WO1998022111A1 - Medicaments anti-helicobacter pylori - Google Patents

Medicaments anti-helicobacter pylori Download PDF

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Publication number
WO1998022111A1
WO1998022111A1 PCT/JP1997/004199 JP9704199W WO9822111A1 WO 1998022111 A1 WO1998022111 A1 WO 1998022111A1 JP 9704199 W JP9704199 W JP 9704199W WO 9822111 A1 WO9822111 A1 WO 9822111A1
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WO
WIPO (PCT)
Prior art keywords
helicobacter pylori
activity
troxipide
neutrophil
effect
Prior art date
Application number
PCT/JP1997/004199
Other languages
English (en)
Japanese (ja)
Inventor
Kenjiro Momo
Yuji Ishibashi
Original Assignee
Kyorin Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kyorin Pharmaceutical Co., Ltd. filed Critical Kyorin Pharmaceutical Co., Ltd.
Priority to AU49675/97A priority Critical patent/AU4967597A/en
Publication of WO1998022111A1 publication Critical patent/WO1998022111A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4462—Non condensed piperidines, e.g. piperocaine only substituted in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention suppresses the migration ability of neutrophils derived from Helicobacter pylori, the production of reactive oxygen species, the activity of myelin peroxidase and the activity of perease, and various diseases associated with the onset or recurrence of Helicobacter pylori.
  • the present invention relates to an anti-Helicobacter pylori drug containing troxypide as an active ingredient for preventing or treating gastrointestinal mucosal disorders, hyperammonemia, hepatitis, liver cirrhosis, gastric cancer, and liver cancer.
  • Conventional technology Conventional technology
  • Pill helicobacter pylori drugs include antibacterial agents such as antibiotics for eradication, bismuth subnitrate, nitroimidazole drugs, proton pump inhibitors or combined use of antibacterial agents with proton pump inhibitors, and Is used in combination with proton pump inhibitors, antibacterial agents, and nitroimidazole drugs.
  • antibacterial agents such as antibiotics for eradication, bismuth subnitrate, nitroimidazole drugs, proton pump inhibitors or combined use of antibacterial agents with proton pump inhibitors, and Is used in combination with proton pump inhibitors, antibacterial agents, and nitroimidazole drugs.
  • antibacterial agents such as antibiotics for eradication, bismuth subnitrate, nitroimidazole drugs, proton pump inhibitors or combined use of antibacterial agents with proton pump inhibitors, and Is used in combination with proton pump inhibitors, antibacterial agents, and nitroimidazole drugs.
  • these combination therapies have poor compliance due to side effects and complicated methods of administration, and
  • Troxipide a mucosal protective factor enhancer
  • Troxipide is known to have an effect of increasing gastric mucosal blood flow, activating gastric mucosal metabolism, normalizing gastric mucosal components, and increasing the amount of prostaglandin in gastric mucosa.
  • it is already used as a medicine for patients with gastritis and gastric ulcer.
  • troxipide has an anti-Helicobacter pylori effect.
  • Helicobacter pylori present in the mucus layer and mucosal epithelial cells releases cytokines such as interleukin-18 from mucosal epithelial cells, causing the migration and activation of inflammatory cells, especially neutrophils, and as a result, becomes active Produces oxygen.
  • Helicobacter i. Pylori produces ammonia by perease contained in itself.
  • monochloramine with high cytotoxicity is produced by these active oxygen and ammonia. Which cause a variety of disease states. Therefore, it is desirable to eradicate Helicobacter pylori and at the same time suppress the enzyme activity and neutrophil migration and activation.
  • the problem to be solved by the present invention is to prevent or treat various diseases associated with the onset or recurrence of Helicobacter pylori, such as gastrointestinal mucosal disorders, hyperammonemia, hepatitis, cirrhosis, gastric cancer, and liver cancer.
  • diseases associated with the onset or recurrence of Helicobacter pylori such as gastrointestinal mucosal disorders, hyperammonemia, hepatitis, cirrhosis, gastric cancer, and liver cancer.
  • the present inventors have conducted intensive studies, and found that troxipide has an effect of suppressing neutrophil migration ability, production of active oxygen, myelin peroxidase activity, perease activity, and the like, and completed the present invention. Reached.
  • the present invention relates to an anti-Helicobacter pylori drug containing troxipide as an active ingredient.
  • the anti-helicopter of the present invention which contains troxipide [chemical name: 3— (3,4,5-trimethoxybenzamide) piperidine] as an active ingredient, is a drug for Helicobacter pylori. It is a drug that has an inhibitory effect on migration, production of active oxygen, urease activity, myeloperoxidase activity, etc. Therefore, it inhibits the growth of Helicobacter pylori and simultaneously suppresses the pathogenesis of various diseases.
  • troxipide chemical name: 3— (3,4,5-trimethoxybenzamide) piperidine
  • FIG. 1 (effect on perase activity) is a graph showing the results of measurement of peroxidase activity of troxipide, the positive control drug and the control obtained in Example 1.
