Alkoxy isoxazole derivative and preparation method and application thereof

A technology of alkoxyisoxazole derivatives, which is applied in the field of alkoxyisoxazole derivatives and their preparation and application, can solve the problem of insignificant anti-tumor activity and achieve a good effect of promoting nerve regeneration Effect

Pending Publication Date: 2020-08-11
EAST CHINA NORMAL UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Only a small part of the compounds reported in the prior art are sigma-2 receptor ligands, and the antitumor activity is not obvious

Method used

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  • Alkoxy isoxazole derivative and preparation method and application thereof
  • Alkoxy isoxazole derivative and preparation method and application thereof
  • Alkoxy isoxazole derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0106] Embodiment (1) Preparation of 3-(2-(cyclobutyl (methyl) amino) ethoxy)-N-phenylisoxazole-5-carboxamide hydrochloride

[0107] 1.1 Preparation of methyl 3-hydroxyisoxazole-5-carboxylate

[0108] Add compound hydroxyurea (7.6g, 100mmol) and DBU (16.7g, 110mmol) into a 250mL three-necked flask. When the system was cooled to 0°C, 50 mL of solvent methanol was added. The compound butynedioic acid dimethyl was slowly added dropwise under the condition of nitrogen protection. After the dropwise addition, the system was orange-yellow and stirred for 1 h under ice-bath conditions. After 1 h, the reaction was removed from the ice bath, slowly raised to room temperature and stirred overnight. After the reaction, the solvent was spin-dried in vacuo, dissolved in 20 mL of water, and adjusted to pH 1 with hydrochloric acid. The system was extracted with ethyl acetate (3*30mL), anhydrous Na 2 SO 4 dry. The ethyl acetate was spin-dried, and the obtained crude product was recrysta...

Embodiment (8

[0129] Embodiment (8) Preparation of 3-(2-(cyclobutyl(methyl)amino)ethoxy)-N-(3-trifluoromethylphenyl)isoxazole-5-carboxamide hydrochloride

[0130] Add the compound 3-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)isoxazole-5-carboxylic acid (350mg, 1.22mmol) prepared in 1.3 to a 100mL round bottom flask, 3 -trifluoromethylaniline (196.6mg, 1.22mmol), EDC (304.8mg, 1.59mmol), HOBt (214.8mg, 1.59mmol) and 3-picoline (0.17mL, 1.71mmol) and 25mLDCM, under nitrogen protection The reaction was stirred overnight at room temperature. After the reaction, the solvent was spin-dried, dissolved in ethyl acetate, washed with water, washed with 1N dilute hydrochloric acid, washed with saturated sodium bicarbonate solution, washed with saturated brine, and dried over anhydrous sodium sulfate. Spin to dry ethyl acetate, after the crude product was obtained by flash column chromatography, add 30mL ethyl acetate hydrochloride and stir overnight, spin to dry ethyl acetate, beat and filter with...

Embodiment (10

[0133] Embodiment (10) Preparation of 3-(2-(cyclobutyl(methyl)amino)ethoxy)-N-(3,5-dichlorophenyl)isoxazole-5-carboxamide hydrochloride

[0134] 3-trifluoromethylaniline is replaced by 3,5-dichloroaniline, and all the other required raw materials, reagents and preparation methods are the same as in Example (8), to obtain the final product 3-(2-(cyclobutyl (methyl )amino)ethoxy)-N-(3,5-dichlorophenyl)isoxazole-5-carboxamide hydrochloride. 1 H NMR (400MHz, CDCl 3 )δ8.49(s,1H),7.61(s,2H),7.14(s,1H),6.64(s,1H),4.32(t,J=5.40 Hz,3H),2.91–2.77(m,1H ),2.66(t,J=5.40Hz,3H),2.16(s,3H),2.07–1.96(m,3H),1.94–1.78(m,2H),1.73–1.54(m,2H). 13 C NMR (101MHz, CDCl 3 )δ172.1, 162.6, 153.7, 138.3, 135.4, 125.3, 118.6, 99.9, 68.3, 60.5, 52.4, 38.6, 27.7, 13.8. HRMS (ESI): calcd for C 17 h 20 Cl 2 N 3 o 3 [M+H] + , 384.0876; found, 384.0905.

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PUM

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Abstract

The invention belongs to the field of medicinal chemistry, and discloses an alkoxy isoxazole derivative shown as a formula (I) and a pharmaceutically acceptable salt thereof, and a synthesis method and application thereof. The alkoxy isoxazole derivative has good affinity to a sigma receptor, part of the compounds have good membrane permeability and nerve regeneration promoting activity, and the alkoxy isoxazole derivative is expected to be developed into a drug for treating central nervous system diseases, especially neurodegenerative diseases. The sigma receptor has two subtypes of sigma 1 and sigma 2, the sigma 1 is a target spot for treating central nervous system diseases, cocaine addiction, analgesia and the like, and the sigma 2 is a treatment target spot for antitumor drugs.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, relates to alkoxyisoxazole derivatives and their preparation methods and applications, in particular to the treatment of central nervous system diseases related to sigma-1 receptors and tumor diseases related to sigma-2 receptors Therapeutic alkoxyisoxazole derivatives and their preparation methods and applications, in particular to a new class of alkoxyisoxazole derivatives with sigma-1 and sigma-2 receptor affinity and their preparation methods with application. Background technique [0002] Sigma-1 receptors (σ1 receptors) and sigma-2 receptors (σ2 receptors) both belong to the sigma receptor family, which were first discovered in 1976 by Martin et al. At present, the sigma-1 receptor has been cloned, consists of 223 amino acids, and is located on the endoplasmic reticulum membrane associated with mitochondria, and contains 90% identical and 95% similar amino acid sequences among th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D261/12C07D413/12A61P25/00A61P25/28A61P25/08A61P9/10A61P25/14A61P21/00A61P25/24A61P25/18A61P25/16A61P35/00A61K31/42A61K31/422
CPCC07D261/12C07D413/12A61P25/00A61P25/28A61P25/08A61P9/10A61P25/14A61P21/00A61P25/24A61P25/18A61P25/16A61P35/00
Inventor 于丽芳施文稳石俊杰杨帆汤杰庞涛王云杰
Owner EAST CHINA NORMAL UNIV
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