WO2000073270A1 - Remedes traitant les maladies paradontales - Google Patents

Remedes traitant les maladies paradontales Download PDF

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Publication number
WO2000073270A1
WO2000073270A1 PCT/JP2000/003483 JP0003483W WO0073270A1 WO 2000073270 A1 WO2000073270 A1 WO 2000073270A1 JP 0003483 W JP0003483 W JP 0003483W WO 0073270 A1 WO0073270 A1 WO 0073270A1
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WO
WIPO (PCT)
Prior art keywords
group
compound
phenyl
oxy
amidino
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Application number
PCT/JP2000/003483
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English (en)
Japanese (ja)
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WO2000073270A8 (fr
Inventor
Kenji Matsushita
Takahisa Imamura
Ikuro Maruyama
Munehiro Tomikawa
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Daiichi Pharmaceutical Co., Ltd.
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Application filed by Daiichi Pharmaceutical Co., Ltd. filed Critical Daiichi Pharmaceutical Co., Ltd.
Priority to AU51028/00A priority Critical patent/AU5102800A/en
Publication of WO2000073270A1 publication Critical patent/WO2000073270A1/fr
Publication of WO2000073270A8 publication Critical patent/WO2000073270A8/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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

Definitions

  • the present invention relates to a prophylactic and / or therapeutic agent for periodontal disease, and more particularly to a prophylactic and / or therapeutic agent for periodontal disease which suppresses the growth of bacteria causing periodontal disease and suppresses inflammation caused by the bacteria.
  • a prophylactic and / or therapeutic agent for periodontal disease which suppresses the growth of bacteria causing periodontal disease and suppresses inflammation caused by the bacteria.
  • Periodontitis is gingival inflammation caused by mixed infections caused by gram-negative bacteria such as Porphyromonas gingivalis (P. gingival is) and Prevotel la intermedia (P. intermedia).
  • P. gingivalis is considered to be the most prominent causative agent of periodontal disease.
  • An object of the present invention is to provide a prophylactic and / or therapeutic agent for periodontal disease that suppresses the growth of periodontal disease-causing bacteria and suppresses inflammation caused by the bacteria. Disclosure of the invention
  • the present inventors have conducted intensive studies on effective drugs for periodontal disease and found that A compound represented by the following general formula (1), which is known as a solid inhibitor, inhibits the growth of P. gingival is and P. intermedia, which are the causative agents of adult periodontal disease.
  • Cultured gingival fibroblasts In the present invention, they found that the production of endogenous pro-inflammatory substance inuichi leukin-6 (IL-6) induced by these bacteria was suppressed, and thus completed the present invention. That is, the present invention provides the following general formula (1)
  • R 1 represents a hydrogen atom or a lower alkoxy group
  • R 2 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group or an alkoxycarbonylalkyl group,
  • R 3 represents a hydrogen atom, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, a carboxyalkoxy group or an alkoxycarbonylalkoxy group,
  • R 4 represents a hydrogen atom, an octogen atom, an amino group, a cyano group, a nitro group, a hydroxyl group, a lower alkyl group or a lower alkoxy group,
  • n indicates a number from 0 to 4,
  • X represents a single bond, an oxygen atom, a sulfur atom or a carbonyl group
  • Y is a substituted or unsubstituted saturated or unsaturated 5- or 6-membered heterocyclic group or ⁇ -hydrocarbon group, an optionally substituted amino group or an optionally substituted substituent;
  • the present invention also provides use of the compound represented by the general formula (1) or a salt thereof as a preventive and / or therapeutic agent for periodontal disease.
  • the present invention provides a method for treating periodontal disease, which comprises administering the compound represented by the general formula (1) or a salt thereof.
