JPH09295938A - Therapeutic agent of digestive ulcer - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject therapeutic agent containing a carbapenem compound-based compound having strong antibacterial activity on a bacterium of the genus Helicobacter, especially Helicobacter pylori as an active ingredient and useful for treatment of ulcer, prevention, etc., of relapse. SOLUTION: This therapeutic agent contains (1R, 5S, 6S)-2-[1-(1,3-thiazolin-2- yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbapen 2-em-3-carboxylic acid or its pharmaceutically permissible salt as an active ingredient. The therapeutic agent is preferably orally administered and the dose is preferably about 0.5 to 200mg/adult/day and the agent can orally be administered at the daily dose in 1-3 portions.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an agent for treating ulcer,
In particular, a therapeutic agent for ulcer containing a carbapenem compound and a pharmacologically acceptable salt thereof having an excellent antibacterial activity, particularly a strong antibacterial activity against Helicobacter genus bacteria such as Helicobacter pylori Regarding

[0002]

2. Description of the Related Art Helicobacter pylori belonging to the genus Helicobacter is a pathogenic bacterium that has attracted particular attention in recent years as a pathogenic bacterium that causes chronic gastritis and peptic ulcer in humans. That is, Helicobacter pylori is a gram-negative bacillus specifically found in the gastric mucosa of the gastric antrum of the human stomach to the intestinal wall, and is highly detected in the gastric mucosa of patients with peptic ulcer such as gastritis, gastric ulcer, and duodenal ulcer. Therefore, the involvement in the development of chronic gastritis and peptic ulcer has been a problem. It is said that this bacterium colonizes and proliferates in the mucosal layer covering the stomach wall as described above, releases proteins that affect gastric epithelial mucosal cells, attracts macrophages and neutrophils, and causes inflammation. According to one statistical study, 65% of patients with gastritis, 86% of patients with gastric ulcer, and almost 100 in patients with duodenal ulcer.
% Helicobacter pylori is detected, whereas in healthy humans of the same age as the patient, about 30%
Only infected. Even more troublesome is that with Helicobacter pylori infection and chronic gastritis, 10
Various experiments have shown that the risk of developing peptic ulcer is increased by 3 to 12 times within 20 years. This is also related to the recurrence of ulcers that once healed, and for gastric ulcers, patients infected with this bacterium have a high rate of 70% and relapse of ulcers within one year, It is said that the recurrence rate of uninfected patients was only about 10%. For example, 50% of patients treated with histamine H ₂ receptor antagonists (H ₂ blockers)
Within a month, 95% are said to have recurred ulcers within 2 years. Thus, the relationship between Helicobacter pylori and the onset of chronic gastritis and peptic ulcer is
Today, it has become a generally accepted theory that if Helicobacter pylori can be completely eradicated, inflammation will completely disappear, but if re-infected, gastritis will also recur. It is known that virtually everyone will develop chronic superficial gastritis if infected.

[0003] Therefore, if a drug capable of erasing Helicobacter pylori resident in the gastric mucosal layer can be developed, it will not only suppress the development of peptic ulcer but also prevent recurrence of the ulcer. To N
IH is the first to recommend a two-week course of antimicrobial treatment as a treatment for ulcers. This NIH recommended therapy is a combination therapy of amoxicillin or tetracycline antibiotics, metronidazole antibacterial agents and bismuth preparations that show only weak antibacterial activity against Helicobacter pylori. In December 1995, the FDA added clarithromycin, a macrolide antibacterial agent, and H ₂
2 in combination with blocker ranitidine or proton pump inhibitor omeprazole and bismuth
Two new 4-week courses of prescription are recommended for approval as a therapy for Helicobacter pylori infection. As long as Helicobacter pylori is completely eradicated by these therapies, recurrence of ulcer is not considered to occur.

[0004]

As described above, the bismuth preparation is the main formulation for eradication of Helicobacter pylori recommended by NIH or FDA for the purpose of treating peptic ulcer or preventing recurrence of ulcer. , Basically, antibiotics with strong antibacterial activity such as amoxicillin or tetracycline, or powerful antibacterial agents such as clarithromycin and metronidazole are used to sterilize Helicobacter pylori that colonizes and grows in the gastric mucosa. The idea is that doing is effective. However, with these antibiotics or antibacterial agents,
Since the drug has been prescribed for a long period of time for the treatment of diseases based on various pathogenic bacteria, the emergence of resistant bacteria has been a problem, and even with regard to metronidazole, Helicobacter pylori, which is resistant, has already been reported. Also,
Since several drugs are used in combination, more caution is required when taking individual drugs, and the occurrence of side effects such as vomiting and diarrhea is a problem. Therefore, under the present circumstances, there is a demand for the development of a drug that can be eradicated by Helicobacter pylori more effectively and has no problem of resistance by single administration, and as a result, an effective therapeutic agent for peptic ulcer. The present invention aims to solve such a point.

