JP2009114120A - Autoinducer-2 inhibitor and agent for preventing and/or treating infectious disease - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a material for inhibiting autoinducer-2, and to provide a material effective for prevention and/or treatment of an infectious disease. <P>SOLUTION: The autoinducer-2 inhibitor includes a compound represented by formula I (wherein, R<SP>1</SP>and R<SP>2</SP>are each independently hydrogen, a hydroxy group, an aryl group or an alkoxy group, or form an oxo group by bonding to each other; R<SP>3</SP>is a halogen; and R<SP>4</SP>is hydrogen, an amino group or a halogen) or a salt thereof as an active ingredient. The agent for preventing and/or treating the infectious disease includes the compound or the salt thereof as an active ingredient. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to an autoinducer-2 inhibitor and an agent for preventing and / or treating infectious diseases.

  In nature, microorganisms must survive in various environments. In addition to oligotrophic, low temperature, high temperature, and pH change, living organisms are forced to survive in environments where phagocytic cells or antibacterial humoral factors (complements, antibodies, lysozyme, etc.) are present. Under these circumstances, bacteria have acquired a mechanism for sensitively sensing changes in their environment. As one of such mechanisms, it is clear that microorganisms sense their concentration in the environment through specific signal-transmitting substances and skillfully control their various biological activities according to the concentration. It has become. Such an information transmission mechanism between cells is called a quorum sensing system.

  Quorum sensing was first reported in the luminescent marine bacteria Vibrio Fischeri and Vibrio Harvey. Recently, however, it has been recognized as a general gene regulatory mechanism in many bacteria. This phenomenon allows bacteria to perform activities such as bioluminescence, warming, biofilm formation, proteolytic enzyme production, antibiotic synthesis, gene acceptability development, plasmid conjugation transfer, pathogenic factor production and sporulation. Can be done.

  Bacteria with a quorum sensing system synthesize and release a signaling molecule called an autoinducer and respond to the signaling molecule to control gene expression as a function of cell density. So far, acyl homoserine lactone has been identified as autoinducer-1, and 4,5-dihydroxy-2,3-pentanedione as autoinducer-2.

  It has been reported that clinically important bacteria such as Vibrio bacteria, Pseudomonas aeruginosa, Serratia and Enterobacter use autoinducer-1 for quorum sensing. In addition, it is reported that Vibrio Harvey uses autoinducer-1 with high species specificity for intra-species communication and uses autoinducer-2 with low species specificity for interspecies communication. (Non-Patent Document 1). More recent studies have also shown that quorum sensing between pathogenic bacterial species by autoinducer-2 regulates the production of virulence factors.

  For example, Non-Patent Documents 2 and 3 report that the amount of biofilm formation decreases in an autoinducer-2 synthase (LuxS) deficient strain of Streptococcus mutans, which is a cariogenic bacterium. Non-patent document 4 reports that the Helicobacter pylori LuxS-deficient strain, which is said to cause gastric ulcer and gastric cancer, reduces bacterial motility and decreases the infection rate of mouse gastric mucosa. . Non-Patent Document 5 reports that production of α-, κ-, and θ-toxins is reduced in a LuxS-deficient strain of Clostridium perfringens, which is a causative bacterium such as food poisoning, gas gangrene, and hemorrhagic enteritis. Therefore, a substance having an activity of inhibiting autoinducer-2 has been demanded.

  In addition, as a substance which inhibits autoinducer-2, until now, 4-hydroxy-2,5-dimethyl-3 (2H) -furanone (patent document 1), 2-methoxy-2,4-diphenyl-3. (2H) -furanone (Patent Document 2), 2-pentyl-2-cyclopenten-1-one (Patent Document 3) and the like have been reported.

Special table 2003-532698 Special table 2003-532698 Special table 2005-506953 Bassler et al., Bacteriol. 179: 4043-4045, 1997 Yoshida A. et al., Appl. Environ. Microbiol. 71 (5), 2372-2380, 2005 Wen Z.T. et al., J. Bacteriol., 189 (9), 2682-2691, 2004 Osaki T. et al., J. Med. Microbiol., 55 (Pt11), 1477-1485, 2006 Ohtani K. et al., Mol. Microbiol., 44 (1), 171-179, 2002

  An object of this invention is to provide the substance which has the activity which inhibits autoinducer-2, and is effective in prevention and treatment of an infectious disease.

  All the above reports showing the relationship between autoinducer-2 and bacterial pathogenicity show only the results of in vitro tests, and the effect of autoinducer-2 on infectious diseases in vivo. Was not known.

  The present inventors have found that the amount of autoinducer-2 and the symptoms of infectious diseases have a correlation in vivo. Furthermore, while having the activity which inhibits autoinducer-2, the effective compound with respect to an infectious disease was discovered, and it came to complete this invention.

