WO2000073270A1 - Remedies for periodontal diseases - Google Patents

Abstract

Preventive and/or therapeutic drugs for periodontal diseases containing as the active ingredient compounds of general formula (1) or salts thereof and being capable of preventing and/or treating effectively various periodontal diseases such as periodontitis, wherein R1 is hydrogen or the like; R2 is hydrogen, lower alkyl, or the like; R3 is hydrogen, carboxyl, or the like; R4 is hydrogen, halogeno, or the like; n is a number of 0 to 4; A is C¿1?-C4 alkylene which may be substituted with one or two members selected from among hydroxyalkyl, carboxyl, and alkoxycarbonyl, or the like, X is a single bond, oxygen, or the like; and Y is an optionally substituted, saturated or unsaturated, five- or six-membered heterocyclic group or the like.

Description

 Description Periodontitis drug Technical field

 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. About the drug. Background art

 Adult 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). In particular, P. gingivalis is considered to be the most prominent causative agent of periodontal disease.

 Therefore, in preventing and treating periodontal disease, it is important to remove the causative bacteria and to suppress gingival inflammation caused by the causative bacteria. In addition, the most common method was to remove the causative organisms such as the reptile in the periodontal pocket.

 However, it is difficult to achieve a sufficient preventive and therapeutic effect only by such mechanical means, and there has been a need for a drug that fundamentally removes the causative bacteria and suppresses gingival inflammation caused by the bacteria.

 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)

Wherein 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,

A is an alkylene group having 1 to 4 carbon atoms which may be substituted by 1 to 2 hydroxyalkyl groups, carboxyl groups, alkoxycarbonyl groups, carboxyalkyl groups or alkoxycarbonylalkyl groups, or a group B—N ( R ⁵ ) — (where B represents a lower alkylene group or a carbonyl group, R ⁵ is a hydrogen atom or a group —D—W—R ⁶ (where D is a group C (= Z) 1 ( Here, Z represents an oxygen atom or a sulfur atom), a group —C (= 〇) —C (= 〇) — or a sulfonyl group, and W represents a single bond or Is a group N (R ⁷ )-(where R ⁷ is a hydrogen atom, a carbamoyl group, a lower alkoxycarbonyl group, a mono- or di-lower alkylaminocarbonyl group, a lower alkylsulfonyl group, a mono or di-lower group An alkylaminothiocarbonyl group, a lower alkyl group which may have a substituent or a lower alkanol group which may have a substituent), and R ⁶ represents a hydroxyl group, a lower alkoxy group, or a substituent. Represents a lower alkyl group which may be substituted, an aryl group which may be substituted or a heteroaryl group which may be substituted)));

 X represents a single bond, an oxygen atom, a sulfur atom or a carbonyl group,

で表される基は、 インドリル、 ベンゾフラニル、 ベンゾチェ二ル、 ベンズィミダ ゾリル、 ベンズォキサゾリル、 ベンゾチアゾリル、 ナフチル、 テトラヒドロナフ チル及びインダニルより選ばれる基を示す〕 で表される化合物又はその塩を有効 成分とする歯周病の予防及び /又は治療薬を提供するものである。 Y is a substituted or unsubstituted saturated or unsaturated 5- or 6-membered heterocyclic group or 澴 -hydrocarbon group, an optionally substituted amino group or an optionally substituted substituent; Represents an aminoalkyl group which may be

Represents a group selected from indolyl, benzofuranyl, benzochenyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, naphthyl, tetrahydronaphthyl, and indanyl.) It is intended to provide a preventive and / or therapeutic agent for periodontal disease as a component.

 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.

 Further, 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. BEST MODE FOR CARRYING OUT THE INVENTION

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.

In the general formula (1) of the present invention,! Each substituent shown as ^ to ⁶ specifically means the following.

 As the lower alkyl group, 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. Examples of 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.

 Examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group, and the like. Examples of the carboxyalkyl group include a carboxymethyl group, a carboxyethyl group, and a carboxypropyl group.

Examples of the alkoxycarbonylalkyl group 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.

 Examples of the alkoxycarbonylalkoxy group include a methoxycarbonylmethoxy group, an ethoxycarbonylmethoxy group, a propoxycarbonylmethoxy group, a methoxycarbonyloxy group, an ethoxycarbonylethoxy group, and the like. Examples of the hydroxyalkyl group include a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, and a hydroxybutyl group.

 Examples of the alkylene group having 1 to 4 carbon atoms 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. Examples of the dialkylaminocarbonyl group 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. Symmetric dialkylaminocarbonyl group di-substituted with, and ethylmethylaminocarbonyl group, methylpropylaminocarbonyl group, ethylpropylaminocarbonyl group, butylmethylaminocarbonyl group, butylethylaminocarbonyl group And an asymmetric dialkylaminocarbonyl group di-substituted by different lower alkyl groups such as butylpropylaminocarbonyl group.

 Lower alkylsulfonyl groups include methylsulfonyl group, ethylsulfonyl

0 Group, propylsulfonyl group, isopropylsulfonyl group, butylsulfonyl group, isoptylsulfonyl group, pentylsulfonyl group, isopentylsulfonyl group, hexylpropyl group, and isohexylpropyl group.

 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. Examples of the dialkylaminothiocarbonyl group include dimethylaminothiocarbonyl, dimethylaminothiocarbonyl, dibutylpyraminothiocarbonyl, diisopropylaminothiocarbonyl, dibutylaminothiocarbonyl, dipentylaminothiocarbonyl, and dipentylaminothiocarbonyl. Symmetric dialkylaminothiocarbonyl group di-substituted with a lower alkyl group such as a group, and ethermethylaminothiocarbonyl, methylpropylaminothiocarbonyl, ethylpropylaminothiocarbonyl, and butyl Unsymmetrical dialkylaminothiol radicals disubstituted with different lower alkyl groups such as methylaminothiocarbonyl, butylethylaminothiocarbonyl, butylpropylaminothiocarbonyl, etc.