[0005]

[Means for Solving the Problems] Among the various antibiotics, the present inventors have focused their attention on a carbapenem antibiotic with a relatively new development in which the problem of resistant bacteria is not recognized, and a methyl group at the 1-position of the carbapenem skeleton. A group has been introduced to provide a completely new carbapenem compound having a specific structure as a substituent at the 2-position. And these compounds proposed by the present inventors, a strong antibacterial activity unprecedented against Helicobacter pylori was observed, it was newly found that Helicobacter pylori is completely sterilized,
As a result, it was confirmed that this compound alone could be an effective therapeutic agent for peptic ulcer, and the present invention was completed. That is, the present invention provides the following formula (I):

[0006]

Embedded image

(1R, 5S, 6S) -2-
[1- (1,3-thiazolin-2-yl) azetidine-
Digestibility of 3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid or a pharmaceutically acceptable salt thereof as an active ingredient An agent for treating ulcer is provided.

Further, the present invention provides, in another aspect, a therapeutic agent for chronic superficial gastritis, which comprises a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient. The present invention also provides, in yet another aspect, an anti-Helicobacter pylori agent containing a compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

BEST MODE FOR CARRYING OUT THE INVENTION

In the present invention, the compound represented by the above formula (I) is a compound that has already been clinically developed as a carbapenem compound having a strong antibacterial activity (Japanese Patent Laid-Open No. 8-53453). ), It has never been known that this compound itself has an antibacterial action against Helicobacter pylori. According to the studies by the present inventors, the compound represented by the formula (I) is particularly superior to amoxicillin or clarithromycin, which is recommended by NIH or FDA for combination therapy against Helicobacter pylori. Since it has antibacterial activity, administration of this compound alone can completely eradicate Helicobacter pylori resident in the gastric mucosa. As a result, the onset of peptic ulcers, chronic superficial gastritis, etc. induced by the presence of such endogenous bacteria can be completely suppressed, and these ulcers and gastritis can be treated, and further, the recurrence of cured ulcers can be prevented. Will be connected. In particular, under the present circumstances where chronic atrophic gastritis among chronic superficial gastritis develops into gastric adenocarcinoma if left untreated, the relationship between Helicobacter pylori and the occurrence of gastric cancer is regarded as a problem. From this point of view, the compound of formula (I), which effectively eradicates Helicobacter pylori, will be effective as a drug for preventing the development of gastric cancer in the future. The compound represented by the above formula (I) can be used as a therapeutic agent for ulcer when administered alone. However, in addition to this compound, other antibacterial agents or other agents such as H ₂ blockers may be appropriately combined. It goes without saying that it can be used.

The antibacterial activity of the compound of the formula (I) of the present invention against Helicobacter pylori is shown below. Anti-Helicobacter pylori action : (Test method) Trypticase Soy Aga containing 10% horse defibrinated blood
Trypti of 5 Helicobacter pylori strains cultivated for 2 days at 37 ° C under microaerobic and high humidity conditions using r (BBL)
Suspend in caseSoy Broth to 10 ⁶ cfu / ml, inoculate this bacterial suspension on 10% horse defibrinated blood agar medium containing the test drug, culture under the same conditions, and then at the minimum inhibitory concentration (MIC value) was measured. The Helicobacter pylori bacterium used was obtained by collecting from the gastric mucosa by endoscopic biopsy from a patient with peptic ulcer at Nagasaki University School of Medicine and culturing and separating it. As a positive control,
Amoxicillin recommended by NIH and FDA,
Clarithromycin and tetracycline antibacterial agent minocycline were placed.

(Test Results) The MIC values of the test compounds are shown in Table 1.
Shown in

[0012]

[Table 1]

As is clear from the results shown in Table 1, the compounds of the formula (I) of the present invention are shown to have a MIC value having an extremely stronger antibacterial activity than amoxicillin, clarithromycin and minocycline. Therefore, it is considered that the compound of formula (I) alone eradicates Helicobacter pylori, and as a result, effectively treats peptic ulcer or chronic superficial gastritis.

