JP2005537294A - Oral care composition comprising a tropolone compound and an essential oil - Google Patents

Abstract

The present invention prevents or treats oral diseases or conditions in warm-blooded animals, including humans, comprising an oral care effective amount of at least one tropolone compound in combination with at least one essential oil and a pharmaceutically acceptable oral carrier. Therefore, it is related with the oral care composition suitable for. The invention further relates to a method for preventing or treating oral diseases or conditions in warm-blooded animals, including humans, by applying an oral care effective amount of an oral care composition to the oral cavity.

Description

The present invention relates generally to oral care compositions, and more particularly to oral care compositions comprising substituted tropolone compounds and essential oils, and methods of using them for oral care.

  Oral odor, plaque, gingivitis, periodontal disease, and tooth discoloration are all undesirable conditions that attack many people. The first oral malodor, also known as halitosis or bad breath, has been estimated to afflict roughly 2 to 90 million people in the United States. In general, the presence of anaerobic bacteria in the mouth, especially gram-negative anaerobic bacteria, is thought to contribute to this condition. Other oral conditions caused by microorganisms include periodontal disease, caries, inflammation and the like.

  Periodontal disease is a leading cause of tooth loss in adults and can appear in young people who are 12 years of age. Periodontal disease affects the periodontal tissue, which is the surrounding and supporting tissue around the teeth (ie periodontal ligament, gingiva, and alveolar bone). Gingivitis and periodontitis are diseases of the gingiva and deeper periodontal tissue, respectively. Periodontal disease is generally associated with the accumulation of plaque on the teeth. The teeth are coated with a salivary proteinaceous material (thin film), after which streptococci adheres to the coating. Gingivitis is generally caused by plaque, and periodontitis is caused by an infection that spreads in the periodontal pocket or the space between the gum and the root of the tooth.

  Many of the current oral care compositions, including toothpastes, gargles, rinses and toothpaste gels, are formulated to clean the oral cavity and kill pathogenic microorganisms. Such oral care compositions typically contain one or more microorganisms to control microorganisms that contribute to both the onset and progression of oral malodor, periodontal disease and other undesirable oral conditions. It is formulated using antibacterial agents. Current oral care compositions include antimicrobial agents and are formulated to maximize antimicrobial kinetics. Antimicrobial agents are dissolved for effective prevention of bad breath, eradication of oral microorganisms, and penetration, reduction and elimination of plaque and gingivitis.

  One well-known preservative is thymol, also known as essential oil, which is utilized in a series of oral care formulations due to its antimicrobial activity. In particular, thymol has been utilized in oral hygiene compositions such as mouthwashes in amounts sufficient to provide the desired beneficial therapeutic effect. LISTERINE® brand oral rinses have been used by millions of people for over 100 years and are effective in killing oral microorganisms that cause plaque, gingivitis and bad breath. It is a well-known antiseptic gargle that has proven to be. Other essential oils such as thymol and methyl salicylate, menthol and eucalyptol are active ingredients (eg antibacterial agents) in antiseptic oral rinses such as LISTERINE®. Even in small amounts, these essential oils are effective antibacterial agents. Without being limited to any particular theory, the potency and taste of antiseptic gargles such as LISTERINE® are attributed to the dissolution and delivery kinetics of these four active agents. It is thought that you can.

Effective oral care compounds and oral care compositions such as gargles or rinses containing them that still have favorable antibacterial kinetics while still exhibiting favorable chemical stability and solubility for effective delivery and antiseptic efficacy You need to provide things. Prevention or treatment of oral diseases and conditions in warm-blooded animals, including humans, by eliminating or suppressing the presence of pathogenic oral microorganisms that still cause plaque, gingivitis and other undesirable oral conditions in the oral cavity There is a need to provide oral care compositions and compounds that are effective to do so.

  The present invention relates to oral care compositions for preventing or treating oral diseases or conditions in warm-blooded animals, including humans, and methods of using the same. In general, the oral care composition comprises a substituted tropolone compound in combination with an amount of one or more essential oils effective to inhibit or eliminate the presence of harmful pathogenic oral microbes in the oral cavity. The oral care composition provides a high level of antibacterial kinetics and efficacy that is useful to prevent, among other things, plaque, gingival disease, and oral malodor. In addition, the oral care compositions include toothpastes, toothpaste gels, toothpastes, mouthwashes, lozenges, chewing gums, toothpastes, threadpicks, oral consumable films and mouth sprays ( (But not limited to these) can be formulated into a series of oral care products.

（式中、Ｒ₁、Ｒ₂、Ｒ₃、Ｒ₄、およびＲ₅は、各々独立して水素、ヒドロキシ、アルキル基、ヒドロキシアルキル基、アルコキシアルキル基、アルキレン基、アルケニレン基、アルカリール基、アルクシクロアルキル基、アルコキシ基、アルケニル基、アルキニル基、アリール基、シクロアルキル基、シクロアルケニル基、場合により１ないし３個のハロゲンで置換されていてもよい脂肪族基、場合により１ないし３個のハロゲンで置換されていてもよい芳香族基、およびカルボニル基から成る群から選択される）
の化合物、およびその異性体および薬学的に受容できる塩；
（ｂ）少なくとも１つの精油；および
（ｃ）薬学的に受容できる口腔用キャリヤー；
を含むオーラルケア組成物が提供される。 In one particular embodiment of the invention,
(A) an oral care effective amount of at least one formula (I)

(Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently hydrogen, hydroxy, alkyl group, hydroxyalkyl group, alkoxyalkyl group, alkylene group, alkenylene group, alkaryl group, An alkcycloalkyl group, an alkoxy group, an alkenyl group, an alkynyl group, an aryl group, a cycloalkyl group, a cycloalkenyl group, an aliphatic group optionally substituted by 1 to 3 halogen atoms, optionally 1 to 3 Selected from the group consisting of an aromatic group optionally substituted with a halogen and a carbonyl group)
And isomers and pharmaceutically acceptable salts thereof;
(B) at least one essential oil; and (c) a pharmaceutically acceptable oral carrier;
An oral care composition is provided.

