JP3490146B2 - Anti-Helicobacter pylori agent - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an anti-Helicobacter pylori agent which is effective as a preventive agent for the development of gastric ulcer, duodenal ulcer, etc., and as a preventive agent for the recurrence of these peptic ulcers.

[0002]

2. Description of the Related Art Helcob
As a pathogenic bacterium that causes chronic gastritis and peptic ulcer in humans, its presence has attracted attention in recent years. In particular, regarding the relationship between ulcer development, which is a type of gastric mucosal lesion, and Helicobacter pylori, Helicobacter pylori is a Gram-negative bacterium specifically found in the antrum of the gastric pylorus, and this bacterium is associated with gastritis / digestion. It has been considered that it is involved in the development of chronic gastritis and peptic ulcer, since it is detected in the gastric mucosa of patients with gastric ulcer at a high rate. For example,
According to a statistical study, Helicobacter pylori is detected in 43% of healthy people, but 65% of them have gastritis and 86 have gastric ulcers.
%, It was reported that Helicobacter pylori was detected in the gastric mucosa of each patient at a high rate of 91% in patients with duodenal ulcer. On the other hand, Helicobacter pylori is considered to be associated not only with the development of chronic gastritis and peptic ulcer, but also with the recurrence of once cured ulcer. For gastric ulcer, 70% of patients have this bacterium.
It was said that the ulcer recurred within a year at a high rate, whereas the recurrence rate in patients without the bacterium was only about 10%.

Therefore, if a drug for eliminating Helicobacter pylori that colonizes and grows on the gastric mucosa is developed, it will not only be a protective agent for suppressing the onset of peptic ulcer, but also useful as a preventive agent for recurrence of ulcer. Can be. Based on these facts, in the United States, NIH has announced a treatment guideline for the prevention of recurrence of peptic ulcer by eradication of Helicobacter pylori, and the conventional antibacterial agent-antiulcer agent combination is appropriately used. Advocating combined therapy. According to the therapeutic guideline published by NIH, it was effective and completely eradicated when a bismuth salt showing weak antibacterial activity against Helicobacter pylori (for example, bismuth salicylate) and an antibacterial agent such as tetracycline were orally administered in combination. It has been reported that recurrence of ulcer is unlikely to occur as long as the condition continues.

[0004]

However, since Helicobacter pylori is a Gram-negative bacterium that colonizes and proliferates in the gastric mucosa, if it is aimed at exterminating itself, β-lactam antibiotics (cephem or penicillin) will be used. It is considered that antibiotics having so-called strong bactericidal or bactericidal activity, such as antibiotics), tetracycline antibiotics, macrolide antibiotics or quinolone antibiotics are more effective. However, although these drugs have strong in vitro antibacterial activity, it is said that they were not so effective in terms of their bactericidal effects based on the actual use results. It is not clear why β-lactam antibiotics, tetracycline antibiotics, macrolide antibiotics, quinolone antibiotics, etc. having such strong antibacterial activity cannot exterminate Helicobacter pylori that has settled in the stomach. Absent. Therefore, development of a more effective anti-Helicobacter pylori drug is desired.

Therefore, the present inventors have found that a so-called peptic ulcer therapeutic agent, which is not an antibacterial agent having a strong antibacterial effect, suppresses the growth of Helicobacter pylori as its mechanism of action together with the protective effect on the gastric mucosa. It was considered that there is a function to do so, and added consideration. As a result, the compound represented by the formula (I), which is a gastric mucosa protective factor enhancer, was observed to have an inhibitory effect on Helicobacter pylori growth, which is an excellent anti-Helicobacter pylori agent and an original gastric mucosa protective effect. The present invention was completed by confirming that it exerts a histamine H ₂ receptor antagonistic effect and can synergistically prevent ulcer development and prevent recurrence of ulcer.

[0006]

Accordingly, the present invention is to provide an anti-Helicobacter pylori agent which is effective as a protective agent for the development of gastric ulcer, duodenal ulcer and the like, and a recurrence preventive agent after the treatment of these peptic ulcers. Specifically, the following formula (I):

[0007]

[Chemical 2]

An anti-Helicobacter pylori agent containing 2- (furfurylsulfinyl) -N- [4- [4- (piperidinomethyl) -2-pyridyl] oxy- (Z) -butenyl] acetamide represented by I will provide a.

[0009]

The compound represented by the formula (I) has a gastric mucosal protective action against various necrotic substances in addition to a persistent gastric acid secretion inhibiting action, and further has an effect on gastric mucosal blood flow and gastric mucus dynamics. Is also a compound having an improving action, and is a compound whose development is being investigated as an anti-ulcer agent. However,
It has never been known that this compound itself has an antibacterial action against Helicobacter pylori.

