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Protein phosphatase 5-based phosphatase recruitment chimera (PHORCs) compound as well as preparation method and medical application thereof

A protein phosphatase and compound technology, applied in the fields of drug combination, organic chemistry, anti-tumor drugs, etc., can solve the problems of accelerated disease process, abnormally active function, etc.

Active Publication Date: 2021-06-29
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, hyperphosphorylation of many disease-causing proteins can lead to abnormal activation of their functions, accelerating disease progression

Method used

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  • Protein phosphatase 5-based phosphatase recruitment chimera (PHORCs) compound as well as preparation method and medical application thereof
  • Protein phosphatase 5-based phosphatase recruitment chimera (PHORCs) compound as well as preparation method and medical application thereof
  • Protein phosphatase 5-based phosphatase recruitment chimera (PHORCs) compound as well as preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Preparation of N-(6-(1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl)-4-palmitoylaminobenzamide (DDO-3701).

[0038] synthetic route:

[0039]

[0040] Compound 1 (50 mg, 0.16 mmol) was dissolved in 3 ml N, N-dimethylformamide, palmitic anhydride (194 mg, 0.39 mmol), N, N-diisopropylethylamine (61 mg, 0.46 mmol) were added, Under the protection of nitrogen, react at 70°C for 5 hours; filter with suction and concentrate the filtrate; add 5ml of ethyl acetate for slurry, filter with suction, rinse with 2ml of ethyl acetate; dry the filter cake at 50°C to obtain 20mg of light yellow solid powder, yield 23 %. 1 H NMR (300MHz, DMSO-d 6 )δ10.21(s, 1H), 9.54(s, 1H), 8.60(s, 1H), 7.85(d, J=9.4Hz, 2H), 7.81(d, J=9.0Hz, 2H), 7.63( d, J=8.6Hz, 2H), 7.60(d, J=9.5Hz, 1H), 7.40(s, 1H), 5.87(s, 2H), 2.38(t, J=7.3Hz, 2H), 1.63( p, J=7.1Hz, 2H), 1.26(s, 26H), 0.90-0.84(m, 3H). HRMS (ESI): found557.35957 (C 33 h 44 N 6 o 2 [M+H] + , requires557.35985).

Embodiment 2

[0042]N-(6-(1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl)-4-(2-(2-(2-(palmitoylaminoethoxy)ethyl Preparation of oxy)acetamido)benzamide (DDO-3702).

[0043] synthetic route:

[0044]

[0045] (1) N-(6-(1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl)-4-(2-(2-(2-(2-palmitoylamino Preparation of ethoxy)ethoxy)acetamido)benzamide (3).

[0046] Dissolve compound 2 (500mg, 1.25mmol) in 15ml of thionyl chloride, add 2 drops of N,N-dimethylformamide, and reflux at 80°C for 3 hours; after concentrating the reaction solution, add 5ml of N,N-dimethylformamide Amide, make the N, N-dimethylformamide solution of the acid chloride for subsequent use; under ice-cooling, add the N, N-dimethylformamide solution (5ml) of the acid chloride dropwise under ice-cooling N,N-dimethylformamide solution, react overnight at room temperature; add saturated sodium bicarbonate solid to adjust the pH of the reaction solution to alkaline; concentrate the reaction solution, column chromatography purification...

Embodiment 3

[0050] N-(6-(1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl)-4-(6-palmitoylaminocaproylamido)benzamide (DDO-3703) preparation.

[0051] synthetic route:

[0052]

[0053] (1) tert-butyl (6-((4-((6-(1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl)carbamoyl)phenyl)amino) - Preparation of 6-oxyhexyl) carbamate (4).

[0054] Dissolve tert-butoxycarbonyl 6-aminocaproic acid (727mg, 3.14mmol) and N,N'-carbonyldiimidazole (510mg, 3.14mmol) in 6ml of anhydrous N,N-dimethylformamide, ice-bath , stirred for 30 minutes; compound 1 (1g, 3.14mmol) was added dropwise in N,N-dimethylformamide solution, and reacted at room temperature for 4 hours; the reaction solution was concentrated and purified by column chromatography (eluent: ethyl acetate) ; Obtain 100 mg of yellow solid powder, yield 6%. 1 H NMR (300MHz, DMSO-d 6 )δ10.24(s, 1H), 9.45(s, 1H), 8.16(s, 1H), 7.81(d, J=8.4Hz, 2H), 7.70(s, 1H), 7.64(d, J=8.5 Hz, 4H), 7.56(d, J=9.4Hz, 1H), 7.16(s, 1H), 6.84(s, 1H), 5.87(s, 2H), 2.94(q, J=7...

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Abstract

The invention discloses a protein phosphatase 5-based phosphatase recruitment chimera (PHORCs) compound as shown in a formula I defined in the description as well as a preparation method and medical application thereof. The compound disclosed by the invention can be used for dephosphorylating p-ASK1 in gastric cancer MKN45 cells to different degrees, and can be used for remarkably inhibiting the activity of the ASK1 in vitro and in vivo, so that cycle-associated proteins are selectively reduced, and the compound has a cell proliferation inhibiting effect. The cell proliferation inhibition effect of the compound DDO-3711 is obviously better than that of an ASK1 small-molecule inhibitor TCASK10 group and a combined administration group of the ASK1 small-molecule inhibitor TCASK10 and a PP5 small-molecule activator P5SA-1, and the compound can be used for preparing medicines for treating related diseases such as gastric cancer and colon cancer.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a phosphatase-recruiting chimera (PHORCs) compound that recruits protein phosphatase 5 (PP5) to target apoptosis signal-regulated kinase 1 (ASK1) dephosphorylation, its preparation method and medicine use. Background technique [0002] The post-translational modification of proteins is responsible for the regulation of various physiological processes in the human body, including ubiquitination, phosphorylation, glycosylation, esterification, etc. Because of the existence of different post-translational modification processes, the activity, localization, stability and physiological functions of proteins are strictly regulated. Many diseases are also accompanied by abnormalities in the function of protein post-translational modification, so it is an effective means of regulation to intervene in the process of protein post-translational modification. PROTACs, which have been hot...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07K7/06A61P35/00A61P35/02
CPCC07D471/04A61P35/00A61P35/02C07K7/06
Inventor 尤启冬王磊张秋月张恒恒徐晓莉郭小可姜正羽陆朦辰
Owner CHINA PHARM UNIV
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