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Compound with PD-L1 (programmed death-ligand 1) inhibitory activity as well as preparation method and application of compound

A compound, C1-C4 technology, applied in the direction of organic active ingredients, active ingredients of heterocyclic compounds, organic chemistry, etc., can solve the problems of easy immunogenicity, high production cost, poor stability, etc.

Active Publication Date: 2019-03-01
SHANGHAI ENNOVABIO PHARM CO LTD
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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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  • Compound with PD-L1 (programmed death-ligand 1) inhibitory activity as well as preparation method and application of compound
  • Compound with PD-L1 (programmed death-ligand 1) inhibitory activity as well as preparation method and application of compound
  • Compound with PD-L1 (programmed death-ligand 1) inhibitory activity as well as preparation method and application of compound

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0144] The preparation of formula I compound

[0145]The following reaction schemes exemplify the preparation of compounds of formula I, their stereoisomers or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein each group is as in the embodiment section of the compound of formula I above mentioned. It is to be understood that in the following reaction schemes, combinations of substituents and / or variables within the general formulae are permissible only if such combinations result in stable compounds. It should also be understood that other general formulas, such as general formula (Ia), (Ib), (Ic), (Id), and other formula I compounds specifically disclosed herein can be disclosed herein by those skilled in the art of organic chemistry ( Preparation is carried out by employing appropriately substituted starting materials and modifying the synthesis parameters as necessary using methods well known to those skilled in the art) or known methods.

[0146] Th...

Embodiment 1

[0189] 2,2,2-Trifluoro-N-((6-((3'-(hydroxymethyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl) Methoxy)-2-methoxypyridin-3-yl)methyl)acetamide

[0190]

[0191] tert-Butyl((6-((3'-(hydroxymethyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)-2- Methoxypyridin-3-yl)methyl)carbamate

[0192]

[0193] To intermediate A (50 mg, 0.20 mmol), tert-butyl ((6-chloro-2-methoxypyridin-3-yl) methyl) carbamate (56 mg, 0.20 mmol), cesium carbonate (134 mg , 0.41mmol) in toluene (1mL) was added palladium acetate (4.6mg, 0.02mmol) and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (17.5mg, 0.041mmol ), replaced with nitrogen for 3 minutes and heated and sealed at 110°C overnight. The reaction liquid was filtered with celite, the filtrate was concentrated, and the residue was separated and purified with a preparative plate (petroleum ether / ethyl acetate=4 / 1) to obtain the target compound (20 mg, 20%) as a yellow oil.

[0194] MS(ESI):m / z=479.3[M+H] + .

[0195] 1 H NMR (400MHz, DMSO-...

Embodiment 2

[0202] N-(2-(((6-((3'-(hydroxymethyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)methoxy)- 2-methoxypyridin-3-yl)methyl)amino)ethyl)acetamide

[0203]

[0204] N-(2-(((6-chloro-2-methoxypyridin-3-yl)methyl)amino)ethyl)acetamide

[0205]

[0206] 6-Chloro-2-methoxynicotinaldehyde (400mg, 2.34mmol) and N-(2-aminoethyl) acetamide (240mg, 2.34mmol) were mixed in ethanol (10mL), stirred at reflux for 2 hours and then reduced Concentrated under reduced pressure, the crude product was redissolved in methanol (10 mL), sodium borohydride (89 mg, 2.34 mmol) was added in portions, and the reaction was stirred at room temperature for 2 hours. After the solvent was removed by concentration under reduced pressure, the crude product was purified by silica gel column chromatography (dichloromethane / methanol 50 / 1-10 / 1 elution) to obtain compound 2A (350 mg, 58%).

[0207] 1 H NMR (400MHz, DMSO-d 6 )δ7.78(brS,1H),7.73(d,J=7.6Hz,1H),7.06(d,J=7.56Hz,1H),3.88(s,3H),3.61(s,2H),3.15- 3.10 (m, 2H)...

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PUM

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Abstract

The invention provides a compound with an effect of preventing and treating PD-L1 (programmed death-ligand 1)-related diseases as well as a preparation method and an application of the compound. Specifically, the invention provides the compound shown as the formula I in the description, as well as a stereoisomer, a raceme or a pharmaceutically acceptable salt of the compound, and provides the application of the compound to preparation of drugs for preventing and treating the PD-L1-related diseases.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, in particular, the invention relates to a compound with PD-L1 inhibitory activity, preparation method and application. Background technique [0002] Programmed death-ligand 1 (PD-L1), also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7homolog1, B7-H1), belongs to Tumor necrosis factor superfamily, is a type I transmembrane glycoprotein composed of 290 amino acid residues, including an IgV-like region, an IgC-like region, a transmembrane hydrophobic region and a 30 amino acid intracellular tail, complete molecular weight is 40kDa. PD-L1 mRNA is expressed in almost all tissues, but PD-L1 protein is only continuously expressed in a small number of tissues, including liver, lung, tonsil, and immune amnesty tissues such as eyes and placenta. PD-L1 is also expressed in activated T cells, B cells, monocytes, dendritic cells, macrophages, etc. [0003] The receptor of PD-L1 is PD...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/56C07D401/14C07D417/14C07D407/14C07D409/14C07D471/04C07D213/82C07D213/81C07D207/12C07D211/40C07D211/60C07D213/69C07D231/56C07D519/00C07D207/36A61P35/00A61P35/02A61P35/04A61P31/00A61P37/00A61P25/28A61P31/10A61P31/12A61P31/04A61P31/02A61P31/14A61P31/20A61K31/44A61K31/4439A61K31/443A61K31/4436A61K31/444A61K31/5365A61K31/437A61K31/536A61K31/455A61K31/40A61K31/445A61K31/416A61K31/4985A61K31/53A61K31/506
CPCA61P25/28A61P31/00A61P31/02A61P31/04A61P31/10A61P31/12A61P31/14A61P31/20A61P35/00A61P35/02A61P35/04A61P37/00C07D207/12C07D207/36C07D211/40C07D211/60C07D213/56C07D213/69C07D213/81C07D213/82C07D231/56C07D401/14C07D407/14C07D409/14C07D417/14C07D471/04C07D519/00A61P25/18C07D405/14C07D231/40C07C233/36C07D213/73C07D213/64C07D213/85A61K31/137A61K31/165A61K31/4155A61K31/437A61K31/44A61K31/444A61K31/4545A61K39/12A61K39/245A61K39/29A61K45/06C07C211/03C07C223/02C07D213/84
Inventor 江磊邓建稳路小丽尚珂寿建勇汪兵吴淡宜徐雪丽徐圆张毅郑明伟
Owner SHANGHAI ENNOVABIO PHARM CO LTD
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