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Substituted pyrazolone secreted aspartic acid protease inhibitor and preparation method thereof

A pyrazolone, monosubstituted technology, applied in the field of medicine, can solve the problems such as synthesis that have not yet been seen, and achieve the effect of good inhibitory activity

Active Publication Date: 2018-01-19
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In order to discover novel small molecule inhibitors of Sap2 with a completely new structure type, 4-[(substituted)phenylenylene]-3-phenyl-1-[(substituted)benzene was obtained through structure-based virtual screening and further structure optimization base]-1H-pyrazolidin-5(4H)-one compounds, which have Candida albicans Sap2 enzyme inhibitory activity, there is no report on the synthesis of this type of compound and its Sap2 enzyme inhibitory activity

Method used

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  • Substituted pyrazolone secreted aspartic acid protease inhibitor and preparation method thereof
  • Substituted pyrazolone secreted aspartic acid protease inhibitor and preparation method thereof
  • Substituted pyrazolone secreted aspartic acid protease inhibitor and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Example 1: 2,4-dihydro-2,5-diphenyl-3H-pyrazolin-3-one (Ⅱ, R 1 =H) Preparation

[0063] Weigh ethyl benzoyl acetate (9.61g, 50mmol, 1.0equiv), phenylhydrazine hydrochloride (8.00g, 55mmol, 1.1equiv), acetic acid 2.0mL in a 100mL eggplant-shaped bottle, and reflux the mixture for 3h, every hour board monitoring. After the reaction was completed, 20 mL of diethyl ether was added to the reaction solution, stirred in an ice bath for 30 min, the precipitate was filtered, washed with 30 mL of diethyl ether (a small amount of times), dried, and recrystallized from ethanol 3 times to obtain 5.1 g of a white solid, yield: 43% . 1 H-NMR (600MHz, DMSO-d 6 )δ: 7.98 (d, 1H, J = 8.26Hz), 7.85 (d, 2H, J = 7.60Hz), 7.50 (d, 2H, J = 7.73Hz), 7.45-7.47 (m, 1H), 7.36- 7.41(t, 2H, J=7.52Hz), 7.31-7.35(t, 2H, J=7.50Hz), 6.46(s, 1H), 3.87(s, 1H).ESI-MS(m / z): 237.43 [M+1].

Embodiment 2

[0064] Example 2: Ethyl 2-(2-{[5-oxo-1,3-diphenyl-1H-pyrazolidine-4(5H)-alkenylene]methyl}phenoxy)acetate (Ⅲ , R 1 = H, R 2 =2-OCH 2 Preparation of COOEt)

[0065] Weigh 2,4-dihydro-2,5-diphenyl-3H-pyrazolin-3-one (0.47g, 0.2mmol, 1.0equiv), ethyl 2-formylphenoxy acetate (0.49g , 0.24mmol, 1.2equiv) into a 25mL eggplant-shaped bottle, add 15mL of absolute ethanol to dissolve, then add 100μL of piperidine, stir and react at 60°C for 6h, a solid precipitates, filter the precipitate, recrystallize from ethanol, and obtain an orange solid 0.53g , Yield: 62%. 1 H-NMR (300MHz, DMSO-d 6 )δ:8.28(s,1),7.95(d,2H,J=7.76Hz),7.70-7.79(m,2H),7.54-7.66(m,4H),7.46(t,2H,J=7.70Hz ),7.07-7.31(m,4H),4.90(s,2H),4.11(dd,2H,J=7.10,14.24Hz),1.13(t,3H,J=7.15Hz).ESI-MS(m / z):427.41[M+1].

Embodiment 3

[0066] Example 3: 2-(2-{[5-oxo-1,3-diphenyl-1H-pyrazolidine-4(5H)-alkenylene]methyl}phenoxy)acetic acid (IV, R 1 = H, R 2 =2-OCH 2 COOH) preparation

[0067] Weigh 2-(2-{[5-oxo-1,3-diphenyl-1H-pyrazolidine-4(5H)-alkenylidene]methyl}phenoxy)ethyl acetate (0.2g, 0.47mmol, 1equiv) and LiOH·H 2 O (0.030g, 0.71mmol, 1.5equiv) in 5mL mixed solvent (THF:MeOH:H 2 (O=3:2:1), stirred at room temperature for 0.5 h. Evaporated the solvent under reduced pressure, added water (20 mL), adjusted the pH to 2.0-3.0 with 1M HCl, and precipitated. The precipitate was filtered, washed with cold water, and recrystallized from ethanol to obtain 0.12 g of an orange-red solid, yield: 64%, m.p.: 113-114°C. 1 H-NMR (300MHz, DMSO-d 6 )δ:13.09(br s,1H),7.85(d,2H,J=7.95Hz),7.73-7.55(m,2H),7.33-7.52(m,4H),7.20-7.30(m,5H), 7.08-7.18(m,2H),4.89(s,2H).ESI-MS(m / z):399.42[M+1].

[0068] All reagents used in the examples are commercially available analytically pure.

[0069] Compounds 2-25 in the table u...

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Abstract

The present invention relates to a substituted pyrazolone compound, a method for preparing the same, and application thereof in drug production, and belongs to the field of pharmaceutical technologies. The substituted pyrazolone compound is a newly discovered inihbitor of fungi Sap 2, and has certain antifungal activity. The prevent invention provides a substituted pyrazolone compound. The structure of the compound is as shown by the structural formula in the specification. The substituted pyrazolone compound provided by the prevent invention has better anti-cholinesterase activity of Sap 2. Compounds of the class can be used to prepare medicines used to treat fungal infections, which provides a new path to further research and development of new antifungal medicines.

Description

technical field [0001] The invention relates to the field of medical technology, and is a novel substituted pyrazolone secretory aspartic acid protease inhibitor——4-[(substituted) phenylenylene]-3-phenyl-1-[(substituted ) phenyl]-1H-pyrazolidin-5(4H)-one compound and its preparation method. Background technique [0002] Fungal infection is a common and frequently-occurring disease that has plagued human health for a long time. Epidemiological surveys show that the morbidity and mortality of invasive fungal infections are increasing year by year around the world. The reasons can be divided into the following aspects, such as the abuse of broad-spectrum antibiotics; tumor radiotherapy and chemotherapy and organ transplantation anti-rejection treatment, which cause low immunity of the body; and the rapid increase of immunodeficiency AIDS patients. The deep fungal infection caused by pathogenic bacteria such as Candida albicans, Cryptococcus neoformans and Aspergillus fumigatu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D231/26A61P31/10A61P35/00A61P9/12A61P7/02
CPCC07D231/26
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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