  • the compound represented by the general formula (1) of the present invention is used as a blood coagulation inhibitor in Japanese Unexamined Patent Application Publication No. 5-209496 and International Publication WO96 / 16940. Stated Although it is a known compound that has been known, it has never been known that such a compound has an action of suppressing the growth of periodontal disease-causing bacteria and suppressing the inflammation caused by the bacteria.
  • any of a straight-chain, branched or cyclic alkyl group having 1 to 6 carbon atoms can be mentioned, and specific examples are a methyl group, an ethyl group, a propyl group, an isopropyl group, Examples thereof include a butyl group, a secondary butyl group, a tertiary butyl group, a pentyl group, a hexyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group.
  • the lower alkyl group may have a substituent.
  • the group that can be substituted with the lower alkyl group include a halogen atom, a carboxyl group, a carbamoyl group, an amino group, a cyano group, a nitro group, a lower alkanoyl group, Lower alkoxy group, lower alkoxy carbonyl group, mono- or di-lower alkylamino group, aryl group, aralkyl group, aryloxy group, mercapto group, lower alkylthio group, lower alkyl carbonyl group, hydroxyl group, hydroxyl group, monol Alternatively, a di-lower alkylaminocarbonyl group and the like can be mentioned.
  • Examples of the lower alkoxy group include those having 1 to 6 carbon atoms. Specific examples include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a secondary butoxy group and a tertiary butoxy group. And the like.
  • alkoxycarbonyl group examples include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group, and the like.
  • carboxyalkyl group examples include a carboxymethyl group, a carboxyethyl group, and a carboxypropyl group.
  • alkoxycarbonylalkyl group examples include a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a propoxycarbonylmethyl group, and a methoxycarbonyl group.
  • examples thereof include a ruethyl group, an ethoxycarbonylethyl group, a methoxycarbonylpropyl group, and an ethoxycarbonylpropyl group.
  • Examples of the carboxyalkoxy group include a carboxymethoxy group, a carboxyethoxy group, and a carboxypropoxy group.
  • alkoxycarbonylalkoxy group examples include a methoxycarbonylmethoxy group, an ethoxycarbonylmethoxy group, a propoxycarbonylmethoxy group, a methoxycarbonyloxy group, an ethoxycarbonylethoxy group, and the like.
  • hydroxyalkyl group examples include a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, and a hydroxybutyl group.
  • alkylene group having 1 to 4 carbon atoms examples include a methylene group, an ethylene group, a trimethylene group, and a tetramethylene group.
  • Mono or di-lower alkylaminocarbonyl groups include monoamino lower alkylaminocarbonyl groups such as methylaminocarbonyl group, ethylamino group, propylaminocarbonyl group, propylaminocarbonyl group, isopropylaminocarbonyl group, butylaminocarbonyl group, Examples thereof include a butylaminocarbonyl group, a pentylaminocarbonyl group, an isopentylaminocarbonyl group, a hexylaminocarbonyl group, and an isohexylaminocarbonyl group.
  • dialkylaminocarbonyl group examples include lower alkyl groups such as a dimethylaminocarbonyl group, a dimethylaminocarbonyl group, a diaminoamino group, a diisopropylaminocarbonyl group, a dibutylaminocarbonyl group, and a dipentylaminocarbonyl group.
  • Lower alkylsulfonyl groups include methylsulfonyl group, ethylsulfonyl
  • Mono- or di-lower alkylaminothiocarbonyl groups include mono-lower alkylaminothiocarbonyl groups such as methylaminothiocarbonyl group, ethylaminothiocarbonyl group, propylaminothiocarbonyl group, isopropylaminothiocarbonyl group, and butylamino. Examples thereof include a thiocarbonyl group, an isobutylaminothiocarbonyl group, a pentylaminothiocarbonyl group, an isopentylaminothiocarbonyl group, a hexylaminothiocarbonyl group, and an isohexylaminothiocarbonyl group.
  • dialkylaminothiocarbonyl group examples include dimethylaminothiocarbonyl, dimethylaminothiocarbonyl, dibutylpyraminothiocarbonyl, diisopropylaminothiocarbonyl, dibutylaminothiocarbonyl, dipentylaminothiocarbonyl, and dipentylaminothiocarbonyl.