According to the study by the present inventors, the above formula (I)
The compound represented by is a β-lactam antibiotic, a tetracycline antibiotic against Helicobacter pylori,
Although it has no strong antibacterial activity like macrolide antibiotics, quinolone antibiotics, etc., it showed a local antibacterial activity concentration sufficient to eradicate Helicobacter pylori in gastric mucus in the stomach. Therefore, the present invention exerts an ulcer treatment effect by the gastric mucosa protective action inherently possessed by the compound of formula (I), histamine H ₂ receptor antagonistic action and the like, and at the same time, prevents recurrence after the treatment of ulcer. It is effective, and in particular, it serves as an anti-Helicobacter pylori agent for preventing the development of ulcer and preventing recurrence of ulcer.

The antibacterial activity of the compound represented by the formula (I) of the present invention against Helicobacter pylori is shown below. I: Anti-Helicobacter pylori action:

1. Isolation and Identification of Helicobacter pylori from Specimens: The tested bacteria were microscopically collected from gastric mucosa by endoscopic biopsy method from patients with gastritis and peptic ulcer at St. Marianna University Hospital Separated by aerobic culture. The property inspection is performed by the method of Itoh et al. (Microbiol. Immunol., No. 3).
Vol. 1, pp. 603-614, 1987), and a total of 20 strains isolated from separate patients were used as test bacteria.

2. Used medium and culture method:
Muller Hilton age containing 7% horse blood
r (BBL Laboratories, USA) plate medium was inoculated, and 6% oxygen, 10% carbon dioxide gas, 84, which were optimal for Helicobacter pylori culture, were placed in an anaerobic jar.
A mixed gas of% nitrogen was prepared and cultured at 37 ° C. for 72 hours under high humidity.

3. Method of dissolving drug and plating medium: 2- (furfurylsulfinyl) -N- [4- [4- (piperidinomethyl) -2-pyridyl] oxy- (Z) -butenyl, a compound of formula (I) ] Acetamide was dissolved in dimethylsulfoxide (DMSO) to give 204.8
Stock solution was mg / ml. Stock solution is 2-fold serially diluted DMS
An O solution was prepared, and each solution was diluted 10 times by adding 9 volumes of physiological saline containing 0.1% polysorbate 80 to 1 volume (vol). This solution was prepared by adding 0.5 volume to 9.5 volume of MullerHilton aga containing 7% horse blood.
It was diluted to r to prepare a drug-containing plate medium (2048 μg /
Only 1 ml of the plate was mixed and diluted with 1 volume of the solution to 9 volumes of the medium).

4. Minimum inhibitory concentration (Minimum I
nhibitory Concentration: M
Measurement of IC): The MIC of the compound (I) was measured according to the agar plate dilution method of the American Society for Microbiology (ASM) (J. Antimicrob. Chemother.,
17: 309-314, 1986). The culture is
brain heart infusion (Difc
o Laboratories, USA) McFar
land No. Suspend to a turbidity of 1 (10
⁷ colony-forming units / m
l), 5 μl each of this bacterial solution was used to inoculate a 2-fold serially diluted drug-containing plate medium using a multi-inocuter (Sakuma Seisakusho). The above-mentioned culture method was used to determine the minimum concentration that inhibited the motive of the test bacteria.

5. Results: The results are shown in the table.

[0017]

[Table 1]

From the results in the table, the MIC of the compound of formula (I) against the test bacterium (Helicobacter pylori) is 6 in total.
512 strains of strains, total 14 strains 1024μg / ml
Is shown. Each plate medium contained 0.5% DMSO as a lysing agent, while Helicobacter pylori contained 2% DMSO.
It has been confirmed that it easily grows even in a medium containing SO. Further, 0.01% of polysorbate 80 is also considered to have no effect. Therefore, judging from the above results, it is considered that the compound of formula (I) exhibits antibacterial activity against clinical isolates of Helicobacter pylori at a local concentration of 1 mg / ml or more.

By the way, since the gastric mucosal epithelium is covered with a thick hydrophobic mucus layer, it is considered difficult for a hydrophilic compound to penetrate a large amount of mucus to reach the mucosal epithelium. Further, the part where Helicobacter pylori, which is said to be the causative bacterium of recurrence of peptic ulcer, is colonized and proliferated is the gastric mucosal epithelium, and there are numerous gastric pits present in the gastric mucosal epithelium. Therefore, even if the antibacterial agent has a strong antibacterial activity, if the antibacterial agent is hydrophilic,
It is judged that Helicobacter pylori cannot be eradicated because it cannot penetrate the mucus layer. Β-lactam antibiotics, tetracycline antibiotics,
It is considered that this is the reason why strong antibacterial agents such as macrolide antibiotics, quinolone antibiotics, etc. cannot fully exert the actual Helicobacter pylori eradication effect. On the other hand, 2- (furfurylsulfinyl) -N- [4- [4- (piperidinomethyl) -2-pyridyl] oxy- (Z) -butenyl] acetamide represented by the formula (I) of the present invention is orally administered. Upon administration, the entire amount of the administered compound flows into the stomach, and since it has a lipophilic property, the compound of formula (I), which becomes fine particles in the stomach, is It is considered that a considerable amount of the substance penetrates the gastric mucus layer and comes into direct contact with the Helicobacter pylori-infected local area to ensure a local concentration of MIC or higher for Helicobacter pylori and effectively eradicate Helicobacter pylori.

