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Aromatic ring-containing compound and application thereof

A compound and aromatic ring technology, applied in the field of aromatic ring-containing compounds, can solve the problems of intravenous injection, poor therapeutic activity of solid tumors, and low bioavailability

Active Publication Date: 2019-08-06
GUANGZHOU WELLHEALTH BIO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The technical problem to be solved by the present invention is that the existing PD-1 / PD-L1 monoclonal antibody drug requires intravenous injection and has poor therapeutic activity on solid tumors, Defects such as low bioavailability, therefore, the invention provides a compound containing an aromatic ring and its application

Method used

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  • Aromatic ring-containing compound and application thereof
  • Aromatic ring-containing compound and application thereof
  • Aromatic ring-containing compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0107] The preparation of embodiment 1 compound I-1

[0108] synthetic route:

[0109]

[0110] Sodium cyanoborohydride (314mg, 5mmol), compound I-1-6 (360mg, 1mmol) and compound I-1-7 (410mg, 4mmol) were mixed in DMF (40mL) and acetic acid (1.6mL), in Stir overnight at room temperature, and monitor with TLC until the reaction is complete. After post-treatment, the obtained crude product is purified by preparative LC / MS to obtain compound I-1, and its purity is 98.0% as assessed by LCMS analysis.

[0111] LC-MS: m / z, [M+H] + =446.

Embodiment 2

[0112] The preparation of embodiment 2 compound I-15

[0113] synthetic route:

[0114]

[0115] Step 1: Synthesis of compound I-15B

[0116] Compound I-15A (10.5g, 50mmol) was dissolved in methanol (100ml), cooled in an ice bath to below 5 degrees Celsius, and then sodium borohydride was added in batches. After the addition, it was reacted at room temperature for two hours. TLC showed that the reaction was complete. Add The reaction was quenched with 10 ml of water, and after the methanol was spun off under reduced pressure, saturated ammonium chloride solution (250 ml) was added. Extracted with ethyl acetate (150mL × 3), the combined organic layer was washed with brine, then dried over anhydrous sodium sulfate, filtered to remove the desiccant, precipitated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / Ethyl acetate=10 / 1), to obtain compound I-15B (9.2 g, light yellow liquid), yield: 86.8%.

[0117] The secon...

Embodiment 3

[0126] The preparation of embodiment 3 compound I-16

[0127] synthetic route:

[0128]

[0129] Step 1: Synthesis of Compound I-16B

[0130] Compound I-16A (15.5g, 100mmol) was dissolved in methanol (100ml), and then 2ml of concentrated sulfuric acid was added, and the resulting reaction solution was reacted overnight at 60 degrees Celsius. After TLC showed that the reaction was over, it was cooled to room temperature, and the methanol was spun off. Saturated ammonium chloride solution (250ml) was added. Extracted with ethyl acetate (150mL × 3), the combined organic layer was washed with brine, then dried over anhydrous sodium sulfate, filtered to remove the desiccant, precipitated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / Ethyl acetate=10 / 1 (volume ratio V / V)) to obtain compound I-16B (15 g, light yellow liquid), yield: 89%.

[0131] MS m / z(ESI):169[M+23].

[0132] The second step: synthesis of compound ...

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PUM

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Abstract

The present invention discloses an aromatic ring-containing compound and an application thereof, and provides an aromatic ring-containing compound represented by formula I, and a pharmaceutically acceptable salt, a hydrate, a solvate, a metabolite, a stereoisomer, a tautomer or a prodrug thereof. The compound I provided by the invention has the advantages of high activity, high bioavailability, stable drug, and oral administration.

Description

technical field [0001] The invention belongs to the field of biomedicine, and relates to a compound containing an aromatic ring and its application. Background technique [0002] The PD-1 / PD-L1 signaling pathway is one of the hottest topics in the field of cancer treatment and research. New immunotherapy drugs that have been approved for marketing in the past two years, such as Merck’s Keytruda and Bristol-Myers Squibb’s Opdivo, all target this signaling pathway, using monoclonal antibodies to bind to PD-1 receptors to prevent signal transmission, thereby activating the body’s own immunity The system launches an attack on the tumor. The two new drugs are already approved to treat cancers such as melanoma, and have shown great promise in clinical trials for a number of other cancers. At present, the US FDA has approved three large-molecule PD-L1 inhibitors for marketing, namely Atezolizumab (Tecentriq, for the treatment of bladder cancer and non-small cell lung cancer, whic...

Claims

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Application Information

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IPC IPC(8): C07D213/69C07D405/14C07D405/12C07D211/60C07D401/04A61K31/44A61K31/4545A61K31/4433A61K31/445A61K31/4725A61K31/4439A61K31/5377A61P37/02
CPCC07D213/69C07D405/14C07D405/12C07D211/60C07D401/04A61P37/02
Inventor 许勇黄璐林当胡海
Owner GUANGZHOU WELLHEALTH BIO PHARMA CO LTD
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