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Substituted thiazole ketones secretory aspartic protease inhibitor and preparation thereof

A thiazolone, single-substitution technology, applied in the field of pharmaceutical compounds

Active Publication Date: 2015-10-07
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The synthesis of {4-oxo-3-(substituted)phenyl-2-[(substituted)phenylimino]thiazolidin-5-enylidene}(substituted)phenyl compounds and their Sap2 inhibitory activity have not been seen yet and related reports of antifungal activity in vivo

Method used

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  • Substituted thiazole ketones secretory aspartic protease inhibitor and preparation thereof
  • Substituted thiazole ketones secretory aspartic protease inhibitor and preparation thereof
  • Substituted thiazole ketones secretory aspartic protease inhibitor and preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0099] Example 1: Preparation of 1,3-diphenylthiourea (II, R 1 =H) Preparation

[0100] Weigh aniline (2.33g, 25mmol, 2equiv), carbon disulfide (1.24g, 16.25mmol, 2equiv), triethanolamine (2.5mL) and sulfur powder (100mg) in 50mL of water, stir and reflux for 6h. The reaction solution was cooled to room temperature, and a white precipitate precipitated out. Filtered and washed with cold water to obtain 1.46 g of white solid, yield: 51%. 1 H-NMR (300MHz, DMSO-d 6)δ:9.78(s,2H,NH),7.47(m,4H,Ar-H),7.32(m,4H,Ar-H),7.11(m,2H,Ar-H).ESI-MS(m / z):229.28[M+1].

Embodiment 2

[0101] Example 2: 3-phenyl-2-(phenylimino)thiazolidin-4-one (Ⅲ, R 1 =H) Preparation

[0102] Weigh 1,3-diphenylthiourea (1.14g, 4.0mmol, 1equiv), anhydrous sodium acetate (1.64g, 20.0mmol, 5equiv), 0.85mL ethyl chloroacetate (0.98g, 8.0mmol, 2equiv) In 20 mL of absolute ethanol, the mixture was stirred at 60° C. for 6 h. The reaction solution was cooled to room temperature, and a precipitate appeared. The precipitate was filtered, washed with ethanol, and recrystallized with ethyl acetate to obtain 0.68 g of an orange solid, yield: 64%, which was directly used in the next reaction without further purification. 1 H-NMR (300MHz, DMSO-d 6 )δ:7.47-7.59(m,2H),7.37-7.46(m,3H),7.25-7.36(m,2H),7.08(t,1H,J=7.8Hz),6.81-6.92(m,2H) ,4.15(s,2H).ESI-MS(m / z):269.35[M+1].

Embodiment 3

[0103] Example 3: Ethyl 2-(2-{[4-oxo-3-phenyl-2-(phenylimino)thiazolidin-5-enylidene]methyl}phenoxy)acetate (IV, R 1 =H) Preparation

[0104] Weigh 3-phenyl-2-(phenylimino)thiazolidin-4-one (0.3g, 1.12mmol, 1equiv), ethyl 2-formylphenoxy acetate (0.28g, 1.35mmol, 1.2equiv) , piperidine (0.095g, 1.12mmol, 1equiv) in 5mL of absolute ethanol, the mixture was stirred at 60°C for 8h. Purification by flash preparative chromatography (PE-EtOAc, 5:1) gave 0.48 g of light yellow solid, yield: 95%. 1 H-NMR (300MHz, DMSO-d 6 )δ:8.07(s,1H),7.44-7.62(m,5H),7.30-7.43(m,4H),7.02-7.22(m,3H),6.90-7.01(m,2H),4.94(s, 2H), 4.16(dd, 2H, J=7.06, 14.02Hz), 1.20(t, 3H, J=7.31Hz). ESI-MS (m / z): 459.40[M+1].

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Abstract

The invention relates to a substituted thiazole ketones secretory aspartic protease inhibitor and a preparation method thereof, and particularly provides a novel thiazole ketones compound. The general structural formula of the novel thiazole ketones compound is shown as follows. The thiazole ketones compound is high in Sap2 enzyme inhibiting activity and nematode and mouse in-vivo antifungal activity, and has good antifungal medicine combination effect on fluconazole resistant bacteria, thereby being capable of being used for preparing medicine for preventing fungal infection or being combined with existing antifungal medicine. A new approach is created for deeply studying and developing novel antifungal medicine.

Description

technical field [0001] The present invention relates to the technical field of pharmaceutical compounds, in particular to a novel substituted thiazolone secretory aspartic acid protease inhibitor——{4-oxo-3-(substituted)phenyl-2-[(substituted ) phenylimino] thiazolidine-5-enylene} (substituted) phenyl compounds and their preparation methods and applications. Background technique [0002] In recent years, with the widespread application of antibiotics, tumor radiotherapy and chemotherapy, and organ transplantation, as well as the sharp increase in the prevalence of AIDS, a large number of patients with deep fungal infections such as Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans increase in magnitude. The increase of drug-resistant Candida has become a major challenge for clinical antifungal treatment, and the existing antifungal drugs have certain limitations. At present, antifungal drugs mainly target four target enzymes: lanosterol 14α-demethylase (a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/54A61K31/426A61P31/10
CPCC07D277/54
Inventor 盛春泉张万年刘杨董国强姚建忠缪震元刘娜
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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