Thus, (1R, 5S, 6S) -2- [1- (1,3-thiazolin-2-yl) azetidin-3-yl] thio-6- represented by the formula (I) of the present invention.
A therapeutic agent for peptic ulcer containing [(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid or a pharmacologically acceptable salt thereof as an active ingredient is
From the viewpoint of its therapeutic purpose, it is preferably administered orally, and its dose is such that this compound is orally administered as a therapeutic agent for peptic ulcer or chronic superficial gastritis and exerts a gastric mucosal protective effect. An amount sufficient to exert anti-Helicobacter pylori activity, or an amount necessary to ensure a local concentration of MIC or more sufficient to eradicate Helicobacter pylori as an anti-Helicobacter pylori agent, Specifically, about 0.
Dosages in the range of 5 to about 200 mg are standard and can be administered orally, usually once daily or 2-3 times daily.

The compound represented by the formula (I), which is the active ingredient of the present invention, can be used as the therapeutic agent of the present invention in the form of itself or a pharmacologically acceptable salt thereof. The formation of such salts is carried out by treating the free base of formula (I) with an organic or inorganic acid. Examples of the organic acid used here include lower fatty acids such as formic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid and trichloroacetic acid; organic acids such as succinic acid, maleic acid and fumaric acid; benzoic acid and p-nitrobenzoic acid. A substituted or unsubstituted benzoic acid; a (halo) lower alkyl sulfonic acid such as methanesulfonic acid and trifluoromethanesulfonic acid; benzenesulfonic acid, p-nitrobenzenesulfonic acid, p-bromobenzenesulfonic acid, p-toluenesulfone A substituted or unsubstituted arylsulfonic acid such as an acid or 2,4,6-triisopropylbenzenesulfonic acid;
An organic phosphoric acid such as diphenyl phosphoric acid can be mentioned. Examples of the inorganic acid include hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, borofluoric acid, perchloric acid, nitric acid and the like. Among them, particularly preferred pharmacologically acceptable salts include organic acid addition salts such as succinate, maleate, fumarate and methanesulfonate; hydrochloride, hydrobromide, sulfate, Inorganic acid salts such as phosphates may be mentioned.

In order to formulate the therapeutic agent for peptic ulcer of the present invention, a formulation technique generally used in pharmaceutically is used to prepare tablets,
It can be formulated into a dosage form suitable for oral administration such as capsules, granules and powders. 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 and polyvinylpyrrolidone; Lubricants such as stearic acid, magnesium stearate, calcium stearate and talc; Disintegrants such as processed starch, calcium carboxymethyl cellulose and hydroxypropyl cellulose; carboxyvinyl polymer Etc.,
It can be formulated into an orally suitable dosage form. Specific examples of formulation examples of the present invention are shown below.

Formulation Example 1 (tablet): Composition: Compound (I) 2 g Lactose 135 g Crystalline cellulose 20 g Corn starch 20 g 3% Hydroxypropylmethylcellulose aqueous solution 100 ml Magnesium stearate 3 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, the granules were sized, mixed with magnesium stearate, made into tablets with a tableting machine, and sugar-coated or film-coated as required to give sugar-coated tablets or film-coated tablets having a weight of 180 mg.

Formulation Example 2 (capsule): Composition: Compound (I) 5.0 g Lactose 125.0 g Cornstarch 48.5 g Magnesium stearate 1.5 g Preparation method: The above components are finely pulverized into a uniform mixture. Mix well until it becomes 18
It was filled in 0 mg increments.

Formulation Example 3 (lozenge): Composition: Compound (I) 20 mg Sucrose 950 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) 20 mg Lactose 980 mg Total 1000 mg Production method: The above components were mixed and made into a powder by a conventional method.

[0021]

Industrial Applicability As described above, the therapeutic agent for peptic ulcer of the present invention is administered orally to Helicobacter in gastric mucus, which is considered to be the causative agent of ulcer onset in the stomach.
By eradicating Helicobacter pylori, it is effective not only for effective treatment of ulcers but also for prevention of recurrence after treatment of ulcers. In this respect, it can be particularly useful for the treatment of chronic superficial gastritis and for the prevention of gastric cancer in the future, and its usefulness is particularly high.

Claims (3)

[Claims] (1) The following formula (I): (1R, 5S, 6S) -2- [1- (1,3
-Thiazolin-2-yl) azetidin-3-yl] thio-6-[(R) -1-hydroxyethyl] -1-methyl-carbapene-2-em-3-carboxylic acid or a pharmaceutically acceptable salt thereof A remedy for peptic ulcer which comprises a salt of an active ingredient. 2. A therapeutic agent for chronic superficial gastritis, which comprises the compound represented by formula (I) or the pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient. 3. An anti-Helicobacter pylori containing the compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
pylori) agent.