  • Examples of the lower alkanoyl group include a formyl group, an acetyl group, a propionyl group, a butyryl group, an isoptyryl group, a valeryl group, an isovaleryl group, a bivaloyl group, and a hexanoyl group. And a butyryl group, more preferably an acetyl group and a propionyl group.
  • the lower alkanoyl group may have a substituent.
  • Examples of groups that can be substituted with lower alkanoyl groups include octylogen, carboxyl, carbamoyl, amino, cyano, nitro, lower alkanoyl, A lower alkoxy group, a lower alkoxycarbonyl group, a mono- or di-lower alkylamino group, an aryl group, an aralkyloxy group, an aryloxy group, a mercapto group, a lower alkylthio group, a lower alkylthiocarbonyl group, a hydroxyl group, a monomeric group, monono or Examples thereof include di-lower alkylaminocarboxy groups.
  • aryl group examples include a phenyl group, a naphthyl group, a biphenyl group, an anthryl group and the like, and the aryl group may have a substituent.
  • heteroaryl group examples include a furyl group, a cyenyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, an isothiazolyl group, an isoxazolyl group, a pyridyl group, a pyrimidinyl group, a quinolyl group, an isoquinolyl group, a quinazolinyl group, a quinolizinyl group, and a quinoxalinyl group.
  • benzimidazolyl group imidazopyridyl group, benzofuranyl group, naphthyridinyl group, 1,2-benzoisoxazolyl group, benzoxazolyl group, benzothiazolyl group, oxazolopyridyl group, isothiazolopyridyl group, benzochedi group And a furyl group, a cyenyl group, a pyrrolyl group, an imidazolyl group, a pyridyl group and the like.
  • the aryl group may have a substituent.
  • Examples of the group which can be substituted with the aryl or heteroaryl group include a norogen atom, a carboxyl group, an amino group, a cyano group, a nitro group, a hydroxyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a mono- or di-alkoxy group.
  • Examples thereof include a lower alkylamino group, a lower alkanoyl group and a lower alkyl group which may have a substituent.
  • each substituent represented by Y is as follows.
  • a heterocyclic group containing 1 to 2 nitrogen atoms or oxygen atoms as a hetero atom is preferable.
  • Specific examples of such a heterocyclic group include pyrrolidine, piperidine, imidazoline, piperazine, tetrahydrofuran, hexahydropyrimidine, pyrrole, imidazole, pyrazine, Examples thereof include those in which a heterocycle such as pyrrolidinone, piberidinone, or morpholine is a substituent.
  • the bonding position is a carbon atom or a nitrogen atom, and the bonding position is preferably a carbon atom.
  • These heterocyclic groups may have a substituent, and the substituent may be a lower alkyl group, a lower alkanoyl group, a carbamoyl group, a monoalkylcarbamoyl group, a dialkyl carbamoyl group, a formimidoyl group, Canoimidoyl group, benzimidoyl group, carboxyl group, alkoxycarbyl group, carboxyalkyl group, alkylcarbonylalkyl group, aminoalkyl group, alkanoylamino group, alkanoylaminoalkyl group, imino group, alkoxycarbonilimino group, etc. Can be mentioned.
  • preferred heterocyclic groups include
  • R 8 and R 9 are each a hydrogen atom, an amidino group or a group R 10
  • Ri represents a lower alkyl group.
  • saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group include a phenyl group, a cyclohexyl group, and a cyclopentyl group.
  • the cyclic hydrocarbon group has a substituent.
  • aminoalkyl group examples include an aminomethyl group, an aminoethyl group, an aminopropyl group and the like.
  • Examples of the group which can be substituted for the amino group of the amino group or the aminoalkyl group include lower alkyl group, pyrrolidinyl group, virazyl group, rubamoyl group, monoalkyl rubamoyl group, dialkyl rubamoyl group, lower alkanoyl group, and formimide.
  • Examples include an yl group, an alkanoimidoyl group, a benzimidoyl group, and an alkoxycarbonyl group.
  • the alkyl group, alkoxy group, alkanol group and the like preferably have 1 to 6 carbon atoms.
  • the group represented by is preferably a group selected from benzofuranyl, benzimidazolyl, indolyl, benzothienyl, benzothiazolyl, naphthyl and tetrahydronaphthyl.