 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.

 Examples of the aryl group include a phenyl group, a naphthyl group, a biphenyl group, an anthryl group and the like, and the aryl group may have a substituent.

 Examples of the heteroaryl group 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. 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. Preferably, 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.

Further, in the general formula (1), specific examples of each substituent represented by Y are as follows. As the saturated or unsaturated 5- to 6-membered heterocyclic group, 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. Further, preferred heterocyclic groups include

(Wherein R ⁸ and R ⁹ are each a hydrogen atom, an amidino group or a group R ¹⁰

 NH

(In the formula, ^Ri represents a lower alkyl group.)) ^Which is a 5- to 6-membered heterocyclic group.

Specific examples of the 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. Lower alkyl group, lower alkanoyl group, carbamoyl group, monoalkyl rubamoyl group, dialkyl rubamoyl group, formimidoyl group, alkanoimidoyl group, benzimidoyl group, carboxyl group, alkoxycarbonyl group, carboxyalkyl group, Alkylcarbonylalkyl group, aminoalkyl group, alkanoylamino group, alkanoylaminoalkyl group, It may be substituted with an imino group, an alkoxycarbonilimino group or the like.

 Examples of the aminoalkyl group 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.

で示される基としては、 ベンゾフラニル、 ベンズイミダゾリル、 インドリル、 ベ ンゾチェニル、 ベンゾチアゾリル、 ナフチル及びテトラヒドロナフチルより選ば れる基が好ましい。 In general formula (1),

The group represented by is preferably a group selected from benzofuranyl, benzimidazolyl, indolyl, benzothienyl, benzothiazolyl, naphthyl and tetrahydronaphthyl.

In the compounds represented by the general formula (1), 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〇 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 substituent shown even better lower Arukanoiru group optionally having a lower alkyl group or a substituent) indicates, R ¹² is Group, a lower alkoxy group, lower which may have a substituent Represents a lower alkyl group, an aryl group which may have a substituent or a heteroaryl group which may have a substituent)));

(Wherein R ⁸ and R ⁹ are each a hydrogen atom, an amidino group or a group

で表される基が、 ベンゾフラニル、 ベンズイミダゾリル、 インドリル、 ベンゾチ ェニル、 ベンゾチアゾリル、 ナフチル又はテトラヒドロナフチル；である化合物 又はその塩が好ましい。 (Wherein, R ^1G represents a lower alkyl group).

Or 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. Specifically, hydrochloride, hydrobromide, hydroiodide, Mineral salts such as phosphates, nitrates and sulfates; organic sulfonates such as methanesulfonate, 2-hydroxyethanesulfonate and p-toluenesulfonate; and acetates, propionates and oxalates 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.

 2-[4-[((3 S) _1 -acetimidoyl-3 _ pyrrolidinyl) oxy] phenyl]-3-(7-amidino-2-naphthyl) propionic acid (Compound 1),

(+) — 2— [4-([(3 S) —1-acetoimidoyl-1-3-pyrrolidinyl) oxy] phenyl] —3- (7-amidino_2-naphthyl) propionic acid (Compound 2),

 (2 S) 1—2— [4 — [((3 S) —1-acetoimidoyl-1-pyrrolidinyl) oxy] phenyl] -3 -— (7-amidino-2-naphthyl) propionic acid (compound 3)

 (2R) -2-[4 — [((3R) 11-acetimidoyl-1-3-pyrrolidinyl) oxy] phenyl] _3— (7-amidinol2_naphthyl) propionic acid (compound 4),

 2- [4-[(1-Acetimidoyl-4-piperidyl) oxy] phenyl] — 3- (7-amidino-2-naphthyl) propionic acid (compound 5),

 (+) — 2— [4-[(1-acetimidoyl-1 4-piperidyl) oxy] phenyl] 13- (7-amidino-2-naphthyl) propionic acid (compound 6)

2- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] — 3- (5-amidinobenzo [b] chen-2-yl) propionic acid (compound 7),

2— [4 — [((2S) —1-acetimidoyl-2-pyrrolidinyl) [Phenyl] -1- (5-amidinobenzo [b] chen-1-2-yl) propionic acid (compound 8),

 (+) — 2 -— [4 — [((2S) —1-acetoimidoyl-2-pyrrolidinyl) methoxy] phenyl] —3 -— (5-amidinobenzo [b] chen-1-yl) propionic acid ( Compound 9),

 3- [4-[[((3 S) —1-acetoimidoyl-3--3-pyrrolidinyl) oxy] phenyl] -1- (5-amidinobenzo [b] chen-2--2- ^) butyric acid (compound 1〇),

 2-[4- [((3 S) — 1-acetimidoyl-3 -pyrrolidinyl) oxy] phenyl] — 3 — (6-amidino-1-ethyl-2 indolyl) propionic acid (compound 11 1),

 2-[4 — [((3R) 11-acetoimidoyl-13-pyrrolidinyl) oxy] phenyl] _ 3 _ (6 _ amidinone 1-ethyl _2-^ Γpindolyl) propionic acid (compound 12),

 2-[4-[(1 _acetimidoyl-1-4-piberidinyl) oxy] phenyl] — 3 -— (6-amidino-1-ethyl-1 -indolyl) propionic acid (compound 13)

 N- [4 -— ((1-acetimidoyl-1-4-piperidyl) oxy] phenyl] —N — [(7-amidino-2-naphthyl) methyl] —N′—methylsulfamide (compound 14)

