| CORP. SALE | HO-C6H3(Me)-CH2-C6H4-Me |
| PATENT ASSIGNEE'S COUNTRY | USA |
| UPDATE | 12.99 |
| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 07.12.99 |
| PATENT TITLE |
Anti-inflammatory and antibacterial benzyl phenol agents and their use in oral compositions |
| PATENT ABSTRACT |
An antibacterial, anti-inflammatory compound for use in oral products, of the formulae: ##STR1## Wherein: R.sub.1 and R.sub.2 are straight chain or branched alkyl substituents or cycloalkyls with one or more alkyl substituents. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | 08.04.98 |
| PATENT REFERENCES CITED |
Offenbacher et al., J. Periodont, Res., 21, 101-112 (1986). Goodson et al., Prostaglandins, 19, 81-85 (1974). Stralfors, Archs. Oral 12, 1375-1385 (1967). Dewhirst, Prostaglandins, 20, No. 2, 209-222 (1980). Offenbacher et al., J. Periodon, Res., 19, 1-13 (1984). |
| PATENT CLAIMS |
What is claimed is: 1. An antibacterial compound having anti-inflammatory prostaglandin inhibitory properties and having the structural formula: ##STR4## Wherein: R.sub.1 and R.sub.2 are straight chain or branched alkyl substituents or cycloalkyls with one or more alkyl substituents. 2. A compound according to claim 1, which compound is 2-t-butyl-4-(4-t-butylbenzyl)-phenol. 3. An antiplaque oral composition comprising an orally acceptable vehicle and an effective antibacterial, anti-inflammatory amount of a compound of the formulae: ##STR5## Wherein: R.sub.1 and R.sub.2 are straight chain or branched alkyl substituents or cycloalkyls with one or more alkyl substituents. 4. A composition according to claim 3, wherein the compound is 2-t-butyl-4-(4-t-butylbenzyl)-phenol. 5. The composition of claim 3, wherein the compound is present in the oral composition in an amount ranging from about 0.003 to about 5% by weight. 6. The composition of claim 3, wherein an anionic polycarboxylate antibacterial enhancing agent is incorporated in the composition. 7. A composition according to claim 3, wherein the composition is in the form of a mouthrinse. 8. A composition according to claim 3, wherein the composition is in the form of a dentifrice containing a polishing agent and a vehicle of water and a humectant. 9. A method of promoting oral hygiene comprising applying to oral surfaces an effective amount of a composition as defined in claim 3. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
FIELD OF THE INVENTION This invention relates to novel antibacterial and anti-inflammatory benzylphenol compounds, which compounds find useful application when used in oral compositions to provide enhanced antiplaque, antigingivitis and anti-periodontal disease benefits. BACKGROUND OF THE INVENTION Plaque bacteria generate toxins that cause oral diseases, including gingivitis and periodontal disease. Gingivitis is the initial stage of such disease, wherein the gums become red and puffy; the gums bleed when subjected to minor abrasion, as with toothbrushing; and there is persistent bad breath. Continued plaque invasion leads to periodontal disease, affecting the periodontium, which is the investing and supporting tissue surrounding a tooth (i.e. the periodontal ligament, the gingiva, and the alveolar bone). Gingivitis and periodontitis are inflammatory disorders of the gingiva and the periodontal ligament, respectively. Gingivosis and periodontosis are more severe conditions involving degenerative disorders of the tissue. Microorganisms contribute to both the initiation and progress of periodontal disease. These microorganisms, such as streptococcus mutans, colonize the pellicle film that surrounds each tooth, forming a soft mass. The plaque at and below the gingival margin, and the hard dental calculus that results from such plaque, causes gingivitis and subsequently periodontal pockets, pathologically deepened gingival sulcus. The body's immune response within such pockets, includes the synthesis of prostaglandins (PG), important immunoregulators, related to inflammatory response and the product of two enzyme isoforms, cyclooxygenase -1 (COX- 1) and cyclooxygenase-2 (COX-2). COX-2 is induced by cytokines, mitogens and endotoxins in inflammatory cells and is