JPH01121272A - Polymorphic substance of benzimidazole derivative - Google Patents

Abstract

NEW MATERIAL:The A-form polymorphic substance of 2-(2-dimethylamino-5- methoxybenzylsulfinyl)benzimidazole expressed by the formula. USE:An antiulcer agent and cell protective agent. PREPARATION:2-(2-Dimethylamino-5-methoxybenzylsulfinyl)benzimidazole is dissolved in methylene chloride and ether is then added thereto. The resultant solution is allowed to stand to afford the aimed A-form polymorphic substance.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the A shadow form of 2-(2-dimethylamino-5-methoxybenzylsulfinyl)benzimidazole represented by the polymorphic form of the benzimidazole derivative.

The present inventors previously discovered that the benzimidazole derivative represented by the above formula (I) has anti-ulcer effects and gastrointestinal cell protective effects, and has filed a patent application (Japanese Unexamined Patent Publication No. 61-221175). . Japanese Patent Publication No. 62-123115).

The present inventors further conducted extensive research on the benzimidazole derivative represented by the above formula (I), and as a result, they discovered an A shadow form that is highly absorbable in the living body, and completed the present invention.

That is, the object of the present invention is to obtain 6.9°, 1°, 0', 12.2°, and 17.0° in the powder xi diffraction spectrum.
A-shape of crystallographically pure 2-(2-dimethylamino-5-methoxybenzylsulfinyl)benzimidazole with peaks at 2°, 2°, 0°, 23.2° and 24.3° It provides form. Furthermore, this polymorph has an infrared absorption spectrum (KBr) of 3
It has an absorption peak at 220 cm-1, and also shows an endothermic peak at 120 to 145°C and an exothermic peak at a temperature higher than the endothermic peak in differential scanning calorimetry.

As used herein, the term "crystallographically substantially pure" means that the content of any other polymorph of the benzimidazole derivative represented by formula (I) is 10% or less, preferably 5%. It means the following A shadow body shape. By the way, the present inventors have discovered that the benzimidazole derivative represented by the above formula (I) exists in at least three different forms, namely A, B and C shadow forms.

Infrared absorption spectra (KBr) are shown in FIGS. 1 to 3, powder X-ray diffraction spectra are shown in FIGS. 4 to 6, and differential scanning calorimetry curves (DSC-TO curves) are shown in FIGS. 7 to 9.

Next, Table 1 shows the characteristic physical property values of the A, B, and C shadow bodies in each spectrum.

Table 1 Physical Properties of Each Crystal Form The measurement equipment and measurement conditions for each spectrum are as follows.

Outside 8 Spectral measurement device: Infrared spectrophotometer (Hitachi model 260-50) Measurement device: Rigaku Corporation TG-DSC measurement conditions: TG: 5mg Full 5caleDSCn±
16mcal/sec Heating rate: 5°/min Next, regarding the bioequivalence of the A shadow shape and the B shadow shape of the benzimidazole derivative represented by the above formula (I), a peagle dog We present the results of a cross-over method using

Experimental Method Experimental Animals Male peagle dogs weighing 8.5 to 13.0 kg were used.

Before dosing - fasted overnight and had free access to water during that time.

Furthermore, water was not given until 2 hours after administration, and food was not given until the end of the test.

Administration and Blood Sampling Method The experiment was conducted using a crossover method with 4 animals per group, and the matcha period was 1 week.

The test drug was suspended in a 1% methylcellulose aqueous solution and administered using a catheter at a dose of 30mg15mJ! ,/kg by force into the stomach.

Approximately 4 mL of blood was collected from the forearm vein over time.

The blood was treated with heparin, immediately cooled on ice, and then rapidly centrifuged to obtain plasma.

Assay method for unchanged drug in plasma: 5ml of plasma, 1M carbonate buffer (pH 9,0)
After adding 1 mL and mixing, add benzene/hexane (1 mL) and mix.
/1) The mixture was extracted with 7HL and analyzed by H-PLC.

The unchanged drug concentration in plasma was calculated by substituting the peak height ratio with respect to the internal standard substance into the equation of a calibration curve prepared in advance.