（式中、
Ｒ^１およびＲ^２は、それぞれ独立して、水素、ヒドロキシ基、アリール基もしくはアルコキシ基であるか、または、Ｒ^１およびＲ^２は一緒になってオキソ基を形成し、
Ｒ^３は、ハロゲンであり、
Ｒ^４は、水素、アミノ基またはハロゲンである）
で表される化合物またはその塩を有効成分とするオートインデューサー−２阻害剤。
（２）式Ｉ：

（式中、
Ｒ^１およびＲ^２は、それぞれ独立して、水素、ヒドロキシ基、アリール基もしくはアルコキシ基であるか、または、Ｒ^１およびＲ^２は一緒になってオキソ基を形成し、
Ｒ^３は、ハロゲンであり、
Ｒ^４は、水素、アミノ基またはハロゲンである）
で表される化合物またはその塩を有効成分とする感染症の予防および／または治療剤。
（３）感染症が歯周病である、（２）記載の感染症の予防および／または治療剤。
（４）齲蝕を予防するための、（２）記載の感染症の予防および／または治療剤。
（５）式Ｉの化合物が４−ブロモ−５−（４−メトキシフェニル）−２（５Ｈ）−フラノンである（１）〜（４）のいずれかに記載の、オートインデューサー−２阻害剤、または感染症の予防および／または治療剤。
（６）式Ｉの化合物が３，４−ジブロモ−５−ヒドロキシ−２（５Ｈ）−フラノンである（１）〜（４）のいずれかに記載の、オートインデューサー−２阻害剤、または感染症の予防および／または治療剤。
（７）式Ｉの化合物が４−ブロモ−５−メトキシ−５−（４−メトキシフェニル）−２（５Ｈ）−フラノンである（１）〜（４）のいずれかに記載の、オートインデューサー−２阻害剤、または感染症の予防および／または治療剤。
（８）式Ｉの化合物が４−｛［３−ブロモ−２−（４−メトキシフェニル）−５−オキソ−２，５−ジヒドロ−２−フラニル］オキシ｝安息香酸である（１）〜（４）のいずれかに記載の、オートインデューサー−２阻害剤、または感染症の予防および／または治療剤。 That is, the present invention includes the following inventions.
(1) Formula I:

(Where
R ¹ and R ² are each independently hydrogen, hydroxy group, aryl group or alkoxy group, or R ¹ and R ² together form an oxo group;
R ³ is halogen,
R ⁴ is hydrogen, amino group or halogen)
The autoinducer-2 inhibitor which uses the compound or its salt represented by these as an active ingredient.
(2) Formula I:

(Where
R ¹ and R ² are each independently hydrogen, hydroxy group, aryl group or alkoxy group, or R ¹ and R ² together form an oxo group;
R ³ is halogen,
R ⁴ is hydrogen, amino group or halogen)
A prophylactic and / or therapeutic agent for infectious diseases comprising a compound represented by the formula or a salt thereof as an active ingredient.
(3) The preventive and / or therapeutic agent for an infectious disease according to (2), wherein the infectious disease is periodontal disease.
(4) The preventive and / or therapeutic agent for infectious diseases according to (2), for preventing caries.
(5) The autoinducer-2 inhibitor according to any one of (1) to (4), wherein the compound of formula I is 4-bromo-5- (4-methoxyphenyl) -2 (5H) -furanone Or preventive and / or therapeutic agents for infectious diseases.
(6) The autoinducer-2 inhibitor or the infection according to any one of (1) to (4), wherein the compound of formula I is 3,4-dibromo-5-hydroxy-2 (5H) -furanone Preventive and / or therapeutic agent.
(7) The autoinducer according to any one of (1) to (4), wherein the compound of formula I is 4-bromo-5-methoxy-5- (4-methoxyphenyl) -2 (5H) -furanone -2 inhibitors, or preventive and / or therapeutic agents for infectious diseases.
(8) The compounds of formula I are 4-{[3-bromo-2- (4-methoxyphenyl) -5-oxo-2,5-dihydro-2-furanyl] oxy} benzoic acid (1)-( 4. The autoinducer-2 inhibitor or the preventive and / or therapeutic agent for infectious diseases according to any one of 4).

  According to the present invention, an autoinducer-2 inhibitor and an agent for preventing and / or treating infectious diseases are provided.

（式中、
Ｒ^１およびＲ^２は、それぞれ独立して、水素、ヒドロキシ基、アリール基もしくはアルコキシ基（好ましくはＣ_１−６アルコキシ基）であるか、または、Ｒ^１およびＲ^２は一緒になってオキソ基を形成し、
Ｒ^３は、ハロゲンであり、
Ｒ^４は、水素、アミノ基またはハロゲンである）
で表される化合物またはその塩を有効成分とするオートインデューサー−２阻害剤に関する。 In one embodiment, the present invention provides compounds of formula I:

(Where
R ¹ and R ² are each independently hydrogen, a hydroxy group, an aryl group or an alkoxy group (preferably a C _1-6 alkoxy group), or R ¹ and R ² together are an oxo group Form the
R ³ is halogen,
R ⁴ is hydrogen, amino group or halogen)
The autoinducer-2 inhibitor which uses as an active ingredient the compound or its salt represented by these.

In the present invention, the aryl group only needs to have a benzene ring, and may have a benzene ring in the condensed ring. The aryl groups in R ¹ and R ² are preferably monocyclic or polycyclic containing from 5 to 25 ring carbon atoms, more preferably from 6 to 20, even more preferably from 6 to 10 ring carbon atoms. It is an aromatic group. Specific examples of the aryl group include a phenyl group, a phenyloxy group, a benzoyloxy group, a naphthyl group, an anthryl group, a phenanthryl group, a fluorenyl group, a pyrenyl group, an indenyl group, an azulenyl group, a heptalenyl group, and an indecenyl group. These groups may have a substituent on the ring.

