Novel crystal of tenofovir prodrug

A technology of crystals and prodrugs, applied in the field of medicinal chemistry, can solve the problems of undisclosed compound crystallography, difficult to obtain single crystals, complex crystal distribution, etc. Effect

Active Publication Date: 2013-10-02
XIAN XINTONG PHARM RES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the prior art does not disclose or suggest a crystallographic study of the compound
[0005] Moreover, when the compound is crystallized, the crystal distribution is very complicated, and most of them crystallize into polycrystals, and it is not easy to obtain single crystals.

Method used

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  • Novel crystal of tenofovir prodrug
  • Novel crystal of tenofovir prodrug
  • Novel crystal of tenofovir prodrug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] (2R,4S)-2-((((R)-(6-amino-9-yl)propane-yl)oxy)methyl)-(3-chlorophenyl)-2oxo-1,3,2 – Preparation and identification of Form I crystal form of dioxaphosphorine succinate (HTS)

[0030] Compound Synthesis:

[0031] The steps of compound synthesis basically refer to the preparation method of Chinese Patent No. 200510098771.X to prepare (2R,4S)-2-((((R)-(6-amino-9-yl)propane-yl)oxy)methyl) -(3-Chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinate succinate (HTS). Specific steps are as follows:

[0032]

[0033] Regent

[0034] Tenofovir (1.32g, 4.60mmol) and N,N-dimethylformamide (0.5g, 4.95mmol) were added to 35ml of dichloromethane, and oxalyl chloride (1.4ml) was slowly added dropwise. The solvent was concentrated under reduced pressure to obtain a crude product, which was dissolved in 25ml of dichloromethane, and the temperature was controlled at 0°C, and pyridine (0.75mL, 9.16mmol) was slowly added. Then the temperature was lowered to -78°C, and another dichloro...

Embodiment 2

[0042] Stability Comparison of Crystals of the Invention and Compounds of the Prior Art

[0043] This example describes the comparative experiment on the stability of the crystal of the present invention (type I crystal prepared in Example 1 is numbered as sample 1) and the compound prepared according to the prior art (Chinese patent application 200510098771.X, numbered as sample 2).

[0044] The high-temperature stability test was carried out at 65°C, and the results are shown in the following table (Table 2), which indicates that the crystal of the present invention is more stable at high temperature than the prior art.

[0045] Table 265°C for high temperature stability test

[0046]

[0047] The stability test was carried out at 40°C for 6 months, and the results are shown in the following table (Table 3), which indicates that the crystals of the present invention are more stable under long-term storage than those of the prior art.

[0048] Table 340 ℃ under the stabil...

Embodiment 3

[0051] Comparison of anti-HBV effect of the crystal of the present invention and compounds of the prior art

[0052] This example describes the in vivo metabolism test of the crystal of the present invention (type I crystal prepared in Example 1). Specifically, male Wistar / SD rats (180-210 g) were fasted overnight before administration. Compounds were administered intragastrically in the form of physiological saline (0.9%) solution (5 mg / ml or 10 mg / ml). Administration with 58.06mg / kg HTS (30mg / kg tenofovir equivalent) (n=3 / group), and 66.38mg / kg tenofovir disoproxil fumarate (30mg / kg tenofovir equivalent) as comparison. Animals were anesthetized with halothane at 1.0, 2.5, 4, 6, 10 and 24 hours after dosing. Take blood from the heart, and take liver and kidney tissue for preservation. At the same time, comparing the drug concentration of the control group taking tenofovir disoproxil fumarate during the same period, it was found that (2R,4S)-2-((((R)-(6-amino-9-yl)propane-...

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PUM

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Abstract

The invention relates to a novel crystal of a tenofovir prodrug (HTS), and specifically discloses the crystal of (2R, 4S)-2-((((R)-(6-amino-9-ly)propane-ly)oxygen)methyl)-(3-chlorophenyl)-2oxygen-1,3,2-dioxaphosphorinsuccinate (HTS), and the prodrug and a preparation method of the crystal.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular, the invention relates to (2R,4S)-2-((((R)-(6-amino-9-yl)propane-9-yl)oxy)methyl)-(3 -Chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinyl succinate (HTS) crystals, pharmaceuticals and preparation methods thereof. Background technique [0002] (2R,4S)-2-((((R)-(6-amino-9-yl)propane-yl)oxy)methyl)-(3-chlorophenyl)-2oxo-1,3,2 – The structure of dioxaphosphorane succinate (herein referred to as HTS) is shown in formula (I): [0003] [0004] The compound is a prodrug compound of tenofovir among the prodrug compounds disclosed in Chinese Patent No. 200510098771.X, and can be used for treating or preventing liver diseases or metabolic diseases, including hepatitis B and the like. However, the prior art does not disclose or suggest crystallographic studies of this compound. [0005] Moreover, when this compound is crystallized, the crystal distribution is very complicated, and most of them...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6574A61K31/675A61P31/14A61P31/18A61P31/20
Inventor 张登科李旭
Owner XIAN XINTONG PHARM RES CO LTD
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