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Proteolytic targeted chimeric compound taking oxygen bridge bicycloheptene compound as estrogen receptor ligand as well as preparation method and application

A technology of estrogen receptor and bicycloheptene, applied in the field of medicine, can solve the problems of triplet activity influence and difficulty in regulation

Active Publication Date: 2020-09-25
WUHAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Protein degradation does not only depend on the affinity of the binary target protein and the ligand, but on the activity of the triplet, and the conformation and position of the connection of PROTAC, the modification of the length and composition of the connecting chain, and the concentration will all affect the triplet. The activity of the body is affected, so it is more difficult to control

Method used

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  • Proteolytic targeted chimeric compound taking oxygen bridge bicycloheptene compound as estrogen receptor ligand as well as preparation method and application
  • Proteolytic targeted chimeric compound taking oxygen bridge bicycloheptene compound as estrogen receptor ligand as well as preparation method and application
  • Proteolytic targeted chimeric compound taking oxygen bridge bicycloheptene compound as estrogen receptor ligand as well as preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] (2S,2R)-1-((2S)-2-(5-(4-((N-ethyl-5,6-bis(4-hydroxyphenyl)-7-oxabicyclo[2.2.1 ]-5-heptene)-2-sulfonamido)phenoxy)pentanamide)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazole-5 -yl)benzyl)pyrrolidine-2-carboxamide (26a)

[0090]

[0091] Under the protection of argon, bishydroxyphenylfuran 22 (35 mg, 0.14 mmol) and dienophile 25a (103 mg, 0.14 mmol) were placed in a round bottom flask, then anhydrous THF (2 mL) was added as a cosolvent . The reaction was stirred under heating at 90° C. for 8 hours. After the reaction was complete as detected by TLC, water was added to quench the reaction, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated, followed by silica gel column chromatography to obtain 87 mg of yellow solid product, 63% yield; m.p.172-173°C; 1 H NMR (400MHz,MeOD)δ8.86(s,1H),7.46(d,J=8.1Hz,2H),7.39(d,J=8.1Hz,2H), 7.12(dd,J=11.6,5.2Hz ,6H),6.82–6.74(m,4H),6.72–6.68(m,2H),5.4...

Embodiment 2

[0093] (2S,2R)-1-((2S)-2-(6-(4-((N-ethyl-5,6-bis(4-hydroxyphenyl)-7-oxabicyclo[2.2.1 ]-5-heptene)-2-sulfonamido)phenoxy)caproylamide)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazole-5 -yl)benzyl)pyrrolidine-2-carboxamide (26b)

[0094]

[0095] Under the protection of argon, bishydroxyphenylfuran 22 (35 mg, 0.14 mmol) and dienophile 25b (106 mg, 0.14 mmol) were placed in a round bottom flask, then anhydrous THF (2 mL) was added as a cosolvent . The reaction was stirred under heating at 90° C. for 8 hours. After the reaction was complete as detected by TLC, water was added to quench the reaction, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated, followed by silica gel column chromatography to obtain 94 mg of yellow solid product, 67% yield; m.p.176-177°C; 1 H NMR (400MHz,MeOD)δ8.82(s,1H),7.43(d,J=8.1Hz,2H),7.35(d,J=8.1Hz,2H), 7.14–7.04(m,6H),6.74 (t,J=9.1Hz,4H),6.68(d,J=7.6Hz,2H),5.42(...

Embodiment 3

[0097] (2S,2R)-1-((2S)-2-(7-(4-((N-ethyl-5,6-bis(4-hydroxyphenyl)-7-oxabicyclo[2.2.1 ]-5-heptene)-2-sulfonamido)phenoxy)heptanamide)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazole-5 -yl)benzyl)pyrrolidine-2-carboxamide (26c)

[0098]

[0099] Under the protection of argon, bishydroxyphenylfuran 22 (35 mg, 0.14 mmol) and dienophile 25c (107 mg, 0.14 mmol) were placed in a round bottom flask, then anhydrous THF (2 mL) was added as an auxiliary solvent. The reaction was stirred under heating at 90° C. for 8 hours. After the reaction was complete as detected by TLC, water was added to quench the reaction, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated, followed by silica gel column chromatography to obtain 91 mg of yellow solid product, 64% yield; m.p.178-179°C; 1H NMR (400MHz,MeOD)δ8.82(s,1H),7.43(d,J=8.2Hz,2H),7.36(d,J=8.1Hz,2H), 7.14–7.06(m,6H),6.79 –6.71(m,4H),6.68(d,J=8.6Hz,2H),5....

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Abstract

The invention discloses a proteolytic targeted chimeric compound taking an oxygen bridge bicycloheptene compound as an estrogen receptor ligand as well as a preparation method and an application. Tworeasonable synthesis modes are adopted, a VHL ligand or a CRBN ligand serves as an E3 ligase ligand part, oxygen bridge bicycloheptene sulfonate or sulfonamide estrogen receptor ligands are connectedthrough alkyl side chains with different lengths, and a series of target product Protac molecules are obtained through synthesis. An action mode of the Protac molecules is different from that of an existing anti-breast cancer drug tamoxifen, and the Protac molecules are targeted estrogen down-regulators. The compound not only retains a certain estrogen receptor binding capacity, but also has goodestrogen receptor alpha down-regulation activity equivalent to that of fulvestrant, can realize event-driven targeted estrogen receptor degradation, and is expected to overcome drug resistance causedby traditional endocrine treatment of the ER positive breast cancer through the method.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a targeted proteolysis chimera with an oxo-bridged bicycloheptene compound as an estrogen receptor ligand, a preparation method thereof, and an application in treating breast cancer by targeting an estrogen receptor . Background technique [0002] Breast cancer is the most common cancer among women worldwide, and its high morbidity and mortality seriously threaten women's health. Among them, estrogen receptor (ER)-positive breast cancer accounts for about 70% of all breast cancers, and endocrine therapy targeting ER signaling pathway is one of the main means of clinical treatment at present. However, endocrine therapy, such as its representative drug tamoxifen, has both agonistic and antagonistic activities on estrogen receptors, and long-term use will cause drug resistance. Drug resistance to endocrine therapy has become an urgent problem in the treatment of ER-positive breast ...

Claims

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Application Information

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IPC IPC(8): C07K5/062C07K1/06C07K1/16C07D493/08A61K31/4439A61K38/05A61P35/00
CPCC07K5/06017C07D493/08A61P35/00A61K38/00
Inventor 周海兵胡志烨宁文涛黄健董春娥
Owner WUHAN UNIV
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