Statistical Analysis Peagle dogs were divided into two groups: Group 1 and Group II. The first administration group was I-1 (form A crystal administration) and II-1 (form A crystal administration).
The second administration group was 1-2 (form B crystal administration) and IL-2 (form A crystal administration).

Based on the data of the maximum plasma concentration (Cffi, ) and the area on the plasma concentration-time curve (AUG, OO) calculated from the unchanged drug concentration in the plasma of each pegle dog, The bioavailability of type B crystals and type A crystals was compared according to ``Method Explanation''.

Experimental Results The plasma concentrations of the unchanged drug after administration of Form A crystals and Form B crystals are shown in FIG. 10, and the pharmacodynamic parameters determined from the plasma concentration values are shown in Table 2.

Regarding bioequivalence of recrystallized forms C□8 and AUCo
The values of −ω were compared. C□. The average value of type B crystals (0,805 u g/mL) and the average value of type A crystals (1,
080 μg/mL) was 25.5χ for type A crystals. In addition, in Auco-oo, the average value of B type crystal (0
, 864 u g-hr/mL) and the average value of type A crystals (1
, 476u g-hr/mf) is 41
．． It was 5%.

A significant difference was observed between the compounds with a hazard rate of 5%.

The method for manufacturing the A shadow body of the present invention is disclosed in, for example, Japanese Patent Application Laid-Open No. 61-22
It can be obtained by dissolving 2-(2-dimethylamino-5-methoxybenzylsulfinyl)benzimidazole obtained by the method described in No. 1175 in methylene chloride, adding ether thereto and leaving it to stand. Also, 2-
Dissolving (2-dimethylamino-5-methoxybenzylsulfinyl)benzimidazole in methylene chloride,
It can be obtained by adding ethyl acetate, cooling, and standing still.

For crystal formation, it is preferable to allow the crystals to stand still under cooling, and it is preferable to filter the crystals as soon as they are precipitated. In addition, it is desirable to inoculate in order to generate crystals.

The pharmaceutical composition containing the A shadow form of the benzimidazole derivative of the present invention is useful both as an antiulcer agent and a cytoprotective agent, and can be administered orally or parenterally.
It is useful for preventing gastric acid secretion, treating symptoms accompanied by excessive gastric acid secretion, and for treating or preventing gastrointestinal inflammatory diseases that are not caused by gastric acid.

The above-mentioned pharmaceutical composition is prepared by adding additional ingredients to the A shadow form of the present invention according to a conventional technique, and is administered orally or parenterally. Examples of dosage forms for oral administration include tablets, capsules, powders, and granules. For their preparation, conventional excipients, disintegrants, binders, lubricants, dyes, diluents, etc. are used. As an excipient,
Glucose, white sugar, lactose, microcrystalline cellulose, etc. are used as disintegrants, starch, carboxymethyl cellulose calcium, etc. are used as lubricants, talc, hydrogenated oil, etc. are used as binders, and hydroxypropylcellulose, gelatin, polyvinylpyrrolidone, etc. are used as binders. is used. In addition,
The above classification of uses of each additive is for convenience and does not limit the action of each additive.

The dosage for oral administration of the A shadow form of the present invention to adults is usually 500 mg or less, preferably about 11 mg per day.
The dosage ranges from 00P to 300mg, but it can be increased or decreased depending on age, symptoms, etc.

As mentioned above, the A shadow form of the benzimidazole derivative represented by formula (1,) of the present invention is bioequivalent to the B shadow form when administered orally using pegle dogs. It was shown that absorption was significantly better in the test of A
Shadow forms are crystalline forms useful as pharmaceuticals.

Next, the present invention will be explained in more detail by giving examples and reference examples.

Reference Example 1 40 g of 2-(2-dimethylamino-5-methoxybenzylthio)benzimidazole was dissolved in 120 ml of methylene chloride.
! , and dissolved in 120 mL of methanol, and under cooling, 30 mg of acetic acid / 3 s mL % of 35 χ hydrogen peroxide solution was added, and then 2.4 g of ammonium metavanadate was added, and 2 to 5
Stir at ℃ for 4 hours.

