Entecavir acid addition salt, preparation method and use thereof

A technology of endecavir and acid addition salt, which is applied in the field of endecavir acid addition salt and its preparation and use, and can solve the problems of low solubility of endecavir and unfavorable preparation of pharmaceutical preparations and the like

Active Publication Date: 2007-02-07
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the low solubility of endecavir in water, it is not conducive to the preparation of pharmaceutical preparations

Method used

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  • Entecavir acid addition salt, preparation method and use thereof
  • Entecavir acid addition salt, preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1 [1S-(1α, 3α, 4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl] -6H-purin-6-one hydrochloride

[0025] [1S-(1α,3α,4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H - Purin-6-one (2.8g) and hydrochloric acid (2ml of 6N hydrochloric acid) were dissolved in 500ml of absolute ethanol, heated to reflux until dissolved, the hot solution was filtered through celite, then slowly cooled under gentle stirring, placed in 0- It was placed in a refrigerator at 5°C for several hours, and the endecavir hydrochloride was filtered out, washed with absolute ethanol, and dried under vacuum at 40°C to obtain 2.2 g of product with a yield of 70%, m.p. 240-243°C.

Embodiment 2

[0026] Example 2 [1S-(1α, 3α, 4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl] -6H-purin-6-one maleate

[0027] [1S-(1α,3α,4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H -Purin-6-one (2.8g) and maleic acid (1.2g) were dissolved in 800ml of absolute ethanol, heated to reflux until dissolved, the hot solution was filtered through celite, then slowly cooled under gentle stirring, at 0 After standing in a -5°C refrigerator for several hours, the endecavir maleate was filtered out, washed with absolute ethanol, and vacuum-dried at 40°C to obtain 2.75 g of product, yield 70%, m.p. 210-212°C.

Embodiment 3

[0028] Example 3 Accelerated Stability Test

[0029] Sample

Taste

time

(moon)

Exterior

Content (%)

A

0

1

2

3

6

off-white

off-white

off-white

off-white

off-white

98.79

98.69

98.61

98.55

98.50

B

0

1

2

3

6

off-white

off-white

off-white

off-white

off-white

99.21

99.06

99.03

99.00

98.88

C

0

1

2

3

6

off-white

off-white

off-white

off-white

off-white

99.51

99.36

99.20

99.05

98.86

[0030] A: [1S-(1α,3α,4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]- 6H-purin-6-one hydrochloride

[0031] B: [1S-(1α,3α,4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]- 6H-purin-6-one maleate

[0032] C: [1S-(1α,3α,4β)]-2...

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PUM

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Abstract

The invention discloses a soluble Endicarwei acid additional salt or tautomer or drug solvate and utility, which resists hepatitis B virus.

Description

technical field [0001] The present invention relates to a new class of entecavir derivatives, preparation methods of these compounds, pharmaceutical compositions containing these compounds, and medicinal uses of these compounds and compositions. Background technique [0002] Endecavir (entecavir), chemical name is [1S-(1α,3α,4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2- Methylenecyclopentyl]-6H-purin-6-one is an antiviral drug for the treatment of hepatitis B virus infection. U.S. Patent 5,206,244 discloses entecavir compounds, their preparation and use in the treatment of hepatitis B. [0003] Chinese patent application "low-dose entecavir preparation and its application" (application number 00126403.6) mentioned: in the process of preparing low-dose entecavir solid preparation, involving the step of dissolving entecavir in water, At this time, it is necessary to increase the solubility of Endecavir by adjusting the pH to be acidic. Due to the low solubility...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/18A61K31/522A61P31/12A61P31/20A61P1/16
Inventor 杨玲张喜全
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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