responsible for the elevated production of PG and inflammation. Offenbacher et al., J. Periodont Res., 21, 101-112 (1986) and Goodson et al., Prostaglandins, 19, 81-85 (1974) showed that extremely high levels of COX-2 are present within inflamed periodontal tissue, while COX-2 was low within such tissue in remission. The COX-2 level within active periodontal pockets approximates 1 .mu.M (Offenbacher et al., J. Periodon. Res., 19, 1-13 (1984)), a level believed to induce vasodilation, bone resorption and other pro-inflammatory responses. Accordingly, an agent having both anti-bacterial and PG inhibition properties is necessary to combat the bacterial formation of plaque and the associated gingivitis; and to inhibit the activity of COX-2, to reduce PG related inflammation and bone resorption associated with periodontal disease. Since the 1860's, when Lister used phenol as a surgical antiseptic, it has been known that nearly all derivatives of phenol have some degree of bactericidal activity, when tested in tube dilution, disc agar, diffusion or similar assays. Dewhirst, in Prostaglandins, 20, No. 2, 209-222 (1980) examined sixty-three phenolic compounds for their ability to inhibit prostaglandin cyclooxygenase, as non-steroidal anti-inflammatory agents. Dewhirst reported that the most potent inhibitors possessing a two aromatic ring structure, connected by a short bridge, wherein one ring was apolar, the other ring contained a phenolic hydroxyl, ortho to the bridge, and the bridge contained a Lewis base such that the compounds could form bidentate metal chelates. Three phenolic substances have been shown to inhibit caries in hamsters without adverse weight loss. Stralfors, Archs. Oral, 12, 1375-1385 (1967). The three phenolic substances were quercetin (pentahydroxyflavone), caffeic acid (3,4-dihydroxycinnamic acid) and protocatechuic acid (3,4-dihydroxybenzoic acid). Other phenolic substances are well know and widely used antimicrobials, such as thymol (2-isopropyl-5-methylphenol), which is found in commercial mouthrinse formulations. U.S. Pat. No. 5,723,500 discloses noncationic antibacterial alkylated phenol compounds for use in oral compositions which are antibacterial and provide antiplaque efficacy. U.S. Pat. No. 3,928,624 disclosed aminoethylphenols containing halogen and alkyl substituents as anti-inflammatory agents. U.S. Pat. Nos. 4,244,956 and 4,563,526 disclosed substituted 2-(arylmethoxy)phenol compounds, as medicinal agents which inhibit the synthesis of prostaglandins, inhibit platelet aggregation and are useful as topical and systemic anti-inflammatory agents. U.S. Pat. Nos. 5,512,561 and 5,677,296 disclose carbamic acid derivatives of substituted bibenzoxazepine compounds as analgesic agents for the treatment of pain, and prostaglandin-E.sub.2 (COX-2) antagonists for the treatment of prostaglandin-E.sub.2 mediated diseases. EP Patent Application 0 528 468 A1 discloses the use of triclosan (2',4,4'-trichloro-2-hydroxy-diphenyl-ether) for the inhibition and/or reduction of periodontitis, wherein triclosan inhibits cyclooxygenase activity and also reduces microbial challenge. There is a continuing need in that art for more effective antibacterial agents compatible with anionic components in oral compositions which inhibit cyclooxygenase and PG activity; to combat plaque, gingivitis, and periodontal disease. SUMMARY OF THE INVENTION The present invention provides antibacterial, anti-inflammatory benzylphenol (AAB) compounds having the following structure, Formula I: ##STR2## Wherein: R.sub.1 and R.sub.2 are straight chain or branched alkyl substituents or cycloalkyls with one or more alkyl substituents. The term "alkyl" as used herein means a saturated hydrocarbon radical having from one to ten carbon atoms, and within which includes one to six carbon atoms, and further within which includes one, two, or three carbon atoms, which can be straight or branch chain. Representative of such radicals are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl and the like. The AAB compounds have particular application in oral compositions, comprising a therapeutically-effective amount of an AAB compound of Formula I, in