 Ethyl N— [N-4-([1-acetimidoyl—4-piperidyl) oxy] phenyl] —N — [(7_amidino—2_naphthyl) methyl] sulfamoyl] lebamate (Compound 15) ,

4 -— [N-4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] —N — [(7-amidino-2-naphthyl) methyl] sulfamoyl] benzoic acid (compound 16) N- [4 -— ((1—acetimidoyl—4-piperidyl) oxy] phenyl] -1-N — [(7-amidino-2-naphthyl) methyl] sulfamoylacetic acid (compound 17),

 Ethyl N— [N— [4-([1-acetimidoyl-1-4-piperidyl) oxy] phenyl] —N — [(7-amidino_2-naphthyl) methyl] sulfamoyl] glycinate (compound 18) ,

 N- [N—4 — [(1—acetimidoyl-1-4-piperidyl) oxy] phenyl] —N — [(7_amidino-2-naphthyl) methyl] sulfamoyl] N—ethoxycarbonyldaricin (Compound 1 9),

 N- [N-4-[[(1-acetoimidoyl-1-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] glycine (compound 20).

 Further, the following compounds 21 to 26 are more preferable.

 (2 S)-2-[4-[((3 S) 1-1 -acetoimidoyl-3-pyrrolidinyl) oxy] phenyl]-3-(7-amidino-1-naphthyl) propionic acid-hydrochloride Hydrate (compound 21),

 (+)-2-[4-[(1 -acetimidoyl-1-4-piperidyl) oxy] phenyl] 13-(7-amidino-2- naphthyl) propionic acid dihydrochloride (compound 22),

 (+) — 2— [4 — [((2S) —1-acetoimidoyl-1-pyrrolidinyl) methoxy] phenyl] —3 -— (5-amidinobenzo [b] chen-2-yl) Lopionic acid dihydrochloride (compound 23),

 N- [4-[[1-acetoimidoyl-1-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoylacetic acid 'dihydrochloride (Compound 24),

Etil N— [N- [4--1 [(1-acetimidyl 4--1-piperidyl) [Phenyl]]-N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] glycinate dihydrochloride (Compound 25),

 -[N—4 — [(1-acetimidyl-1-4-piperidyl) oxy] phenyl]--[(7-amidino-2-naphthyl) methyl] sulfamoyl] glycin dihydrochloride (Compound 26).

 The method for synthesizing the compound represented by the general formula (1) or a salt thereof of the present invention is described in JP-A-5-209946 and International Publication WO96 / 169400. It can be manufactured by any of these methods or a method analogous thereto.

 As shown in the test examples, 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.

 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. Of various oral administration preparations. Here, 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. Of these, 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. In other words, 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. To these “dispersions” and “liquids”, in addition to the above-mentioned substances, stabilizers, flavors and flavoring agents may be appropriately added.

 In addition, 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, polyε-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. Further, together with the compound represented by the general formula (1) of the present invention or a salt thereof, 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, cephalexin, clindamycin, erythromycin, chloramphenicol, and sulfuric acid Antibacterial agents such as fradiomycin, ofloxacin, levofloxacin, tetracycline, and hinokitiol may be added.

 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. Example

 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. 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.

 Test example 1

 Antiproliferative activity against P. gingivalis 381 and P. intermedia ATCC25611

0.1 μg 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).

_{5% C0 2: 5, H} ,: 90%, under anaerobic conditions by N ₂ mixed gas, at 3 7 ° C,

Cultured for 24 hours. After adjusting the turbidity of the bacterial solution with a GAM broth liquid medium using a spectrophotometer (Spectronic 20A; Shimadzu Corporation) so that the OD 660 nm becomes 0.5, Add 1 OO iL of the same bacterial solution to (2 S)-2-[4-[((3 S) — 1

3-pyrrolidinyl) oxy] phenyl] — 3- (7-amidino-2-naphthyl) propionic acid · hydrochloride · pentahydrate (compound 21) to 0, 25, 100, 200,

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).

 table 1

試験例 2

Test example 2

 Inhibitory effect of P. gingivalis 381 on LPS-induced IL-6 production in gingival fibroblasts

 IOO L suspension of HGF (cultured human gingival fibroblasts) [10% FBS (fetal calf serum;

A suspension of ⁵ × 10 ⁵ cells in 1 mL of DMEM (Dulbecco's modified minimum essential medium; Nissui Pharmaceutical) containing GIBC0 Life Technologies Inc., Y, USA] was added to a 96-well microculture plate (Nunc; Roskilde). , Denmark) and cultured until confluent. Then, the medium was replaced with DMEM medium without FBS, and the cells were cultured for 24 hours, and further replaced with fresh DMEM medium IOOL containing O. IBS. Compound 21 was added to this medium at a final concentration of 0, 1, 10, 100 g / mL, and the cells were incubated for 30 minutes. Thereafter, LPS (lipopolysaccharide) extracted from P. 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.

試験例 3

Test example 3

 Inhibitory effect of dried cells of P. gingival is 381 on IL-6 production in gingival fibroblasts

100 L of HGF suspension (5 × 10 ⁵ gingival fibroblasts suspended in ImL of DMEM medium containing 10% FBS) were seeded on a 96-well microculture plate, and cultured until confluent. Then, the medium was replaced with DMEM medium without FBS, and the cells were cultured for 24 hours. Then, the cells were replaced with 100 xL of fresh DMEM medium containing 0.1¾FBS. Compound 21 was added to this medium to a final concentration of 0, 1, 10, 100 ^ g / mL, and the cells were incubated for 30 minutes. Thereafter, dry cells of P. gingival is 381 were added to a final concentration of 4 ig / mL, and the cells were further cultured for 12 hours. After completion of the culture, the culture supernatant was collected, and the IL-6 concentration in the supernatant was measured using a human IL-6 ELISA Kit. Table 3 shows the inhibitory effect of compound 21 on IL-6 production. Table 3

Industrial applicability

 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.