Examples of the substituent on the ring include halogen, hydroxy group, nitro group, amino group, mercapto group, cyano group, isocyanate group, carboxy group, alkyl group (preferably C _1-6 alkyl group), alkenyl group ( Preferred are a C _2-6 alkenyl group), an alkoxy group (preferably a C _1-6 alkoxy group) and the like, and a C _1-6 alkoxy group is preferred. When a plurality of substituents are present, each substituent may be the same or different. The number of substituents is preferably 1 to 3.

In R ¹ and R ² of formula I, the aryl group is preferably a 4-alkoxyphenyl group, a benzoyloxy group, or a 4-carboxyl-1-benzoyloxy group, more preferably a 4-methoxyphenyl group.

When ^one of R ¹ and R ² is an aryl group, the other is preferably a hydrogen, a hydroxy group or an alkoxy group. Also, when ^one of R ¹ and R ² is hydrogen, the other is preferably not hydrogen.

  In the present invention, examples of the halogen include fluorine, chlorine, bromine and iodine.

Compounds of formula I include 4-halo-5- (4-alkoxyphenyl) -2 (5H) -furanone, 3,4-dihalo-5-hydroxy-2 (5H) -furanone, 4-halo-5- Alkoxy-5- (4-alkoxyphenyl) -2 (5H) -furanone, 4-{[3-halo-2- (4-alkoxyphenyl) -5-oxo-2,5-dihydro-2-furanyl] oxy } Benzoic acid, 3-halo-2,5-furandione. Here, halo represents halogen and alkoxy is preferably C _1-6 alkoxy.

  Examples of the compound of formula I include 4-bromo-5- (4-methoxyphenyl) -2 (5H) -furanone represented by the following formula, 3,4-dibromo-5-hydroxy-2 (5H) -furanone, 4-bromo-5-methoxy-5- (4-methoxyphenyl) -2 (5H) -furanone, 4-{[3-bromo-2- (4-methoxyphenyl) -5-oxo-2,5-dihydro 2-furanyl] oxy} benzoic acid, 3-bromo-2,5-furandione are preferred, especially 4-bromo-5- (4-methoxyphenyl) -2 (5H) -furanone, 3,4-dibromo- 5-Hydroxy-2 (5H) -furanone and 4-bromo-5-methoxy-5- (4-methoxyphenyl) -2 (5H) -furanone are preferred.

  The salt of the compound of the formula I is not particularly limited as long as it is a pharmaceutically acceptable food or cosmetically acceptable salt, and examples thereof include acid addition salts and base addition salts. Examples of the acid addition salt include salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and salts with organic acids such as acetic acid, malic acid, succinic acid, tartaric acid and citric acid. Base addition salts include salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, and salts with amines such as ammonium and triethylamine.

  Compounds of formula I also include their stereoisomers (eg, geometric and optical isomers). Hereinafter, the compound of formula I and salts thereof may be collectively referred to as the compound of the present invention.

  In the present invention, autoinducer-2 (AI-2) includes formula (II):

で表される４，５−ジヒドロキシ−２，３−ペンタンジオン（ＤＰＤ）、およびＤＰＤが有するオートインデューサー−２活性と同等のオートインデューサー−２活性を有する化合物が包含される。式（II）のＤＰＤは、細菌のオートインデューサー−２受容体と結合するときにボロンを取り込んで、以下の式（III）：

And a compound having an autoinducer-2 activity equivalent to the autoinducer-2 activity of DPD, and 4,5-dihydroxy-2,3-pentanedione (DPD). The DPD of formula (II) incorporates boron when binding to the bacterial autoinducer-2 receptor, and has the following formula (III):

で表されるフラノシルボレートジエステルに変換される。フラノシルボレートジエステルはＤＰＤと同等のオートインデューサー−２活性を有することから、本発明においてオートインデューサー−２には、上記式（III）で表されるフラノシルボレートジエステルも包含される。

Into the furanosyl borate diester represented by Since furanosyl borate diester has autoinducer-2 activity equivalent to that of DPD, in the present invention, autoinducer-2 includes the furanosylborate diester represented by the above formula (III).

  Inhibiting autoinducer-2 in the present invention refers to inhibiting the effect of autoinducer-2 on bacteria via quorum sensing, inhibiting autoinducer-2 activity, This includes degrading inducer-2, inhibiting the binding of autoinducer-2 to the autoinducer-2 receptor, and the like.

  In the present invention, autoinducer-2 activity promotes the activity of autoinducer-2 on bacteria having a quorum sensing system, that is, the function of bacteria brought about by quorum sensing via autoinducer-2. Refers to activity. Bacteria are luminescent, swarming, biofilm formation, proteolytic enzyme production, antibiotic synthesis, gene acceptability development, plasmid conjugation transmission, pathogenic factor production and spore by quorum sensing via autoinducer-2 It is known to form. Therefore, autoinducer-2 activity is, in other words, bioluminescence, swarming, biofilm formation, proteolytic enzyme by a bacterium that recognizes autoinducer-2, that is, a bacterium having an autoinducer-2 receptor. Production, antibiotic synthesis, development of gene acceptability, plasmid conjugation transfer, virulence factor production or sporulation activity. In the present invention, autoinducer-2 activity particularly refers to bacterial pathogenic factor production activity.

