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A kind of smo inhibitor based on itraconazole and its preparation method and application

A technology for itraconazole and inhibitors, applied in the field of itraconazole-based Smo inhibitors and its preparation, capable of solving problems such as drug resistance, achieving good inhibitory activity and overcoming drug-resistant mutations

Active Publication Date: 2022-07-29
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, three small molecule inhibitors against Smo protein have been approved by the FDA, Vismodegib (GDC-0449), Sonidegib (NVP-LDE-225) and Glasdegib (PF-04449913), these small molecule inhibitors are used in cancer treatment Some achievements have been made, but drug resistance is gradually produced, such as the Smo receptor D473H mutation, so it is urgent to develop new inhibitors with good inhibitory activity

Method used

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  • A kind of smo inhibitor based on itraconazole and its preparation method and application
  • A kind of smo inhibitor based on itraconazole and its preparation method and application
  • A kind of smo inhibitor based on itraconazole and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] The synthetic route of compound H-(1-11) is shown below:

[0025]

[0026] 1. The preparation of compound 3, namely 4-[4-nitrophenyl]-1-piperazinyl phenol

[0027]

[0028] Compound 1, namely, 4-piperazinylphenol (7.42 g), and compound 2, namely, 1-chloro-4-nitrobenzene (6.3 g), were added to anhydrous DMSO (80 ml) in a round-bottomed flask. join K 2 CO 3 (6.0g) and phase transfer catalyst TBAB, reflux at 120 degrees Celsius for 10-12h, use TLC dot plate to check whether the reaction is complete, after the reaction is complete, cool the reaction to RT, add water, and precipitate a solid, filter the solid and dry it , and purified by column chromatography to obtain pure compound 3.

[0029] The detection data of compound 3 are as follows:

[0030] 1 H NMR (600MHz, DMSO) δ8.91(s,1H), 8.12-8.02(m,2H), 7.15-7.01(m,2H), 6.88-6.79(m,2H), 6.73-6.65(m,2H) ), 3.63–3.55 (m, 4H), 3.15–3.03 (m, 4H).

[0031] MS calcd for C 16 H 17 N 3 O 3 [M+H] + m / z:300.1270,foun...

Embodiment 2

[0122] In vitro activity evaluation of target compounds

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PUM

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Abstract

The invention discloses an itraconazole-based Smo inhibitor, a preparation method and application thereof, and the structural formula of the Smo inhibitor is shown in formula (I); the invention also discloses a preparation method and application thereof. The present invention takes itraconazole as the lead compound, and optimizes and transforms it on the basis to obtain a Smo inhibitor with good inhibitory activity.

Description

technical field [0001] The present invention relates to a Smo inhibitor, in particular to an itraconazole-based Smo inhibitor and a preparation method and application thereof. Background technique [0002] The Hedgehog signaling pathway plays a key role in human embryonic development and adult tissue homeostasis, and it contains several key components (1) Hh ligand; (2) Patched receptor (Ptch); (3) Smoothened receptor (Smo) ; (4) Glial cell-associated oncogene homolog (Gli). Abnormalities in the Hedgehog signaling pathway lead to many human diseases including cancer, the most typical being basal cell carcinoma (BBC), tumor blastoma, etc. The use of inhibitors against Smo protein to inhibit the Hh signaling pathway is currently the most active research field. At present, three small molecule inhibitors targeting Smo protein have been approved by the FDA, Vismodegib (GDC-0449), Sonidegib (NVP-LDE-225) and Glasdegib (PF-04449913), these small molecule inhibitors are in the pr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/06A61K31/496A61P35/00
Inventor 蔡进黄铭祺吉民王雨红陈茜茜杨镇永李晓静
Owner SOUTHEAST UNIV