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Substituted triaminotriazine secreting-type aspartic protease inhibitor and preparation method thereof

A technology of triazines and triamines, which is applied in the field of medicine, can solve the problems that are in the initial stage, and there is no such compound Sap2 enzyme inhibitory activity and antifungal activity.

Inactive Publication Date: 2015-10-14
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

Meanwhile, research on small molecule inhibitors of Sap2 is still in its infancy
[0004] In order to discover novel small molecule inhibitors of Sap2 with completely new structural types, through structure-based virtual screening and further structural modification, N 2 -(furan-2-ylmethyl)-6-[2-(substituted-ylmethenyl)hydrazino]-N 4 -Substituted-1,3,5-triazine-2,4-diamine compound, which has Sap2 enzyme inhibitory activity, and there is no report on the synthesis of this type of compound and its Sap2 enzyme inhibitory activity and nematode antifungal activity in vivo

Method used

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  • Substituted triaminotriazine secreting-type aspartic protease inhibitor and preparation method thereof
  • Substituted triaminotriazine secreting-type aspartic protease inhibitor and preparation method thereof
  • Substituted triaminotriazine secreting-type aspartic protease inhibitor and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0131] Example 1: Preparation of 4,6-dichloro-N-phenyl-1,3,5-triazine-2-amine (II, R 1 = ) preparation

[0132] Dissolve cyanuric chloride (9.22 g, 50 mmol, 1 equiv) in 30 mL of acetone, and stir in an ice bath to 0°C. Slowly add 20 mL of acetone solution dissolved in aniline (4.66 g, 50 mmol, 1 equiv) dropwise. Stirring was continued for 2 h under ice bath, followed by 2 h at room temperature. After the reaction was completed, 20 mL of ice water was added. After the solid was completely precipitated, it was filtered with suction to obtain 10.85 g of a white solid, yield: 90%. 1 H-NMR (300MHz, DMSO-d 6 )δ: 11.12 (s, 1H, NH), 7.69 (d, 2H, J = 2.36, 7.95Hz), 7.36 (d, 2H, J = 8.35Hz), 7.16 (t, 1H, J = 7.40Hz). ESI-MS(m / z):239.24[M-1].

Embodiment 2

[0133] Example 2: 6-Chloro-N 2 -(furan-2-ylmethyl)-N 4 -Phenyl-1,3,5-triazine-2,4-diamine (Ⅲ, R 1 = ) preparation

[0134] Dissolve 4,6-dichloro-N-phenyl-1,3,5-triazin-2-amine (2.41g, 10mmol, 1equiv) in 30mL tetrahydrofuran, add 2-furanmethylamine (0.92mL, 10mmol ,1equiv) and 5% Na 2 CO 3 The solution was 30 mL, stirred at room temperature for 12 hours, filtered to precipitate a solid, and washed 2-5 times with water to obtain 2.81 g of a white solid, yield: 93%. 1 H-NMR (300MHz, DMSO-d 6)δ:10.07(brs,1H,NH),8.59(brs,1H,NH),7.49-7.81(m,3H),7.19-7.38(m,2H),7.02(t,1H,J=7.18Hz) ,6.31-6.48(m,1H),6.15-6.30(m,1H),4.48(d,2H,J=5.05Hz).ESI-MS(m / z):302.49[M+1].

Embodiment 3

[0135] Example 3: N 2 -(furan-2-ylmethyl)-6-hydrazino-N 4 -Phenyl-1,3,5-triazine-2,4-diamine (IV, R 1 = ) preparation

[0136] 6-Chloro-N 2 -(furan-2-ylmethyl)-N 4 -Phenyl-1,3,5-triazine-2,4-diamine (1.51g, 5mmol, 1equiv) was dissolved in 50mL of dichloromethane, and hydrazine (0.64mL, 20mmol, 4equiv) was added to reflux and stirred for 12h. After the reaction, wash with 50 mL of water and 50 mL of saturated NaCl solution × 2, and dry over anhydrous sodium sulfate. The solution is added with 100 mL of petroleum ether, and the solid is filtered to obtain 0.99 g of a white solid, yield: 67%. 1 H-NMR (300MHz, DMSO-d 6 )δ:9.03(brs,1H,NH),7.92(brs,1H,NH),7.46-7.83(m,3H),7.24-7.44(brs,2H,NHNH 2 ),7.19(t,2H,J=7.92Hz),6.88(t,1H,J=7.07Hz),6.30-6.44(m,1H),6.12-6.29(m,1H),4.46(d,2H, J=5.21Hz),4.21(brs,1H,NHNH 2 ).ESI-MS(m / z):298.33[M+1].

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Abstract

The invention relates to a substituted triaminotriazine compound and its preparation method and use in pharmacy. The substituted triaminotriazine compound has a general structural formula shown in the following description, and in the formula, R1 represents substituted phenyl ring and R2 represents substituted aromatic ring, naphthalene ring or heterocyclic aromatic. Through structure-based virtual screening and further structure reconstruction, the novel substituted triaminotriazine compound is synthesized. The novel substituted triaminotriazine compound is a fungus Sap2 inhibitor with a novel structure, has good enzyme inhibition activity and nematode in-vivo antifungal activity, provides a novel approach for deep research and development of novel-structure antifungal drugs and can be used for preparation of antifungal drugs and drugs for combination with the existing antibacterial drugs.

Description

technical field [0001] The invention relates to the technical field of medicine, specifically, a novel substituted triaminotriazine secretory aspartic acid protease inhibitor——N 2 -(furan-2-ylmethyl)-6-[2-(substituted-ylmethenyl)hydrazino]-N 4 - Substituted-1,3,5-triazine-2,4-diamine compounds and methods for their preparation. Background technique [0002] The morbidity and associated mortality of invasive fungal infections has increased enormously in recent years. Clinically, Candida albicans (lethal rate: 20% to 40%), Cryptococcus neoformans (lethal rate: 20% to 70%) and Aspergillus fumigatus (lethal rate: 50% to 90%) have been confirmed as invasive Three major causes of fungal infections. At present, antifungal drugs can be roughly divided into four categories: polyenes (such as amphotericin B, which acts on fungal cell membrane lipids), flucytosines (such as 5-fluorocytosine, which acts on fungal nucleic acids), azoles (such as fluconazole, itraconazole, voriconazol...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12A61K31/53A61P31/10A61P35/00A61P9/12A61P7/02
CPCC07D405/12
Inventor 张万年盛春泉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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