Neutralize acetic acid with saturated NaHCO3 water, separate the organic layer, 1
Wash with 0% sodium thiosulfate. INN in this water layer
After adding 130 mL of aOH and shaking, separate the aqueous layer. Next, 20% HH4CL and methylene chloride were added to the aqueous layer and after shaking, the organic layer was separated and dried over Na2SO4. The drying agent is filtered off, 17.28 g of 28% sodium methylate (methanol solution) is added to the filtrate, methylene chloride is distilled off under reduced pressure, and 120 n+L of ethyl acetate is added to the residue, followed by stirring.

The precipitated crystals were filtered off to obtain 3.8 g of crude crystals of the sodium salt of the title compound. This crude crystal was mixed with ethyl acetate 60+
Suspend in ++L and dissolve by adding 12ml (L) of methanol.

This was distilled off under reduced pressure until the content became about 50 g, and 90 mL of ethyl acetate was added and stirred for 1 hour. The precipitated crystals were filtered off to obtain 22.0 g of the sodium salt of the title compound. This was suspended in 90 ml of methylene chloride, and 10% N
Add H4CL aqueous solution, shake, separate organic layer, and Na2S
Dry with O4. Methylene chloride was distilled off under reduced pressure, 90 mL of ethyl acetate was added to the oily residue, and the mixture was allowed to stand for 2 hours under water cooling. The precipitated crystals were collected by filtration and dried under reduced pressure at room temperature to obtain 13.3 g (31, a%) of the title compound as white crystals.

121 Example I A No. 1 0g of the compound obtained in Reference Example 1 was dissolved in 80m2 of methylene chloride with heating, and the mixture was heated in a hot bath at 40 to 45°C until the remaining amount of methylene chloride became 20g. Concentrate. After returning to room temperature, add 60 mL of ether and let stand for 3 hours. The precipitated crystals are collected by filtration, washed and immediately dried under reduced pressure.

Note that during filtration and washing, handle the crystals as gently as possible. From the above operations, 7.0 g of type A crystals are obtained.

Example 2 Concentrate until the remaining amount is about 70 g. Add 600ml of ice-cooled ethyl acetate to this? , and let stand at -40 to 20°C for 4 hours. The precipitated crystals are collected by filtration, washed and immediately dried under reduced pressure. Note that during filtration and washing, handle the crystals as gently as possible. From the above operations, 86 g of type A crystals are obtained.

Reference Example 2 50 g of the compound obtained in Reference Example 1 was dissolved in 180 INNNNaOH and filtered. This was added dropwise to a mixed solution of 230 mfL of lNH34C color and 230 mL of ethanol over 30 minutes.
Stir for an additional hour. The precipitated crystals were collected by filtration, thoroughly washed with water, and dried under reduced pressure to obtain 47.8 g of type B crystals.
get.

Reference Example 3 Production method of C-shape body 5.00 g of the compound obtained in Reference Example 1 was added to methylene chloride
0m, l! , and concentrated under reduced pressure at a bath temperature of 45°C. Before crystals precipitate, 30 mL of 98χ hydrous ethyl acetate is added to make the mixture uniform, and the mixture is allowed to stand for 4.5 hours under water cooling. The precipitated crystals are collected by filtration, washed and immediately dried under reduced pressure. Note that during filtration and washing, handle the crystals as gently as possible. By the above operations, 3.8 g of type C crystals are obtained.

[Brief explanation of the drawing]

1 to 3 show infrared absorption spectra of A, B, and C shadow bodies, FIGS. 4 to 6 show powder X-ray diffraction spectra, and FIGS. 7 to 9 show differential scanning calorimetry curves. (
psc-Ta curve) is shown. FIG. 10 shows changes in the plasma unchanged drug concentration after administration of A shadow shape and B shadow shape in pegle dogs. In each spectrum of FIGS. 1 to 9, the symbol "ma" indicates a characteristic peak.

Claims (1)

[Claims] In the powder X-ray diffraction spectrum, 6.9°, 10.0
Crystallographically pure 2-(2-dimethylamino-5-methoxy) with peaks at Form A polymorph of benzylsulfinyl)benzimidazole.