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CD47/SIRP (signal regulatory protein) alpha blocking agent and application thereof

A technology for use, α protein, applied in the field of compounds that block the interaction between SIRPα protein and CD47, which can solve the problems of easy immunogenicity and high production cost

Active Publication Date: 2019-03-05
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are no reports of small-molecule blockers targeting SIRPα, and large-molecule antibody drugs have the disadvantages of high production costs and easy immunogenicity.

Method used

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  • CD47/SIRP (signal regulatory protein) alpha blocking agent and application thereof
  • CD47/SIRP (signal regulatory protein) alpha blocking agent and application thereof
  • CD47/SIRP (signal regulatory protein) alpha blocking agent and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0157] Example 1. Synthesis of 1.1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline ethyl acetate (D3)

[0158] 1. The synthetic route of 1.1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline ethyl acetate (D3) is as follows:

[0159]

[0160] Experimental steps:

[0161] 1) Synthesis of ethyl 2,4-dichloro-5-fluorobenzoylacetate

[0162]

[0163] First put NaH (466mg, 24.3mmol) into a 100mL dry three-neck flask, add anhydrous THF and diethyl carbonate to dissolve, protect with argon, stir at 45°C for 30 minutes, slowly add 2,4-di Chloro-5-fluoroacetophenone (1g, 4.9mmol) in diethyl carbonate solution, keep the internal temperature at 50-55°C, drop it, stir for 5 hours, the reaction is complete, pour the reaction solution into ice water containing acetic acid , extracted with ethyl acetate, and passed through a silica gel column (PE:DCM=15:1) to obtain 0.65 g of a yellow oil with a yield of 48%. The input amount obtained 4.1...

Embodiment 2

[0173] Example 2. Synthesis of 1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline acetic acid methyl ester (D2)

[0174]

[0175] Put the above raw material drug (500mg, 1.2mmol) in a 50mL reaction bottle, add methanol 10mL and concentrated sulfuric acid 1.5mL, heat to reflux, and the reaction is complete after 5 hours. Under ice bath, add NaOH to neutralize to pH = 8-9, add DCM to extract, and spin dry the organic phase to obtain 360 mg of white solid with a yield of 76.1%. 1 H NMR (400MHz, DMSO-d 6 )δ8.39(s,1H),7.80(d,J=13.6Hz,1H),7.76(dd,J1=4.8Hz,J2=4Hz,2H),7.52(t,J=8.8Hz,2H), 6.26 (d, J=7.2Hz, 1H), 3.72 (s, 3H), 2.88-2.86 (m, 4H), 2.78-2.77 (m, 4H).

Embodiment 3

[0176] Example 3.1-Synthesis of 1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline acetamide (D4)

[0177]

[0178] Put the methyl ester product (50mg, 0.13mmol) in a 25mL reaction flask, add n-butylamine to dissolve, stir at 66°C, and complete the reaction in 6 hours. The solvent was spin-dried to obtain 40mg of a yellow product with a yield of 72.7%. 1 H NMR (400MHz, CD 3 OD) δ8.63(s, 1H), 7.95(d, J=13.6Hz, 1H), 7.64(dd, J1=4.8Hz, J2=4.4Hz, 2H), 7.45(t, J=8.4Hz, 2H ),6.42(d,J=7.2Hz,1H),3.43(t,J=6.8Hz,2H),3.09-3.07(m,4H),3.01-2.98(m,4H),1.65-1.58(m, 2H), 1.50-1.41 (m, 2H), 0.98 (t, J=7.6Hz, 3H). HRMS(ESI)(m / z):[M+H]+calcd for C 24 h 27 f 2 N 4 o 2 , 441.2102; found, 441.2100.

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PUM

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Abstract

The invention relates to a compound of a blocking agent for CD47 / SIRP alpha interaction, in particular to a compound as shown in a formula I, a medicine composition containing the compound as shown inthe formula I and an application of the compound to treatment of CD47 / SIRP alpha interaction mediated diseases and preparation of a medicine for treating the CD47 / SIRP alpha interaction mediated diseases.

Description

technical field [0001] The invention relates to the field of medicinal chemistry; specifically, the invention relates to a compound for blocking the interaction between SIRPα protein and CD47 and its application. Background technique [0002] Signal regulatory protein α (Signal regulatory protein α, SIRPα) is a class of widely expressed glycoprotein molecules, also known as the protein tyrosine phosphatase substrate containing the SHP-2 domain, and belongs to the transmembrane protein of the immunoglobulin superfamily. SIRPα contains Immune-receptor tyrosin-based inhibitory motif (ITIM) in cells. When cells are stimulated by growth factors, SIRPα can be phosphorylated by ITIM to inhibit the activity of corresponding growth factors. SIRPα can be widely expressed on the surface of myeloid cells such as macrophages and dendritic cells. CD47, also known as Integrin-associated protein (IAP), belongs to the membrane protein of the immunoglobulin superfamily, and is mainly highly ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07D215/56C07D471/04C07D491/056C07D455/04C07D498/06A61K31/55A61K31/496A61K31/4709A61K31/47A61K31/4741A61K31/4375A61K31/5383A61K31/5377A61P35/00A61P35/02A61P31/12A61P31/14A61P31/20A61P31/16A61P31/22A61P31/04A61P31/10A61P29/00A61P19/02A61P21/04A61P37/06A61P7/06
CPCC07D215/56C07D401/04C07D455/04C07D471/04C07D491/056C07D498/06A61K31/4375A61K31/47A61K31/4709A61K31/4741A61K31/496A61K31/5377A61K31/5383A61K31/55A61P7/06A61P19/02A61P21/04A61P29/00A61P31/00A61P31/04A61P31/10A61P31/12A61P31/14A61P31/16A61P31/20A61P31/22A61P35/00A61P35/02A61P37/06C07D498/00Y02A50/30
Inventor 李洪林朱丽丽徐玉芳赵振江全丽娜王婉琦温迪莎
Owner EAST CHINA UNIV OF SCI & TECH
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