Claims

The scope of the claims 1. The following general formula (1)

Wherein 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, a halogen 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, A is an alkylene group or a group having 1 to 4 carbon atoms which may be substituted by 1 to 2 hydroxyalkyl groups, carbonyl groups, alkoxycarbyl groups, carboxyalkyl groups or alkoxycarbonylalkyl groups; ⁵ ) Ichi (where B represents a lower alkylene group or a carbonyl group; R ⁵ is a hydrogen atom or a group _D—W -R ⁶ (where D is a group — C (= Z) 1 (where Z represents an oxygen atom or a sulfur atom), group — C (= 〇) 1 C (= 〇) — or sulfonyl W is a single bond or a group N (R ⁷ ) 1 (where R ⁷ is a hydrogen atom, a carbamoyl group, a lower alkoxycarbonyl group, a mono- or di-lower alkylaminocarbonyl group, a lower alkyl group) And R ⁶ represents a hydroxyl group, a sulfonyl group, a mono- or di-lower alkylaminothiocarbonyl group, a lower alkyl group which may have a substituent or a lower alkanoyl group which may have a substituent. A lower alkoxy group, a lower alkyl group which may have a substituent, an aryl group which may have a substituent or a heteroaryl group which may have a substituent)).  X represents a single bond, an oxygen atom, a sulfur atom or a carbonyl group, Y represents a saturated or unsaturated 5- or 6-membered heterocyclic group or cyclic hydrocarbon group which may have a substituent, an amino group which may have a substituent or a substituent. Represents an aminoalkyl group which may be

Is a group selected from indolyl, benzofuranyl, benzochenyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, naphthyl, tetrahydronaphthyl, and indanyl.) A preventive and / or therapeutic agent for periodontal disease as an ingredient. 2. Expression

2. The preventive and Z or therapeutic agent for periodontal disease according to claim 1, wherein the group represented by is selected from benzofuranyl, benzimidazolyl, indolyl, benzothienyl, benzothiazolyl, naphthyl and tetrahydronaphthyl. 3. The saturated or unsaturated 5- or 6-membered heterocyclic group represented by Y is a group NR ⁸ or NR ⁹ (Wherein, R ^s and R ⁹ are each a hydrogen atom, an amidino group or a group

(Wherein ^Ri represents a lower alkyl group)) The preventive and Z or therapeutic agent for periodontal disease according to claim 1 or 2. Four . ! ^ To ⁴ are hydrogen atoms; n is 0; X is oxygen atom; A may be substituted with one hydroxyalkyl group, carboxyl group, alkoxycarbonyl group, carboxyalkyl group or alkoxycarbonylalkyl group An alkylene group or group having 2 carbon atoms—CH ₂ —N (R ¹¹ ) 1 (where R ¹¹ is a hydrogen atom or group—S〇 ₂ —W ¹ —R ¹² (where W ¹ is a single bond or a group — N (R ¹³ )-(where R ¹³ is a hydrogen atom, a rubamoyl group, a lower alkoxycarbonyl group, a mono- or di-lower alkylamino carbonyl group, a lower alkylsulfonyl group, a mono- or di-lower alkyl Represents an aminothiocarbonyl group, a lower alkyl group which may have a substituent or a lower alkanol group which may have a substituent), and R ¹² represents a hydroxyl group, a lower alkoxy group, or a substituent. Y represents a lower alkyl group which may be substituted, a aryl group which may be substituted or a heteroaryl group which may be substituted))); NR ⁸ or

(Wherein R ⁸ and R ⁹ are each a hydrogen atom, an amidino group or a group

( ^Wherein , R ^lfl represents a lower alkyl group));