In a preferred embodiment of the present invention, the oral care composition comprises an oral care effective amount of at least one of R ₂ , R ₃ , and R ₅ each independently hydrogen, an alkyl group having 1 to 6 carbons. A hydroxyalkyl group having 1 to 6 carbons, and the “alkoxy” and “alkyl” moieties are each selected from the group consisting of alkoxyalkyl groups having 1 to 6 carbons, and R ₁ and R ₄ Including compounds of formula (I), each of which is hydrogen.

  Preferably the essential oil is selected from the group consisting of thymol, eucalyptol, menthol, methyl salicylate and combinations thereof.

  In another aspect of the invention, there is provided a method for preventing or treating an oral disease or condition comprising administering to a warm-blooded animal, including a human, an oral care effective amount of an oral care composition of the invention. Is done.

  The present invention relates to oral microorganisms that cause microbes, particularly undesirable diseases or conditions in the oral cavity, including oral malodor, plaque formation, etc., and the consequent resulting tooth and gingival diseases. The present invention aims at an oral care composition having an antibacterial effect. The oral care composition includes, for example, mouthwash, toothpaste, toothpaste, toothpaste cream, threadpick, liquid, gel, chewing gum, liquid centered gum, mint, lozenge, and mouth-consumable film. The form can be selected from the above. One preferred embodiment of the present invention is directed to an oral care composition containing an effective amount of a substituted tropolone compound having at least one antimicrobial activity in combination with one or more essential oils. In a particularly preferred embodiment of the present invention there is provided an oral care composition, preferably an gargle, containing an effective amount of at least one substituted tropolone compound in combination with at least one essential oil.

  Essential oils are volatile aromatic oils that can be synthetic or can be extracted from a plant by distillation, expression or extraction and usually carry the odor or flavor of the plant from which they are obtained. In the oral care composition of the present invention, the essential oil provides antiseptic activity. Some of these essential oils also act as flavoring agents. The essential oils of the present invention include thymol, menthol, methyl salicylate (winter green oil), eucalyptol, carvacrol, camphor, anethole, carvone, eugenol, isoeugenol, limonene, osimen, n-decyl alcohol, citronel (Citronel), a-salpineol, methyl acetate, citronellyl acetate, methyl eugenol, cineol, linalool, ethyl linalaol, saflora vanillin, spearmint oil, mint oil, orange oil Oil, sage oil, rosemary oil, cinnamon oil, pimento oil, laurel oil, eucalyptus oil, gerianol Berbenone, anise oil, bay oil, benzaldehyde, bergamot oil, bitter tonsil, chlorothymol, cinnamaldehyde, citronella oil, clove oil, coal tar, eucalyptus oil, guaiacol, lavender oil, mustard oil, phenol, phenyl salicylate, pine oil, These include, but are not limited to, pine leaf oil, sassafras oil, spike lavender oil, strax, thyme oil, trubal sum, turpentine oil, clove oil, and combinations thereof. Preferred essential oils are selected from thymol, methyl salicylate, eucalyptol, menthol and combinations thereof.

  The present invention is effective for cleaning the oral cavity and / or treating oral diseases and conditions including, but not limited to, gingivitis, periodontitis, oral malodor, caries and the like. The oral care composition of the present invention comprises Fusobacterium nucleatum, Prevotella, which is responsible for microbes, particularly oral malodor and plaque and calculus formation, and the resulting dental and gingival disease that will follow. Intermedia (Prevotella intermedia), Actinomyces viscosus (Campylobacter rectus), Porphyromonas gingus recto s mutans, Actinobacillus, Bacteroides, Capnocytophaga, Eikenella, Propionibacterium and ic, and C. Provides a high degree of antibacterial efficacy against pathogenic oral microorganisms, including but not limited to.

  The present invention also cleanses the oral cavity in warm-blooded animals, including humans, and / or treats or prevents oral diseases or conditions by applying an oral care effective amount of the oral care composition of the present invention to the oral cavity. Also aimed at the method.

  As used herein, the term “oral disease or condition” refers to periodontal disease, gingivitis, periodontitis, periodontitis, adult and juvenile periodontitis in warm-blooded animals, including humans, and Meant to encompass oral diseases including other oral tissue inflammatory conditions, plus caries, necrotizing ulcerative gingivitis, and other conditions such as oral malodor or unpleasant tongue touch, However, it is not limited to these. The compositions and methods of treatment and oral care provided by the present invention are particularly effective for preventing or treating periodontal disease (gingivitis and / or periodontitis) and oral malodor in warm-blooded animals including humans It is.

（式中、Ｒ₁、Ｒ₂、Ｒ₃、Ｒ₄、およびＲ₅は、各々独立して水素、ヒドロキシ、アルキル基、ヒドロキシアルキル基、アルコキシアルキル基、アルキレン基、アルケニレン基、アルカリール基、アルクシクロアルキル基、アルコキシ基、アルケニル基、アルキニル基、アリール基、シクロアルキル基、シクロアルケニル基、場合により１ないし３個のハロゲンで置換されていてもよい脂肪族基、場合により１ないし３個のハロゲンで置換されていてもよい芳香族基、およびカルボニル基から成る群から選択される）
の化合物、およびその異性体および薬学的に受容できる塩；
（ｂ）少なくとも１つの精油；および
（ｃ）薬学的に受容できる口腔用キャリヤー；
を含むオーラルケア組成物が提供される。 In one particular embodiment of the invention,
(A) an oral care effective amount of at least one formula (I)

(Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently hydrogen, hydroxy, alkyl group, hydroxyalkyl group, alkoxyalkyl group, alkylene group, alkenylene group, alkaryl group, An alkcycloalkyl group, an alkoxy group, an alkenyl group, an alkynyl group, an aryl group, a cycloalkyl group, a cycloalkenyl group, an aliphatic group optionally substituted by 1 to 3 halogen atoms, optionally 1 to 3 Selected from the group consisting of an aromatic group optionally substituted with a halogen and a carbonyl group)
And isomers and pharmaceutically acceptable salts thereof;
(B) at least one essential oil; and (c) a pharmaceutically acceptable oral carrier;
An oral care composition is provided.

In a preferred embodiment of the present invention, the oral care composition comprises an oral care effective amount of at least one of R ₂ , R ₃ , and R ₅ each independently hydrogen, an alkyl group having 1 to 6 carbons. A hydroxyalkyl group having 1 to 6 carbons, and the “alkoxy” and “alkyl” moieties are each selected from the group consisting of alkoxyalkyl groups having 1 to 6 carbons, and R ₁ and R ₄ Including compounds of formula (I), each of which is hydrogen.

