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Substituted tetrahydrofuran water-soluble derivatives and application thereof

A hydrate and solvate technology, applied in the field of medicinal chemistry, can solve problems such as poor water solubility, pain, and patient inconvenience

Inactive Publication Date: 2016-09-21
NANJING MAJOR BIOLOGICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the structural characteristics of this type of compound, its water solubility is poor, and the preparation for intravenous administration needs to be configured as a test solution with a pH of 2.6. Peripheral intravenous administration has obvious vascular irritation, and central venous administration is required in clinical use to reduce phlebitis. occurrence, causing inconvenience and pain to patients

Method used

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  • Substituted tetrahydrofuran water-soluble derivatives and application thereof
  • Substituted tetrahydrofuran water-soluble derivatives and application thereof
  • Substituted tetrahydrofuran water-soluble derivatives and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment 1: the synthesis of MJ10821

[0049] (1) Synthesis of intermediate M21

[0050]

[0051] Dissolve Cbz-Val-Ala-OH (322mg, 1mmol) in 3ml N,N-dimethylformamide (DMF), cool down to -5°C, add DIC (63.1mg, 0.5mmol) under stirring, and react at room temperature 30min, continue to cool down to -5°C, add II3 (350mg, 0.5mmol) in 2ml DMF solution, triethylamine (60.7mg, 0.6mmol), catalytic amount of 4-dimethylaminopyridine (DMAP), and react at room temperature for 4h, After the reaction was completed, it was poured into 15ml of water, extracted 3 times with 15ml of ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was spin-dried to obtain a yellow solid, which was separated by silica gel column chromatography to obtain 281 mg of off-white powder (M21). Yield 56%. MS(m / z): 1005.5[M+1] + .

[0052] (2) Synthesis of MJ10821

[0053]

[0054] Dissolve M21 (251mg, 0.25mmol) in 3ml of methanol, add 200mg of 5% Pd / ...

Embodiment 2

[0055] Embodiment 2: the synthesis of MJ10807

[0056] Refer to the synthesis of MJ10821, the difference is that Cbz-Gly-Pro-OH and II3 are selected as starting materials, and after condensation and deprotection, MJ10807 is finally obtained. MS(m / z): 855.4[M+1] + .

Embodiment 3

[0057] Embodiment 3: the synthesis of MJ10808

[0058] Refer to the synthesis of MJ10821, the difference is that Cbz-Ala-Pro-OH and II3 are selected as starting materials, and after condensation and deprotection, MJ10808 is finally obtained. MS(m / z): 869.4[M+1] + .

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PUM

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Abstract

The invention discloses substituted tetrahydrofuran water-soluble derivatives and application thereof, as shown as general formula I, pharmaceutically acceptable acid salt, solvate or hydrate, wherein x1, x2 and R1 are defined as the description. In addition, the invention also discloses a synthetic method of the compound, pharmaceutical compositions and application thereof in preparation of medicine for preventing or treating fungal infection. Compared with the prior art, the novel substituted tetrahydrofuran derivatives disclosed by the invention has the characteristics that the fungal infection resistant activity is remarkable, the bioavailability is high, the water solubility is very good, the preparation of a preparation is convenient, the preparation has small vascular irritation, intravenous administration does not cause phlebitis and the like. The general formula I is shown in the description.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry and relates to a tetrahydrofuran derivative, in particular to a substituted tetrahydrofuran water-soluble derivative or its pharmaceutically acceptable acid salt, solvate or hydrate, their preparation method and pharmaceutical composition And their use in the preparation of medicines for preventing or treating fungal infections. Background technique [0002] It was applied in China on May 30, 1996, and the patent application number is 96190848.3 discloses a tetrahydrofuran fungicide. In addition, the US FDA has approved posaconazole (posaconazole) for refractory diseases or other drug resistance Caused by fungal infections (such as aspergillosis, tuberculosis and fusarium disease, etc.), the State Food and Drug Administration of China has also approved posaconazole oral suspension. However, due to the structural characteristics of this type of compound, its water solubility is poor, a...

Claims

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Application Information

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IPC IPC(8): C07K5/062C07K5/065C07K5/078C07K5/072C07K5/068A61K38/05A61P31/10
CPCA61K38/00C07K5/06026C07K5/06034C07K5/06043C07K5/06052C07K5/0606C07K5/06069C07K5/06078C07K5/06086C07K5/06095C07K5/06104C07K5/06113C07K5/06147C07K5/06156C07K5/06165
Inventor 不公告发明人
Owner NANJING MAJOR BIOLOGICAL TECH
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