  Examples of bacterial pathogenic factors include enterotoxin, adenylate cyclase toxin, adhesin, alkaline protease, hemolytic toxin, anthrax toxin, APX toxin, alpha toxin, beta toxin, delta toxin, C2 toxin, C3 toxin, botulinum toxin, bundled form Pili structure subunit, C5A peptidase, cardiotoxin, chemotaxis, cholera toxin, ciliary toxin, clostridial cytotoxin, clostridial neurotoxin, collagen adhesion gene, cytolysin, vomiting toxin, endotoxin, epidermal exfoliating toxin, Exotoxin, extracellular elastase, fibrinogen, fibronectin binding protein, fibrillar hemagglutinin, fimbria, gelatinase, hemagglutinin, leukotoxin, lipoprotein signal peptidase, listeriolysin O, M protein, neurotoxin, non-fimbriad ad Hesins, edema factor Examples include, but are not limited to, permease, pertussis toxin, phospholipase, pili, pore-forming toxin, proline permease, serine protease, Shiga toxin, tetanus toxin, thiol-activated cytolysin, tracheal cell lysin, and urease. .

  Bacteria that can be affected by the compounds of the present invention, in other words, bacteria that can inhibit the growth of the compounds of the present invention, function by autoinducer-2, such as bioluminescence, warming, biofilm formation. It is a bacterium that promotes production of proteolytic enzymes, synthesis of antibiotics, development of gene acceptability, plasmid conjugation transfer, pathogenic factor production and sporulation. For example, a bacterium having an autoinducer-2 receptor, preferably a bacterium having an autoinducer-2 receptor and producing autoinducer-2 can be used.

  Autoinducer-2 activity can be measured by a bioassay using a reporter bacterium that emits light upon recognition of autoinducer-2, preferably a bacterium having an autoinducer-2 receptor and luciferase (Keersmaecker SCJ et al., J. Biol. Chem., 280 (20), 19563-19568, 2005). Specifically, Vibrio Harvey BB170 strain is used as a reporter bacterium, cultured in the presence of a test compound, and the autoinducer-2 activity is measured by measuring the luminescence intensity after the culture with a chemiluminescence meter or the like. be able to.

  Examples of bacteria that can be affected by inhibiting autoinducer-2 or that can suppress proliferation include, for example, bacteria belonging to the genus Vibrio, bacteria belonging to the genus Pseudomonas, bacteria belonging to the genus Porphyromonas Yersinia bacteria, Escherichia bacteria, Salmonella bacteria, Haemophilus bacteria, Helicobacter bacteria, Bacillus bacteria, Borrelia bacteria, Neisseria genus, Campylobacter genus, Deinococcus genus, Mycobacterium genus, Enterococcus genus, Streptococcus genus, Shigella Bacteria, Aeromonas , Eikenella bacteria, Clostridium bacteria, Staphylococcus bacteria, Lactobacillus bacteria, Actinobacillus bacteria, Actinomyces bacteria, Bacteroides (Bacteroides), Capnocytophaga, Klebsiella, Halobacillus, Fusobacterium, Erwinia, Elbenella Bacteria, Lactobacillus genus bacteria, Listeria genus bacteria, Mannheimia genus bacteria, Peptococcus genus bacteria, Prevotella genus bacteria, Proteus genus bacteria, Serratia genus Bacteria and Beironella (Vei llonella) and the like. More specifically, Vibrio harveyi, Vibrio fischeri, Vibrio cholerae, Vibrio parahaemolyticus, Vibrio alginolyticus, Pseudomonium phosphoreum (Pseudomone phosphore) ), Polyphyromonas gingivalis, Yersinia enterocolitica, Escherichia coli, Salmonella typhimurium, Haemophilus influenzae, Helicobacter pyl (Helicober pyl) Bacillus subtilis, Borrelia burgfdorferi, Neisseria meningitidis, Neisseria gonorrhoeae, Yersinia pestis, Campylobacter jejuni, Deinococcus radiodurans, Mycobacterium tuberculosis, Enterococcus faecalis, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus mutogen Staphylococcus aureus, Shigella flexneri, Shigella boydii, Bacillus cereus, Bacillus cubtilis, Aeromonas hydrophila, typhoid (Salmonella enterica), Eikenella corrodens, Helicobacter hepaticus, Clostridium perfringens, Staphylococcus haemolyticus, La Lactobacillus gasseri, Lactobacillus acidophilus, Lactobacillus reuteri, Lactobacillus salivarius, Lactobacillus sans guineas (Lactobacillus sans) , Streptococcus anginosus, Streptococcus oralis, Streptococcus bovis, Streptococcus gordonii, Streptococcus octom Actinobacillus actinomycetemcomitans), Vibrio vulnificus (Vivrio vulnificus), Vibrio mimicus (Vibrio mimicus) ), Vibrio anguillarum, Lactobacillus rhamnosus, Erwinia amylovora, Erwinia carotovara, Halabacilus thiarumia halophilus , Serratia marcescens, Bacteroides fragilis, Bacteroides vulgatus, Bacteroides distasonis, Listeria monocytogenecus, Staphylococcus epidermidis), Clostridium difficile, Aeromonas hydrophilia, Manheimia Emnotica (Mannhemia haemolytica), Klebsiella pneumoniae, Bacillus anthracis, Campylobacter coli, Campylobacter rectus, bilis Proteus mirabilis Naeslandi (Actinomyces naeslundii), Peptococcus anaerobius, Fusobacterium nucleatum, Veillonella parvula, Capnocytophaga sputtera media ) And the like.

