JPH0930970A - Antibacterial agent - Google Patents

Abstract

(57) [Summary] [Objective] To provide a compound effective for eradication of Helicobacter pylori. [Constitution] Formula [Formula 1] An antibacterial agent comprising a compound represented by: or a pharmaceutically acceptable salt thereof as an active ingredient.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an antibacterial agent.
More specifically, it relates to an antibacterial agent having an anti-Helicobacter action.

[0002]

2. Description of the Related Art Conventionally, since hydrochloric acid exists in the stomach, an environment not suitable for the growth of bacteria has been created, and it has been considered that bacteria do not inhabit the stomach. However, recently helicobacter pylori (Helicobacter pylori)
ori) was isolated (Goodwin, C, S. et a
Int. J. Syst. Bact. 39: 397-405, 1989). Furthermore, it has been revealed that Helicobacter pylori is involved in more than 80% of the causes of gastritis, and it is becoming clear that it is one of the largest causes of recurrence of peptic ulcer, especially duodenal ulcer. Moreover, it is becoming clear that persistent Helicobacter pylori infection causes atrophy of gastric mucosa and in turn metaplasia of intestinal epithelium, and is closely related to the development of gastric cancer, particularly differentiated gastric cancer.

Although a perfect eradication method for Helicobacter pylori has not been found yet, the combination of bismuth preparation, metronidazole, amoxicillin or tetracycline is considered to be most effective. In addition, anti-Helicobacter pylori action was observed for proton pump inhibitors,
Combination therapy with a proton pump inhibitor and amoxicillin is also under consideration (Iwahi, T. et al. Antimicrob. Agent
S. Chemother 35: 490-496, 1991). It has also been reported that the recurrence rate of duodenal ulcer and gastric ulcer was clearly lower in Helicobacter pylori-positive patients than in the Helicobacter pylori-positive group (Hentschel, E. et al. N. Engl. J.
Med. 328: 308-312,1993, Graham, DY et al. Ann. I
ntern. Med. 116: 705-708, 1992).

[0004]

As described above, eradication of Helicobacter pylori is useful as a fundamental treatment method for preventing recurrence of peptic ulcer, which has been impossible by any of the above treatment methods. In addition, Helicobacter pylori infection also has a character as a chronic infectious disease, and is diversified due to differences in the time of infection and bacterial species, and differences in the immune reaction against Helicobacter pylori on the host side.

[0005]

[Means for Solving the Problems] In view of the above problems, the present inventors have conducted various studies on compounds effective for eradication of Helicobacter pylori, and as a result, certain aminoalkylpyridyloxy derivatives have an antibacterial action against Helicobacter pylori. The present invention has been completed and the present invention has been completed. That is,
The present invention uses the formula

Embedded image It is an antibacterial agent containing a compound represented by or a pharmaceutically acceptable salt as an active ingredient.

1-amino-2- [4- <4- (1-piperidinomethyl) pyridyl-2-oxy> -cis-2-butenylamino] -1 represented by the formula (I) which is an active ingredient of the present invention. -Cyclobutene-3,4-dione compound (hereinafter referred to as the compound of the present invention) is disclosed in JP-A-61-85365.
It is a known compound disclosed in Example 1 of the publication. It is clarified in this publication that this compound has a histamine H ₂ receptor antagonistic action, an inhibitory effect on gastric acid secretion in animals, and a protective effect on mucous membranes and a mucus secretion promoting effect. However, the publication does not describe or suggest that the compound of the present invention has an antibacterial activity as an antibacterial agent, particularly against Helicobacter pylori.

The pharmaceutically acceptable salts of the present invention are salts of mineral acids such as hydrochlorides and sulfates, and organic acid salts such as maleates, malonates, oxalates and tartrates. JP-A-3
-251571 discloses the hydrochloride salt of the compound of the present invention. The publication discloses the utility of this hydrochloride salt, ie that the hydrochloride salt shows a stable composition even in the surrounding wet state. However, in this publication, there is no description or suggestion that the compound of the present invention has an antibacterial action against Helicobacter pylori, especially as an antibacterial agent. This hydrochloride is particularly useful as an active ingredient of the antibacterial agent of the present invention.