  Isomers, mixtures thereof, of the compounds of formula (I) having the desired antimicrobial activity are included within the scope of the present invention.

  Furthermore, hydrates and solvates with pharmaceutically acceptable organic solvents, as well as prodrugs of the compounds of the present invention are also encompassed by the present invention.

  Furthermore, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be present in the form of addition products with water or various solvents, and these addition products are also within the scope of the present invention. Is included.

  The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. These are well known in the art and include various organic and inorganic cations, including, for example, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, as well as hydrochloride, hydrobromide, tartrate, It can be derived from anions such as mesylate, acetate, maleate, oxalate and the like. When the compound of the present invention is basic, salts can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic acid, benzene sulfonic acid, benzoic acid, camphor sulfonic acid, citric acid, ethane sulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, Examples include malic acid, mandelic acid, methanesulfonic acid, mucus acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like. Particularly preferred are citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. Salts derived from inorganic bases include salts from aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, etc. .

  Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include arginine, betaine, caffeine, choline, N, N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine , Ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, Primary, secondary and tertiary amines such as tripropylamine, tromethamine, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic There is a salt of the ion-exchange resin. Those skilled in the art will recognize a variety of non-toxic pharmaceutically acceptable addition salts.

  The term “alkyl” is preferably a monovalent straight chain having about 1 to 18 carbon atoms, more preferably about 1 to 14 carbon atoms, more preferably about 1 to 6 carbon atoms, and Refers to a branched alkyl group. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, n-octyl, tert-octyl and the like.

The term “alkylene” refers to a divalent alkylene group preferably having from about 1 to 18 carbon atoms, and more preferably from about 1 to 14 carbon atoms, which can be linear and branched. Point to. The term includes such as methylene (—CH ₂ —), ethylene (—CH ₂ CH ₂ —), propylene isomers (eg, —CH ₂ CH ₂ CH ₂ — and —CH (CH ₃ ) CH ₂ —), and the like. Illustrated by the group.

The term “alkenylene” can be straight or branched and has at least 1, preferably 1 to 2, sites of alkenyl unsaturation, preferably about 2 to 18 carbon atoms, More preferably it refers to a divalent alkenylene group having about 2 to 14 carbon atoms. The term includes groups such as ethenylene (—CH═CH—), propenylene isomers (eg, —CH═CHCH ₂ — and —C (CH ₃ ) ═CH— and —CH═C (CH ₃ ) —) and the like. Is exemplified by

  The term “alkaryl” refers to an -alkylene-aryl group preferably having from about 1 to 18 carbon atoms in the alkylene moiety and from about 6 to 14 in the aryl moiety. Such alkaryl groups are exemplified by benzyl, phenethyl and the like.

The term “alkcycloalkyl” preferably refers to an -alkylene-cycloalkyl-group having about 1 to 18 carbon atoms in the alkylene moiety and about 3 to 14 in the cycloalkyl moiety. Such alkcycloalkyl groups, -CH ₂ - cyclopropyl, -CH ₂ - cyclopentyl, -CH ₂ CH ₂ - is exemplified cyclohexyl and the like.

  The term “alkoxy” refers to the group “alkyl-O—”. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, and preferably have about 1 to 6 carbon atoms. The term “alkoxyalkyl” refers to the group “alkyl-O-alkyl”, preferably the alkyl portion of the group has 1 to 6 carbon atoms, and the alkoxy portion of the group has 1 to 6 carbon atoms. Has carbon atoms.

The term “alkenyl” preferably has about 2 to 18 carbon atoms, more preferably about 2 to 14 carbon atoms, and at least 1, and preferably 1 to 2, alkenyl. An alkenyl group having an unsaturated site. Such alkenyl groups are exemplified by ethenyl (—CH═CH ₂ ), n-propenyl (—CH ₂ CH═CH ₂ ), isopropenyl (—C (CH ₃ ) ═CH ₂ ), and the like.

The term “alkynyl” preferably has about 2 to 18 carbon atoms, more preferably about 2 to 14 carbon atoms, and has at least 1, preferably 1 to 2, sites of alkynyl unsaturation. An alkynyl group having Such alkynyl groups are exemplified by ethynyl (—C≡CH), propargyl (—CH ₂ —C≡CH), and the like.

  The term “aryl” refers to an unsaturated aromatic carbocyclic group of about 6 to 18 carbon atoms having a single ring (eg, phenyl) or fused polycycle (eg, naphthyl or anthryl). Examples of aryl include phenyl, naphthyl and the like. Unless otherwise bound by the definition for individual substituents, such aryl groups are optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, acyloxy, hydroxy, and the like. be able to.

  The term “cycloalkyl” refers to a cyclic alkyl group of about 3 to 18 carbon atoms having a monocyclic or fused polycycle, optionally substituted with 1 to 3 alkyl groups. Such cycloalkyl groups include, by way of example, polycyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or adamantanyl, and the like. .

The term “cycloalkenyl” refers to a cyclic alkenyl group of about 4 to 18 carbon atoms having a single ring and at least one point of internal unsaturation, optionally substituted with 1 to 3 alkyl groups. Point to. Examples of suitable cycloalkenyl groups include, for example, cyclopent-3-enyl, cyclohex-2-enyl, cyclooct-3-enyl and the like.

  Preferred tropolone compounds of formula (I) for use in the oral care composition of the present invention include 2-hydroxy-7-methyl-2,4,6-cycloheptatrien-1-one; 2-hydroxy-7 -Heptyl-2,4,6-cycloheptatrien-1-one; 2-hydroxy-7- (methoxymethyl) -2,4,6-cycloheptatrien-1-one; 2-hydroxy-4-methyl- 2,4,6-cycloheptatrien-1-one; 2-hydroxy-4-dimethylethyl-2,4,6-cycloheptatrien-1-one; and 2-hydroxy-7- (hexyloxymethyl)- There are compounds selected from the group consisting of 2,4,6-cycloheptatrien-1-one, and combinations thereof.

