H), 6.43 (d, J = 8.3Hz, 1H), 4.98 (s, 2H), 4.53(t,J=5.4Hz,1H...

Embodiment 2

[0067] Compound 2 was prepared by the following steps:

[0068]

[0069] The first step: N-tert-butoxycarbonyl-N'-benzyloxycarbonyl-D-ornithine 2a (25g, 68mmol), triethylamine (11.5mL, 81.9mmol) were dissolved in tetrahydrofuran (100mL), in Isobutyl chloroformate (10mL, 79mmol) was added dropwise in ice bath, stirred for half an hour in ice bath, sodium borohydride (7.8g, 205mmol), water (3mL, slowly added dropwise) were added successively, and the mixture was continued under ice bath Stir for 2 hours. LC-MS monitored the completion of the reaction, quenched with water (150 mL), extracted the aqueous phase (150 mL*3) with ethyl acetate, combined the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 2b (22 g), a colorless oil Liquid, 91% yield. ESI-MS(m / z):353.6[M+H] + .

[0070] Step 2: Dissolve compound 2b (22g, 56mmol) in dichloromethane (200mL), add hydrogen chloride-1,4-dioxane solution (4N, 75mL, 300mmol), and stir o...

Embodiment 3

[0083] Compound 3 was prepared by the following steps:

[0084]

[0085] Step 1: Dissolve compound 2j (200mg, 0.48mmol) in N,N-dimethylformamide (4mL), and add compound 3a (200mg, 1mmol) and cesium carbonate (326mg, 1mmol) sequentially. The reaction mixture was stirred overnight at 70°C. After the reaction was monitored by LC-MS, water (20 mL) was added, and the aqueous phase (50 mL*3) was extracted with ethyl acetate. The organic phase was combined and separated by silica gel column chromatography to obtain compound 3b (235 mg ), white solid, yield 84%. ESI-MS(m / z):576.6[M+H] + .

[0086] The second step: compound 3b (235 mg, 0.4 mmol) was dissolved in methanol (20 mL), and ammonia water (8 mL) was added. Then sodium dithionite (350 mg, 2 mmol) was dissolved in water (6 mL), and the reaction solution was slowly added at room temperature, and the stirring was continued for half an hour. LC-MS monitored the completion of the reaction, added water (50 mL), extracted the a...

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PUM

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Abstract

The present disclosure provides compounds of Formula (III) and pharmaceutical compositions thereof, and methods of using compounds of Formula (III) to prevent and / or treat immune-related disorders.

Description

[0001] This application is a divisional application, the Chinese patent application number of the parent case is 201980005220.4, and the application date of the parent case is August 22, 2019. [0002] This application claims the priority of the following patent applications: (1) the priority of the Chinese patent application 201810996231.0 with the title of "A Highly Active STING Protein Agonist" submitted to the China Patent Office on August 29, 2018, and (2) ) priority of the Chinese patent application 201811407028.1 submitted to the China Patent Office on November 23, 2018 with the title of "A Highly Active STING Protein Agonist", the contents of which are incorporated herein by reference in their entirety. technical field [0003] The invention relates to a heterocyclic compound, in particular to a highly active STING protein agonist and its application. Background technique [0004] A positive response to immunotherapy often relies on the interaction of tumor cells wit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/06A61P35/00
CPCC07D498/06A61P35/00A61P31/08A61K45/06C07D487/06C07D498/22C07D471/06C07D519/00A61K31/5383A61K31/675A61K31/4985A61K31/541A61K31/553A61K31/551A61K2300/00A61P31/12A61P37/06A61P25/28A61K31/437A61K31/5386
Inventor 陈宇锋陈凯旋李磐刘灿丰王骥邱庆崇路杨
Owner ADLAI NORTYE BIOPHARMA CO LTD