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Acryloyl group-containing nuclear transport modulator and uses thereof

一种烷基、基团的技术，应用在CRM1蛋白调节剂领域，能够解决代谢性质差、毒副作用强、易穿过等问题

Inactive Publication Date: 2020-09-01
WIGEN BIOMEDICINE TECH SHANGHAI CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] KPT-330 still has the disadvantages of easy crossing the blood-brain barrier, poor metabolic properties and strong side effects

Method used

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  • Acryloyl group-containing nuclear transport modulator and uses thereof
  • Acryloyl group-containing nuclear transport modulator and uses thereof
  • Acryloyl group-containing nuclear transport modulator and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0153] Production Example 1 (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (I-1) synthesis

[0154]

[0155] Synthesis of 3,5-bis(trifluoromethyl)thiobenzamide (M2)

[0156] 3,5-Bis(trifluoromethyl)benzonitrile (47.82g, 0.2mol) was dissolved in DMF (250mL), NaSH (22.42g, 2.0eq) and MgCl were added 2 (38.08g, 2.0eq), stirred at room temperature for 3h, the mixture was poured into ice-water (2L), extracted with EA (250mL*3), the organic layers were combined, washed with saturated aqueous sodium chloride solution (100mL*2), after Dry over sodium sulfate, filter and concentrate under reduced pressure to obtain the crude product 3,5-bis(trifluoromethyl)thiobenzamide (46.97g, yield 86%).

[0157] Synthesis of 3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazole(M3)

[0158] 3,5-bis(trifluoromethyl)thiobenzamide (46.44g, 0.17mol) was dissolved in DMF (250mL), and hydrazine hydrate (16.5mL, 2.0eq) was added dropwise, and stirring was continued for 1...

Embodiment 1

[0164]Example 1 (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-(2-oxo Synthesis of azetidinyl-1-yl)acrylamide (compound 1)

[0165]

[0166] (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (105mg, 0.3mmol) and 1- Aminoazetidinyl-2-one (39mg, 0.45mmol) was dissolved in dry EA (10mL), under nitrogen protection and cooled to -60°C, the one in the reaction system was added to T 3 P (0.3mL, 2M EA solution), then add DIPEA (77mg, 0.6mmol), and continue to stir the reaction for 3h, add a little ice water to quench the reaction, wash with water (20mL), and extract the aqueous phase with EA (20mL*2) , combined organic layers, washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography (DCM / MeOH=1 / 100 to 1 / 30) to obtain product (Z)-3 -(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-(2-oxoazetidinyl-1 -yl)acrylamide ...

Embodiment 2-89

[0168] Synthesis of Embodiment 2-89 (Compound 2-89)

[0169] Using I-1 as raw material, reacting with different hydrazides, similar to the synthesis of compound 1, compound 2-89 can be obtained.

[0170] Table 2. Mass spectrum and NMR data of compound 2-71

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PUM

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Abstract

The invention relates to a novel acryloyl-containing compound as well as a preparation method and application thereof. Specifically, the invention relates to an acryloyl-containing compound as shown in a formula (1) and a preparation method thereof, and application of the compound as shown in the formula (1) and pharmaceutically acceptable salts thereof in preparation of drugs for treating, regulating and / or preventing diseases related to physiological conditions related to CRM1.

Description

technical field [0001] The invention belongs to the fields of pharmacology, medicinal chemistry and pharmacology, and more specifically relates to a class of acrylamide-containing CRM1 protein regulators, a preparation method thereof and applications of such compounds. Background technique [0002] The normal function of cells depends on the correct localization of specific functional proteins in cells, and the transport of proteins in and out of the nucleus plays an important role in maintaining the stable balance of cells. Some specific proteins of organisms are transported into or exported from the nucleus through specific transport proteins, and these transport proteins are divided into import proteins and export proteins. The nuclear export of protein depends on exportin 1 (Exportin 1), also known as Chromosome region maintenance 1, CRM1, also called XPO1, which mediates the nuclear export of more than 200 proteins, most of which are tumor suppressor proteins, Cell cyc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12C07D401/12C07D491/107C07D471/10C07D487/10C07D413/12C07D471/04C07D403/14C07D401/14C07D471/08A61K31/4196A61K31/454A61K31/55A61K31/438A61K31/439A61K31/513A61K31/5377A61K31/496A61K31/501A61K31/437A61K31/497A61K31/4985A61P35/00A61P35/02
CPCC07D403/12C07D401/12C07D491/107C07D471/10C07D487/10C07D413/12C07D471/04C07D403/14C07D401/14C07D471/08A61P35/00A61P35/02A61K31/4196A61K31/454A61K31/4985A61K31/496A61K31/497C07D487/04C07D498/10A61P35/04A61K31/499A61K2300/00A61K31/55A61K31/438A61K31/506A61K31/5386A61K9/0053C07B2200/07C07B2200/13
Inventor 樊后兴谢雨礼
Owner WIGEN BIOMEDICINE TECH SHANGHAI CO LTD