  It will be appreciated that some of the compounds described above can exist in the form of a salt. In such cases, these compounds can be ionized and optionally accompanied by a pharmaceutically acceptable anion or cation. Most commonly the cation is a monovalent substance such as sodium, potassium or ammonium, but it can also be a multivalent cation in combination with a pharmaceutically acceptable monovalent anion, such as chloride, bromide. , Iodide, hydroxide, nitrate, sulfonate, acetate, tartrate, oxalate, succinate, pamoate, or calcium in combination with similar anions; magnesium in combination with such anions; Zinc combined with such anions;

  The term “oral care composition” is meant to include products that are held in the oral cavity for a time sufficient to contact the dental surface and / or oral mucosal tissue to exhibit the desired oral activity. The term “oral care effective amount” as used herein is intended to prevent or treat an oral disease or condition without causing side effects within the scope of safe medical and dental judgment, or the oral cavity. Means an amount of at least one tropolone compound sufficient to significantly eliminate or at least inhibit the presence of undesirable microorganisms therein. The oral care effective amount of the tropolone compound of the present invention is dependent on the particular condition being treated (eg treating oral disease or malodor), the age and physical condition of the patient being treated, the severity of the condition, the treatment The duration of the combination therapy will vary depending on the nature of the combination therapy, the particular form (ie salt) of the tropolone compound used, and the particular carrier to which the tropolone compound is applied.

  The concentration of the tropolone compound in the oral care composition of the present invention is due to differences in the efficacy of the composition in contact with tissue and teeth, and because of the amount of the composition commonly used. Depending on the type of composition (eg toothpaste, rinses and rinses, lozenges, gums, etc.) used to apply to the gingiva / mucosal tissue and / or teeth. The concentration also depends on the disease or condition being treated.

  In a preferred embodiment, the oral care composition of the present invention is about 0.001% to 10.0% by weight, preferably about 0.01% to 5.0% by weight, based on the total weight of the oral care composition. %, More preferably from about 0.1% to 2.0% by weight of the tropolone compound of the present invention, with the remainder of the formulation serving as essential oil, carrier and oral care composition ingredients in the art. And other substances known in the art. Such additional ingredients include buffers, surfactants, solubilizers, preservatives, emulsifiers, isotonizers, stabilizers, pH adjusters, sweeteners, colorants, and the like. Can do.

The oral care composition of the present invention contains an antimicrobial effective amount of an antimicrobial compound having the structure of formula (I) in combination with one or more antimicrobially effective essential oils as an active ingredient. Such antimicrobially effective essential oils include thymol, menthol, methyl salicylate (winter green oil), eucalyptol, carvacrol, camphor, anethole, carvone, eugenol, isoeugenol, limonene, osimen, n -Decyl alcohol, citronel, a-salpineol, methyl acetate, citronellyl acetate, methyl eugenol, cineol, linalool, ethyl linalaol, safola vanillin, spearmint oil, mint oil , Lemon oil, orange oil, sage oil, rosemary oil, cinnamon oil, pimento oil, laurel oil, laurel oil, gerianol (ge ianol), berbenone, anise oil, bay oil, benzaldehyde, bergamot oil, bitter tonsil, chlorothymol, cinnamon aldehyde, citronella oil, clove oil, coal tar, eucalyptus oil, guaiacol, lavender oil, mustard oil, phenol, phenyl salicylate, Pine oil, pine leaf oil, sassafras oil, spike lavender oil, strax, thyme oil, trout balsam, turpentine oil, clove oil and the like can be included. The composition generally takes the form of a solution containing these components in water.

  Mixtures of antimicrobial compounds of formula (I) and antimicrobial essential oils, preferably those selected from the group consisting of thymol, menthol, eucalyptol, methyl salicylate, and combinations thereof, provide a synergistic antimicrobial effect.

  In the present oral care composition, the essential oil is used in an amount sufficient to provide oral care including removal or inhibition of oral microorganisms in the oral cavity. In general, the essential oil is in an amount of about 0.001% to 8.0% by weight, preferably in an amount of about 0.004% to 3.0% by weight, and more preferably by weight, based on the total weight of the composition. In an amount of about 0.007% to 2.0%; in the oral care composition of the present invention. The amount used in the oral care composition can vary depending on the form of the composition and can be readily ascertained by one skilled in the art. The compositions of the present invention generally contain thymol and / or one or more other essential oils. Preferably, the additional essential oil is eucalyptol, menthol or methyl salicylate, or mixtures thereof. Most preferably, the composition contains all of these four essential oils.

Formula 5-methyl-2- (1-methylethyl) known thymol by phenol _{((CH 3) 2 CHC 6} H 3 (CH 3) OH; isopropyl -m- cresol), is an effective antimicrobial agent , And typically from the essential oils of Thymus vulgaris Labiatae and Monarda puncta Labiatae. Thymol is a white crystalline powder with an aromatic odor and taste that is soluble in organic solvents but only slightly soluble in deionized water. Thymol is in an amount of about 0.001% to 2.0% by weight based on the total weight of the composition; preferably in an amount of about 0.01% to 0.6% by weight; more preferably by weight. In an amount of about 0.02% to 0.5%; can be in the oral care composition of the present invention.

Menthol (CH ₃ C ₆ H ₉ (C ₃ H ₇ ) OH; hexyl hydroxythymol) also has antiseptic properties and gives a cold, stinging sensation. Menthol is primarily isolated from Mentha arvensis oil. In its commercial form, menthol is available as L-menthol crystals obtained from the process involving cooling of this oil. Fractional distillation of mint oil, which usually contains about 40% to about 65% menthol, is another important source of menthol. Synthetic L-menthol is also available. Menthol is in an amount of about 0.001% to 2.0% by weight based on the total weight of the composition; preferably in an amount of about 0.01% to 0.7% by weight; more preferably by weight. In an amount of about 0.01% to 0.6%; can be in the oral care composition of the present invention.

Eucalyptol (C ₁₀ H ₁₈ O; cineol), another essential oil with antiseptic properties, is derived from the eucalyptus tree. Eucalyptol is a terpene ether that provides a cold, spicy flavor and antiseptic activity. Due to its camphor-like scent and cooling flavor, this essential oil is often combined with other essential oils such as menthol in a sugar preparation to add a medicinal effect. The combination of menthol and eucalyptol is widely used. A particularly preferred use of the menthol-eucalyptol combination is in accordance with the invention a dentifrice such as a toothpaste or toothpaste gel. Eucalyptol in an amount of about 0.001% to 2.0% by weight based on the total weight of the composition; preferably in an amount of 0.005% to 0.5% by weight; more preferably by weight In an amount of about 0.007% to 0.4%; in the oral care composition of the present invention.