Is a group selected from benzofuranyl, benzimidazolyl, indolyl, benzothienyl, benzothiazolyl, naphthyl and tetrahydronaphthyl; the prevention of periodontal disease according to any one of claims 1 to 3, and Z or Therapeutic drugs. 5. The preventive and Z or therapeutic agent for periodontal disease according to any one of claims 1 to 4, wherein the compound represented by the general formula (1) or a salt thereof is selected from the following compounds 1 to 20: :  2— [4 — [((3S) 111-acetoimidoyl_3_pyrrolidinyl) oxy] phenyl] —3- (7-amidino-2-naphthyl) propionic acid (compound 1), (+) — 2— [4— [((3 S) — 1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] — 3- (7-amidino-2-naphthyl) propionic acid (Compound 2),  (2 S)-2-[4-[((3 S)-1-acetoimidoyl-1-3-pyrrolidinyl) oxy] phenyl]-3- (7-amidino-2 _ naphthyl) propionic acid (Compound 3),  (2R) -2- [4-([(3R) _1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] _3- (7-amidino-2-naphthyl) propionic acid (compound 4),  2- [4-[(1-acetimidoyl-1-4-piperidyl) oxy] phenyl] — 3— (7-amidino 2-naphthyl) propionic acid (compound 5), (+) — 2— [4 — [(1-acetimidoyl—4-piperidyl) oxy] phenyl] 13 _ (7-amidino-2-naphthyl) propionic acid (compound 6), 2-[4-[(1 -acetimidoyl-1 4-piperidyl) oxy] phenyl]-3-(5 -amidinobenzo [b] chen-1-2-yl) propionic acid (compound 7),  2- [4-[((2S) _1-acetimidoyl-2-pyrrolidinyl) meloxy] phenyl] -13- (5-amidinobenzo [b] chen-1-yl) propionic acid (Compound 8 ),  (+)-2-[4- [((2 S) — 1-acetoimidoyl-2-pyrrolidinyl) methoxy] phenyl] 13_ (5-amidinobenzo [b] chen-1 2 ^^) propionic acid ( Compound 9),  3— [4 — [((3S) —1-acetoimidoyl—3-pyrrolidinyl) oxy] phenyl] —4- (5-amidinobenzo [b] chen-2-yl) butyric acid (compound 10),  2- [4-[((3S) -111-acetoimidoyl-3--3-pyrrolidinyl) oxy] phenyl] —3- (6-amidinol 1-ethyl-2-indolyl) propionic acid (compound 11 1),  2-[4-[((3 R) — 1-acetoimidoyl-3- 3-pyrrolidinyl) oxy] phenyl] — 3- (6-amidinol 1-ethyl-2 indolyl) propionic acid (compound 12),  2— [4 — [(1-acetimidoyl-1-4-piberidinyl) oxy] phenyl] — 3 -— (6-amidino-1-ethyl-2_indolyl) propionic acid (compound 13), N- [4-[[1-acetimidyl-doyl-4-piperidyl) oxy] phenyl] '-N-[(7-amidino-2-naphthyl) methyl] -N'-methylsulfamide (compound 14) Ethyl N— [N-4-[[(1-acetimidoyl) -4-piperidyl) oxy] phenyl] -1-N — [(7-amidino-2-naphthyl) methyl] sulfamoyl] carbamate (compound 15),  4- [N-4-[[(1-acetoimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] benzoic acid (compound 16),  N— [4-[(1-acetimidoyl-1-4-piperidyl) oxy] phenyl] —N — [(7-amidinol 2-naphthyl) methyl] sulfosmoylacetic acid (compound 17),  Ethyl N— [N— [4 — [(1-acetoimidoyl-4-piperidyl) oxy] phenyl] —N — [(7-amidino-2-naphthyl) methyl] sulfamoyl] glycinate (compound 18),  N- [N-4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] N-ethoxycarbonyldaricin (Compound 19),  N- [N—4 — [(1-Acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] glycine (Compound 20).  6. The compound represented by the general formula (1) or a salt thereof is selected from the following compounds 21 to 26, the prevention of periodontal disease and the prevention of Z or Chaa (2S)-2-[4-[((3S)-1-acetoimidyl-1-3-pyrrolidinyl) oxy] phenyl] 1-3-(7_amidino-2-naphthyl) propionic acid 'hydrochloride · 5 Hydrate (compound 21), (+)-2-[4-[(1 -acetimidoyl-4--piperidyl) oxy] phenyl] 13-(7-amidino-2-naphthyl) propionic acid · dihydrochloride (compound Thing 2 2),  (10) — 2— [4 — [((2S) —1—acetimidoyl-2-pyrrolidinyl) methoxy] phenyl] -1-3- (5-amidinobenzo [b] chen-1-yl) propionic acid · Dihydrochloride (compound 23),  N— [4-([1-acetimidyl-1-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoylacetic acid 'dihydrochloride (Compound 24)  Ethyl N— [N- [4-[(1_acetimidoyl—4-piperidyl) oxy] phenyl] —N — [(7-amidino-2-naphthyl) methyl] sulfamoyl] glycinate dihydrochloride (compound twenty five),  N- [N—4 — [(1-acetoimidoyl—4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] glycin dihydrochloride (Compound 26 ).  7. The compound represented by the general formula (1) or a salt thereof is (2S) -2- [4-[[((3S) —1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] —3-— (7-amidino-2-naphthyl) The preventive and / or therapeutic agent for periodontal disease according to any one of claims 1 to 4, which is propionic acid or a salt thereof.  8. The prophylactic and / or therapeutic agent for periodontal disease according to any one of claims 1 to 7, wherein the dosage form is a preparation for oral administration.  9. The oral administration preparation according to claim 8, wherein the preparation for oral administration is selected from an ointment, a periodontal pocket insert, a periodontal filler, a gargle, a spray, a troche, a toothpaste and a gum. Prophylactic and Z or therapeutic agents. 10. The following general formula (1)

Wherein R ¹ represents a hydrogen atom or a lower alkoxy group; R ² is 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, a halogen 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, A represents an alkylene group having 1 to 4 carbon atoms which may be substituted by 1 to 2 hydroxyalkyl groups, carboxyl groups, alkoxycarbonyl groups, carboxyalkyl groups or alkoxycarbonylalkyl groups, or a group —B—N ( R ⁵ )-(where B represents a lower alkylene group or a carbonyl group; R ⁵ is a hydrogen atom or a group —D—W—R ⁶ (where D is a group C (= Z) — (where Z is an oxygen atom or Represents a sulfur atom), a group C (= 〇) -C (= 〇) — or a sulfonyl group, and W is a single bond or a group N (R ⁷ )-(where R ⁷ is hydrogen Atom, carbamoyl group, lower alkoxycarbonyl group, mono- or di-lower alkylaminocarbonyl group, lower alkylsulfonyl group, mono- or di-lower alkylaminothiocarbonyl group, lower group which may have a substituent R ⁶ represents a hydroxyl group, a lower alkoxy group, or a substituent, which represents an alkyl group or a lower alkanoyl group which may have a substituent). A lower alkyl group which may be substituted, an aryl group which may have a substituent or a heteroaryl group which may have a substituent)))  X represents a single bond, an oxygen atom, a sulfur atom or a carbonyl group, Y represents a saturated or unsaturated 5- or 6-membered heterocyclic group or cyclic hydrocarbon group which may have a substituent, an amino group which may have a substituent or a substituent. Represents an aminoalkyl group which may be

Represents a group selected from indolyl, benzofuranyl, benzochenyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, naphthyl, tetrahydronaphthyl, and indanyl.) Prevention of disease and use for the manufacture of Z or therapeutic drugs. 1 1. Expression

