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Programmed death receptor 1 gene inhibitor and its preparation method and application

A programmed death and receptor technology, applied in the direction of non-central analgesics, anti-inflammatory agents, antiviral agents, etc., can solve the problems of high storage conditions, unfavorable transportation and storage, and low yield

Active Publication Date: 2020-03-06
SHENZHEN INST OF ADVANCED TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The production process of antibody drugs is complex and the output is low, which is not conducive to large-scale production; antibody drugs are proteins with poor stability and high storage conditions, which are not conducive to transportation and storage

Method used

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  • Programmed death receptor 1 gene inhibitor and its preparation method and application
  • Programmed death receptor 1 gene inhibitor and its preparation method and application
  • Programmed death receptor 1 gene inhibitor and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] The preparation method of embodiment 1 compound 1A

[0077] (a) Resin swelling: Add 400mg Fmoc-protected phenylhydrazine resin (0.66mmol / g, 0.264mmol) and 3mL CH to a 10mL solid phase reactor 2 Cl 2 , the resin was swollen for 30min, and the CH 2 Cl 2 ,spare;

[0078] (b) Remove the Fmoc protecting group: add 3mL of 20% piperidine / DMF solution to the resin after step (a) swelling, N 2 Bubble and mix well, after 10min, remove the solvent, then add 3mL 20% piperidine / DMF solution, N 2 Bubble and mix well, after 10min, wash the resin with DMF (4×3mL), then wash the resin with 3mL anhydrous DMF, set aside;

[0079](c) Amino acid condensation: 4-tert-butoxycarbonylamino-1-methyl-1H-pyrrole-2-carboxylic acid (254 mg, 1.056 mmol) and triphosgene (BTC, 128 mg, 0.433 mmol) were dissolved in 2 mL of anhydrous THF, slowly add collidine (collidine, 488μL, 3.696mmol) dropwise to the solution, the reaction immediately produces a large amount of white precipitate, after adding t...

Embodiment 2

[0101] The preparation method of embodiment 2 compound 1B

[0102] The peptide loaded on the phenylhydrazine resin shown in formula (7) was prepared in the same steps as in Example 1,

[0103]

[0104] Take out the resin obtained above, add 1mL DMF, 200μL N,N-bis(3-aminopropyl)methylamine, shake at 90°C for 1h, cool to room temperature, filter the resin, and wash with 20mL CH 2 Cl 2 The resin was washed; the organic phase was concentrated and the residue was purified by semi-preparative HPLC: 10% acetonitrile-H 2 O (containing 1% TFA) isocratic elution 5min, 10% to 100% acetonitrile-H 2 O (containing 1% TFA) gradient elution for 25min, retention time T R =16min, the product was collected and freeze-dried to obtain a light yellow solid, which was set aside;

[0105] Dissolve 4 mg (3 μmol) of the above solid in 0.5 mL of anhydrous DMF, add Horst acid derivative Ht-2 (2.7 mg, 6 μmol), PyBOP (3.1 mg, 6 μmol) and DIEA (5 μL, 30 μmol), shake at room temperature Reaction 2h, ...

Embodiment 3

[0113] The preparation method of embodiment 3 compound 1C

[0114] The peptide loaded on the phenylhydrazine resin shown in formula (7) was prepared in the same steps as in Example 1,

[0115]

[0116] Take out the resin obtained above, add 1mL DMF, 200μL N,N-bis(3-aminopropyl)methylamine, shake at 90°C for 1h, cool to room temperature, filter the resin, and wash with 20mL CH 2 Cl 2 The resin was washed; the organic phase was concentrated and the residue was purified by semi-preparative HPLC: 10% acetonitrile-H 2 O (containing 1% TFA) isocratic elution 5min, 10% to 100% acetonitrile-H 2 O (containing 1% TFA) gradient elution for 25min, retention time T R =16min, the product was collected and freeze-dried to obtain a light yellow solid, which was set aside;

[0117] Dissolve 4 mg (3 μmol) of the above solid in 0.5 mL of anhydrous DMF, add folic acid FA (1.8 mg, 6 μmol), PyBOP (3.1 mg, 6 μmol) and DIEA (5 μL, 30 μmol), shake at room temperature for 2 h, use semi-preparati...

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PUM

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Abstract

The invention provides a programmed death acceptor 1 (PD1) gene inhibitor and a preparation method and application thereof. Specifically, disclosed is a compound for inhibiting expression of the programmed death acceptor 1 and pharmaceutically-acceptable salt. The compound has a structure shown as the formula I in the description. In the formula, A is selected from C or N, R1 is selected from H, CH3, (CH2)3-N(CH3)2, (CH2)2-N(CH3)2, CH2-N(CH3)2, and (CH2)3-N(CH3)CH2CH2NHR3, R2 is selected from H and CH3, and R3 is selected from H and CH3. The polyamide molecules disclosed in the invention belong to polypeptide micromolecules and are available for chemical synthesis. The method is beneficial for massive production and provides more methods for inhibition of PD1 functions.

Description

technical field [0001] The invention relates to the field of medicines, in particular to an expression inhibitor of programmed death receptor 1. Background technique [0002] PD-1 (programmed death receptor 1) is an immune checkpoint protein, a type I transmembrane protein, composed of 268 amino acids encoded by the PDCD1 gene, and an important member of the CD28 / CTLA4 family. The main function of PD-1 is to suppress the activity of T cells when an immune response occurs. Its protein structure is divided into three parts: the extracellular immunoglobulin variable region, the transmembrane domain and the intracellular domain; motif) containing phosphorylation sites, among which the ITSM motif is related to the inhibitory function of PD-1. When the PD-1 molecule on the surface of T cells binds to the receptor PDL-1 / PDL-2 on the surface of antigen-presenting cells, ITSM is phosphorylated, and then the phosphatases SHP-1 and SHP-2 bind to ITSM, directly leading to Signaling m...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/14C07D487/04A61K31/4178A61K31/496A61K31/519A61P35/00A61P35/02A61P31/12A61P37/06A61P29/00A61P5/14A61P17/00A61P19/02A61P21/04A61P3/10
CPCC07D403/14C07D487/04Y02P20/55
Inventor 粟武王伟潘正银成哲宏武春雷房丽晶
Owner SHENZHEN INST OF ADVANCED TECH
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