WO1999033470A1 - ANTI $i(HELICOBACTER PYLORI) - Google Patents

ANTI $i(HELICOBACTER PYLORI) Download PDF

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Publication number
WO1999033470A1
WO1999033470A1 PCT/JP1998/005876 JP9805876W WO9933470A1 WO 1999033470 A1 WO1999033470 A1 WO 1999033470A1 JP 9805876 W JP9805876 W JP 9805876W WO 9933470 A1 WO9933470 A1 WO 9933470A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
carbons
phenyl
carbon atoms
hydrogen
Prior art date
Application number
PCT/JP1998/005876
Other languages
English (en)
Japanese (ja)
Inventor
Motohiro Suzuki
Naohiro Yamada
Hisanori Wakita
Original Assignee
Toray Industries, Inc.
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 Toray Industries, Inc. filed Critical Toray Industries, Inc.
Publication of WO1999033470A1 publication Critical patent/WO1999033470A1/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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/558—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes
    • A61K31/5585—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes having five-membered rings containing oxygen as the only ring hetero atom, e.g. prostacyclin

Definitions

  • the present invention contemplates a drug for preventing or treating a medically or silently related disease associated with Helicobacter genus bacterial infection, and a method for preventing or treating the disease.
  • the present invention relates to a medicament for preventing or treating a disease associated with Helicobacter pylori infection, particularly peptic ulcer, and a method for preventing or treating the same in humans. . Background art
  • Helicobacter pylori is a gram-negative bacillus (La nc et :, 1, 1273–1275, 1983) isolated from gastric mucosa of gastric ulcer patients in 1983 by Australia's Marsha 11 and Warren, and has recently become chronic. It has been attracting attention as a causative factor in human upper gastrointestinal diseases such as gastritis, gastric and duodenal ulcers, gastric cancer and lymphoma.
  • Helicopter from the dog's intestinal tract-Helicobacter cisterc anis Helicobacter mustera from the stomach of Ferret, Helicobacter b. Ferris from the stomach of dogs and cats.
  • Helic ob ac terfe 1 is
  • Helicobacter heirmani Helicobacter obac ter heilmanni
  • Helicobacter hepatics from the liver and intestine of mice.
  • helicopter * kita ** bilis Helic ob ac terbi 1 is), helicopter muridalum (He 1 ic ob ac ter mu ridar um), etc. have been found in the intestinal tract of rats.
  • helicobacter ferris not only infects humans and induces gastritis, but also infects animal species that are carcinogenic, such as by infecting mice. It has also been reported to cause lesions.
  • Prostaglandins are a group of naturally occurring substances with a wide variety of biological activities and have a common prostanoic acid skeleton.
  • Naturally occurring PGs are classified into PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs, PGJs due to their five-membered structural characteristics. It is further classified into subclasses such as 1, 2, and 3 depending on the degree of unsaturation and oxidation state. Many synthetic analogs of these PGs are also known.
  • an object of the present invention is to provide a clinically useful anti-helicopter agent and a method for preventing or treating the same. Disclosure of the invention
  • the present invention relates to an anti-Helicobacter agent comprising a prostanoic acid derivative or a pharmaceutically acceptable salt thereof as an active ingredient, and a prophylactic or therapeutic method using the same.
  • the brostanoic acid derivative of the present invention is any of PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs, and PGJs having a prostanoic acid skeleton. It may also be a derivative of any of the subclasses such as 1, 2, and 3, which are classified according to the degree of unsaturation and the state of oxidation.
  • the brostanoic acid derivative of the present invention includes not only natural but also any synthetic derivative.
  • the carbon number of the basic skeleton of brostanoic acid is generally 20, but the carbon number of the prostanoic acid derivative of the present invention is not particularly limited.
  • pro Stan acid derivative used in the present invention may be a PG 1 2 derivatives or any salt thereof, but further good Mashiku the following general formula (I)
  • Z is a valence bond, or a linear or branched alkylene represented by C t H 21 ,
  • R 3 is a substituted consequent opening alkyl cycloalkyl, or R 4 of 1-3 carbon atoms substituted with 3-12 of 3 to 12 carbon atoms, R 4 is hydrogen Or alkyl having 1 to 5 carbon atoms,
  • n is an integer from 1 to 5
  • R 5 is hydrogen or benzoyl
  • R s is phenyl, P-bromophenyl, p-chlorophenyl, p-biphenyl, p-nitrophenyl, p-penzamide phenyl, 2-naphthyl,
  • R 7 is hydrogen or straight or branched alkyl having 1 to 30 carbon atoms or aralkyl
  • P is an integer from 1 to 5, or
  • R 8 is alkyl or acyl having 1 to 30 carbon atoms
  • R 9 is hydrogen, linear alkyl having 1 to 12 carbons, branched alkyl having 3 to 12 carbons, cycloalkyl having 3 to 12 carbons, cycloalkylalkylene having 4 to 13 carbons, phenyl, Substitution! : Nil (wherein the substituent is as defined in the above (A) 5)), aralkyl having 7 to 12 carbon atoms or one S02R 1 . And R 1 .
  • R 9 Represents alkyl having 1 to 10 carbons, cycloalkyl having 3 to 12 carbons, phenyl, substituted phenyl (where substituted grave is the same as in the case of (A) 5) above), and aralkyl having 7 to 12 carbons,
  • Two R 9 s may be the same or different, but one is — SOzR 1 .
  • Other R 9 shall not be -S 0 2 R 1 °, or
  • Y is hydrogen, alkyl having 1 to 4 carbon atoms, chlorine, bromine, fluorine, formyl, methoxy, or nitro
