Hydrate of medicinal salt of Fasudil

A technology of fasudil and medicinal salts, which is applied in the directions of drug combinations, medical preparations containing active ingredients, medicinal formulas, etc., can solve the problems of limited clinical application, instability to humidity, etc.

Inactive Publication Date: 2007-12-26
SHANDONG XUANZHU PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Currently on the market is fasudil hydrochloride hemihydrate (C 14 h 17 N 3 o 2 S·HCl·1 / 2H 2 O), has hygroscopicity, is unstable to humidity, needs shading airtight preservation, has limited its clinical application

Method used

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  • Hydrate of medicinal salt of Fasudil
  • Hydrate of medicinal salt of Fasudil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] The preparation of embodiment 1 Fasudil

[0052] (1) Weigh 100g (0.48mol) of 5-isoquinolinesulfonic acid and add it to a 2000ml four-necked bottle equipped with reflux condensation and a constant pressure dropping funnel, add 400ml of thionyl chloride, stir and heat up, and drop Add 80 ml of dimethylformamide (DMF). After the addition was completed, the temperature was raised to 80° C., and the reaction was carried out with heat preservation, the color gradually changed to dark yellow, and the reaction was completed in 2 hours. Concentrate the reaction solution to dryness, add 1000ml of dichloromethane, stir evenly, freeze for 4 hours, filter with suction, and vacuum-dry the filter cake to obtain 110g of white powder, which is 5-isoquinolinesulfonyl chloride hydrochloride.

[0053] (2) Add the 5-isoquinolinesulfonyl chloride hydrochloride obtained in the previous step into ice water, adjust the pH value to 5-6 with saturated sodium bicarbonate solution under stirring,...

Embodiment 2

[0055] Example 2 Preparation and Structure Confirmation of Fasudil Nitrate and Its Hydrate

[0056] 2.1 Preparation and structure confirmation of fasudil nitrate

[0057] Take by weighing 20 g (about 69 mmol) of the pale yellow oil obtained in Example 1, be dissolved in 50 ml of absolute ethanol, and under ice bath and stirring condition, adjust the pH value to 3 with 10% nitric acid ethanol solution, and the obtained The solution was frozen for 4 hours and filtered, the filter cake was washed once with a small amount of absolute ethanol, filtered, and the filter cake was dried at 120°C for 8 hours to obtain 22.1 g of fasudil nitrate anhydrous white solid, yield: 88.6%, melting point: 218~220℃.

[0058] Elemental analysis (C 14 h 17 N 3 o2 S·HNO 3 ): C, 47.39%; H, 5.17%; N, 15.80%; S, 9.02%; Theoretical: C, 47.45%; H, 5.12%; N, 15.81%; S, 9.05%.

[0059] IR(KBr)cm -1 : 3378, 2915, 2538, 1620, 1466, 1324, 1150, 1133, 1015, 950, 824, 759, 711.

[0060] 2.2 Preparation ...

Embodiment 3

[0066] Example 3 Preparation and Structure Confirmation of Fasudil Sulfate and Its Hydrate

[0067] 3.1 Preparation and structure confirmation of fasudil nitrate

[0068] Take by weighing 20g (about 69mmol) of light yellow oily matter gained in Example 1, be dissolved in the dehydrated alcohol of 50ml, under ice-bath and stirring condition, adjust pH value to 3 with 10% sulfuric acid ethanol solution, obtain The solution was frozen for 4 hours and filtered, the filter cake was washed once with a small amount of absolute ethanol, filtered, and the filter cake was dried at 120° C. for 8 hours to obtain 20.3 g of a white solid, namely fasudil anhydrous sulfate. Yield: 84.7%, melting point: 215-220°C.

[0069] Elemental analysis (C 14 h 17 N 3 o 2 S 1 / 2H 2 SO 4 ): C, 49.35%; H, 5.37%; N, 12.33%; S, 14.12%; Theoretical: C, 49.40%; H, 5.33%; N, 12.34%; S, 14.13%.

[0070] IR(KBr)cm -1 : 3384, 2918, 2543, 1625, 1460, 1330, 1159, 1140, 1017, 956, 831, 765, 718.

[0071] 3....

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Abstract

This invention discloses hydrates of pharmaceutical salts of hexahydro-1-(5-sulfonylisoquinoline)-1H-1,4-diaza, i.e., fasudil, especially semi-hydrates of nitrate, sulfate, hydrobromide and mesylate of fasudil, their preparation method, and their application in drugs for preventing and / or treating cardio-cerebrovascular diseases. The hydrates of pharmaceutical salts of fasudil have such advantages as high stability and high solubility, and can be manufactured into various preparations with other active components and / or pharmaceutically acceptable carriers. The method has such advantages as simple process, high drug purity, high yield, and stable product quality, and is suitable for industrial production.

Description

1. Technical field [0001] The present invention relates to the hydrate of hexahydro-1-(5-sulfonylisoquinoline)-1H-1,4-diazepine that is the medicinal salt of fasudil, especially fasudil nitrate, The hemihydrate of sulfate, hydrobromide and methanesulfonate, and its preparation method and application belong to the technical field of medicine. 2. Background technology [0002] Fasudil is an isoquinoline sulfonamide derivative, the chemical name is hexahydro-1-(5-sulfonylisoquinoline)-1H-1,4-diazepine, the English name is fasudil, and it is produced by Japan Asahi Kasei Co., Ltd. The Rho-kinase inhibitor researched and developed by Asahi Kasei Pharma has a powerful vasodilator effect and the effect of protecting ischemic brain tissue. Launched in Japan in 1995, it is used to improve cerebral vasospasm after subarachnoid hemorrhage and subsequent cerebral ischemic symptoms. Launched in China in 2002, the indication is the improvement of symptoms of ischemic cerebrovascular dis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12A61K31/551A61P9/00A61P9/10
Inventor 黄振华
Owner SHANDONG XUANZHU PHARMA TECH CO LTD
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