  The compounds of the present invention are Streptococcus mutans, Polyphyromonas gingivalis, Streptococcus oralis, Streptococcus gordonii, Streptococcus sanguinis, Streptococcus mittis, Actinomyces naeslandi, Peptococcus anaerobius Activinos It is particularly preferably used for inhibition of autoinducer-2 against Comitans, Fusobacterium nucleatum, Beironella parla, Capnocytofaga sputigena, Prevotella intermedia, Lactobacillus salivarius and the like.

  Furthermore, the present inventors have found that the amount of autoinducer-2 and the symptoms of infectious diseases have a correlation in vivo, and that the symptoms of infectious diseases can be reduced by administering the compound of the present invention. It was. Therefore, in one embodiment, the present invention relates to an agent for preventing and / or treating infectious diseases comprising the compound of formula I or a salt thereof as an active ingredient.

  An infectious disease that can be prevented and / or treated by administering a compound of the invention is an infectious disease that can be prevented and / or treated by inhibiting autoinducer-2, in other words, Bacteria having a quorum sensing system that utilizes autoinducer-2, specifically, infections associated with bacteria such as those described above that can be affected by inhibiting autoinducer-2.

  Specific examples of infectious diseases that can be prevented and / or treated by administering the compound of the present invention include infectious diseases in the oral cavity, skin, vagina, digestive (GI) tract, esophagus and respiratory tract. More specifically, caries caused by Streptococcus mutans, etc .; periodontal disease (including gingivitis) caused by Porphyromonas gingivalis, etc .; opportunistic infections caused by opportunistic organisms; Streptococcus pneumoniae and Haemophilus influenzae Acute otitis media (AOM) and exudative otitis media (OME) caused by, etc .; influenza caused by Haemophilus influenzae; duodenal and gastric ulcers caused by Helicobacter pylori; cholera caused by Vibrio cholerae; plague caused by Plasmodium pestis; Meningitis caused by Neisseria meningitidis; Salmonella poisoning caused by Salmonella bacteria such as Salmonella typhimurium; and diarrhea caused by Escherichia coli and the like.

  In the present invention, prevention of infectious diseases includes suppressing and delaying the onset of infectious diseases, and includes not only prevention before infectious diseases but also prevention of recurrence of infectious diseases after treatment. In the present invention, treatment of infectious diseases includes curing infectious diseases, improving symptoms, and suppressing progression of symptoms.

  The administration target of the autoinducer-2 inhibitor of the present invention and the preventive and / or therapeutic agent for infectious diseases is preferably a mammal. As used herein, a mammal refers to a warm-blooded vertebrate, for example, primates such as humans and monkeys, rodents such as mice, rats and rabbits, companion animals such as dogs and cats, and cattle, horses and Examples include livestock such as pigs. The autoinducer-2 inhibitor of the present invention and the preventive and / or therapeutic agent for infectious diseases are suitable for administration to primates, particularly humans. It is particularly preferred to administer to a human suffering from an infectious disease, a human being diagnosed with an infectious disease, a human being likely to suffer from an infectious disease, or a human in need of preventing the infectious disease.

  The autoinducer-2 inhibitor of the present invention and the preventive and / or therapeutic agent for infectious diseases are not particularly limited. For example, they are pharmaceutical compositions, food compositions and cosmetic compositions, or are incorporated in these. can do.

  When preparing a pharmaceutical composition, it is usually prepared as a preparation containing the compound of the present invention and preferably a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier generally refers to an inert, non-toxic, solid or liquid, bulking agent, diluent or encapsulating material that does not react with the active ingredients of the present invention, for example, , Water, ethanol, polyol (eg, glycerol, propylene glycol, liquid polyethylene glycol, etc.), suitable mixtures thereof, solvents or dispersion media such as vegetable oils, and the like.

  The pharmaceutical composition can be administered orally, parenterally, e.g., into the skin, subcutaneously, mucosal, intravenously, intraarterially, intramuscularly, intraperitoneally, intravaginally, into the lungs, into the brain, Administered to the eye and intranasally. Examples of oral preparations include tablets, granules, fine granules, powders, capsules, chewables, pellets, syrups, solutions, suspensions and inhalants. As parenteral preparations, suppositories, retention enemas, drops, eye drops, nasal drops, pessaries, injections, mouth washes, ointments, creams, gels, controlled release patches and patches Skin external preparations, and the like. The pharmaceutical compositions of the invention are administered parenterally in the form of sustained-release subcutaneous implants or in the form of targeted delivery systems (eg, monoclonal antibodies, vector delivery, ion implantation, polymer matrices, liposomes and microspheres). May be.

