JPH0971582A - 1-(5-isoquinolinesulfonyl)homopiperazine hydrochloride hemihydrate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new 1-(5-isoquinolinesulfonyl)homopiperazine hydrochloride hemihydrate which is excellent in temperature stability with no problem on its storability and production, has the vasodilator action and is useful in improvement of cerebrovascular spasm and cerebral ischemic diseases accompanied by the spasm. SOLUTION: This homopiperazine has the following properties: the water content: 2.5-3.1% (according to the Karl Fischer method); the infrared absorption spectrum (in Nujol): 1620, 1592, 1140cm<-1> . This compound is prepared by allowing homopiperazine with 5-isoquinolinesulfonyl chloride, dissolving the product, 1-(5-isoquinolinesulfonyl)homopiperazine hydrochloride anhydrous crystal in heated water, filtering the solution with a membrane filter and crystallizing out the 1-(5-isoquinolinesulfonyl)homopiperazine hydrochloride trihydrate, as the filtrate is kept at 5 deg.C and drying the crystals at 40 deg.C for 10hours.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention has a property of excellent stability and is easily obtained in the production process 1- (5-
Isoquinolinesulfonyl) homopiperazine [1- (5-
isoquinolinesulfonyl) homo
piperazine] hydrochloride.

[0002]

2. Description of the Related Art 1- (5-Isoquinolinesulfonyl) homopiperazine (hereinafter abbreviated as [fasudil]) is an isoquinoline sulfonic acid amide compound discovered by Asahi Kasei Kogyo Co., Ltd. Known [Japanese Patent Laid-Open No. 61-227581, USP
4,678,783, EP publication 0,187,3
71, etc.]. The hydrochloride salt (fasudil hydrochloride) is an anhydrous crystal having a melting point of 217 to 223 ° C., which is easily soluble in water.

Fasudil hydrochloride has an excellent vasodilatory effect and is a trade name of Eril Injection (registered trademark; Asahi Kasei Co., Ltd.), which is used as a preparation for oral administration or a preparation for injection.
It is clinically applied for the purpose of improving cerebral vasospasm after subarachnoid hemorrhage and cerebral ischemic symptoms accompanying it. The dosage and administration is usually 30 times for adults as Fasudil hydrochloride once.
Dilute mg to an appropriate amount of electrolyte or sugar solution and
Infuse intravenously 3 times over 30 minutes. The administration of this drug should be started early after the operation after subarachnoid hemorrhage, and it is desirable to administer it for 2 weeks, and 30 mg / ampoule is intravenously administered 3 times a day.

Conventionally, the crystals of fasudil hydrochloride were anhydrous.
Only crystals have been reported and the anhydrous crystals are single
Contains less than a certain amount of water (hereinafter referred to simply as%) (curl)
Fisher method; the same applies hereinafter). To the anhydrous crystals
Infrared absorption spectrum with an infrared spectrophotometer (Nujo
Method; hereinafter the same) is as shown in FIG.
8 cm^-1Vicinity (Skeletal vibration based on the isoquinoline skeleton, ν
aromatic), 1588cm^-1Neighborhood (in the isoquinoline skeleton
Based skeletal vibration, νaromatic), 1338 cm ^-1near
(Antisymmetric stretching vibration of sulfonamide, νantisymmetricS
O2), 1160 cm^-1Near (symmetrical expansion and contraction of sulfonamide
Vibration and νsymmetric SO2)
X-ray diffraction (manufactured by Rigaku Denki Kogyo;
-7, Target: Cu, Kv-mA: 30-10,
The diffraction angle (2θ) of Filter: Ni;
14.7, 16.6, 17.5, 20.5, 24.6,
Around 25.5 (with an error range of ± 0.2)
, A characteristic diffraction angle is recognized especially near 17.5 and 24.6.
Can be

Thermal analysis (manufactured by Rigaku Denki Kogyo; TAS-2)
In (00), the anhydrous crystal of fasudil hydrochloride showed only the endothermic peak at the melting point peculiar to the anhydrous crystal as shown in FIG.

