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Indoline compounds and preparing method and application thereof

A compound, indoline technology, applied in the field of medicine, can solve the problems of difficult preparation and purification, high production cost, immunogenic toxicity and side effects, etc.

Active Publication Date: 2019-05-21
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although monoclonal antibody drugs have shown advantages in clinical treatment, there are also obvious defects such as difficulty in preparation and purification, high production costs; easy to be decomposed by proteases, and short half-life; they cannot be taken orally and can only be administered by injection; the immunogen of monoclonal antibody Sex causes serious toxic side effects

Method used

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  • Indoline compounds and preparing method and application thereof
  • Indoline compounds and preparing method and application thereof
  • Indoline compounds and preparing method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] Example 1: (4-(((2-hydroxyethyl)amino)methyl)phenyl)(4-phenylindolin-1-yl)formyl

[0078] Step 1: 4-Phenyl-1H-indole

[0079] At room temperature, 4-bromo-1H-indole (10g, 51.29mmol), phenylboronic acid (6.26g, 51.29mmol), tetrakistriphenylphosphine palladium (1.78g, 1.54mmol), potassium carbonate (21.23g, 153.94 mmol) was dissolved in a mixed solvent of dioxane and water (volume ratio 4:1, 250 mL). Under the protection of nitrogen, the temperature was raised to 60° C. for 10 hours. Cool to room temperature, suction filter with celite, extract the filtrate with dichloromethane, wash the organic layer with saturated brine, concentrate under reduced pressure, and separate by column chromatography to obtain 6.66 g of white solid with a yield of 67.2%.

[0080] Step 2: 4-Phenylindoline

[0081]

[0082] At room temperature, 4-phenyl-1H-indole (1.5g, 7.77mmol) was dissolved in glacial acetic acid (9mL), and sodium cyanoborohydride (1.47g, 23.32mmol) was added slowly, ...

Embodiment 2

[0091] Example 2: N-(2-((4-(4-phenylindoline-1-formyl)benzyl)amino)ethyl)acetamide

[0092]

[0093] ESI-MS m / z:414.2[M+H] + ; 1 H NMR (600MHz, DMSO-d 6 )δ7.81(s,1H),7.54(d,J=7.8Hz,2H),7.46(dd,J=11.5,6.0Hz,6H),7.41–7.35(m,1H),7.29(s,1H ), 7.09(d, J=7.0Hz, 1H), 4.00(t, J=8.0Hz, 2H), 3.76(s, 2H), 3.18–3.09(m, 4H), 2.56(t, J=6.4Hz ,2H),1.79(s,3H),1.23(s,1H).

Embodiment 3

[0094] Example 3: (S)-(4-((2-(Hydroxymethyl)pyrrolidin-1-yl)methyl)phenyl)(4-phenylindoline-1-yl)formyl

[0095]

[0096] ESI-MS m / z:413.2[M+H] + ;

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PUM

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Abstract

The invention belongs to the technical field of medicines, and discloses indoline compounds having a general formula I in which substitutes R1, R2, R3, R4 and R5 are defined in the specification and apreparing method and application thereof. The indoline compounds, stereisomers thereof, pharmaceutically acceptable salts thereof and pharmaceutical compositions containing the compounds can be usedfor preparing medicines treating diseases related to PD-1 / PD-L1 protein / protein interactions, such as cancer and virus infection.

Description

Technical field: [0001] The invention belongs to the technical field of medicine, and relates to indoline compounds and their preparation methods and applications, in particular to indoline compounds, their preparation methods and pharmaceutical compositions containing the compounds. The present invention also relates to such compounds and their stereoisomers and pharmaceutically acceptable salts in the preparation of drugs for treating diseases related to PD-1 / PD-L1 signaling pathways, such as cancer, infectious diseases, and autoimmune diseases the use of. Background technique: [0002] Immunotherapy is a hot field of tumor treatment in recent years, and was rated as the top ten scientific breakthroughs by "Science" in 2013. Programmed death 1 (PD-1) is a T cell surface receptor that produces negative immunoregulatory signals when it binds to programmed death ligand 1 (PD-L1), thereby inhibiting T cell activation , proliferation and the release of cytokines such as inter...

Claims

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Application Information

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IPC IPC(8): C07D209/08C07D403/10C07D405/12C07D401/10C07D405/04C07D405/14C07D401/12C07D401/14A61K31/404A61K31/4439A61K31/4545A61K31/454A61P35/00A61P31/00A61P37/00A61P35/02A61P31/04A61P31/12A61P37/06A61P37/02A61P25/00A61P19/02A61P17/06A61P9/00A61P3/10A61P1/00A61P7/06
Inventor 秦铭泽宫平赵燕芳刘亚婧
Owner SHENYANG PHARMA UNIVERSITY
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