  The pharmaceutical composition may further contain additives conventionally used in the pharmaceutical field. Such additives include, for example, excipients, binders, disintegrants, lubricants, antioxidants, colorants, flavoring agents, and the like, and can be used as necessary. In order to achieve sustained release so that it can act for a long time, it can also be coated with a known retarder or the like. Examples of excipients include sodium carboxymethylcellulose, agar, light anhydrous silicic acid, gelatin, crystalline cellulose, sorbitol, talc, dextrin, starch, lactose, sucrose, glucose, mannitol, magnesium aluminate metasilicate, calcium hydrogen phosphate Etc. can be used. Examples of the binder include gum arabic, sodium alginate, ethanol, ethyl cellulose, sodium caseinate, sodium carboxymethyl cellulose, agar, purified water, gelatin, starch, tragacanth, lactose, hydroxycellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, etc. Is mentioned. Examples of the disintegrant include carboxymethyl cellulose, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, crystalline cellulose, starch, hydroxypropyl starch and the like. Examples of the lubricant include stearic acid, calcium stearate, magnesium stearate, talc, hydrogenated oil, sucrose fatty acid ester, waxes and the like. Examples of the antioxidant include tocopherol, gallic acid ester, dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), ascorbic acid and the like. Other additives and drugs as necessary, such as antacids (sodium bicarbonate, magnesium carbonate, precipitated calcium carbonate, synthetic hydrotalcite, etc.), gastric mucosa protective agents (synthetic aluminum silicate, sucralfate, copper chlorophyllin sodium, etc.) ) May be added.

  When preparing a food composition, the form in particular is not restrict | limited, A drink is also included. In addition to general foods, foods and drinks that indicate the concept of prevention and improvement of infectious diseases (specifically, periodontal diseases such as gingivitis and alveolar pyorrhea), that is, health foods and functional foods Also included are foods for patients and foods for specified health use. Health foods, functional foods, foods for the sick, and foods for specified health use are specifically formulated as various pharmaceutical forms such as fine granules, tablets, granules, powders, capsules, syrups, liquids, liquid foods, etc. Can be used for these formulations. A food composition in the form of a preparation can be produced in the same manner as a pharmaceutical preparation. The compound of the present invention can be prepared by adding a food acceptable carrier such as a suitable excipient (eg, starch, processed starch, lactose, glucose, water). Etc.) can be prepared using conventional means. In addition, food compositions include soups, juices, milk beverages, tea beverages, coffee beverages, cocoa beverages, jelly-like beverages and other liquid food compositions, pudding, yogurt and other semi-solid food compositions, breads, udon Such as noodles such as cookies, chocolate, candy, gum, rice crackers and the like, spreads such as sprinkles, butter, jam and the like. The food also includes feed.

  Food compositions include various food additives such as antioxidants, fragrances, various esters, organic acids, organic acid salts, inorganic acids, inorganic acid salts, inorganic salts, pigments, emulsifiers, preservatives, seasonings Additives such as additives, sweeteners, acidulants, fruit juice extracts, vegetable extracts, nectar extracts, pH adjusters, and quality stabilizers may be used alone or in combination.

  When preparing a cosmetic composition, the form is not particularly limited, and any form such as a solution, emulsion, powder, water-oil two-layer system, water-oil-powder three-layer system, gel, aerosol, mist, and capsule It can be. The product form of the cosmetic composition is also arbitrary, for example, body cosmetics such as massage agents and foot sprays, facial cosmetics such as lotions, emulsions, creams and packs, foundations, funny, blushers, lipsticks, eye Makeup cosmetics such as shadow, eyeliner, mascara and sunscreen, makeup remover, skin cleansers such as face wash and body shampoo, hair cosmetics such as hair rinse and shampoo, bath preparation, ointment, quasi-drug, oil Examples include papers and aromatic cosmetics.

  The cosmetic composition comprises other components commonly used in cosmetics, quasi drugs and pharmaceuticals, such as powder components, liquid fats and oils, solid fats and oils, waxes, hydrocarbons, higher fatty acids, higher alcohols, esters, silicones, anions. Surfactant, cationic surfactant, amphoteric surfactant, nonionic surfactant, humectant, water-soluble polymer, thickener, film agent, UV absorber, sequestering agent, lower alcohol, polyhydric alcohol , Sugar, amino acids, organic amines, polymer emulsions, pH adjusters, skin nutrients, vitamins, antioxidants, antioxidant auxiliaries, fragrances, water, etc. may be blended as necessary and manufactured by conventional methods. it can.

  Examples of other components that can be incorporated into the cosmetic composition include preservatives (ethyl paraben, butyl paraben, etc.), anti-inflammatory agents (eg, glycyrrhizic acid derivatives, glycyrrhetinic acid derivatives, salicylic acid derivatives, hinokitiol, zinc oxide, allantoin, etc. ), Whitening agents (for example, placenta extract, saxifrage extract, arbutin, etc.), various extracts (for example, buckwheat, auren, shikon, peonies, assembly, birch, sage, loquat, carrot, aloe, mallow, iris, grape , Yokuinin, Loofah, Lily, Saffron, Senkyu, Pepper, Hypericum, Onionis, Garlic, Pepper, Chimpi, Toki, Seaweed, etc.), Activator (eg, Royal Jelly, Photosensitizer, Cholesterol Derivative, etc.), Blood circulation promoter (eg, , Wallenylami nonylate Nicotinic acid benzyl ester, nicotinic acid β-butoxyethyl ester, capsaicin, gingerone, cantalis tincture, ictamol, tannic acid, α-borneol, nicotinic tocopherol, inositol hexanicotinate, cyclandrate, cinnarizine, trazoline, acetylcholine, And verapamil, cephalanthin, γ-oryzanol, etc.), antiseborrheic agents (eg, sulfur, thianthol, etc.), anti-inflammatory agents (eg, tranexamic acid, thiotaurine, hypotaurine, etc.).

