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Tricyclic isoxazole derivative, preparation method thereof and application

A technology of isoxazoles and derivatives, which can be used in pharmaceutical formulations, medical preparations containing active ingredients, organic active ingredients, etc., and can solve problems such as drug resistance, narrow antibacterial spectrum, toxic and side effects, etc.

Active Publication Date: 2017-11-03
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although azole drugs have an irreplaceable role in clinical practice, more and more shortcomings of this class of drugs have been exposed, such as narrow antibacterial spectrum, drug resistance, toxic and side effects, and drug interactions. Antifungal drugs with low toxicity and diversified administration methods have always been an important research topic in this field

Method used

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  • Tricyclic isoxazole derivative, preparation method thereof and application
  • Tricyclic isoxazole derivative, preparation method thereof and application
  • Tricyclic isoxazole derivative, preparation method thereof and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Example 1: Preparation of (S)-2-(4,5-dihydronaphthoisoxazole-2-carboxamido)-3-(1H-imidazol-1-yl)propionic acid methyl ester

[0084]

[0085] The synthetic route is as follows:

[0086]

[0087] Reagents and conditions: a) diethyl oxalate, LiHMDS, tetrahydrofuran; b) hydroxylamine hydrochloride, glacial acetic acid; c) 1N sodium hydroxide, ethanol; d) thionyl chloride, methanol; e) EDCI, HOBt, DMF; f ) CDI, imidazole, acetonitrile.

[0088] 3.0g (20.5mmol) of 1-tetralone and 3.6g (24.6mmol) of diethyl oxalate were dissolved in 60mL of tetrahydrofuran, and LiHMDS solution (1M in THF,) was slowly added dropwise under ice-bath conditions. After reacting at room temperature for 4 h, TLC detected that the reaction was complete, and the reaction solution was evaporated to dryness and used directly for the next reaction.

[0089] The concentrate from the previous step was dissolved in 60 mL of glacial acetic acid, 1.70 g (24.6 mmol) of hydroxylamine hydrochloride was add...

Embodiment 2

[0095] Example 2: Preparation of (S)-2-(4,5-dihydronaphthoisoxazole-2-carboxamido)-3-(1H-imidazol-1-yl)propionic acid isopropyl ester

[0096]

[0097] 1 H NMR (600MHz, DMSO-d 6 )δ9.23(d, J=8.1Hz, 1H), 7.67(t, J=8.4Hz, 1H), 7.62(s, 1H), 7.39(ddd, J=10.3, 7.3, 2.1Hz, 3H), 7.20(s,1H),6.85(s,1H),4.96(m,1H),4.82(m,1H),4.51(dd,J=14.1,5.0Hz,1H),4.41(dd,J=14.1, 9.7Hz, 1H), 3.01(t, J=7.9Hz, 2H), 2.89–2.79(m, 2H), 1.20(t, J=6.5Hz, 6H). 13 C NMR (100MHz, DMSO-d 6 )δ168.43, 166.47, 159.34, 154.86, 137.78, 136.86, 130.52, 128.79, 128.00, 127.24, 123.80, 121.47, 119.99, 113.12, 68.97, 53.26, 45.68, 27.472, 27

Embodiment 3

[0098] Example 3: (S)-2-(4,5-dihydronaphthoisoxazole-2-carboxamido)-3-(1H-imidazol-1-yl)propionic acid isobutyl ester

[0099]

[0100] 1 H NMR (600MHz, DMSO-d 6 )δ9.29(d,J=8.2Hz,1H),7.66(d,J=7.3Hz,1H),7.63(s,1H),7.40(ddd,J=13.3,6.9,3.1Hz,3H), 7.21(s,1H),6.86(s,1H),4.90(ddd,J=10.0,8.3,4.8Hz,1H),4.55(dd,J=14.1,4.7Hz,1H),4.44(dd,J= 14.1,10.0Hz,1H),3.91(m,2H),3.01(t,J=7.9Hz,2H),2.83(dd,J=16.7,8.1Hz,2H),1.88(m,1H),0.88( dd,J=6.7,1.6Hz,6H). 13 C NMR (100MHz, DMSO-d 6 )δ169.39, 166.94, 159.84, 155.28, 138.28, 137.30, 130.98, 129.24, 128.81, 127.69, 124.25, 121.93, 120.31, 113.56, 71.27, 53.63, 45.95, 18.28, 297

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Abstract

The invention discloses a tricyclic isoxazole derivative, belongs to the technical field of medicines, and provides a compound with a general formula (1) as shown in the specification, a geometrical isomer of the compound or pharmaceutically acceptable salt, hydrates, solvates and prodrugs of the compound and preparation methods of the salt, the hydrates, the solvates and the prodrugs. The compound has good antifungal activity for various superficial and deep fungi and the advantages of high efficiency, low toxicity, wide antifungal spectrum and the like as compared with existing clinically-applied antifungal drugs, and the compound can be used for preparing antifungal drugs.

Description

technical field [0001] The invention belongs to the technical field of medicines, and relates to a class of novel tricyclic isoxazole derivatives, pharmaceutically acceptable salts, hydrates, solvates or prodrugs of the compounds, their preparation methods and their use as treatments for fungal Use in medicine for various diseases caused by infection. Background technique [0002] Fungal infection is a common disease that can cause fungal infections in superficial places such as skin, hair, and nails, as well as fungal infections in deep tissues such as subcutaneous tissue and intima. It is mainly divided into superficial fungal infections and Systemic fungal infection. In recent years, with the widespread development of organ transplantation operations, the use of immunosuppressants has increased significantly, and the radiation and chemotherapy of malignant tumor patients have damaged the normal immune function of the human body, making fungal infection an increasingly co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/12A61K31/423A61P31/10
CPCC07D413/12
Inventor 赵冬梅赵世振程卯生赵立雨张向前魏鹏吴梦雅王德鑫
Owner SHENYANG PHARMA UNIVERSITY
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