Methyl salicylate (C ₆ H ₄ OHCOOCH ₃ ), also known as winter green oil, is a major component in many essential oils, and is about the same as that of oils from winter green and sweet birch (Betula lenta). Make up 99%. Methyl salicylate with a unique refreshing fragrance is widely used in gargles, chewing gums and other oral and pharmaceutical formulations. In addition to its antibacterial function, methyl salicylate can simultaneously impart flavoring and sensory stimulating flavor tendencies to the oral care composition. Methyl salicylate is in an amount of about 0.001% to 2.0% by weight based on the total weight of the composition; preferably in an amount of about 0.004% to 0.6% by weight; more preferably by weight In an amount of about 0.01% to 0.6%; in the oral care composition of the present invention.

  The oral care composition of the present invention may contain the following percentage essential oils by weight based on the total weight of the oral care composition: (a) about 0.001% to 2.0% thymol by weight (B) about 0.001% to 2.0% menthol by weight; (c) about 0.001% to 2.0% eucalyptol by weight; and (d) about 0.001% by weight. To 2.0% methyl salicylate.

  In a preferred embodiment of the oral care composition of the present invention, the oral care composition can contain the following percentage essential oils by weight based on the total weight of the oral care composition: (a) about by weight 0.01% to 0.6% thymol; (b) about 0.01% to 0.7% menthol by weight; (c) about 0.005% to 0.5% eucalyptol by weight; And (d) about 0.004% to 0.6% methyl salicylate by weight.

  In a more preferred embodiment of the oral care composition of the present invention, the oral care composition may contain the following percentage of essential oils by weight based on the total weight of the oral care composition: (a) by weight About 0.02% to 0.5% thymol; (b) about 0.01% to 0.6% menthol by weight; (c) about 0.007% to 0.4% eucalyptol by weight. And (d) about 0.01% to 0.6% methyl salicylate by weight.

  The oral care compositions of the present invention containing a tropolone compound of formula (I) and thymol and / or at least one other essential oil provide effective antimicrobial activity. The oral care composition can further include other antimicrobial agents if desired. Typical antibacterial agents include chlorhexidine, chitosan, triclosan, cetylpyridinium chloride, domifene bromide and the like. The amount of such antimicrobial agent used in the compositions of the present invention can be readily determined by one skilled in the art. The carrier for the oral care compositions of the present invention, and in particular for essential oil-containing compositions, is an aqueous medium. This aqueous medium can be a water-alcohol mixture, generally a water-ethanol or water-1-propanol mixture. The ethanol content level is about 0.01% to 70% by weight based on the total weight of the composition to solubilize and deliver the antimicrobial agent and to provide a clear, aesthetically attractive liquid medium. Can be. The preferred amount of ethanol for enhancing sensory irritation of the oral care composition, in particular the gargle composition, is about 0.1% to 30% by weight, although lower amounts can be used if desired. More preferably, it can range from about 20% to 30% by weight. Alternatively, the aqueous medium is water.

  This oral care composition is, for example, gargle or rinse, toothpaste, toothpaste, toothpaste, threadpick, liquid, gel, chewing gum, liquid-filled gum, mint, lozenge, oral film formation It can be selected from the group consisting of dentifrice, mouth consumable film and the like.

  The oral care composition of the present invention comprises an appropriate amount of a pharmaceutically acceptable oral carrier to accommodate other ingredients of the formulation. The term “pharmaceutically acceptable oral carrier” is an excipient that can be mixed with an active ingredient for delivery to the intended target in the oral cavity and will not cause harm to warm-blooded animals, including humans. Refers to the form. The oral carrier further includes substantially preventing or treating oral disease or condition in warm-blooded animals, including humans, according to the stability of the composition and / or the compositions and methods of the invention. Ingredients of the composition that can be mixed without interaction that would reduce efficacy for oral care are included.

  The pharmaceutically acceptable oral carrier of the oral care composition can include one or more compatible solid or liquid filler diluents or encapsulating materials suitable for oral administration. The carrier or additive of the present invention can be in any form suitable for the mode of delivery, such as solution, colloidal dispersion, emulsion, suspension, rinse, gel, foam, powder, solid, etc. Ordinary and common ingredients for toothpaste (including gels and gels for subgingival applications), mouthwashes and rinses, mouth sprays, chewing gum, mouth-consumable films and lozenges (including breath mint) Can be included. Suitable carriers for the production of the compositions of the present invention are well known in the art. Their selection will depend on secondary requirements such as cost of taste and storage stability.

  Carrier types that can be included in the oral compositions of the present invention include abrasives, fluoride ions, thickeners, humectants, flavoring and sweetening agents, anticalculus agents, alkali metal bicarbonates, Surfactants, including nonionic and amphoteric surfactants and anionic surfactants, and miscellaneous carriers such as water, titanium dioxide, anti-inflammatory agents, and the like.

  Preferred compositions of the present invention are gargles, rinses and mouth sprays. Such gargle, rinse and mouth spray ingredients typically include water present in an amount of about 45% to 95% by weight, up to 70% ethanol, up to 50% humectant, about 0.01% to 7% surfactant, about 0.04% to 2% flavoring agent, about 0.1% to 3% sweetener and about 0.001% to 0.5% colorant. One or more of the above are included. Such gargles, rinses and mouth sprays are also among about 0.05% to 0.3% of caries preventives (eg, fluoride ions) and about 0.1% to 3% of anticalculus agents. One or more can also be included.

  Another preferred composition of the invention is a dentifrice solution. The components of such toothpaste solutions generally include about 90% to 99% water by weight, based on the total weight of the oral care composition, and about 0.01% to 0.5% preservative, 5% % Thickener, about 0.1% to 3% flavoring agent and up to 5% surfactant or more.