  The dosage of the autoinducer-2 inhibitor of the present invention and the preventive and / or therapeutic agent for infectious diseases is an amount capable of inhibiting autoinducer-2 or an amount capable of preventing and / or treating infectious diseases. It may be sufficient, and can be appropriately determined depending on the administration method, age, symptoms and the like. Based on the mass of the compound of formula I which is an active ingredient, the dose is usually 0.001 to 100 mg, preferably 0.01 to 10 mg per day per kg body weight.

  The content of the compound of the present invention in the autoinducer-2 inhibitor of the present invention and the preventive and / or therapeutic agent for infectious diseases can be appropriately determined so as to achieve the above dose. For example, the compound of the present invention is usually contained in an amount of 0.001 to 5 mass%, preferably 0.05 to 1 mass%, based on dry mass.

  By administering the compound of the present invention, autoinducer-2 can be inhibited, and thus infectious diseases can be prevented and / or treated.

  Antibiotics have been administered to prevent and treat conventional infections. However, since bacteria acquire drug resistance, the effectiveness of antibiotics is diminished. On the other hand, if autoinducer-2 is inhibited, it becomes possible to control its pathogenicity using a system inherent to bacteria, and therefore, an effect can be expected for bacteria having drug resistance.

  EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to the range of an Example.

(Example 1) Screening of a substance that inhibits autoinducer-2 Vibrio harveyi BB170 strain is used as an autoinducer-2 (AI-2) reporter bacterium and is an indicator of AI-2 activity. The luminescence intensity of the reporter bacterium was measured in the same manner as De Keersmaecker SCJ et al., J. Biol. Chem., 280 (20), 19563-19568, 2005. Specifically, Vibrio Harvey BB170 strain was prepared to be diluted 4500 times in a medium, preincubated with each test compound solution at room temperature for 10 minutes, and then 4,5-dihydroxy-2,3-pentanedione (DPD). ) And aerobic shaking culture at 30 ° C., and the luminescence intensity after 4 hours was measured with a chemiluminescence meter. The final concentration of the reporter bacterial solution was 5000 times diluted, and the final concentration of each test compound solution and DPD was 10 μM. A sample to which only DPD was added was used as a control and expressed as a relative value to the control (FIG. 1). At the same time, the AI-2 activity of the test compound was also examined.

  As test compounds, 4-bromo-5- (4-methoxyphenyl) -2 (5H) -furanone (Compound 1; SIGMA), 3,4-dibromo-5-hydroxy-2 (5H) -furanone (Compound 2) SIGMA), 4-bromo-5-methoxy-5- (4-methoxyphenyl) -2 (5H) -furanone (compound 3; SIGMA), 4-{[3-bromo-2- (4-methoxyphenyl); -5-oxo-2,5-dihydro-2-furanyl] oxy} benzoic acid (compound 4; SIGMA), and three compounds known as autoinducer-2 inhibitory compounds as positive controls: 4 -Hydroxy-2,5-dimethyl-3 (2H) -furanone (compound 5), 2-methoxy-2,4-diphenyl-3 (2H) -furanone (compound 6), 2-pentyl-2 It was also measured AI-2 inhibitory activity for cyclopenten-1-one (Compound 7).

  Compounds 1 to 3 were shown to have AI-2 inhibitory activity equivalent to or higher than that of known AI-2 inhibitory compounds 4 to 6. In addition, none of the compounds showed AI-2 activity alone.

(Example 2) Relationship between the amount of AI-2 in dental plaque and the degree of gingival inflammation The subject who collected a sample in the morning stopped brushing after morning brushing on the day before the test, and the afternoon subject after brushing on the morning of the test day. . In addition, eating, drinking and smoking were prohibited 30 minutes before sampling.

  Subgingival plaque adhering to the upper and lower labial cheek sides was collected with a dental scaler according to the gingival inflammation index. The collected plaque was dispersed in 1 ml of PBS and crushed with 0.3 g of zirconia / silica beads. After centrifugation, the supernatant was passed through a 0.22 μm filter and a filter with a molecular weight of 3000 cut to prepare a sample. AI-2 activity was measured according to the above in the Vibrio Harvey bioassay. Vibrio Harvey BB170 strain was used as an autoinducer-2 (AI-2) reporter bacterium, cultured overnight, then diluted 5000 times with the medium, mixed with the sample at a ratio of 9: 1, and then at 30 ° C. The culture was aerobically shaken, and the luminescence intensity after 4 hours was measured with a chemiluminescence meter.

  The results are shown in FIG. The Gingival Index (GI) was used as a gingival inflammation index. The gingival condition on the upper and lower lip buccal sides was evaluated in four stages by inserting (probing) a dental probe into the periodontal pocket. The GI score was determined as follows.

0: Normal gingiva 1: Inflamed gingiva. No bleeding due to probing 2: Inflammation of gingiva. Probing causes bleeding 3: Spontaneous bleeding / ulcer formation From the results shown in FIG. 2, the amount of AI-2 in plaque has a correlation with the degree of gingival inflammation (p <0.1). 2 has been shown to be involved in gingivitis.

