Compound ST-246 containing a crystal water, crystal thereof and preparation method thereof

A technology of compound and monoclinic crystal system, which is applied in the field of compound ST-246 containing one crystal water and its crystal and preparation, can solve the problems of easy moisture absorption, inability to effectively reduce the impurity content in the final product, and harsh preparation conditions, and achieve Easy crystallization, large-scale production, and convenient preparation effects

Active Publication Date: 2009-06-03
INST OF BIOENG ACAD OF MILITARY MEDICAL SCI OF THE CHINESE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] The current preparation method mainly has the following disadvantages: 1) it cannot effectively reduce the content of impurities in the final product, especially the content of exoisomers; It is obtained by crystallization in medium, the preparation conditions are harsh, and it is easy to absorb moisture

Method used

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  • Compound ST-246 containing a crystal water, crystal thereof and preparation method thereof
  • Compound ST-246 containing a crystal water, crystal thereof and preparation method thereof
  • Compound ST-246 containing a crystal water, crystal thereof and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1, ST-246·H 2 Preparation of O and its crystals

[0026] 1. Synthesis of tropane anhydride

[0027] 1000g of cycloheptatriene solution (Sigma company, 90% by mass) and 1104g of maleic anhydride (Beijing Chemical Plant, analytically pure) were dissolved in 1400ml of xylene, and heated to reflux for 10 hours under nitrogen protection. Cool at 0°C, filter, wash with petroleum ether (boiling range 60-90°C) three times, 500ml each time, and dry to obtain 1586g light yellow tropane anhydride (4,4a,5,5a,6,6a-hexahydro-4 , 6-ethoxy-1hydro-cyclopropane[f]isobenzofuran-1,3-(3ahydro)-dione) crude solid. Melting point: 93-95°C, yield 81.5%.

[0028] The above 1586g crude product of tropane anhydride was heated and dissolved with 5000ml of absolute ethanol (Beijing Chemical Plant, analytically pure), and the solution was first cooled at room temperature for 3 hours, then placed at 0°C for 3 hours and then filtered. Wash twice with absolute ethanol, 500ml each time, and d...

Embodiment 2

[0064] Example 2, ST-246·H 2 Hygroscopicity test of O crystal

[0065] The ST-246 H obtained in the above step 1 2 O crystal thermal decomposition experiment, the results show that the mixed crystallization solvent composed of ethyl acetate and n-hexane crystallized ST-246·H 2 O crystal (the solvent may contain a small amount of water) and the recrystallized product of 90% (volume percent) ethanol aqueous solution both contain a crystal water (after drying at 42°C for 48 hours), and the crystal water content is 4.50% and 4.61%, respectively. Take the ST-246·H recrystallized from the above two solvents respectively 2 O crystals 2.0073g and 1.9759g were placed in a sealed container at 25-30°C and 75% humidity for 2 months. After 2 months, the ST-246 H recrystallized from the above two solvents were measured respectively 2 The weights of O crystals were 2.0081g and 1.9768g respectively, and the weights were basically unchanged compared with 2 months ago, indicating that ST-24...

Embodiment 3

[0073] Embodiment 3, anti-orthopoxvirus experiment

[0074] The ST-246 H obtained in the above-mentioned embodiment 1 2 O crystals were dissolved in DMSO and prepared as a 10 mM stock solution. The virus strain used in the experiment is the Tiantan strain of vaccinia virus with GFP fluorescent labeling (Wuhan University Collection Center), the infected cells are Vero cells (Wuhan University Collection Center), and the fluorescence intensity and quantity are observed through plaques and under a fluorescent microscope To determine the ST-246 H obtained in Example 1 above 2 The activity of inhibiting virus replication of O crystals, the specific process is as follows:

[0075] Inoculate 10,000 Vero cells / well into a 96-well plate, suck out the culture medium after 20 hours, and add 100 μL of DMEM to dilute the concentration of 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM respectively and 0.003 μM of the ST-246 H obtained in Example 1 above 2 A solution of O crystals. ...

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Abstract

The invention discloses a compound ST-246 containing a crystal water, known as ST-246.H2O. The ST-246.H2O is prepared according to the following method: in the presence of organic base and organic solvent and being under protection of nitrogen, tropane anhydride and p-trifluoromethyl benzoylhydrazine are heated and return flow and reaction solution is cooled and filtered, thereby obtaining the ST-246.H2O. The ST-246.H2O prepared by the method is steady at room temperature, is difficult to lose the crystal water or absorb moisture, is difficult to agglomerate after micronization and is beneficial for improving bioavailability. The compound can be used for preparing anti-poxvirus medicines.

Description

technical field [0001] The invention relates to a compound ST-246 containing one crystal water and its crystal and preparation method. Background technique [0002] ST-246 is an anti-orthopoxvirus compound (Yang G, et al.J Virol.2005, 79(20): 13139-49.) researched by Siga Corporation of the United States. This drug can inhibit the growth of orthopoxvirus in vitro. Can effectively treat multiple orthopoxvirus infections in animal models (Quenelle DC, et al.Antimicrob Agents Chemother.2007, 51 (2): 689-95; Sbrana E, et al.Am J Trop Med Hyg.2007, 76 (4): 768-73.), safe and well tolerated. At present, the drug has initially completed Phase I clinical trials. The structural formula of ST-246 is as figure 1 shown. [0003] The current preparation method mainly has the following disadvantages: 1) it cannot effectively reduce the content of impurities in the final product, especially the content of exoisomers; It is obtained by crystallization in medium, and the preparation con...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/56A61K31/403A61P31/12
Inventor 戴秋云董铭心胡洁
Owner INST OF BIOENG ACAD OF MILITARY MEDICAL SCI OF THE CHINESE
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