  • B is one X-C ( R: 1) (R 12) oR 13 wherein R 11 is hydrogen or alkyl having 1 to 4 carbon atoms, R 1 3 is hydrogen, Ashiru 1 to 14 carbon atoms, 6 to 15 carbon atoms Aroiru, tetrahydro Vilanyl, tetrahydrofuranyl, 1-ethoxyshethyl or t-butyl, and X is
  • R 12 is
  • Ar 2 is phenyl, ⁇ -naphthyl, ⁇ -naphthyl), or at least one of chlorine, bromine, fluorine, iodine, trifluoromethyl, and carbon atoms having 1 to 4 carbon atoms. Alkyl, nitro, cyano, methoxy, phenyl or phenyl substituted phenyl; or
  • C t H 2t is the same as defined above, and R ′′ is a straight-chain alkyl having 1 to 6 carbons, a branched alkyl having 3 to 6 carbons, phenyl, at least one chlorine, bromine, fluorine, iodine, and trifur.
  • Substituted with 1 to 4 carbon atoms such as orthomethyl, alkyl having 1 to 4 carbon atoms, nitro, cyano, methoxy, phenyl or phenoxy-substituted phenyl, cyclopentyl, cyclohexyl, or linear alkyl having 1 to 4 carbon atoms Represents cyclopentyl or cyclohexyl,
  • R 1S and R 16 represent hydrogen, methyl, ethyl, propyl or butyl, or
  • u is an integer of 1 to 7
  • C u H 2 u represents a linear or branched alkylene
  • R 17 represents a linear alkyl having 1 to 6 carbons
  • E is hydrogen, or —OR 18, where R 18 is a C 1-12 acyl, a C 7-15 aroyl or R 2 (where R 2 is the same as defined above), and the general formula is d Body, 1 body or 1 d body]
  • the prostanoic acid derivative of the present invention can be produced by a known method.
  • the compound represented by the general formula (I) or a salt thereof is disclosed in Japanese Patent Publication No. 5-3672, Japanese Patent Publication No. 2-2122, Japanese Patent Publication No. 2-5 758 Can be produced by the method described in
  • prostanoic acid derivative represented by the above general formula (I) include, for example, the following derivatives.
  • salts of the above-mentioned exemplified compounds include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, methylamine salt, dimethylamine salt and trimethylamine. Salts, amine salts such as methylpiperidine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt and lysine salt, ammonium salt, and basic amino acid salt.
  • the brostanic acid derivative according to the present invention can be administered orally or parenterally for prevention or treatment.
  • solid preparations such as tablets, granules, capsules and powders, or liquid preparations such as syrups and elixirs can be used.
  • parenteral administration preparations such as injection preparations, rectal preparations, skin external preparations, inhalants and the like can also be used.
  • the prostanoic acid derivative in the present invention can be administered by adding excipients, stabilizers, and the like that are commonly used in the formulation of drugs.
  • excipients include, for example, animal oils, vegetable oils, paraffin, gum arabic, or sugars such as flour, lactose, saccharose, fructose, dextrin, mannitol, etc.
  • Inorganic salts such as calcium carbonate, calcium sulfate, etc .
  • organic acid salts such as sodium citrate, sodium lactate, magnesium stearate
  • water-soluble such as methylcellulose, gelatin, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, hydroxyethyl cellulose
  • alcohols such as anionic polymers, ethanol, glycerin, propylene glycol, and sorbitol, surfactants such as sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, and glycerin fatty acid ester are used.
  • the brostanic acid derivative of the present invention is effective for the prevention and treatment of medical or veterinary diseases associated with infection with Helicobacter bacteria, and in humans, Helicobacter pylori. It is effective, but not limited to, in the prevention and treatment of infection-related diseases, especially peptic ulcers.
  • the dosage of the brostanic acid derivative of the present invention varies depending on the age, body weight, disease state, dosage form, etc. of the patient, but usually 1 to 1000 mg per adult is administered once or several times a day. can do.
  • a disc was placed on each medium coated with the bacteria, and the test compound dissolved in dimethylsulfoxide was impregnated with 101, and then cultured at 37 ° C in 100% air for 1 to 2 days. After completion of the culture, the diameter of the growth arresting circle formed around the disc was measured, and the diameter was determined according to the calculation formula of Hu1tmark et al. (The EMBO Journal, 2, 571—576, 1983). The bactericidal concentration (LC) of each test compound was calculated. From these results, it was confirmed that the prostanoic acid derivative did not act on bacteria other than the genus Helicobacter, and that the antibacterial activity of the prostanoic acid derivative was selectively expressed in bacteria belonging to the genus Helicobacter (Table 4). ).
  • the brostanic acid derivative of the present invention or a pharmaceutically acceptable salt thereof exhibits a selective eradication effect against Helicobacter genus bacteria. Therefore, the use of the compound of the present invention makes it possible to safely prevent or treat medical or medical diseases related to infection with Helicobacter bacteria, such as peptic ulcers.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur un anti Helicobacter pylori contenant comme principe actif un dérivé de l'acide prostanoïque ou l'un de ses sels médicocompatibles, lesquels ont une action stérilisante sélective sur les hélicobactères et peuvent sûrement prévenir ou guérir les infections leur étant dues, chez l'homme et l'animal.
PCT/JP1998/005876 1997-12-25 1998-12-24 ANTI $i(HELICOBACTER PYLORI) WO1999033470A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP8/358243 1997-12-25
JP35824397 1997-12-25
JP10/17087 1998-01-29
JP1708798 1998-01-29