  • 1 ⁇ to 1 4 are hydrogen atoms; eta is 0; X is oxygen atom; Alpha is one hydroxy group, a carboxyl group, an alkoxycarbonyl group, carboxyalkyl group Or an alkylene group or a group having 2 carbon atoms, which may be substituted with an alkoxycarbonylalkyl group, —CH 2 —N (R ”) 1 (where R 11 is a hydrogen atom or a group S ⁇ 2 —W 1 — R 12 (wherein, W 1 represents a single bond or a group _ N (R 13) i (wherein, R '3 represents a hydrogen atom, a force Rubamoiru group, a lower alkoxycarbonyl group, mono- or di-lower alkylaminocarbonyl group, a lower alkyl a sulfonyl group, mono- or di - lower alkylamino Chio carbonyl group, optionally having a
  • R 8 and R 9 are each a hydrogen atom, an amidino group or a group
  • R 1G represents a lower alkyl group.
  • R 1G represents a lower alkyl group.
  • a salt thereof wherein the group represented by is benzofuranyl, benzimidazolyl, indolyl, benzothienyl, benzothiazolyl, naphthyl or tetrahydronaphthyl;
  • the compound represented by the general formula (1) may have an asymmetric carbon atom. In such a case, an optical isomer or a stereoisomer based on the asymmetric carbon atom exists. Both optical isomers, stereoisomers and mixtures thereof are included in the present invention.
  • the salt of the compound represented by the general formula (1) is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • Organic salts such as organic acid salts, malonates, succinates, glutarates, adipates, tartrates, maleates, malates, and mandelates.
  • the compound represented by the general formula (1) or a salt thereof can exist not only in an unsolvated form but also as a hydrate or a solvate. Therefore, the compound of the present invention or a salt thereof includes all crystal forms and hydrates or solvates thereof.
  • the prophylactic and / or therapeutic agent for periodontal disease of the present invention comprises the compound represented by the above general formula (1) or a salt thereof as an active ingredient. From the viewpoint of suppression, the following compounds 1 to 20 are particularly preferable.
  • the thus-obtained compound represented by the general formula (1) or a salt thereof inhibits the growth of P. gingivalis and P. intermedia which are the causative bacteria of adult periodontal disease. In addition, it suppresses the production of endogenous pro-inflammatory substance interleukin-6 (IL-6) induced by those bacteria in cultured gingival fibroblasts. Therefore, it is useful for various periodontal diseases and can be administered as a prophylactic and / or therapeutic agent for periodontal disease.
  • IL-6 interleukin-6
  • Dosage forms include ointments and periodontal pocket inserts called periodontal pockets, which are injected into the gap between the teeth and gums, periodontal packing agents, gargles, spray formulations, troches, toothpastes, gums, etc.
  • the periodontal filler is called dental cement or dental pasta, and is used for periodontal bandages. It is also conceivable to put the drug into the artificial root.
  • ointments, periodontal pocket inserts and periodontal packing agents are preferred, and ointments and periodontal pocket inserts are preferred.
  • Such a preparation can be produced by a known preparation technique.
  • the periodontal filler can be manufactured by a known technique of dental cement or dental paste.
  • the periodontal packing material is composed of “dispersion” and “liquid”, and when both are kneaded together immediately before use for treatment, a preparation having an appropriate hardness is obtained.
  • the compound represented by the general formula (1) of the present invention or a salt thereof is mixed in powder form as powder. Or dissolve or suspend in “liquid”.
  • the “dispersion” is composed of one or more substances selected from rosin, asbestos, calcium hydroxide, etc., mainly composed of zinc oxide, and the “liquid” is a vegetable oil such as olive oil or foliage oil, or other vegetable oil. It is composed of one or more substances selected from pharmaceutically acceptable solvents.
  • stabilizers, flavors and flavoring agents may be appropriately added.
