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A pyrrolopyridone bifunctional molecular compound based on vhl ligand-induced bet degradation

A technology of pyrrolopyridone and bifunctional molecules, which is applied in the fields of organic chemistry, pharmaceutical formulations, and drug combinations, etc., can solve the problems of few tested cell lines for anti-tumor effect, description of compound protein degradation efficacy, weak activity, etc.

Active Publication Date: 2022-03-29
JIANGSU PROVINCE INST OF TRADITIONAL CHINESE MEDICINE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Patent CN 106749513A discloses a bifunctional molecule based on VHL ligand-induced BET degradation and its preparation and application. The compound of this patent example has weak inhibitory activity on BET protein, and the anti-tumor effect test cell lines are few and the activity is weak , at the same time, the protein degradation efficacy of the compound is not explained, so it is necessary to develop drugs that more effectively degrade BET protein

Method used

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  • A pyrrolopyridone bifunctional molecular compound based on vhl ligand-induced bet degradation
  • A pyrrolopyridone bifunctional molecular compound based on vhl ligand-induced bet degradation
  • A pyrrolopyridone bifunctional molecular compound based on vhl ligand-induced bet degradation

Examples

Experimental program
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Effect test

Embodiment 1

[0093] Preparation of 4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonamido)phenyl)-N-((1-(2-(2-(((S)-1 -((2S,4R)-4-Hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl Base-1-oxobut-2-yl)amino)-2-oxoethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-6-methyl -7-oxo-6,7-dihydro-1H-pyrrole [2,3-c]pyridine-2-carboxamide (1), its structural formula is as follows:

[0094]

[0095] Step 1: Preparation of 2-hydroxyethyl-4-methylbenzenesulfonate (1a)

[0096]

[0097] Dissolve ethylene glycol (3.91g, 62.95mmol) in 5mL of pyridine, add p-toluenesulfonyl chloride (6g, 31.47mmol) in batches, stir at room temperature for 4 hours, add 6mol / L hydrochloric acid (40mL), wash with ethyl acetate Extract, wash with saturated brine, collect the organic layer, dry over anhydrous sodium sulfate, evaporate the organic solvent under reduced pressure, and purify the residue by silica gel column chromatography using petroleum ether / ethyl acetate (V / V=20 / 1-10 / 1) was eluted to...

Embodiment 2

[0118] Preparation of 4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonamido)phenyl)-N-((1-(2-(2-(2-(((S )-1-((2S,4R)-4-hydroxyl-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3 -Dimethyl-1-oxobut-2-yl)amino)-2-ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl )-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (2), its structural formula is as follows:

[0119]

[0120] The ethylene glycol in the embodiment 1 step 1 is changed to diethylene glycol, and the synthetic method is the same as in the embodiment 1.

[0121] 1 H NMR (400MHz, DMSO) δ (ppm): 12.35(s, 1H), 9.83(s, 1H), 8.92(d, J=38.3Hz, 2H), 8.60(s, 1H), 7.99(s, 1H ), 7.45(d, J=10.3Hz, 1H), 7.36(s, 7H), 7.23(d, J=6.1Hz, 1H), 7.05(s, 1H), 6.98(s, 1H), 6.92(d , J=8.7Hz, 1H), 6.89(s, 1H), 5.18(s, 1H), 4.50(s, 6H), 4.35(s, 2H), 4.27(s, 1H), 3.93(s, 2H) , 3.83(s, 2H), 3.62(s, 2H), 3.55(d, J=15.9Hz, 7H), 3.11(s, 2H), 2.42(s, 3H), 2.06(s, 1H), 1.91( s, 1H), 1.23 (s, 3H), 0.92 (s, 9H).

[012...

Embodiment 3

[0124] Preparation of 4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonamido)phenyl)-N-((1-((S)-13-((2S,4R) -4-Hydroxy-2-((4--(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14dimethyl-11-oxo- 3,6,9-trioxa-12-azapentadecyl)-1H-1,2,3-triazol-4-yl)methyl)-6-methyl-7-oxo-6 , 7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (3), its structural formula is as follows:

[0125]

[0126] The ethylene glycol in the step 1 of embodiment 1 is replaced with triethylene glycol, and the synthetic method is the same as in embodiment 1.

[0127] 1 H NMR (300MHz, DMSO) δ (ppm): 12.34(s, 1H), 9.82(s, 1H), 9.00(s, 1H), 8.86(s, 1H), 8.59(t, J=6.0Hz, 1H ), 7.96(s, 1H), 7.44(s, 1H), 7.39(s, 4H), 7.37-7.30(m, 3H), 7.23(dd, J=8.8, 2.7Hz, 1H), 7.12-7.03( m, 1H), 7.01(dd, J=7.0, 4.1Hz, 1H), 6.93(d, J=8.7Hz, 1H), 6.89(d, J=2.2Hz, 1H), 5.16(d, J=3.6 Hz, 1H), 4.57(d, J=9.5Hz, 1H), 4.49(d, J=5.2Hz, 3H), 4.48-4.40(m, 2H), 4.36(t, J=7.9Hz, 2H), 4.25(dd, J=15.7, 5.8Hz, 1H), 3.94(s, 2H), 3....

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Abstract

The present invention relates to a new class of bifunctional molecules of pyrrolopyridones and their pharmaceutically acceptable salts, hydrates, prodrugs, and pharmaceutical combinations with the compounds as active ingredients, as well as preparation of these compounds and their pharmaceutical combinations Drugs and their applications in the treatment or prevention of tumors, inflammation, immunity and other diseases. The bifunctional molecule involved in the present invention is a proteolysis targeting chimera (PROTAC), which connects the BET protein small molecule inhibitor and the Von Hippel-Lindau (VHL) protein ligand in the E3 ubiquitin ligase complex through a linker The bifunctional molecule is obtained, and the obtained compound can selectively induce the degradation of BET protein, and has remarkable antitumor effect.

Description

technical field [0001] The invention relates to the field of medical technology, in particular to a class of pyrrolopyridone bifunctional PROTAC molecular compounds targeting to degrade BET proteins, and their pharmaceutically acceptable salts, hydrates, prodrugs and the compound as an active ingredient The combination of medicines, and the preparation of these compounds and their pharmaceutical compositions and their use in the treatment or prevention of tumors, inflammation, metabolism and other diseases. Background technique [0002] Histone lysine acetylation is an important post-translational modification of gene transcription. BET protein plays a role through the recognition of acetyllysine (KAc) by the bromodomain in its structure, and the abnormal function of BET is related to various diseases such as tumors, inflammation, and metabolism. Inhibiting the combination of BET protein and KAc can effectively inhibit various diseases such as tumor and inflammation. [00...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/437A61P35/00A61P35/02
CPCC07D471/04A61P35/00A61P35/02
Inventor 曹鹏张惠斌张剑魏清筠周金培郑培源王涛
Owner JIANGSU PROVINCE INST OF TRADITIONAL CHINESE MEDICINE