Therefore, 2 represented by the formula (I) of the present invention
The anti-Helicobacter pylori agent of the present invention containing-(furfurylsulfinyl) -N- [4- [4- (piperidinomethyl) -2-pyridyl] oxy- (Z) -butenyl] acetamide as an active ingredient is For therapeutic purposes, it is preferably administered orally, and the dose is such that this compound is orally administered as an anti-ulcer agent, and exerts anti-Helicobacter pylori activity while exerting a gastric mucosal protective action. A sufficient amount, or an amount necessary to secure a local concentration of MIC or more sufficient to eradicate Helicobacter pylori as an anti-Helicobacter pylori agent, specifically, about 50 to 50 Dosages in the range of about 1,000 mg are standard and will usually be given orally once daily or 2-3 times daily.

In order to formulate the anti-Helicobacter pylori agent of the present invention, a formulation technique which is widely used in pharmaceutically is used, and tablets, capsules, granules, powders and the like are made into dosage forms suitable for oral administration. It can be formulated. For example, the above-mentioned pharmaceutical composition is an inorganic or organic pharmaceutical carrier conventionally used in pharmaceutical preparations, for example, an excipient such as starch, lactose, sucrose, crystalline cellulose, calcium hydrogen phosphate; acacia, Binders such as hydroxypropyl cellulose, alginic acid, gelatin, polyvinylpyrrolidone; lubricants such as stearic acid, magnesium stearate, calcium stearate, talc; processed starch,
It can be formulated into an orally suitable dosage form together with a disintegrating agent such as calcium carboxymethyl cellulose or hydroxypropyl cellulose; a carboxyvinyl polymer or the like. Specific examples of formulation examples of the present invention are shown below.

Formulation Example 1 (tablet): Composition: Compound (I) 25 g Lactose 130 g Crystalline cellulose 20 g Corn starch 20 g 3% Hydroxypropylmethylcellulose aqueous solution 100 ml Magnesium stearate 2 g Manufacturing method: Compound (I) with lactose, crystalline cellulose and corn starch Was sieved with a 60-mesh sieve, mixed uniformly, put in a kneading machine, and kneaded by adding a 3% hydroxypropylcellulose aqueous solution. Then, the mixture was sieved with a 16-mesh sieve, granulated, and blow-dried at 50 ° C. After drying, sizing was performed, magnesium stearate was mixed, and the mixture was tableted with a tableting machine, and then sugar-coated or film-coated as required to give a sugar-coated tablet or film-coated tablet having a weight of 200 mg.

Formulation Example 2 (capsule): Composition: Compound (I) 25 g Lactose 125 g Corn starch 48.5 g Magnesium stearate 1.5 g Manufacturing method: The above ingredients are finely powdered and mixed sufficiently to form a uniform mixture. After that, put this in a gelatin capsule for 20
It was filled in 0 mg increments.

Formulation Example 3 (lozenge): Composition: Compound (I) 200 mg Sucrose 770 mg Hydroxypropylcellulose 5 mg Magnesium stearate 20 mg Flavor 5 mg 1 tablet 1000 mg Preparation method: The above ingredients are mixed and tableted by a conventional method. I used it as an agent.

Formulation Example 4 (Powder): Composition: Compound (I) 200 mg Lactose 800 mg Total 1000 mg Manufacturing method: The above components were mixed and made into a powder by a conventional method.

[0026]

As described above, the anti-Helicobacter pylori agent of the present invention is orally administered to eradicate Helicobacter pylori in gastric mucus, which is said to be the causative bacterium of ulcer development in the stomach. At the same time, the gastric mucosal protective action inherently possessed by the compound of formula (I), histamine H ₂
It also exerts a therapeutic effect on ulcers by antagonizing the receptor. Therefore, it is effective not only for the treatment of ulcers by eradication of Helicobacter pylori, which has no effective therapeutic effect with conventional antibacterial agents, but also for the prevention of recurrence after the treatment of ulcers. It is also useful as an agent for preventing recurrence of ulcer.

─────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-6-107638 (JP, A) JP-A-2-256623 (JP, A) Tetsuo ARAKAWA, Therapeutic Success with the Supplementary on the Helicopter surfactant. Gastric Ulcers, DIGESTIVE ENDOSC OPY, 1994, vol. 6,275-280 (58) Fields surveyed (Int.Cl. ⁷ , DB name) C07D 405/12 CAPLUS (STN) MEDLINE (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. The following formula (I): 2- (furfurylsulfinyl) -N-
Anti-Helicobacter pylori (Helicoba) containing [4- [4- (piperidinomethyl) -2-pyridyl] oxy- (Z) -butenyl] acetamide as an active ingredient
cter pylori) agent. 2. The anti-Helicobacter pylori agent according to claim 1, which is in the form of oral administration.