[0006]

DISCLOSURE OF THE INVENTION The present inventors first of all,
A new fasudil hydrochloride trihydrate was found to be good for tableting fasudil hydrochloride (Japanese Patent Application No. 7-163341), and the trihydrate was about 1: 1.
It contains water of 4.0 to 15.5% (theoretical value of 14.2%), and the infrared absorption spectrum by the infrared spectrophotometer is as shown in Fig. 3, around 1630 cm ^-1 (skeletal vibration based on the isoquinoline skeleton). , Νaromatic), around 1598 cm ^-1 (skeletal vibration based on the isoquinoline skeleton, νaromatic), 11
Around 50 cm ^-1 (symmetric stretching vibration of sulfonamide, νsy
mmetricSO2) has a characteristic infrared absorption spectrum for each wave number, and the powder X-ray diffraction diffraction angle (2θ) is 14.2,
It is in the vicinity of 16.3, 16.9, 23.1, 25.7 and 36.8, and a characteristic diffraction angle is recognized particularly in the vicinity of 23.1 and 36.8.

Thermal analysis (manufactured by Rigaku Denki Kogyo; TAS-2)
(00), fasudil hydrochloride trihydrate showed an endothermic peak peculiar to the trihydrate as shown in FIG. However, under the conditions of 40 ° C. and 75% relative humidity (RH), the water content of this fasudil trihydrate decreased from around 14.1% with the passage of time, and finally decreased from 2.8% to 3.0%.
%, It was found that the water content changed.

Therefore, when storing fasudil hydrochloride trihydrate, it is necessary to control the temperature below 40 ° C., which is extremely difficult in reality, and there is a problem in storage and production, and one having good stability is required. It was wanted.

[0009]

Under the circumstances, the inventors of the present invention have made various studies to solve the above-mentioned problems, and as a result, new crystals other than this fasudil hydrochloride trihydrate are present, and the crystals are temperature stable. It was found that the property is good. This crystal is a hemihydrate of fasudil hydrochloride,
It is a stable one with no change in water content under the conditions of 40 ° C and 75% RH for 96 hours, and as a result, about 2.5 to 3.1% (theoretical value 2.67%). The infrared absorption spectrum of the infrared spectrophotometer is as shown in FIG. 5, and the moisture content is around 1620 cm ⁻¹ (skeleton vibration based on the isoquinoline skeleton, νaromatic), 159
Around 2 cm ^-1 (skeletal vibration based on the isoquinoline skeleton, ν
aromatic), having a characteristic infrared absorption spectrum at each wave number near 1140 cm ^-1 (symmetric stretching vibration of sulfonamide, νsymmetricSO2), and diffraction angle (2θ) of powder X-ray diffraction
Is 8.4, 12.4, 14.0, 16.2, 16.8,
It is around 18.2, 19.5, 22.4, 25.6,
In particular, characteristic diffraction angles are recognized around 14.0 and 18.2.

Also in the thermal analysis, fasudil hydrochloride 1 /
As shown in FIG. 6, the dihydrate showed an endothermic peak peculiar to the hemihydrate. The present invention has been completed based on the above findings, and provides a fasudil hydrochloride hemihydrate characterized by having the following properties. (1) Water content 2.5-3.1% (Karl Fischer method) (2) Infrared absorption spectrum (Nujol method) Absorption near 1620, 1592, 1140 cm ^{-1 In} producing the crystal of the present invention, for example, The anhydrous crude crystals of fasudil hydrochloride, which can be produced by the method described in the literature relating to the above-mentioned chemical synthesis method, are dissolved in warm water of 40 to 80 ° C. to a concentration of 40 to 50%, and the solution is a membrane filter. After filtration with, the mixture is stirred under a temperature condition of 0 to 5 ° C. for 2 days and cooled for crystallization. The precipitated crystals are dried at 20 to 25 ° C. to produce Fasudil hydrochloride trihydrate, and the Fasudil hydrochloride trihydrate is dried at 40 ° C. to 70 ° C. for 2 to 100 hours. As a result, the target fasudil hydrochloride hemihydrate can be obtained.

