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Resorcinol formaldehyde derivative containing substituted biphenyl and application thereof

A technology of resorcinol methyl ether and derivatives, applied in drug combination, nitrile/isonitrile active ingredients, organic chemistry, etc., can solve the problem of unsatisfactory PD-1/PD-L1 inhibitory effect

Inactive Publication Date: 2019-05-17
SOUTHERN MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the inhibitory effect of the compounds disclosed in the above PCT patent application on PD-1 / PD-L1 is not satisfactory, and the IC50 detected by HTRF method is only 146nM

Method used

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  • Resorcinol formaldehyde derivative containing substituted biphenyl and application thereof
  • Resorcinol formaldehyde derivative containing substituted biphenyl and application thereof
  • Resorcinol formaldehyde derivative containing substituted biphenyl and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Embodiment 1 (preparation C1)

[0047] The structural formula is The preparation method of the compound consists of the following steps:

[0048] Step 1: Preparation of Compound V

[0049]

[0050] 4g 5-chloro-2,4-dihydroxybenzaldehyde (compound VII) and 5g (3-(2,3-dihydrobenzo[b][1,4]dioxan-6-yl)- 2-methylphenyl)methanol (compound VI), 8.4g triphenylphosphine (PPh 3 ) was added in 50ml of anhydrous tetrahydrofuran, stirred for 15 minutes, 8.2mL of diisopropyl azodicarboxylate (DIAD) was dripped into the reaction solution in small quantities in batches, reacted for 10 hours, monitored by thin layer chromatography (TLC), and the reaction ended Afterwards, the reaction solution was poured into 100mL water, extracted with ethyl acetate (100mL×5), allowed to stand for liquid separation, and the organic phase was washed with 5% sodium bicarbonate (NaHCO 3 ) (80mL×3), washed with saturated brine (80mL×3), then dried with anhydrous magnesium sulfate, filtered with suct...

Embodiment 2

[0062] Embodiment 2 (preparation C2)

[0063] The structural formula is The preparation method of the compound consists of the following steps:

[0064] Step 1: Preparation of C2

[0065]

[0066]Add 40mg of compound III and 50mg of (R)-pyrrolidine-3-carboxylic acid, 2 drops of glacial acetic acid into 5ml of anhydrous methanol, stir, heat to 60°C, react for 4 hours, then add 40mg of sodium cyanoborohydride (NaBH 3 CN), reacted at room temperature for 12 hours, monitored by TLC, after the reaction was completed, the solvent was spin-dried, and the reactant was poured into 100mL water, extracted with ethyl acetate (20mL×3), left to separate liquids, and the organic phase was respectively washed with 5% NaHCO 3 (20mL×3), washed with saturated brine (20mL×3), then dried over anhydrous magnesium sulfate, filtered with suction, removed ethyl acetate under reduced pressure, and then performed column chromatography V (dichloromethane): V (methanol) =20:1 yielded 6 mg of whit...

Embodiment 3

[0069] Embodiment 3 (preparation C3)

[0070] The structural formula is The preparation method of the compound consists of the following steps:

[0071] Step 1: Preparation of C3

[0072]

[0073] Add 40mg of compound III and 55mg (R)-3-pyrrolidinol, 2 drops of glacial acetic acid into 5ml of anhydrous methanol, stir, heat to 60°C, react for 4 hours, then add 50mg of sodium cyanoborohydride (NaBH 3 CN), reacted at room temperature for 12 hours, monitored by TLC, after the reaction was completed, the solvent was spin-dried, and the reactant was poured into 100mL water, extracted with ethyl acetate (20mL×3), left to separate liquids, and the organic phase was respectively washed with 5% NaHCO 3 (20mL×3), washed with saturated brine (20mL×3), then dried over anhydrous magnesium sulfate, filtered with suction, removed ethyl acetate under reduced pressure, and then performed column chromatography V (dichloromethane): V (methanol) =20:1 yielded 4 mg of white solid compound ...

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PUM

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Abstract

The invention relates to a resorcinol formaldehyde derivative. The chemical structure of the composition is as shown in a formula (I) below; in the formula (I), R<1> is glycine group, (R)-pyrrolidine-3-formyl, (R)-3-pyrrolidine alcoholic group, (S)-pyrrolidine-3-formyl, (S)-3-pyrrolidine alcoholic group, azetidine-3-carboxylic acid group, (3R, 5S)-5- hydroxy methyl-3-pyrrolidine alcoholic group, trans-4-fluo-3-hydroxy pyrrolidyl, 3-methyl-3-azacyclo-butanol group, 4-(hydroxymethyl) pyrrolidine-3-alcoholic group, N,N-dimethyl ethylenediamine, 3-hydroxy pyrrolidyl, 2-methyl alanine and 3-hydroxy-azacyclo-butyl, and R<2> is hydrogen, 1,4-dioxane. The resorcinol formaldehyde derivative containing substituted biphenyl can inhibit mutual combination of programmed cell death receptor 1 / programmedcell death ligand 1(PD-1 / PD-L1), can be applied to preparing a PD-1 / PD-L1 inhibitor, and the inhibitor has an outstanding effect. (The formula (I) is shown in the description).

Description

technical field [0001] The present invention relates to organic compounds, in particular to a resorcinol methyl ether derivative containing substituted biphenyl, which can inhibit programmed cell death receptor 1 / programmed cell death ligand 1 (PD-1 / PD -L1) can be used to treat tumors. Background technique [0002] Tumor immunotherapy is increasingly used in the field of cancer treatment. At present, the main drugs used in tumor immunotherapy are macromolecular biological antibodies. Among them, inhibitors of PD-1 / PD-L1 (also known as immune checkpoint inhibitors) are effective for a variety of tumors. Therefore, in recent years, PD-1 / PD-L1 has become one of the most attractive targets in the design of anti-tumor drugs, and has also been listed as one of the most promising targets for tumor therapy, so it has attracted much attention. [0003] PD-1 / PD-L1 antibody drugs have the advantages of target-specific specificity and high efficiency in terms of their pharmacodynamic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D319/18C07D405/12C07C255/54C07D207/12C07D205/04C07D207/16A61P35/00
CPCA61K31/277A61P35/00C07C255/54C07D205/04C07D207/12C07D207/16C07D319/18C07D405/12
Inventor 陈建军程斌斌
Owner SOUTHERN MEDICAL UNIVERSITY