10. The use according to claim 10, wherein the group represented by is selected from benzofuranyl, benzimidazolyl, indolyl, benzothienyl, benzothiazolyl, naphthyl and tetrahydronaphter.  12. A saturated or unsaturated 5- or 6-membered heterocyclic group represented by Y is a group NR ⁸ or

(Wherein R ⁸ and R ⁹ are each a hydrogen atom, an amidino group or a group

(Wherein R ^1D represents a lower alkyl group)) ₍ 13. RR ⁴ is a hydrogen atom; n is 0; X is an oxygen atom; A is one hydroxy group). An alkyl group, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group or an alkylene group having 2 carbon atoms which may be substituted by an alkoxycarbonylalkyl group or a group —CH ₂ —N (R ¹¹ ) — (where, R ¹¹ is a hydrogen atom or a group S 02— W ¹ — R ¹² (where W ′ is a single bond or a group—N (R ¹³ )-(where R ¹³ is a hydrogen atom, a rubamoyl group, a lower alkoxy group) It has a carbonyl group, a mono- or di-lower alkylaminocarbonyl group, a lower alkylsulfonyl group, a mono- or di-lower alkylaminothiocarbonyl group, a lower alkyl group which may have a substituent or a substituent. Lower alkano Shows the shows the Le group), R ¹² represents a hydroxyl group, had low-grade alkoxy group, an optionally substituted lower alkyl group, a yo have a substituent I Ariru group or a substituted group Represents a heteroaryl group which may be present)); To NR ⁸ or

(Wherein R ⁸ and R ⁹ are each a hydrogen atom, an amidino group or a group

(Wherein, R '° represents a lower alkyl group));

The use according to any one of claims 10 to 12, wherein the group represented by is a group selected from benzofuranyl, benzimidazolyl, indolyl, benzothienyl, benzothiazolyl, naphthyl and tetrahydronaphthyl.  14. The use according to any one of claims 10 to 13, wherein the compound represented by the general formula (1) or a salt thereof is selected from the following compounds 1 to 20:  2- [4-[[((3S) -1-1acetoimidoyl-1-3-pyrrolidinyl) oxy] phenyl] -13- (7-amidino_2-naphthyl) propionic acid (compound 1), (+) — 2— [4-([(3S) —1-acetoimidoyl—3-pyrrolidinyl) oxy] phenyl] 1-3— (7 _ amidino 2 _ naphthyl) propionic acid (compound 2),  (2 S)-2-[4-[((3 S)-1-acetimidoyl- 3-pyrrolidinyl) oxy] phenyl]-3- (7-amidino-2-naphthyl) propionic acid (Compound 3),  (2R) 1-2-[4-[((3R)-1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] 1-3-(7-amidino-2-naphthyl) propionic acid (compound 4),  2- [4-[(1-acetimidoyl-1-4-piperidyl) oxy] phenyl] -3- (7-amidino_2-naphthyl) propionic acid (compound 5),  (+) 1—2— [4 — [(1—acetimidoyl—4—piperidyl) oxy] phenyl] 1—3— (7-amidino-2-naphthyl) propionic acid (compound 6), 2- (4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -13- (5-amidinobenzo [b] chen-12-2-yl) propionic acid (compound 7) 2 -— [4 -— (((2S) -1-1-acetimidoyl-2-pyrrolidinyl) meloxy] phenyl] —3- (5-amidinobenzo [b] chen-2-yl) propionic acid (Compound 8 ),  (+) 1—2— [4 — [((2S) —11-acetoimidoyl—2-pyrrolidinyl) methoxy] phenyl] —13— (5-amidinobenzo [b] chen—12-yl) propionic acid ( Compound 9),  3-[4 — [((3 S) — 1-acetimidoyl—3-pyrrolidinyl) oxy] phenyl] —4 -— (5-amidinobenzo [b] chen—2 — ^^) butyric acid (compound 10),  2— [4 — [((3 S) —1-Acetimidoyl—3-pyrrolidinyl) oxy] phenyl] —3- (6-amidino_1-ethyl—2-pentyl) propionic acid (compound 11)  2-[4-[((3 R) — 1-acetoimidoyl— 3-pyrrolidinyl) oxy] phenyl] — 3 — (6-amidino — 1-ethyl — 2-indolyl) propionic acid (Compound 12),  2— [4 — [(1-acetimidoyl-4—piperidinyl) oxy] phenyl] 13— (6-amidino-11-ethyl-2-indolyl) propionic acid (compound 13),  N— [4-[[1-acetimidyl-doyl-4-piperidyl) oxy] phenyl] -N-[(7-amidinol 2-naphthyl) methyl] — N'—methylsulfamide (compound 14)  Ethyl N— [N-4-[(1-acetimidoyl-1-4-piperidyl) oxy] phenyl] —N — [(7-amidino-2-naphthyl) methyl] sulfamoyl] carbamate (compound 15 ), 4- [N-4-1 [(1-acetimidoyl- 4--piperidyl) oxy] phenyl] — N — [(7-amidino-2- naphthyl) methyl] sulfamoyl] benzoic Acids (compound 16),  -[4 — [(1—acetimidoyl-1-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoylacetic acid (compound 17),  Ethyl N— [N- [4-I-((1-acetimidoyl-1-4-piperidyl) oxy] phenyl] —N — [(7-amidino-2-naphthyl) methyl] sulfamoyl] glycinate (compound 18)  N— [N-4-[((1-acetimidoidyl—4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] -1-N-ethoxycarbonyldaricin (compound 1 9),  N- [N-4-[((1-acetoimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-12-naphthyl) methyl] sulfamoyl] glycine (compound 20).  15. The use according to any one of claims 10 to 13, wherein the compound represented by the general formula (1) or a salt thereof is selected from the following compounds 21 to 26:  (2 S)-2-[4-[((3 S) _ 1-acetoimidoyl-3- 3-pyrrolidinyl) oxy] phenyl] — 3 — (7-amidino-2-naphthyl) propionic acid 'hydrochloride · pentahydrate Hydrate (compound 21),  (+) — 2 -— [4-[(1-acetimidoidyl-4-piperidyl) oxy] phenyl] 13— (7-amidinol 2-naphthyl) propionic acid 'dihydrochloride (compound 22),  (+)-2-[4-[((2S) 1-1 -acetimidoyl-2-pyrrolidinyl) methoxy] phenyl] _ 3-(5-amidinobenzo [b] chen-1-2-yl) propionic acid Dihydrochloride (compound 23),  -[4 — [(1—acetimidyl—4-piperidyl) oxy] phenyl] -N- [(7-amidino-2-naphthyl) methyl] sulfamoylacetic acid '2HCl Salt (compound 24),  Ethyl N— [N- [4 — [(1-acetimidoyl-4-piperidyl) oxy] phenyl] —N — [(7-amidino-2-naphthyl) methyl] sulfamoyl] glycinate dihydrochloride (compound twenty five),  N- [N-4-[(1-acetimidoidyl-4-piperidyl) oxy] phenyl] —N — [(7-amidino_2-naphthyl) methyl] sulfamoyl] glycine dihydrochloride (Compound 26) .  16. When the compound represented by the general formula (1) or a salt thereof is (2S) -2- [4-([((3S) -11-acetoimidoyl-3-pyrrolidinyl) oxy] phenyl] -13_ (7-amidino-2-naphthyl) The use according to any one of claims 10 to 13, which is propionic acid or a salt thereof.  17. Use according to any one of claims 10 to 16, wherein the dosage form is a formulation for buccal administration. 18. The use according to claim 17, wherein the preparation for oral administration is selected from an ointment, a periodontal pocket insert, a periodontal filler, a mouthwash, a spray, a troche, a toothpaste and a gum.  19. The following general formula (1)

