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WO1996008247A1 - Agent anti-helicobacter - Google Patents

Agent anti-helicobacter Download PDF

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Publication number
WO1996008247A1
WO1996008247A1 PCT/JP1995/001811 JP9501811W WO9608247A1 WO 1996008247 A1 WO1996008247 A1 WO 1996008247A1 JP 9501811 W JP9501811 W JP 9501811W WO 9608247 A1 WO9608247 A1 WO 9608247A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
hydrogen atom
alkyl group
salt
active ingredient
Prior art date
Application number
PCT/JP1995/001811
Other languages
English (en)
Japanese (ja)
Inventor
Kenji Yonezawa
Hisanari Shibata
Yukio Mori
Original Assignee
Toyama Chemical 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 Toyama Chemical Co., Ltd. filed Critical Toyama Chemical Co., Ltd.
Priority to AU34842/95A priority Critical patent/AU3484295A/en
Publication of WO1996008247A1 publication Critical patent/WO1996008247A1/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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/345—Nitrofurans
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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

Definitions

  • the present invention relates to the general formula [1]
  • R 1 represents a hydrogen atom, alkoxycarbonyl, nitrofurfurylidenealkyl or hydroxyiminoalkyl group
  • R 2 represents a hydrogen atom or an alkoxycarbonylalkyl group
  • R 3 represents amidino, alkamoyl or A thiocarbamoyl group
  • R 4 represents a hydrogen atom, a halogen atom or an alkyl group.
  • a salt thereof as an active ingredient
  • Helicobacter pylori is a specific bacterium that has been implicated in gastritis, stomach 'duodenal ulcer, and gastric cancer [Japanese clinical practice, Vol. Year)] o
  • nitrofuran derivative represented by the general formula [1] used in the present invention is a known compound. ) Eighth Edition (1981), Pharmaceutical Tojihosha].
  • H. pylori has been used as an antibacterial agent to eradicate H. pylori such as ampicillin, amoxicillin, bacampicillin, and nitrofurantoin. These antibacterial agents also show strong antibacterial activity against intestinal bacteria, and thus have side effects such as diarrhea.
  • An anti-Helicobacter agent is an agent that specifically exhibits antibacterial activity against a bacterium of the genus Helicobacter [Japanese clinical practice, Vol. 51, No. 5, pp. 16-16 (1993)].
  • the alkyl group e.g., methyl, Echiru, n- propyl, iso- propyl, n - butyl, iso- butyl, Ten- butyl, pentyl, hexyl, and ci _ s alkyl group such as butyl and Okuchi Le to;
  • the alkoxycarbonyl group is a -C00-alkyl group (the alkyl group is the above-mentioned alkyl group); the nitrofurfurylidenealkyl group is nitrofurfurylidenemethyl, nitrofurfurylideneethyl, or nitrofurfurylidene.
  • Fg ⁇ means a group having 5 or less carbon atoms.
  • alkyl group lower alkyl groups are preferred, and methyl, ethyl and propyl groups are particularly preferred.
  • Alkoxycarbonyl groups include lower alkoxycarbonyl Le group are preferred, particularly preferred ethoxycarbonyl Nirumotoka f.
  • hydroxyiminoalkyl group a hydroxyimino lower alkyl group is preferable, and a hydroxyiminomethyl group is particularly preferable.
  • alkoxycarbonylalkyl group a lower alkoxycarbonyl lower alkyl group is preferable, and an ethoxycarbonylmethyl group is particularly preferable.
  • R is preferably a hydrogen atom, a lower alkoxycarbonyl, a nitrofurfurylidene lower alkyl or a hydroxyimino lower alkyl group, more preferably a hydrogen atom, ethoxycarbonyl, nitrofurfurylidenemethyl or hydroxyiminomethyl group.
  • R 2 is preferably a hydrogen atom or a lower alkoxycarbonyl lower alkyl group, particularly preferably a hydrogen atom.
  • R 3 an amidino group is preferable.
  • R 4 is preferably a hydrogen atom, a halogen atom or a lower alkyl group, more preferably a hydrogen atom, a chlorine atom, a bromine atom, an iodine atom or a methyl group, and particularly preferably a hydrogen atom.
  • Examples of the salt of the nitrofuran derivative represented by the general formula [1] include pharmaceutically acceptable salts, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; fumaric acid, maleic acid, malic acid and citric acid And sulfonic acids such as methanesulfonic acid, P-toluenesulfonic acid and naphthalenedisulfonic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid
  • sulfonic acids such as methanesulfonic acid, P-toluenesulfonic acid and naphthalenedisulfonic acid.
  • the nitrofuran derivative represented by the general formula [1] or a salt thereof includes isomers (geometric isomers and optical isomers), hydrates, solvates and crystal forms.
  • nitrofuran derivative represented by the general formula [1] or a salt thereof is described in, for example, Japanese Patent Publication No. 27-2673, No. 9382, No. 39-5030, No. 39-5031 and No. 39-6530. It can be manufactured by the method described.
  • the drug of the present invention is orally administered as capsules, powders, granules, pills, tablets, suspensions, emulsions, liquids or syrups in a usual manner.
  • the administration method, dosage, and number of administrations may be appropriately adjusted according to the age and symptoms of the patient, but usually 100 mg / kg per day for adults is divided into one to several doses. I just need.
  • the active ingredient In order to make a nitrofuran derivative of the general formula [1] or a salt thereof into a pharmaceutical preparation as an active ingredient, the active ingredient must contain excipients such as lactose, anhydrous lactose, mannitol, corn starch and microcrystalline cellulose, if necessary. Binders such as hydroxypropylcellulose, polyvinylpyrrolidone and methylcellulose; disintegrants such as carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose and partially a-starch; magnesium stearate, calcium stearate, stealine.
  • excipients such as lactose, anhydrous lactose, mannitol, corn starch and microcrystalline cellulose, if necessary.
  • Binders such as hydroxypropylcellulose, polyvinylpyrrolidone and methylcellulose
  • disintegrants such as carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropyl
  • Lubricants such as acid and talc; Coating agents such as hydroxypropylmethylcellulose, methacrylic acid-acrylic acid copolymer and hydroxypropylmethylcellulose phthalate; P-oxo Using a preservative such as methyl benzoate; a pigment such as Yellow No. 5; and a glossing agent such as Carnauba wax, etc., in a manner usually performed by those skilled in the art, for example, capsules, powders, granules, pills, Tablets, suspensions, emulsions, solutions, syrups and the like may be used.
  • a preservative such as methyl benzoate
  • a pigment such as Yellow No. 5
  • a glossing agent such as Carnauba wax, etc.
  • Test compound 1,5-bis (5-nitro-2-furyl) -11,4-pentagen-3-one-amidinohydrazone hydrochloride [hereinafter referred to as diflazone. ] Test example
  • the minimum inhibitory concentration (MIC) for Helicobacter pylori was determined by the agar plate method. Measured. Helicobacter pylori was treated with 7% horse defibrinated blood and Brain Heart Infusion Agar (manufactured by Tanabe Seiyaku Co., Ltd.) in a 5% oxygen / 10% carbon dioxide atmosphere at 37 for 1 week ( HT—1 share) or 4 days
  • MI C ⁇ gAnl
  • the MIC for Escherichia coli was measured based on the standard method of the Japanese Society of Chemotherapy [CHEMOTH ERAPY], Vol. 29, No. 1, pp. 76-79 (1981). Sunawa Chi, with 37 Myurahin tons' broth (Mueller Hinton broth) [Difco (Difco) Co.], and cultured for 20 hours, saline bacteria amount was adjusted to 10 6 cells / ml in bacterial solution 1 loopful Was inoculated into Mueller Hinton Agar medium (Difco) containing the drug, cultured at 37 for 20 hours, and the presence or absence of bacterial growth was observed. The minimum concentration at which growth was inhibited was defined as MIC (/ gAnl).
  • Tablets are prepared according to a conventional method using the above formula, and the resulting uncoated tablets are subjected to film coating according to the following formula according to a conventional method to obtain tablets.
  • Granulation is carried out by the usual method according to the above formulation, and the obtained granules are filled into No. 2 capsule to obtain a force bushing agent.
  • Powders are obtained according to the above formula by a conventional method. Industrial applicability
  • the compound of the present invention has a strong antibacterial activity against bacteria of the genus Helicobacter, but hardly acts on intestinal bacteria, and has almost no oral absorption, so that it is useful as an anti-helicopter agent. .