  • known pharmaceutical additives can be arbitrarily added to the various dosage forms. Specific examples include, but are not limited to, the following. These substances can be used alone or in combination of two or more, and the kind thereof may be appropriately selected according to the drug and the dosage form.
  • Magnesium chloride triacetin, methylcellulose, ethylcellulose, cellulose acetate, hydroxymethylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, liquid paraffin, white petrolatum, glycerin, Eudragit L, sodium alginate, propylene glycol alginate Ester, tragacanth, xanthan gum, chitosan, polyethylene oxide, polyvinylpyrrolidone, polydalicholate, polylactic acid, polytetramethyldalicollide, polygetyldaricolide, poly ⁇ -force prolactone, poly (DL-decalactone), Poly (alkylene adipate), polyvinyl alcohol, polyacrylic acid, polymethacrylic acid, methacrylic acid Chill, dimethyl ⁇ amino acetate, such as collagen and ⁇ terrorism collagen and the like.
  • ibuprofen indomethacin, ketoprofen, mefenamic acid, antipyrine, tiaramid sulfate, prednisolone, dexamethasone, triamcinolone acetonide, prostaglandin,
  • Anti-inflammatory drugs such as cortisone; anti-plasmin drugs such as tranexamic acid and epsilon aminocaproic acid; plaque dissolving drugs such as dextranase and amylase; local anesthetics such as tetracaine hydrochloride and ethyl ethyl benzoate;
  • Antihistamines such as lamin and diphenhydramine;
  • Fungicides such as lorhexidine, silver protein, silver glycerin, phenol, benzolconidum chloride, and cetylpyridinium chloride, ampicillin, benzylperidiline, cephal
  • the daily dose of the agent for preventing and / or treating periodontal disease according to the present invention varies depending on the form of the administered drug, the age of the patient, the size of the affected area, the degree of the disease, and the like.
  • the compound to be shown is 0.001 g to 10 Omg, preferably 0.01 Zg to 10 mg, more preferably 0.1 g to 5 mg, which can be administered once or once to several times a day. I do.
  • the compound or a salt thereof according to the present invention inhibits the growth of P. gingival is and P. intermedia, which are the causative bacteria of adult periodontal disease, and induces gingival fibroblast inflammation by these bacteria.
  • P. gingival is and P. intermedia, which are the causative bacteria of adult periodontal disease, and induces gingival fibroblast inflammation by these bacteria.
  • a specific test shows that the suppression of the production of interleukin-6 (IL-6), an endogenous pro-inflammatory substance, occurs when the treatment is performed.
  • IL-6 interleukin-6
  • 0.1 ⁇ g of freeze-dried cells of P. gingivalis 381 and P. intermedia ATCC25611 were each suspended in ImL of sterilized GAM broth liquid medium. From each suspension, a small amount of bacterial solution was collected with a platinum loop, smeared on a Heige blood agar medium, and separated and cultured. Next, a single colony of each strain was inoculated into 3 mL of sterile GAM bouillon medium, and anaerobically cultivated (Model 1024; Forma Scientific, Mich., OH, USA).
  • the cells were inoculated on each GAM broth liquid medium containing 400, 800, 160 g / mL and cultured for 24 hours under the above anaerobic conditions. After the completion of the culture, the turbidity of the bacterial solution was measured using an OD660 body to determine the degree of bacterial growth. Table 1, compound 2 1 of IC 5 against P. gingivalis 381 and P. intermedia ATCC25611. (50% growth inhibitory concentration).
  • HGF cultured human gingival fibroblasts
  • FBS fetal calf serum
  • gingivalis 381 by the phenol-War Yuichi method was added to a final concentration of 0.4 / xg / mL, and the cells were further cultured for 12 hours. After the culture is completed, The culture supernatant was collected, and the IL-6 concentration in the supernatant was measured using a human IL-6 ELISA Kit (Gengyme, MA, USA). Table 2 shows the inhibitory effect of compound 21 on IL-6 production.
  • ADVANTAGE OF THE INVENTION According to the prophylactic and therapeutic agent for periodontal disease of the present invention, it is possible to inhibit the growth of periodontal disease-causing bacteria and suppress the inflammation caused by the bacteria. Various periodontal diseases such as inflammation) can be effectively prevented and Z or treated.