  Other preferred compositions of the invention are mouth consumable films or thin strips. Mouth-consumable films typically include thin film excipients based on rapidly dissolving non-self-adhesive polymers. Such compositions are typically administered to the oral cavity where they dissolve rapidly as soon as they come into contact with saliva to deliver the active ingredient rapidly. Morris Plains, PFIZER, Inc. LISTERINE® POCKETPAKS ™ brand oral care strip products manufactured by the United States of America, New Jersey, are probably therapeutic agents, particularly in the form of LISTERINE® essential oils. It is an example of the most successful edible film composition effective for delivering an antimicrobial agent to the oral cavity. The components of such compositions generally include, but are not limited to, water soluble film forming polymers, including but not limited to water, up to 75% water, up to 25% water, about 0.01%. A flavoring agent in the amount of 10% to 10% is included, up to 5% of the surfactant, and optionally an amount of about 0.01% to 5% of the copper salt.

  Other preferred compositions of the present invention are in the form of dentifrices such as toothpastes, toothpaste gels and toothpastes. The components of such toothpastes and toothpaste gels are generally about 10% to 50% dental abrasive, generally about 0.5% to 10% anionic, nonionic or zwitterionic detergent by weight. About 0.1% to 5% thickener, about 10% to 55% humectant, about 0.04% to 2% flavoring agent, about 0.1% to 3%. % Sweetener, 0.01% to 0.5% colorant, and about 2% to 45% water. Such toothpastes or toothpaste gels also include one or more of about 0.05% to 0.3% of caries preventives (eg, fluoride ions) and about 0.1% to 13% of anticalculus agents. The above can also be included. The liquid and solid are proportioned to form a creamy or gelled mass that can be extruded from a pressurized container or collapsible tube. Toothpaste, of course, contains substantially all non-liquid ingredients.

  Other preferred compositions of the invention are in the form known as microcaps or more commonly gel beads, which are generally flavoring agents in amounts of about 0.1% to 10% by weight, It comprises a lipophilic filler in an amount of about 1% to 60%, an emulsifier in an amount of about 0.1% to 5% and a sweetener in an amount of about 0.01% to 3%.

  The chewing gum composition is typically one of about 50% to 99% by weight gum base, about 0.4% to 2% flavoring and about 0.01% to 5% sweetener by weight. Or more.

  The term “lozenge” as used herein includes: fast-dissolving solid forms (cakes, cachets, thin films, and tablets), including: breath mint, troches, pastels, microcapsules, and lyophilized forms Includes fast-dissolving solid forms including compressed tablets. The term “fast-dissolving solid form” as used herein refers to a solid dosage form that is less than about 60 seconds, preferably less than about 15 seconds, more preferably about 15 seconds after placing the solid dosage form in the oral cavity. It means to dissolve in less than 5 seconds. Lozenges include discoidal solids containing therapeutic agents in a flavored base. The base can be a hard sugar candy, glycerin gelatin, or a combination of sugar and enough glue to give it shape. Lozenge compositions (compressed tablet form) typically include one or more fillers (compressible sugar), flavoring agents and lubricants.

Surfactants (surfactants) can be used in the compositions of the present invention. These help to disperse the ingredients including the active agent and flavoring oil throughout the solution as well as disperse the formulation throughout the oral cavity and provide a clear and uniform appearance that appeals to the composition more aesthetically. It is an organic substance that makes it possible to give. Preferably, the surfactant used in the compositions of the present invention is a nonionic surfactant or an anionic surfactant used in an amount sufficient to help solubilize the active ingredient. . By sufficient amount, it is meant that the surfactant is present in an amount that effectively aids the solubilization and delivery system rate of the tropolone compound and essential oil.

  Additional ingredients can be added as known by those skilled in the art. For example, acidic preservatives such as sorbic acid or benzoic acid can be added to lower the pH level. A buffer system may be necessary to control the pH of the composition to an optimum level. This is generally achieved by the addition of a weak acid and its salt or a weak base and its salt. Useful systems include sodium benzoate and benzoic acid in an amount of about 0.01% to 4.0% by weight, and sodium citrate and citric acid in an amount of about 0.001% to 0.2% by weight. I found out. Preferably, the buffering agent is added in an amount that maintains the pH at a level of about 3.5 to 9.0, more preferably about 4.0 to 7.0.

  In another aspect of the present invention, there is provided a method for treating or preventing oral diseases or conditions in warm-blooded animals, including humans, by applying an oral care effective amount of the oral care composition of the present invention to the oral cavity. Is done. The oral care effective amount of the oral care composition of the present invention is preferably the oral mucosal tissue, oral cavity in one or more conventional manners for the treatment or prevention of oral diseases or conditions described above. Applied to gingival tissue and / or tooth surface. For example, sufficient time, preferably about 10 seconds to 10 minutes, more preferably about 30 seconds to 60 seconds, the gingiva or mucosal tissue is rinsed with a solution containing the composition of the present invention (eg, mouthwash, rinse) If a dentifrice (eg toothpaste, toothpaste gel or toothpaste) is used, the gingiva / mucosal tissue or teeth can be bathed in the liquid and / or foam generated by brushing the teeth Can;

  The methods of the present invention generally further include a major portion of the composition after such contact. The frequency of such contact is preferably about once per week to about 4 times per day, more preferably about 3 to 3 times per week, more preferably about 1 to 1 per day. Twice a day. The duration of such treatment typically ranges from about 1 day to life. For a particular oral disease or condition, the duration of treatment depends on the severity of the oral disease or condition being treated, the particular delivery form used and the patient's response to treatment. As with the treatment of periodontal disease, if delivery to the periodontal pocket is desired, the mouthwash or rinse can be delivered to the periodontal pocket using, for example, a syringe or water infusion device. After cleaning, the patient can also swirl the mouth in the mouth to cover the back of the tongue and other periodontal / mucosal surfaces. In addition to toothpaste, non-abrasive gels, toothpaste gels, etc. can be brushed on the surface of the tongue and other gingival and mucosal tissues of the oral cavity.

  Other non-limiting examples include chewing gum containing a composition of the present invention that chews or sucks a breath tablet or lozenge. Preferred methods of applying the oral care composition of the present invention to gingiva / mucosal tissue and / or teeth include rinsing with a gargle or rinse solution and brushing with a dentifrice. Other methods of applying the compositions of the present invention to gingival / mucosal tissue and tooth surfaces will be apparent to those skilled in the art.