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

Abstract

Agent anti-hélicobacter renfermant un dérivé nitrofurane représenté par la formule générale (I) ou un sel de ce dérivé en tant que principe actif, utile comme substance médicamenteuse présentant une sélectivité élevée du fait qu'il n'affecte guère les bactéries intestinales. Dans la formule, R1 représente hydrogène, alcoxycarbonyle, nitrofurfurylidènealkyle ou hydroxyiminoalkyle; R2 représente hydrogène ou alcoxycarbonylalkyle; R3 représente amidino, carbamoyle ou thiocarbamoyle; et R4 représente hydrogène, halogéno ou alkyle.
PCT/JP1995/001811 1994-09-16 1995-09-13 Agent anti-helicobacter WO1996008247A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU34842/95A AU3484295A (en) 1994-09-16 1995-09-13 Anti-helicobacter agent

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP6/246710 1994-09-16
JP24671094 1994-09-16
JP7/248284 1995-09-04
JP7248284A JPH08133971A (ja) 1994-09-16 1995-09-04 抗ヘリコバクター剤

Publications (1)

Publication Number Publication Date
WO1996008247A1 true WO1996008247A1 (fr) 1996-03-21

Family

ID=26537868

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1995/001811 WO1996008247A1 (fr) 1994-09-16 1995-09-13 Agent anti-helicobacter

Country Status (3)

Country Link
JP (1) JPH08133971A (fr)
AU (1) AU3484295A (fr)
WO (1) WO1996008247A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140200241A1 (en) * 2011-05-24 2014-07-17 Northeastern University Prodrugs for treating microbial infections

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992018143A1 (fr) * 1991-04-15 1992-10-29 Applied Microbiology, Inc. Compositions pharmaceutiques contre les troubles gastriques
WO1993002709A1 (fr) * 1991-07-31 1993-02-18 Microcarb Inc. Conjugues comprenant un recepteur, destines a cibler des medicaments et autres agents
JPH05194413A (ja) * 1991-10-02 1993-08-03 Euroresearch Srl ５−ニトロ−１−メチル−イミダゾリル−３−ターシャリーブチル−２−ヒドロキシアリール−カルビノール、その製剤の製法、及び関連せる治療組成物。
WO1993024480A1 (fr) * 1992-06-01 1993-12-09 Yoshitomi Pharmaceutical Industries, Ltd. Compose de pyridine et son utilisation medicinale
JPH05339218A (ja) * 1992-01-16 1993-12-21 Sigma Tau Ind Farmaceut Riunite Spa アシルカルニチンエステル類および抗菌活性医薬組成物

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992018143A1 (fr) * 1991-04-15 1992-10-29 Applied Microbiology, Inc. Compositions pharmaceutiques contre les troubles gastriques
WO1993002709A1 (fr) * 1991-07-31 1993-02-18 Microcarb Inc. Conjugues comprenant un recepteur, destines a cibler des medicaments et autres agents
JPH05194413A (ja) * 1991-10-02 1993-08-03 Euroresearch Srl ５−ニトロ−１−メチル−イミダゾリル−３−ターシャリーブチル−２−ヒドロキシアリール−カルビノール、その製剤の製法、及び関連せる治療組成物。
JPH05339218A (ja) * 1992-01-16 1993-12-21 Sigma Tau Ind Farmaceut Riunite Spa アシルカルニチンエステル類および抗菌活性医薬組成物
WO1993024480A1 (fr) * 1992-06-01 1993-12-09 Yoshitomi Pharmaceutical Industries, Ltd. Compose de pyridine et son utilisation medicinale

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, 111:112197, (1989). *
YAKUGAKU ZASSHI, 88(4), 369-74, (1968). *

Also Published As

Publication number Publication date
JPH08133971A (ja) 1996-05-28
AU3484295A (en) 1996-03-29

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