Benzyloxy aromatic ring structure compound and preparation method and application thereof

A compound and alkyl technology, applied in the field of drug synthesis, can solve the problems of poor stability, easy to produce immunogenicity and high production cost

Active Publication Date: 2020-12-04
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, antibody drugs have their own characteristics, such as high production costs, poor stability, need to be administered by injection, and are prone to immunogenicity, etc.

Method used

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  • Benzyloxy aromatic ring structure compound and preparation method and application thereof
  • Benzyloxy aromatic ring structure compound and preparation method and application thereof
  • Benzyloxy aromatic ring structure compound and preparation method and application thereof

Examples

Experimental program
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preparation example Construction

[0241] The present invention also provides a preparation method of a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of general formula (I) or its crystal form, pharmaceutically acceptable salt, hydrate or The solvates are mixed to form a pharmaceutical composition.

[0242] The present invention also provides a treatment method, which includes the step of: administering the compound of general formula (I) described in the present invention, its stereoisomer, enantiomer or pharmaceutically acceptable salt, or administer the pharmaceutical composition of the present invention for inhibiting PD1-PDL1 interaction.

[0243] The preparation of formula I compound

[0244] Methods of preparing compounds of Formula I are described in the following Schemes and Examples. Starting materials and intermediates were purchased from commercial sources, prepared by known procedures, or otherwise illustrated. In some cases, ...

Embodiment 1

[0380] Example 1: Synthesis of N-(3-((2-((3-cyanobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4] Dioxin-6-yl)-2-methylbenzyl)oxy)-5-methylbenzyl)(methyl)amino)propyl)but-2-yneamide (ZA89)

[0381]

[0382] Step 1: Synthesis of (3-bromo-2-methylphenyl)methanol (ZA01)

[0383] Dissolve 3-bromo-2-methylbenzoic acid (5.0g, 23.4mmol) in dry THF (tetrahydrofuran) (100ml), cool down in an ice-water bath, and then add LiAlH 4 (1.06g, 27.9mmol), react overnight at room temperature. After the reaction, the reaction solution was poured into saturated NaHCO 3 Quenched in , filtered, rinsed with dichloromethane (DCM), and the organic phase was dried with anhydrous sodium sulfate and then spin-dried to obtain the target product (2.0 g). 1 H NMR (400MHz, Chloroform-d) δ7.53(dd, J=1.2,8.0Hz,1H),7.36–7.29(m,1H),7.07(t,J=7.8Hz,1H),4.72(s, 2H), 2.43(s, 3H).

[0384] Step 2: Synthesis of (3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenyl)methanol (ZA03)

[0385] Dissolve ZA01 (198mg, 1....

Embodiment 2

[0394] Example 2: Synthesis of 3-((5-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl )oxy)-4-methyl-2-((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)phenoxy)methyl ) Benzonitrile (ED01)

[0395]

[0396] ZA80 (0.08mmol, 40mg), D-glucosamine (0.33mmol, 60mg) were dissolved in THF (4mL) and methanol (4mL), stirred at room temperature for 1 hour, and NaBH was added 4 (80mg, 2.1mmol), stirred overnight. After the reaction was completed, it was quenched with dilute hydrochloric acid, concentrated to obtain the crude product, and the crude product was purified by reverse liquid phase to obtain the trifluoroacetate (3.1 mg) of the target compound. 1 H NMR (400M, MeOD-d4): 7.90(s, 1H), 7.82(d, J=7.98Hz, 1H), 7.71(d, J=7.84Hz, 1H), 7.59(t, J=7.70Hz, 1H), 7.34(dd, J=7.07, 1.64Hz, 1H), 7.24-7.14(m, 3H), 6.88(d, J=8.03Hz, 1H), 6.80(s, 1H), 6.76-6.71(m ,2H),5.30(s,3H),5.15(s,3H),4.28(s,4H),4.21(q,J=12.34Hz,2H),4.11-4.05(m,1H),3.85(dd, J=4.44,1.36Hz,1H),3.77(dd,J...

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Abstract

The invention provides a benzyloxy aromatic ring structure compound represented by a general formula (I), a stereoisomer, an enantiomer or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the same, and uses thereof. The compound shown in the general formula (I) can be used for preparing a small-molecule inhibitor of PD1/PDL1 interaction, and can be used for preventing and/or treating diseases related to PD1/PDL1 interaction, especially cancers, such as non-small cell lung cancer, small cell lung cancer, melanoma, head and neck cancer, kidney cancer, bladder cancer, local advanced or metastatic urothelial cancer, breast cancer, cervical cancer, metastatic Merkel cell cancer, prostate cancer, liver cancer, intestinal cancer, stomach cancer, multiple myeloma, mantle cell lymphoma, diffuse large B cell lymphoma, liver cancer, hodgkin lymphoma, chronic lymphocytic leukemia, squamous cell carcinoma and the like.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and specifically relates to a class of compounds with a benzyloxy aromatic ring structure, stereoisomers, enantiomers or pharmaceutically acceptable salts thereof, a preparation method and application thereof. Background technique [0002] Under normal circumstances, immune cells in the human body, such as CD4 / CD8+ T cells, have a killing effect on cancer cells, so that people with normal immune functions can avoid cancer. However, after the PD-1 (Programmed death 1) receptor on the surface of the T cell membrane is bound by the PD-L1 (Programmed death-ligand 1) protein expressed by the tumor cell, the immune function of the T cell is severely inhibited, and the immune function cannot be performed normally. Its ability to inhibit cancer cell proliferation is severely impaired (the New England Journal of Medicine, 2012, 366, 2517). Using the PD-L1 protein of tumor cells to bind to the PD-1...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D319/18C07F9/655C07D407/12C07D405/12C07C255/54C07D213/69C07D213/85C07D405/14A61K31/357A61K31/665A61K31/497A61K31/4433A61K31/277A61K31/44A61K31/444A61P35/00A61P35/02A61P31/04A61P31/10A61P31/18A61P31/14A61P31/20A61P31/22A61P31/16
CPCA61P31/04A61P31/10A61P31/14A61P31/16A61P31/18A61P31/20A61P31/22A61P35/00A61P35/02C07C255/54C07D213/69C07D213/85C07D319/18C07D405/12C07D405/14C07D407/12C07F9/65522A61K31/047A61K31/277A61K31/357A61K31/36A61K31/44A61K31/4433A61K31/444A61K31/4545A61K31/497A61K31/665C07D213/84C07D319/10C07D413/12C07D413/14C07F9/655C07H15/18C07H15/26
Inventor 赵玉军朱棣周飞龙严子琴刘成龙张希晨
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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