Publications (1)

Publication Number Publication Date
WO1999033470A1 true WO1999033470A1 (fr) 1999-07-08

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1998/005876 WO1999033470A1 (fr) 1997-12-25 1998-12-24 ANTI $i(HELICOBACTER PYLORI)

Country Status (1)

Country Link
WO (1) WO1999033470A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3287134A1 (fr) 2016-08-26 2018-02-28 Orthogen AG Thérapie combinée utilisant une préparation de sang et une préparation helminthique

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0212226B2 (fr) * 1980-08-05 1990-03-19 Toray Industries
WO1996005843A1 (fr) * 1994-08-25 1996-02-29 Enosys S.A. Compositions pharmaceutiques comprenant un gel de sucralfate et un polyalcool seches en meme temps

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0212226B2 (fr) * 1980-08-05 1990-03-19 Toray Industries
WO1996005843A1 (fr) * 1994-08-25 1996-02-29 Enosys S.A. Compositions pharmaceutiques comprenant un gel de sucralfate et un polyalcool seches en meme temps

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3287134A1 (fr) 2016-08-26 2018-02-28 Orthogen AG Thérapie combinée utilisant une préparation de sang et une préparation helminthique
WO2018036657A1 (fr) 2016-08-26 2018-03-01 Orthogen Ag Polythérapie utilisant une préparation sanguine et une préparation helminthique

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