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Pyrrolopyridone bifunctional molecular compound based on VHL ligand-induced BET degradation

A technology of pyrrolopyridone and bifunctional molecules, which can be applied in organic chemistry, drug combination, pharmaceutical formulation, etc., can solve the problems of weak activity, few cell lines for anti-tumor effect test, weak BET protein inhibitory activity, etc.

Active Publication Date: 2019-08-20
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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  • Pyrrolopyridone bifunctional molecular compound based on VHL ligand-induced BET degradation
  • Pyrrolopyridone bifunctional molecular compound based on VHL ligand-induced BET degradation
  • Pyrrolopyridone bifunctional molecular compound based on VHL ligand-induced BET degradation

Examples

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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 invention relates to a novel kind of pyrrolopyridone bifunctional molecule and its pharmaceutically acceptable salt, hydrate and prodrug and a pharmaceutical composition using the compounds as active ingredients, and application in the preparation of these compounds and their pharmaceutical composition and in the treatment or prevention of tumors, inflammation, diseases related immunity, etc.The bifunctional molecule involved in the invention is a proteolytic targeting chimera (PROTAC). A small molecule inhibitor of BET protein and a Von Hippel-Lindau (VHL) protein ligand in E3 ubiquitinligase complex are linked by a connecting arm to obtain the bifunctional molecule. The obtained compound can selectively induce the degradation of BET protein, and has significant anti-tumor 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 Applications(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
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