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Indoline compound and its preparation method and application

A compound, the technology of indoline, applied in the field of medicine, can solve the problems of only injection administration, immunogenic side effects, decomposition, etc., and achieve the effect of novel chemical structure and high inhibitory activity

Active Publication Date: 2021-08-24
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 compound and its preparation method and application
  • Indoline compound and its preparation method and application
  • Indoline compound and its preparation method and application

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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Abstract

The invention belongs to the technical field of medicine, and discloses indoline compounds having the structure of general formula I and their preparation methods and uses, wherein the substituent R 1 , R 2 , R 3 , R 4 , R 5 have the meaning given in the specification. The indoline compounds and their stereoisomers, pharmaceutically acceptable salts or pharmaceutical compositions containing the compounds can be used to prepare and treat diseases related to PD-1 / PD-L1 protein / protein interaction, such as Drugs for various diseases such as cancer and viral 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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Patent Type & Authority Patents(China)
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