The substituted tropolone compounds of formula (I) of the present invention for use in the present invention can be prepared from readily available starting materials using the following general methods and procedures. It is understood that given typical or preferred manufacturing conditions (ie reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other manufacturing conditions can be used unless otherwise stated. It will be. Optimum reaction conditions may vary with the particular reactants or solvent used, however, such reaction conditions can be determined by one skilled in the art by routine optimization procedures.

As shown in Scheme 1, the compound of formula (I) is prepared by reacting dichloroacetyl chloride with an R ₂ -substituted cyclopentadiene compound in the presence of a base such as triethylamine to form a cycloadduct of formula (III) ( (cycloload) can be manufactured. The cycloaddition of formula (III) is then treated with an acid such as acetic acid and a base such as triethylamine to give the final desired product, the 4-alkyltropolone compound. When R ₂ is isopropyl, the resulting compound is the hinokitiol used as a starting material in Scheme 2.

The compound of formula (I) is further converted to a carbonyl compound such as formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde and the like (R ₆ ═O, where hinokitiol is present in the presence of a base such as potassium hydroxide, as shown in Scheme 2. And R ₆ is an alkyl group), and then an acid such as hydrochloric acid can be added to produce a 4-isopropyl-7-hydroxyalkyltropolone compound. The 4-isopropyl-7-hydroxyalkyl tropolone compound is then treated with a chlorinating agent such as SOCl ₂ in the presence of a base such as pyridine to give the 4-isopropyl-7-chloroalkyl tropolone compound. This 4-isopropyl-7-chloroalkyltropolone compound is reacted with an alcohol such as methanol, ethanol, propanol or the like (R ₇ OH; where R ₇ is an alkyl group) under heating to give the corresponding 4- An isopropyl-7-alkoxyalkyl tropolone compound is obtained.

The compound of formula (I) can be further prepared as shown in Scheme 3 by reacting 4-isopropyl-7-hydroxymethyl tropolone with an oxidizing agent such as MnO ₂ to produce 4-isopropyl-7-formyltropolone. Can do. The starting compound, 4-isopropyl-7-hydroxymethyl tropolone, can be prepared by reacting hinokitiol with formaldehyde in the presence of a base such as potassium hydroxide and then treating the reaction with an acid such as hydrochloric acid. . 4-Isopropyl-7-formyltropolone is reacted with an alkylmagnesium bromide compound (R ₈ MgBr; where R ₈ is an alkyl group) and the reaction is quenched with an acid such as hydrochloric acid to give 4-isopropyl A -7-hydroxyalkyltropolone compound is obtained. The 4-isopropyl-7-hydroxyalkyl-tropolone compound is treated with a reducing agent such as phosphorus, preferably red phosphorus in the presence of an acid such as acetic acid, and then an oxidizing agent such as iodine is added to the reaction, The final product 4-isopropyl-7-alkyltropolone compound is obtained.

  The following examples are provided only to illustrate the present invention and should not be construed as limitations thereon. For example, optimal reaction conditions will vary with the particular reactants or solvent used, however, such reaction conditions can be determined by one skilled in the art by routine optimization procedures.

〔Example〕
Example 1
A gargle composition containing a compound of formula (I) and an essential oil was prepared with the following ingredients shown in Table 1 below.

  This composition was prepared by adding essential oils (thymol, menthol, methyl salicylate and eucalyptol) and compounds of formula (I), flavoring oil, poloxamer 407 and benzoic acid to the alcohol followed by 250 ml of water. . Sorbitol, saccharin, and dye were added to the mixture thus obtained, followed by water to prepare a 1000 ml sample of the gargle composition.

Example 2

As illustrated in Scheme A, a solution containing 25 mL of triethylamine and 100 mL of hexane was prepared from methylcyclopentadiene (prepared from decomposing methylcyclopentadiene dimer) 48 in 200 mL of hexane mixture at 0 ° C. Add dropwise to a solution containing 0.5 g and 22.5 g of dichloroacetyl chloride. The mixture was stirred for about 1 hour and then poured into 150 mL of water at about 0 ° C. The layers were separated and the aqueous phase was extracted with two 75 mL portions of hexane. The combined organic layers were washed twice with water, then dried over Na ₂ SO ₄ and concentrated to give an oil. Fractional distillation was performed under vacuum to give a cycloadduct of formula (III), which was dissolved in 80 mL of acetone. The resulting solution was then added to a solution containing 28.5 mL acetic acid, 82.5 mL triethylamine, 36 mL water and 100 mL acetone. The mixture was refluxed for about 4 hours under nitrogen. Acetone was removed from the mixture under reduced pressure. An additional 100 mL of water was added and the solution was extracted 3 times with 100 mL each of ether. The combined organic extracts were washed with water and dried over MgSO ₄ . The final product, 4-methyltropolone, was recrystallized from hexane to give a white solid.

Example 3
Synthesis of 4-isopropyl-7-methoxymethyl tropolone

As illustrated in Scheme B, a solution containing 10 g hinokitiol and 18.8 mL 25% aqueous KOH was heated to 60 ° C. under argon. Formaldehyde was added in 1 mL every 30 minutes until a total of 10 mL was added. The reaction mixture was concentrated until a yellow paste was obtained, and 300 mL of acetone was added. The resulting yellow solid was collected and washed with acetone. This solid was suspended in 250 mL of dichloromethane and 50 mL of 2.0 M HCl was added. The aqueous layer was washed with dichloromethane and the combined organic layers were washed with water and then dried over Na ₂ SO ₄ . Removal of the solvent in vacuo left an oil that solidified upon trituration with petroleum ether. An ice-cold solution of 4.0 g 4-isopropyl-7-hydroxymethyl tropolone and 1.8 mL pyridine in 100 mL diethyl ether was stirred vigorously for 2 hours while adding a solution of SOCl ₂ (2.5 mL) in 80 mL ether. . The resulting mixture was concentrated to give a solid. Boiling petroleum ether was added to the solid. The resulting mixture was filtered and the filtrate was cooled to give 4-isopropyl-7-chloromethyltropolone in the form of a solid. The solid product was then refluxed in methanol for about 2 hours under nitrogen and then concentrated to give a golden oil. 4-isopropyl-7-methoxymethyl tropolone was obtained in the form of a pale yellow solid through a stream of N ₂ gas until it solidified onto the oil.