Although the dose of the compound of the present invention varies depending on the symptoms, a single dose for an adult is usually 1 mg to 100 m.
g, preferably 5 mg to 80 mg. The dosage form may be oral, injection, or rectal suppository. When preparing an injection, a pH adjusting agent, a buffer, a stabilizer, an excipient, etc. may be added to the above-mentioned main drug. When preparing a solid preparation for oral use, an excipient, and if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent, a flavoring agent, etc. are added, and then tablets and coatings are carried out by a conventional method. Tablets, granules, powders, capsules and the like can be made.

[0009]

According to the present invention, an antibacterial agent having an anti-Helicobacter pylori action is provided. According to the present invention,
By eradicating Helicobacter pylori, it is effective in preventing recurrence of peptic ulcer such as duodenal ulcer and gastric ulcer, and is also useful in preventing gastric cancer.

[0010]

EXAMPLES The present invention will be specifically described below with reference to examples and test examples. Example 1 (Liquid formulation) Compound of the present invention 5 parts by weight Sodium chloride 10 parts by weight Water 85 parts by weight It was manufactured according to the item of General Rules for Injectable Preparations of the Japanese Pharmacopoeia.

Example 2 (Tablet formulation) Compound of the present invention 10 parts by weight Lactose 39 parts by weight Starch 40 parts by weight Hydroxypropyl cellulose 10 parts by weight Magnesium stearate 1 part by weight Manufactured in accordance with the Japanese Pharmacopoeia General Rules Injection. .

Example 3 (Granule formulation) Compound of the present invention 10 parts by weight Mannitol 54.4 parts by weight Starch 30 parts by weight Hydroxypropyl cellulose 5 parts by weight Magnesium stearate 0.5 parts by weight It was manufactured according to.

Test Example 1 (Sample) The compound of the present invention was prepared from dimethyl sulfoxide (DMS).
O) and dissolved in DMSO to make a 2-culture dilution series. When measuring the antibacterial activity, the solution and the medium were mixed at a ratio of 1:99. The chemical names and structural formulas of the compounds of the present invention used are shown below. (Z) -3-Amino-4- [4- [4- (4-piperidinomethyl) -2-pyridyloxy] -2-butenylamino] -3-cyclobutene-1,2-dione monohydrochloride.

Embedded image

(Test method) The antibacterial activity was measured by the agar plate dilution method according to the standard method of the Japanese Society of Chemotherapy. As a susceptibility measurement medium, Blood Agar Base No2 (manufactured by OXOID) supplemented with horse defibrinated blood (manufactured by Japan Biomaterials Center) at 5% was used. Inoculate the medium with 10 ⁶ cfu / ml of the bacterium, and under the condition of 10% carbon dioxide gas, at 35 ° C, 72
Cultured for hours. Antibacterial activity is the minimum drug concentration (MIC: minimum inhibitory concentration, μg /
ml).

(Results) The results are shown in Table 1. Table 1 H.pylori H.pylori H.pylori Test compound ATCC43504 ATCC43579 ATCC43629 Compound of the present invention 50 25 25 Famotidine> 800 800> 800 Cimetidine>800>800> 800 Ranitidine>800>800> 800 *: Not a simultaneous comparison. It is shown in the table as a reference value. As is clear from Table 1, the antibacterial activity (MIC) of the compound represented by formula (I), which is the active ingredient of the present invention, against Helicobacter pylori was 25 to 50 μg / ml.

Claims (1)

[Claims] (1) Formula (1) An antibacterial agent comprising a compound represented by: or a pharmaceutically acceptable salt thereof as an active ingredient.