  • FIG. 2 (effect on neutrophil migration ability by fMLP stimulation) is a graph showing the results of measurement of neutrophil migration of troxipide and control on fMLP obtained in Example 2.
  • Figure 3 (Effect on migration ability by rh-IL-8 stimulation) was obtained in Example 2.
  • 9 is a graph showing the results of measurement of neutrophil migration of troxipide and control against rh-IL-8.
  • FIG. 4 (effect on neutrophil migration ability by PAF stimulation) is a graph showing the results of measurement of neutrophil migration of troxipide and control on PAF obtained in Example 2.
  • Fig. 5 (Effect on neutrophil migration ability by stimulation of H. py 1 ori intracellular extract) shows the neutrophil migration of trocipid and control against Helicobacter pylori intracellular extract obtained in Example 2. It is a graph which shows a measurement result.
  • Fig. 6 (Effect of rh-IL-18 stimulation on neutrophil reactive oxygen production) shows the results of measuring the active oxygen content of troxipide, the positive control drug and the control for rh-IL-18 obtained in Example 3. It is a graph shown.
  • FIG. 7 (Effect on neutrophil reactive oxygen production by stimulation of H. py 1 ori intracellular extract) shows the activity of troxipide, a positive control drug, and the control on the Helicobacter pylori intracellular extract obtained in Example 3. It is a graph which shows the measurement result of the amount of oxygen.
  • FIG. 8 (effect on human sputum-derived MPO activity) is a graph showing the results of measurement of human sputum-derived MPO activity of troxipide obtained in Example 4, a positive control drug, and a control.
  • FIG. 9 (effect on guinea pig neutrophil-derived MPO activity) is a graph showing the results of measurement of troxipide obtained in Example 4, the positive control drug, and control guinea pig neutrophil-derived MPO activity.
  • Helicobacter pylori produces ammonia by rarease, causing gastrointestinal mucosal damage. Therefore, by inhibiting the protease activity, it is possible to suppress the production of ammonia from Helicobacter pylori. So Toro We examined whether or not xipide suppressed the helicobacter pylori perease activity. Helicobacter pylori obtained from a clinical isolate was cultured on Brucella agar medium containing 10% equine defibrinated blood for 3 days, and further cultured on Brucella medium containing 2.5% fetal calf serum for 2 days and centrifuged.
  • the cells obtained in this manner were added with ImM ethylenediamine tetrasodium acetate sodium phosphate buffer solution (pH 7.0) containing lmM2-mercaptoethanol, and the cells were sonicated to destroy the cells, and the cell extract was collected. Obtained.
  • phosphate buffer (pH7. 0) 1 N hydrochloric acid solution Torokishipido diluted with (lxl 0- 6, 1 X 10- 5, lxl O_ 4 M) in Ureaze activity which was boss measured by India phenol method. The test was performed using L-arginine hydrochloride as a positive control.
  • FIG. 1 shows the measurement results of the urease activity value.
  • Enhanced neutrophil migration by Helicobacter pylori or interleukin-8 causes mucosal damage through the production of reactive oxygen species. Therefore, mucosal damage can be suppressed by suppressing neutrophil migration ability. Therefore, we examined whether troxipide could suppress neutrophil migration.
  • the results Torokishipido inhibited the migration in a concentration-dependent manner neutrophils at a concentration of from 1 X 10- 8 1 X 10- 4 M.
  • the percent inhibition of the 1 X 1 0- 5 M of Torokishipido is 23. 0 ⁇ respect f MLP 2. 8%, 29. 6 ⁇ 3 against rh-IL- 8. The concentration was 59.0%, 49.0 ⁇ 7.8% for PAF, and 42.7 ⁇ 10.2% for Helicobacter pylori extract.
  • Figure 2 shows the measurement results of neutrophil migration for fMLP
  • Figure 3 shows the measurement results for rh-IL-18
  • Figure 4 shows the measurement results for PAF.
  • Fig. 5 shows the results.
  • active oxygen is produced with a 1/180 dilution of Helicobacter pylori extract extracted with Hank's solution and lxl O- 8 gZm1 of rh-IL-8. To this was added a solution of troxipide, and the amount of active oxygen was measured by chemiluminescence method (MCLA). Superoxide dismutase (SOD) was used as a positive control.
  • MCLA chemiluminescence method
  • SOD superoxide dismutase
  • the presence of ammonia under these conditions produces monochloramine, which has a strong tissue-damaging effect. Therefore, mucosal damage can be suppressed by suppressing MPO activity. Therefore, 0.5% hexadecyltrimethoxyammonium bromide solution was added to human sputum MPO and guinea pig neutrophils, and this was sonicated to extract MP0.
  • MPO activity was measured by the method of Krawis et al. In addition, force cod was used as a positive control.
  • various diseases caused by Helicobacter pylori infection are closely related to ammonia produced by perease activity produced by itself and this urease activity.
  • By inhibiting the growth of bacteria it suppresses the production of ammonia necessary for the survival of the bacteria, and has the effect of preventing or suppressing the growth of bacteria and the onset or recurrence of gastric mucosal damage caused by ammonia.
  • it has effects such as suppression of neutrophil migration ability, suppression of active oxygen production and suppression of MP0 activity, and has the purpose of treating gastritis and gastric ulcer and preventing recurrence.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