1 of the fasudil hydrochloride thus obtained
/ 2 hydrate LD ₅₀ in mice (male) oral acute toxicity test was 280~285mg / kg, rat LD ₅₀ for the (male) oral acute toxicity test 345-36
It was 0 mg / kg. On the other hand, in terms of efficacy, increased femoral artery and vertebral artery blood flow in dogs was intravenously administered 0.3 m
When measured in g / kg, the increase in blood flow in the femoral artery is 45
%, An increase in blood flow in the vertebral artery was observed at 198%, which was a good result.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION Next, the present invention will be specifically described with reference to Reference Examples, Examples and Test Examples, but the present invention is not limited thereto.

[0013]

Reference Example 1 A chloroform solution (40 l) of 5-isoquinolinesulfonyl chloride (5.0 kg) was added dropwise to a chloroform solution (40 l) of homopiperazine (8.8 kg) under ice cooling for 1 hour. After stirring and reaction for 1 hour under ice cooling, the reaction solution was extracted with a 2N aqueous hydrochloric acid solution. The aqueous layer was adjusted to pH 10 with 10% aqueous sodium hydroxide solution and extracted with chloroform (80 l). The chloroform layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue is silica gel (Wako gel C-200) 1
It was separated by column chromatography using 50 kg of a developing solvent 5% methanol / chloroform (volume ratio) to obtain Fasudil (6.01 kg, 89%). Elemental analysis value; () Theoretical value C: 57.59% (57.71%), H: 5.92%
(5.88%), N: 14.29% (14.42%),
S: 10.83% (11.00%) 2.0 kg of this fasudil was suspended in methanol (10 l), water (10 l) and 1N hydrochloric acid aqueous solution 6.57 l
Was added, and the mixture was heated to 40 ° C. and dissolved. The solution was evaporated to dryness under reduced pressure and recrystallized with 5 l of water: methanol (volume ratio 2: 1),
The precipitated fasudil hydrochloride was dried at 120 ° C. for 8 hours to obtain fasudil hydrochloride (2.01 kg, 89%). Elemental analysis value; theoretical value in parentheses C: 51.01% (51.29%), H: 5.47%
(5.53%), N: 12.80% (12.82%),
S: 10.14% (9.78%), Cl: 10.53%
(10.81%) The water content of this product is 0.33% (Karl Fischer method)
1, the infrared absorption spectrum is shown in FIG. 1, and the diffraction angles (2θ) of the powder X-ray diffraction are 14.7, 16.6, 17.5,
It was around 20.5, 24.6, and 25.5. Also in the thermal analysis, as shown in FIG. 2, the analysis result peculiar to the anhydride was shown.

[0014]

Reference Example 2 210 g of anhydrous fasudil hydrochloride crystals obtained in Reference Example 1 above was dissolved in 525 ml of water heated to 50 ° C., filtered through a membrane (0.8 μm) filter, and the filtrate was kept at 5 ° C. Crystallization was performed by cooling by stirring for 2 days. The precipitated crystals are suction filtered and then at 25 ° C.
After drying for 6 hours, 190 g (yield 78%) of fasudil hydrochloride trihydrate was obtained.

The water content of this product is 14.0% to 15.5%.
(Theoretical value of Karl Fischer method is 14.2%), and the infrared absorption spectrum is shown in FIG.
θ) is 14.2, 16.3, 16.9, 23.1, 2
It was around 5.7 and 36.8, and the thermal analysis also showed the analysis result peculiar to the trihydrate as shown in FIG.