combination with an orally acceptable vehicle; wherein, when such compositions are applied to oral surfaces there is provided enhanced antibacterial and anti-inflammatory benefits. The AAB compounds are also useful for application in antibacterial personal care products, such as skin creams and lotions and household surface care products, where germ killing and reduction of skin irritation are desired. DETAILED DESCRIPTION OF THE INVENTION In one aspect, the present invention provides AAB compounds comprising the structure of Formula I, as described and defined above. A preferred embodiment of this invention is 2-t-butyl-4-(4-t-butylbenzyl)-phenol, whose structure is shown below as Formula II: ##STR3## Compounds of the present invention, such as 2-t-butyl-4-(4-t-butylbenzyl)-phenol, exhibit activity as antibacterial agents and prostaglandin antagonists and as such would be useful in treating bacterial infections and PG mediated diseases. Preparation of the preferred 2-t-butyl-4-(4-t-butylbenzyl)-phenol compound is representative of that of many of the compounds of the present invention, which are by means generally known in the art The preferred 2-t-butyl-4-(4-t-butylbenzyl)-phenol compound is prepared by the Friedal-Crafts alkylation of 4-benzylphenol (4-hydroxydiphenylmethane), available from Aldrich Chemical Company, Milwaukee, Wis., 53233. The Friedal-Crafts alkylation is a typical electrophilic aromatic substitution, in which, in the presence of a Lewis acid catalyst, such as aluminum chloride (AlCl.sub.3), an alkyl halide is used to alkylate benzene to an alkylbenzene. The AAB compounds of the present invention may be incorporated with other ingredients to form oral compositions, such compositions may be a solution of ingredients, such as a mouthwash; or a semisolid, such as a toothpaste or gel, which may contain 0 to 75% of a polishing agent; or a chewing gum; or a solid lozenge; or the like. In the use wherein the oral composition is a gel or paste dentifrice, a therapeutically-effective amount of the AAB compound of Formula I, is contained within a vehicle suitable for use in the oral cavity, which contains water, humectant, surfactant and a polishing agent or abrasive. The humectant used in the preparation of a gel or paste dentifrice composition of the present invention is generally a mixture of humectants, such as glycerol, sorbitol and polyethylene glycol of a molecular weight in the range of 200-1,000, but other mixtures of humectants and single humectants may also be employed. The humectant content within the dentifrice is in the range of about 10 to about 30% by weight, and preferably about 10 to about 20% by weight. The water content is from about 30 to about 60% by weight, and preferably from about 40 to about 55% by weight. As incorporated in the oral compositions of the present invention, an effective bactericidal and prostaglandin inhibiting, non-toxic amount of the AAB compound is typically in a range of about 0.003 to about 5%, preferably about 0.005 to about 3%, more preferably about 0.02 to about 1% by weight. To enhance the antibacterial activity of the AAB compound, an antibacterial enhancing agent may be included in the oral composition. The use of such antibacterial enhancing agents in combination with water-insoluble noncationic antibacterial compounds is known to the art, as for example, U.S. Pat. Nos. 5,188,821 and 5,192,531. Antibacterial enhancing agents preferred for use in the practice of the present invention include a natural or synthetic anionic polymeric polycarboxylate having a molecular weight of about 1,000 to about 5,000,000, preferably about 30,000 to about 500,000. Synthetic anionic polymeric polycarboxylates are generally employed in the form of their free acids or preferably partially or more preferably fully neutralized water soluble alkali metal (e.g. potassium and preferably sodium) or ammonium salts. Preferred are 1:4 to 4:1 copolymers of maleic anhydride or acid with another polymerizable ethylenically unsaturated monomer, preferably methyl vinyl either/maleic anhydride having a molecular weight (M.W.) of about 30,000 to about 1,000,000, most preferably about 30,000 to about 