(Example 3) Relationship between the amount of AI-2 in dental plaque and the alveolar bone resorption depth A silk thread was ligated to the lower left and right first molar necks of Syrian hamster (7W, heel), and the teeth after 4 days, 1 week and 2 weeks The plaque and mandible were removed under anesthesia. In accordance with the above, the plaque was treated for AI-2 activity measurement, and the amount of AI-2 in the plaque was measured by Vibrio Harvey bioassay. The mandibular bone was completely trimmed from the surrounding tissue, and then the alveolar bone resorption depth was measured. The evaluation site was the lingual side of the extracted mandible, the extracted mandible was photographed under a stereomicroscope, and the obtained photograph was subjected to image analysis. The alveolar bone resorption depth was the vertical distance from the first molar mesial cusp to the alveolar crest (Mori et al., Gifu Univ., 43, 758-767, 1995).

  The results are shown in FIG. From the results shown in FIG. 3, the amount of AI-2 in plaque and the alveolar bone resorption depth have a correlation (r = 0.65, p <0.01). Therefore, AI-2 in the plaque is the alveolar bone. It was shown to be involved in absorption.

(Example 4) In vivo test using AI-2 inhibitory compound Syrian hamster (7W, heel) ligated silk thread to the lower left and right first molar neck of the mandible, and the test sample was applied twice a day to the same ligation site from the next day. It was dripped for 2 weeks. Test samples were 4-bromo-5- (4-methoxyphenyl) -2 (5H) -furanone (compound 1 of Example 1) and 3,4-dibromo-5-hydroxy-2 (prepared to 10 μM in a solvent). 5H) -furanone (Compound 2 of Example 1) was used as the solution, and the control was only the solvent. As a solvent, PBS containing 1% DMSO was used.

  After the breeding, the mandible was removed under anesthesia and photographed under a stereomicroscope (FIG. 4). The evaluation site was the lingual side of the extracted mandible, and the obtained photograph was subjected to image analysis. The alveolar bone resorption depth was defined as the change from the value after 2 weeks to the initial value in the vertical distance from the first molar mesial cusp to the alveolar crest. The results are shown in FIG.

  The AI-2 inhibitory compound selected in the in vitro bioassay system of Example 1 remarkably suppresses bacterial pathogenicity even in an in vivo model, and is therefore effective in the prevention and treatment of infectious diseases. It has been shown.

2 is a graph showing the results of measuring the AI-2 activity of each compound in Example 1. It is a graph which shows the relationship between the amount of AI-2 in dental plaque and the degree of gingival inflammation. It is a graph which shows the relationship between the amount of AI-2 in dental plaque and the alveolar bone resorption depth. Syrian hamsters were administered 4-bromo-5- (4-methoxyphenyl) -2 (5H) -furanone and 3,4-dibromo-5-hydroxy-2 (5H) -furanone, and after 2 weeks the mandible was A photograph taken under a stereomicroscope is shown. Syrian hamster was administered 4-bromo-5- (4-methoxyphenyl) -2 (5H) -furanone and 3,4-dibromo-5-hydroxy-2 (5H) -furanone to increase the alveolar bone resorption depth to 2 It is a graph which shows the result measured as a variation | change_quantity of an after-week value-initial value.

Claims (8)

Formula I:

(Where
R ¹ and R ² are each independently hydrogen, hydroxy group, aryl group or alkoxy group, or R ¹ and R ² together form an oxo group;
R ³ is halogen,
R ⁴ is hydrogen, amino group or halogen)
The autoinducer-2 inhibitor which uses the compound or its salt represented by these as an active ingredient. Formula I:

(Where
R ¹ and R ² are each independently hydrogen, hydroxy group, aryl group or alkoxy group, or R ¹ and R ² together form an oxo group;
R ³ is halogen,
R ⁴ is hydrogen, amino group or halogen)
A prophylactic and / or therapeutic agent for infectious diseases comprising a compound represented by the formula or a salt thereof as an active ingredient.   The preventive and / or therapeutic agent for an infectious disease according to claim 2, wherein the infectious disease is periodontal disease.   The preventive and / or therapeutic agent for infectious diseases according to claim 2, for preventing caries.   The compound of formula I is 4-bromo-5- (4-methoxyphenyl) -2 (5H) -furanone, or an autoinducer-2 inhibitor or an infectious disease according to any one of claims 1 to 4. Preventive and / or therapeutic agent.   5. The compound of formula I is 3,4-dibromo-5-hydroxy-2 (5H) -furanone, the autoinducer-2 inhibitor or the prevention of infectious diseases according to any one of claims 1 to 4 and / Or therapeutic agent.   5. The autoinducer-2 inhibitor according to any one of claims 1 to 4, wherein the compound of formula I is 4-bromo-5-methoxy-5- (4-methoxyphenyl) -2 (5H) -furanone. Or preventive and / or therapeutic agents for infectious diseases.   The compound of formula I is 4-{[3-bromo-2- (4-methoxyphenyl) -5-oxo-2,5-dihydro-2-furanyl] oxy} benzoic acid. The autoinducer-2 inhibitor or the preventive and / or therapeutic agent for an infectious disease according to 1.

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