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

Abstract

L'invention porte sur des médicaments préventifs ou curatifs des maladies paradontales contenant comme principe actif des composés de formule générale (1) ou leurs sels et susceptibles de traiter efficacement différentes maladies paradontales telles que la parodontite. Dans la formule (1), R1 est H, ou analogue, R2 est H, alkyle inférieur, ou analogues, R3 est H, carboxyle, ou analogues, R4 est H, halogéno, ou analogues, A est C¿1?-C4 alkylène facultativement substitué par l'un de deux éléments choisis parmi hydroxyalkyle, carboxyle, alkoxycarbonyle ou analogue, X est une liaison simple, oxygène, ou analogue, et Y est un groupe hétérocyclique saturé ou non facultativement substitué à cinq ou six éléments, ou analogue.
PCT/JP2000/003483 1999-05-31 2000-05-31 Remedes traitant les maladies paradontales WO2000073270A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU51028/00A AU5102800A (en) 1999-05-31 2000-05-31 Remedies for periodontal diseases

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP11/151721 1999-05-31
JP15172199 1999-05-31

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Publication Number Publication Date
WO2000073270A1 true WO2000073270A1 (fr) 2000-12-07
WO2000073270A8 WO2000073270A8 (fr) 2001-03-01

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5238030A (en) * 1975-07-04 1977-03-24 Gaba Ag Mouth and tooth reparing agent
JPH06345360A (ja) * 1993-06-02 1994-12-20 Fujita Corp 仮設昇降装置
JPH07267839A (ja) * 1994-03-30 1995-10-17 Sunstar Inc 口腔粘膜付着性軟膏組成物
JPH0820532A (ja) * 1994-07-05 1996-01-23 Dai Ichi Seiyaku Co Ltd 抗膵炎剤
US5576343A (en) * 1991-10-31 1996-11-19 Daiichi Pharmaceutical Co., Ltd. Aromatic amidine derivatives and salts thereof
WO1999024407A1 (fr) * 1997-11-10 1999-05-20 Array Biopharma, Inc. Composes inhibant l'activite de la tryptase

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5238030A (en) * 1975-07-04 1977-03-24 Gaba Ag Mouth and tooth reparing agent
US5576343A (en) * 1991-10-31 1996-11-19 Daiichi Pharmaceutical Co., Ltd. Aromatic amidine derivatives and salts thereof
JPH06345360A (ja) * 1993-06-02 1994-12-20 Fujita Corp 仮設昇降装置
JPH07267839A (ja) * 1994-03-30 1995-10-17 Sunstar Inc 口腔粘膜付着性軟膏組成物
JPH0820532A (ja) * 1994-07-05 1996-01-23 Dai Ichi Seiyaku Co Ltd 抗膵炎剤
WO1999024407A1 (fr) * 1997-11-10 1999-05-20 Array Biopharma, Inc. Composes inhibant l'activite de la tryptase

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AU5102800A (en) 2000-12-18

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