Wherein 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 is a hydrogen atom, a carboxyl group, an alkoxycarbonyl group, A kill group, an alkoxycarbonylalkyl group, a carboxyalkoxy group or an alkoxycarbonylalkoxy group, R ⁴ represents a hydrogen atom, a halogen 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, A is an alkylene group having 1 to 4 carbon atoms which may be substituted by 1 to 2 hydroxyalkyl groups, carboxyl groups, alkoxycarbonyl groups, carboxyalkyl groups or alkoxycarbonylalkyl groups or a group B—N ( R ⁵ ) — (where B represents a lower alkylene group or a carbonyl group, R ⁵ is a hydrogen atom or a group D—W—R ⁶ (where D is a group—C (= Z) — ( Here, Z represents an oxygen atom or a sulfur atom), a group C (= 〇) -C (= 〇) — or a sulfonyl group, and W represents a single bond or a group—N (R ⁷ ) (Where R ⁷ represents a hydrogen atom, a carbamoyl group, a lower alkoxycarbonyl group, a mono- or di-lower alkylaminocarbonyl group, a lower alkylsulfonyl group, a mono- or di-lower alkylaminothiocarbonyl group, Low-grade alky that may have R ⁶ represents a hydroxyl group, a lower alkoxy group, a lower alkyl group which may have a substituent, or a substituent. Represents an aryl group or a heteroaryl group which may have a substituent)))  X represents a single bond, an oxygen atom, a sulfur atom or a carbonyl group, Y represents a saturated or unsaturated 5- or 6-membered heterocyclic group or cyclic hydrocarbon group which may have a substituent, a substituted or unsubstituted diamino group or a substituted or unsubstituted substituent; Represents an aminoalkyl group which may be

The groups represented by are indolyl, benzofuranyl, benzochenyl, and benzimida Zolyl, benzoxazolyl, benzothiazolyl, naphthyl, tetrahydronaphthyl and indanyl] or a salt thereof. 20. Expressions

The method according to claim 19, wherein the group represented by is selected from benzofuranyl, benzimidazolyl, indolyl, benzothienyl, benzothiazolyl, naphthyl, and tetrahydronaphthyl.  21. The saturated or unsaturated 5- or 6-membered heterocyclic group represented by Y is NR ⁸ or

(Wherein R ⁸ and R ⁹ are each a hydrogen atom, an amidino group or a group

(Wherein, R ^1G is a lower alkyl shows a group)) according to claim 1 9 or 2 0, wherein the method _c 22. RR ⁴ is a hydrogen atom; n is 0; X is an oxygen atom; A is a hydroxyalkyl group, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group or a substituted alkoxycarbonylalkyl group CH ₂ —N (R ¹¹ ) 1 (where R ¹ ′ is a hydrogen atom or a group—S 0 ₂ —W ¹ — R ¹² (where, W ¹ is a single bond or a group —N (R ¹³ ) — (where, R ¹³ is a hydrogen atom, a rubamoyl group, a lower alkoxycarbonyl group, a mono or di-lower alkylaminoamino group, a lower Alkylsulfonyl group, mono- or di-lower alkyl R ¹² represents a hydroxyl group, a lower alkoxy group, a substituent, or a lower alkyl group which may have a substituent or a lower alkyl group which may have a substituent or a lower alkanol group which may have a substituent. Y represents a lower alkyl group optionally having a substituent, a aryl group optionally having a substituent or a heteroaryl group optionally having a substituent));

(Wherein R ⁸ and R ⁹ are each a hydrogen atom, an amidino group or a group

(Wherein, R ^1Q represents a lower alkyl group));