[0016]

Example 1 Fasudil hydrochloride 3 obtained in Reference Example 2 above
190g of hydrate is dried at 40 ° C for 10 hours (75% RH)
And 167 g of fasudil hydrochloride hemihydrate (yield 100
%) Was obtained. The water content of this product was 2.5% to 3.1% (Karl Fischer method theoretical value 2.67%), and the infrared absorption spectrum is shown in FIG. 5 and the diffraction angle (2θ) of powder X-ray diffraction is shown in FIG.
Is 8.4, 12.4, 14.0, 16.2, 16.8,
It is around 18.2, 19.5, 22.4, 25.6,
Further, in the thermal analysis, as shown in FIG. 6, the analysis result peculiar to the hemihydrate was shown.

[0017]

Test Example 1 Fasudil hydrochloride hemihydrate of the present invention and 200 mg of the anhydrous crystals of fasudil hydrochloride obtained in Reference Example 1 were accurately weighed, and each using a 8 mmφ, 12R die and hand press. Tableting pressure (400-1,4
00 Kg) was used for tableting, and the tableting height was measured (TS-50N, manufactured by Okada Seiko) to compare and investigate the moldability of hemihydrate and anhydrous crystals.

The results are shown in Table 1.

[0019]

[Table 1]

As shown in FIG. As is clear from Table 1, the tablet hardness of anhydrous crystals increased as the tableting pressure increased, but the tableting pressure of 1,400 Kg was necessary to obtain the tablet hardness of 8 Kg. On the other hand, hemihydrate shows higher tablet hardness due to lower tableting pressure than the case of anhydrous crystals,
Good moldability was exhibited.

[0021]

[Test Example 2] 20 g each of Fasudil hydrochloride hemihydrate and Fasudil hydrochloride trihydrate of the present invention were placed in a Petri dish and kept at 40 ° C. and 75% RH in a constant temperature and humidity chamber (PH-2G). The mold was left in an open state and the change in water content with time was measured by a Karl Fischer device. The temperature stability of trihydrate and hemihydrate was compared and examined by measuring the change with time of water content under these conditions.

The results are shown in Table 2 and FIG. 7 (in the figure, ●-● indicates a trihydrate, and ○-○ indicates a hemihydrate).

[0023]

[Table 2]

As shown in Table 2, in the case of fasudil hydrochloride trihydrate, the water content changed from 14.11% to 2.1 after 2 hours.
The hemihydrate of the present invention showed good temperature stability, while the water content did not change, while it was unstable, changing to 99%. Further, the hemihydrate of the present invention was stable even after 96 hours under the same conditions.

[0025]

INDUSTRIAL APPLICABILITY The fasudil hydrochloride hemihydrate of the present invention is considered to be a crystalline form which is more stable against temperature than the fasudil hydrochloride trihydrate and has no problems in storage and production. .

[Brief description of drawings]

FIG. 1 is an infrared absorption spectrum diagram of anhydrous fasudil hydrochloride.

FIG. 2 is a thermal analysis chart of fasudil hydrochloride anhydrous.

FIG. 3 is an infrared absorption spectrum diagram of fasudil hydrochloride trihydrate.

FIG. 4 is a thermal analysis chart of fasudil hydrochloride trihydrate.

FIG. 5 is an infrared absorption spectrum diagram of fasudil hydrochloride hemihydrate.

FIG. 6 is a thermal analysis chart of fasudil hydrochloride hemihydrate.

FIG. 7 is a time-dependent change diagram of water content of Fasudil hydrochloride hemihydrate and Fasudil hydrochloride trihydrate at 40 ° C. and 75% RH.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display area C07D 243: 08)

Claims (1)

[Claims] 1. A 1-characterized product having the following properties:
(5-Isoquinolinesulfonyl) homopiperazine hydrochloride hemihydrate (1) Water content 2.5-3.1% (Karl Fischer method) (2) Infrared absorption spectrum (Nujol method) 1620, 1592, 1140 cm Absorption near ^-1