500,000. These copolymers are available, for example, as Gantrez.RTM., AN 139 (M.W. 500,000), AN 119 (M.W. 250,000); and preferably S-97 Pharmaceutical Grade (M.W. 700,000), from ISP Technologies, Inc., Bound Brook, N.J. 08805. Other polymeric polycarboxylates useful in the practice of the present invention include the 1:1 copolymers of maleic anhydride with ethyl acrylate, hydroxyethyl methacrylate, N-vinyl-2-pyrollidone, or ethylene, the latter being available, for example, as Monsanto EMA.RTM. No: 1103, M.W. 10,000 and Grade 61, and 1:1 copolymers of acrylic acid with methyl or hydroxyethyl methacrylate, methyl or ethyl acrylate, isobutyl methacrylate, isobutyl vinyl ether or N-vinyl-2-pyrrolidone. Additional operative useful polycarboxylate compounds include copolymers of maleic anhydride with styrene, isobutylene or ethyl vinyl either, polyacrylic, polyitaconic and polymaleic acids, and sulfonacrylic oligomers of M.W. as low as 1,000 available as Uniroyal.RTM. ND-2. Also useful in the practice of the present invention are the so-called carboxyvinyl polymers, commercially available, for example, under the trademarks Carbopol.RTM. 934, 940 and 941 from B.F. Goodrich, Cleveland, Ohio 44131, these polymers consisting of a colloidally water-soluble polymer of polyacrylic acid crosslinked with from about 0.75% to about 2.0% of polyallyl sucrose or polyallyl pentaerythritol as a cross linking agent, often with M.W.'s up to 4-5 million or more. The antibacterial enhancing agent, when employed, is incorporated in the compositions of the present invention in weight amounts of about 0.05 to about 5%, preferably about 0.1 to about 3%. Linear molecularly dehydrated polyphosphate salts can be optionally employed herein as anticalculus agents. They are well known, being generally employed in the form of their wholly or partially neutralized water soluble alkali metal (e.g. potassium or preferably sodium) or ammonium salts, and any mixtures thereof. Representative examples include sodium tripolyphosphate, monosodium triacid,-, disodium diacid-, trisodium monoacid-, and tetrasodium-pyrophosphates, the corresponding potassium salts and the like. In the present invention, they can be employed in the oral compositions in approximate weight amounts of about 0.1 to about 3%, typically about 1 to about 2.5%, more typically about 1.5 to about 2%, especially about 2%. Particularly desirable anticalculus agents are tetraalkali metal pyrophosphates such as tetrasodium and tetrapotassium pyrophosphates, and mixtures thereof. Fluoride ions may desirably also be included in the oral compositions of the present invention to provide an anticaries effect. Among these materials are inorganic fluoride salts, such as soluble alkali metal fluoride salts, for example, sodium fluoride, potassium fluoride, ammonium fluoride, sodium monofluorophosphate, and sodium hexafluorosilicate. Alkali metal and tin fluorides, such as sodium and stannous fluorides, sodium monofluorophosphate and mixtures thereof, are preferred. The amount of fluorine-providing salt is generally present in the oral composition at a concentration of about 0.0005 to about 3.0% by weight. Any suitable minimum amount of such salt may be used, but it is preferable to employ sufficient fluoride salt to release about 300 to 2,000 ppm, more preferably about 800 to about 1,500 ppm, of fluoride ion. When the oral composition is substantially semi-solid or pasty in character, such as a toothpaste or gel, the dentifrice vehicle may contain a dentally acceptable abrasive material such as sodium bicarbonate, sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, dihydrated dicalcium phosphate, anhydrous dicalcium phosphate, calcium pyrophosphate, calcium carbonate, aluminum silicate, hydrated alumina, calcined alumina, silica, and/or bentonite. The abrasive material is generally present in the paste or gel composition in weight concentrations of about 0% to about 75% by weight, preferably about 0% to about 30% by weight in a gel and about 25% to about 60% by weight in a paste. Toothpastes as well as gels typically contain a natural or synthetic thickener in proportions of about 0.1 to about 10% by