10. The method according to claim 19, wherein the group represented by is a group selected from benzofuranyl, benzimidazolyl, indolyl, benzothienyl, benzothiazolyl, naphthyl, and tetrahydronaphthyl.  23. The method according to claim 19, wherein the compound represented by the general formula (1) or a salt thereof is selected from the following compounds 1 to 20:  2- [4-([((3S) -1-1acetoimidoyl-13-pyrrolidinyl) oxy] phenyl] -13- (7-amidino-2-naphthyl) propionic acid (compound 1), (+) — 2— [4— [((3 S) — 1—acetimidyl-1-3-pyrrolidinyl) oxy] phenyl] -1-3— (7-amidino-2-naphthyl) propionic acid (compound Thing 2),  (2 S) 1-2-[4-[((3 S)-1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] 1-3-(7-amidino-2-naphthyl) propionic acid (compound 3),  (2 R) 1-2-[4-[((3 R)-1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] 1-3-(7-amidino 2 _ naphthyl) propionic acid (compound 4),  2- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] — 3 -— (7_amidino_2_naphthyl) propionic acid (compound 5),  (+) — 2— [4 — [(1-acetimidoyl—4-piperidyl) oxy] phenyl] —3- (7_amidino-2-naphthyl) propionic acid (compound 6), 2- [4-[((1-acetoimidoyl-4-piperidyl) oxy] phenyl] -13- (5-amidinobenzo [b] chen-2-yl) propionic acid (compound 7)  2- [4 -— (((2S) — 1-acetimidoyl—2-pyrrolidinyl) meloxy] phenyl] —3- (5-amidinobenzo [b] chen-1-yl) propionic acid (Compound 8 ),  (+) — 2- [4-[((2S) — 1-acetimidoyl-2-pyrrolidinyl) methoxy] phenyl] — 3 -— (5-amidinobenzo [b] chen-1-2- ^ propyl) propionic acid (Compound 9),  3— [4 — [((3S) —1-Acetoimidoyl—3-pyrrolidinyl) oxy] phenyl] 1-41- (5-amidinobenzo [b] chen-12-2-yl) butyric acid (Compound 10), 2- [4-[((3S) 1-1-acetoimidoyl-3_pyrrolidinyl) oxy] phenyl] -3-3- (6-amidino-1-ethyl-2-indolyl) propionic acid (compound 11 1), 2— [4 — [((3R) —1—acetimidoyl—3-pyrrolidinyl) oxy] phenyl] 1-3— (6-amidino—1—ethyl—2-indolyl) propionic acid (compound 12)  2-[4-[(1 -acetimidyl-1-4-piberidinyl) oxy] phenyl]-3-(6-amidino-1 _ethyl _ 2-^ f undolyl) propionic acid (compound 13),  N— [4 -— ((1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl] 1-N'-methylsulfamide (compound 14),  Ethyl N— [N—4 — [(1-acetimidyl-1-4-piperidyl) oxy] phenyl] —N — [(7_amidino-2-naphthyl) methyl] sulfamoyl] pothambamate (compound 15)  4- [N-4-[(1-acetimidoyl-1-4-piperidyl) oxy] phenyl] -1-N — [(7-amidino-2-naphthyl) methyl] sulfamoyl] benzoic acid (compound 16),  N— [4-[(1-acetoimidoyl-1-4-piperidyl) oxy] phenyl] —N — [(7-amidino-2-naphthyl) methyl] sulfamoylacetic acid (compound 17),  Ethyl N— [N- [4-[(1-acetimidoyl-1-4-piperidyl) oxy] phenyl] —N — [(7-amidino-2-naphthyl) methyl] sulfamoyl] glycinate (compound 18)  N— [N—4 — [(1-acetoimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] N-ethoxycarbonyldaricin (compound 19 ), N— [N-4-[[(1-acetimidoyl-1-4-piperidyl) oxy] phenyl] -1-N — [(7-amidinol-2-naphthyl) methyl] sulfamoyl] glyci (Compound 20).  24. The method according to claim 19, wherein the compound represented by the general formula (1) or a salt thereof is selected from the following compounds 21 to 26:  (2 S) 1-2-[4-[((3 S) 1 1 1 -acetoimidyl-3-pyrrolidinyl) oxy] phenyl] 1-3 _ (7-amidino 2-naphthyl) propionic acid-hydrochloride · 5 water Hydrate (compound 21),  (+)-2-[4 -— [(1-acetimidyl-1-4-piperidyl) oxy] phenyl] — 3 -— (7-amidino-2-naphthyl) propionic acid dihydrochloride (compound 22),  (+) — 2— [4— [((2 S) — 1-acetimidoyl-1-2-pyrrolidinyl) methoxy] phenyl] -3 -— (5-amidinobenzo [b] chen-2-yl) propionic acid Dihydrochloride (compound 23),  N- [4-[((1-acetoimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoylacetic acid 'dihydrochloride (Compound 24),  Ethyl N— [N- [4-[(1_acetimidoyl—4-piperidyl) oxy] phenyl] -1-N — [(7-Amidino-2-naphthyl) methyl] sulfamoyl] glycinate dihydrochloride (Compound 25 ),  N- [N- 4-[(1_acetimidoyl-1-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] glycin dihydrochloride (Compound 26) .  25. When the compound represented by the general formula (1) or a salt thereof is (2S) -2- [4-[((3S) 111-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] — 3-— 10. The method according to claim 19, which is (7-amidino-2-naphthyl) propionic acid or a salt thereof. 26. The administration form according to any one of claims 19 to 25, wherein the administration form is an oral administration preparation. Method.  27. The method according to claims 19 to 25, wherein the dosage form is selected from an ointment, a periodontal pocket insert, a periodontal filler, a mouthwash, a spray, a troche, a toothpaste and a gum. A method according to any one of the preceding claims.