L'invention concerne des médicaments anti-hélicobacter pylori, contenant un tropixide en tant que principe actif, et utiles dans la prévention ou le traitement de diverses maladies à l'apparition et la récurrence desquelles Hélicobacter pylori participe, par exemple les troubles des muqueuses gastro-intestinales, l'hyperammoniémie, l'hépatite, la cirrhose, le cancer de l'estomac et du foie.
PCT/JP1997/004199 1996-11-20 1997-11-19 Medicaments anti-helicobacter pylori WO1998022111A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU49675/97A AU4967597A (en) 1996-11-20 1997-11-19 Anti-helicobacter pylori drugs

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP30954696 1996-11-20
JP8/309546 1996-11-20
JP30671297A JP4237837B2 (ja) 1996-11-20 1997-11-10 抗ヘリコバクター・ピロリイ用薬
JP9/306712 1997-11-10

Publications (1)

Publication Number Publication Date
WO1998022111A1 true WO1998022111A1 (fr) 1998-05-28

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Application Number Title Priority Date Filing Date
PCT/JP1997/004199 WO1998022111A1 (fr) 1996-11-20 1997-11-19 Medicaments anti-helicobacter pylori

Country Status (3)

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JP (1) JP4237837B2 (fr)
AU (1) AU4967597A (fr)
WO (1) WO1998022111A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5028436B1 (fr) * 1968-05-06 1975-09-16
JPS6130660B2 (fr) * 1979-11-15 1986-07-15 Kyorin Seiyaku Kk

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5028436B1 (fr) * 1968-05-06 1975-09-16
JPS6130660B2 (fr) * 1979-11-15 1986-07-15 Kyorin Seiyaku Kk

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF MEDICINAL CHEMISTRY, Vol. 14, No. 4, (1971), IRIKURA TSUTOMU et al., "New Antiulcer Agents. 1. Syntheses and Biological Activities of 1-Acyl-2-,-3-, and -4-Substituted Benzamidopiperidines", p. 357-361. *
PHARMACOMETRICS, Vol. 15, No. 4, (1978), TSUTOMU IRIKURA et al., "Therapeutic Effects of 3-(3,4,5-Trimethoxybenzamido) Piperidine (KU-54) on Experimental Chronic Gastric Ulcer and Combined Effects Resulting from Combination Thereof with Other Drug (in Japanese)", p. 641-651. *
PHARMACOMETRICS, Vol. 17, No. 3, (1979), TSUTOMU IRIKURA et al., "Prophylactic Effects of 3-(3,4,5-Trimethoxybenzamido) Piperidine (KU-54) on Experimental Acute Gastroduodenal Ulcer (in Japanese)", p. 371-382. *
STRIDES OF MEDICINE, Vol. 179, No. 1, (5 October 1996), TOSHIO FUJIOKA et al., "Sterile Therapy for H. Pylori Infection -- Including the Appearance of Drug-Resistant Bacteria (in Japanese)", p. 104-105. *

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JP4237837B2 (ja) 2009-03-11
AU4967597A (en) 1998-06-10
JPH10203984A (ja) 1998-08-04

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