Example 4
Synthesis of 4-isopropyl-7-hexyltropolone

As illustrated in Scheme C, 4-isopropyl-7-methoxymethyl tropolone as prepared in Example 2 was oxidized in the presence of MnO ₂ to give 0.85 g of 4-isopropyl-7-formyltropolone. It was. 4-Isopropyl-7-formyltropolone was added to ether to obtain a solution which was stirred at 0 ° C. under N ₂ . 5 mL of a 2.0M solution of pentylmagnesium bromide was added to this solution via a syringe. The mixture was stirred for about 45 minutes and then quenched with 20 mL of water. 10 mL of 0.5M HCl and 100 mL of ether were added to the mixture. The layers were separated and the organic layer was dried over Na ₂ SO ₄ . The solvent was removed and the resulting oil was triturated with petroleum ether to give 4-isopropyl-7-hydroxyhexyl tropolone in the form of a yellow oil. This oily product was mixed in 2 mL water, 1 g red phosphorus and 15 mL acetic acid. The mixture was stirred well and 1 g of I ₂ was added. The reaction mixture was refluxed for about 1 hour and then filtered. 150 mL of water was added to the filtrate. K ₂ CO ₃ was added to the mixture to give a basic pH. This mixture was extracted with petroleum ether. The organic layer was washed with Na ₂ S ₂ O _3, then washed with water, and dried over Na ₂ SO _4, was obtained 4-isopropyl-7-hexyl tropolone in the form of an oil.

  The foregoing discussion discloses and describes merely exemplary embodiments of the present invention. Those skilled in the art will recognize from this discussion and the appended claims that various changes, modifications, and variations may be made therein without departing from the spirit and scope of the present invention as defined in the claims. You will readily appreciate that you can.

Claims (15)

(A) an effective amount of at least one formula (I)

(Wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently hydrogen, hydroxy, alkyl group, hydroxyalkyl group, alkoxyalkyl group, alkylene group, alkenylene group, alkaryl group, An alkcycloalkyl group, an alkoxy group, an alkenyl group, an alkynyl group, an aryl group, a cycloalkyl group, a cycloalkenyl group, an aliphatic group optionally substituted by 1 to 3 halogen atoms, optionally 1 to 3 Selected from the group consisting of an aromatic group optionally substituted with a halogen and a carbonyl group)
And pharmaceutically acceptable salts thereof;
(B) optionally at least one essential oil; and (c) optionally a pharmaceutically acceptable oral carrier;
A composition comprising   The alkyl group has 1 to 6 carbon atoms, the hydroxyalkyl group has 1 to 6 carbon atoms, and the alkoxy and alkyl portions of the alkoxyalkyl group each have 1 to 6 carbon atoms The composition of claim 1.   The composition according to claim 1 or 2, wherein the oral effective amount of the compound of formula (I) is 0.001% to 10% by weight, based on the total weight of the composition.   At least one essential oil is thymol, menthol, methyl salicylate (winter green oil), eucalyptol, carvacrol, camphor, anethole, carvone, eugenol, isoeugenol, limonene, osimene, n-decyl alcohol, citronel, a- Salpineol, methyl acetate, citronellyl acetate, methyl eugenol, cineol, linalool, ethyl linaraol, saflora vanillin, spearmint oil, peppermint oil, lemon oil, orange oil, sage oil, rosemary oil, cinnamon oil, pimento oil, laurel oil , Eucalyptus oil, gerianol, berbenone, anise oil, bay oil, benzaldehyde, bergamot oil, bitter tonsil, chlorothymol, cinnamic aldehyde, citronella oil, clove oil, coal tar, eucalyptus oil, g Selected from the group consisting of Yacoal, Lavender Oil, Mustard Oil, Phenol, Phenyl Salicylate, Pine Oil, Pine Leaf Oil, Sassafras Oil, Spike Oil, Strax, Thyme Oil, Truval Sam, Turpentine Oil, Clove Oil and Combinations thereof The composition according to any one of claims 1 to 3.   The composition according to any one of claims 1 to 4, wherein the at least one essential oil is selected from the group consisting of thymol, eucalyptol, menthol and methyl salicylate and mixtures thereof.   6. A composition according to any one of the preceding claims, wherein the oral care effective amount of thymol is 0.001% to 2.0% by weight based on the total weight of the composition.   7. A composition according to any one of the preceding claims, wherein the oral care effective amount of eucalyptol is 0.001% to 2.0% by weight based on the total weight of the composition.   8. A composition according to any one of the preceding claims, wherein the oral care effective amount of methyl salicylate is 0.001% to 2.0% by weight based on the total weight of the composition.   9. A composition according to any preceding claim, wherein the oral care effective amount of menthol is from about 0.001% to 2.0% by weight based on the total weight of the composition.   At least one compound of formula (I) is 4-methyl-7-hydroxymethyl tropolone, 4-methyl-7-methoxymethyl tropolone, 4,7-dimethyl tropolone, 7-methyl-4-isopropyl tropolone, 7-hexyl- 4-isopropyl tropolone, 4-t-butyl tropolone, 5-t-butyl tropolone, 4-isopropyl tropolone, 4-methyl tropolone, 7-methoxymethyl-4-isopropyl tropolone, 7-hexyloxymethyl-4-isopropyl tropolone and 10. A composition according to any one of claims 1 to 9, selected from the group consisting of combinations thereof.   11. A composition according to any one of the preceding claims, wherein the effective amount of at least one essential oil is 0.001% to 8.0% by weight based on the total weight of the composition.   An effective amount of at least one essential oil is 0.064% by weight thymol, 0.092% by weight eucalyptol, 0.060% by weight methyl salicylate and 0.042% by weight, each based on the total weight of the composition. The composition according to any one of claims 1 to 11, comprising   13. The composition of any one of claims 1-12, further comprising an alcohol in an amount of about 0.01% to 70% by weight based on the total weight of the composition.   The composition according to any one of claims 1 to 13, wherein the alcohol is ethanol.   The effective amount of the compound of formula (I) is about 0.03% to 2% by weight based on the total weight of the oral care composition, and the effective amount of at least one essential oil is each based on the total weight of the composition 15. A composition according to any one of claims 1 to 14, which is 0.064% by weight thymol, 0.092% by weight eucalyptol, 0.060% by weight methyl salicylate and 0.042% by weight menthol. Composition.