Compound for degrading TGF-beta1 through targeted ubiquitination, and preparation method and application thereof

A technology of TGF- and compounds, applied in the fields of organic chemistry, drug combination, respiratory diseases, etc.

Active Publication Date: 2020-09-11
ZHEJIANG MEDICAL COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At this stage, people can only reduce the side effects of pirfenidone by reducing the dose or stopping treatment
There is no report on the intervention of IPF with compounds based on PROTAC technology

Method used

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  • Compound for degrading TGF-beta1 through targeted ubiquitination, and preparation method and application thereof
  • Compound for degrading TGF-beta1 through targeted ubiquitination, and preparation method and application thereof
  • Compound for degrading TGF-beta1 through targeted ubiquitination, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Example 1 Preparation of TGF-β small molecule ligand

[0043] 1-(4-hydroxyl-phenyl)-5-methyl-1H-pyridin-2-one (II, R is CH 3 )

[0044] According to the method disclosed in the Chinese invention patent with the application number 200810201706.9, it is prepared. m.p.167-169°C. 1 HNMR (δ, CDCl 3 ): 7.34-7.37 (m, 1H), 7.14 (s, 1H), 6.97-7.00 (d, 2H), 6.68 (s, 1H), 6.62-6.66 (m, 2H), 2.12 (s, 3H).

[0045]

Embodiment 2

[0046] Example 2 Preparation of E3 Ligase Ligand

[0047] (1) Hydroxythalidomide (IV a)

[0048]

[0049] 10.0 g (0.06 mol) of 3-hydroxyphthalic anhydride, 10.0 g (0.06 mol) of 3-amino-2,6-piperidinedione hydrochloride and 100 mL of toluene were successively added into the three-necked flask. Under the protection of nitrogen, the reaction was heated under reflux for 12 hours, a gray solid was precipitated, and the reaction was monitored by TLC. Cool to room temperature, suction filter and dry to obtain 12.0 g off-white powder. Yield 73%. HRMS m / z(ESI)calcd for C 13 h 10 N 2 o 5 [M+Na] + :297.0487; found: 297.0489. 1 H NMR (400MHz, DMSO-d 6 )δ11.21(s,1H),11.13(s,1H),7.66(dt,J=11.7,5.9Hz,1H),7.37-7.30(m,1H),7.27(d,J=8.4Hz,1H ),5.10(dd,J=12.8,5.4Hz,1H),3.05-2.78(m,1H),2.59(ddd,J=21.9,14.5,11.0Hz,2H),2.16-1.87(m,1H). 13 C NMR (100MHz, DMSO-d 6 ) δ 173.30, 170.51, 167.65, 166.30, 155.93, 136.84, 133.61, 124.47, 124.02, 114.80, 49.11, 31.44, 22.51.

[0050] (2) Propa...

Embodiment 3

[0053] The preparation of embodiment 3 connecting chain

[0054] (1) Azidodiethylene glycol p-toluenesulfonate (1)

[0055]

[0056] Add 415 mg (1 mmol) of diethylene glycol di-p-toluenesulfonate and 65 mg (1 mmol) of sodium azide into the three-necked flask respectively. Add 10 mL of anhydrous DMF, and stir at 60° C. for 4 h under nitrogen protection. TLC monitored the end of the reaction. Cool to room temperature, add 40 mL of cold water, extract several times with a small amount of ethyl acetate, dry over anhydrous sodium sulfate, filter, combine and concentrate the filtrate to obtain a yellow oil. 80 mg of light yellow liquid was obtained by column chromatography, yield: 28%. HRMS m / z(ESI)calcd for C 11 h 15 N 3 o 4 S[M+Na] + :308.0681; found: 308.0688.

[0057] (2) Azide triethylene glycol p-toluenesulfonate (2)

[0058]

[0059] Refer to Example 3(1) for the operation process, and use triethylene glycol di-p-toluenesulfonate instead of diethylene glycol d...

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PUM

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Abstract

The invention discloses a compound (I) for targeted ubiquitination degradation of TGF-beta1. The compound (I) for degradation of TGF-beta1 through targeted ubiquitination is formed by connecting a TGF-beta1 micromolecular ligand and an E3 ubiquitin ligase recognition ligand through PEG connecting chains of different units. The invention further discloses a preparation method of the compound I. Theinvention further discloses application of the compound for degrading TGF-beta1 through targeted ubiquitination and pharmaceutically acceptable salt of the compound in preparation of medicines for treating idiopathic pulmonary fibrosis diseases. The novel compound has a good anti-pulmonary fibrosis application prospect.

Description

technical field [0001] The invention relates to a compound targeting ubiquitination to degrade TGF-β1, a pharmaceutically acceptable salt, a preparation method thereof, and an application in the preparation of drugs for preventing or treating idiopathic pulmonary fibrosis. Background technique [0002] Organ fibrosis is an important disease that seriously endangers human health and life, such as pulmonary fibrosis, renal fibrosis, liver fibrosis, myocardial fibrosis, etc. In recent years, with global industrialization and changes in people's lifestyles and diets, the incidence of fibrotic diseases has increased significantly. [0003] Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic interstitial lung disease of unknown cause, confined to the lungs, and characterized by common interstitial pneumonia. IPF invades the alveolar wall and alveolar space and develops into diffuse pulmonary interstitial fibrosis, which eventually leads to respiratory attenuatio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61P11/00
CPCA61P11/00C07D401/14
Inventor 马臻陈圻王尊元黄文海沈正荣
Owner ZHEJIANG MEDICAL COLLEGE
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