weight, preferably about 0.5 to about 5% by weight. Suitable thickeners include Irish moss, iota-carrageenan, kappa-carrageenan, gum tragacanth, starch, polyvinylpyrrolidone, hydroxyethyl propyl cellulose, hydroxybutyl methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose and sodium carboxymethyl cellulose. In the aspect of the present invention wherein the oral composition is substantially liquid in character such as a mouthwash or rinse, the vehicle is typically a water-alcohol mixture. Generally, the weight ratio of water to alcohol is in the range of from about 3:1 to 10:1 and preferably about 4:1 to about 6:1. The alcohol is a non-toxic alcohol such as ethanol or isopropanol. A humectant such as glycerine, sorbitol or an alkylene glycol such as polyethylene glycol or preferably propylene glycol may be present in amount of about 10-30% by weight. Mouthrinses typically contain about 50-85% of water, about 0 to 20% by weight of a non-toxic alcohol and about 10-40% by weight of the humectant. Surfactants are used in the compositions of the present invention to achieve increased prophylactic action and assist in achieving thorough and complete dispersion of the AAB compound throughout the oral cavity. The surfactant is preferably anionic, suitable examples which include water-soluble salts of higher fatty acid monoglyceride monosulfates, such as the sodium salt of the monosulfated monoglyceride of hydrogenated coconut oil fatty acids, higher alkyl sulfates such as sodium lauryl sulfate, alkyl aryl sulfonates such as sodium dodecyl benzene sulfonate, higher alkyl sulfoacetates, higher fatty acid esters of 1,2- dihydroxy propane sulfonate, and the substantially saturated higher aliphatic acyl amides of lower aliphatic amino carboxylic acid compounds, such as those having 12 to 16 carbons in the fatty acid, alkyl or acyl radicals and alkoyl taurines, and the like. Examples of the last mentioned amides and taurates are N-lauroyl sarcosine, and the sodium, potassium and ethanolamine salts of N-lauroyl, N-myristoyl, or N-palmitoyl sarcosine which should be substantially free from soap or similar higher fatty acid material as well as N-methyl-N-cocoyl (or oleoyl or palmitoyl) taurines. Any suitable flavoring or sweetening material may also be employed. Examples of suitable flavoring constituents are flavoring oils, e.g. oil of spearmint, peppermint, wintergreen, sassafras, clove, sage, eucalyptus, cinnamon, lemon, and orange, and methyl salicylate. Suitable sweetening agents include sucrose, lactose, maltose, xylitol, sodium cyclamate, perillartine, aspartyl phenyl alanine methyl ester, saccharine and the like. Suitably, flavor and sweetening agents may each or together comprise from about 0.1% to 5% or more of the preparation. Agents used to diminish teeth sensitivity such as potassium nitrate and potassium citrate can also be included in the oral compositions of the present invention at concentrations of about 0.1 about 10% by weight. Various other materials may be incorporated in the oral compositions of this invention including whitening agents such as urea peroxide, hydrogen peroxide, preservatives, such as sodium benzoate, vitamins and chlorophyll compounds. These adjuvants, when present, are incorporated in the compositions in amounts which do not substantially adversely affect the properties and characteristics desired. The oral compositions of the present invention may be prepared by suitably mixing the ingredients. For instance, in the preparation of a mouthrinse, the AAB compound is dispersed in a mixture of ingredients, e.g. alcohol, humectants, surfactants, and salts such as sodium fluoride and flavor are then added and mixed. The ingredients are then mixed under vacuum for about 15-30 minutes. The resulting rinse product is then packaged. Dentifrices are prepared similarly, additional thickener and polishing agents being included in the last or penultimate step. The AAB compounds of this invention can be incorporated in lozenges, or in chewing gum or other products, e.g. by stirring into a warm gum base or coating the outer surface of a gum base, illustrative of which may be mentioned jelutone, rubber latex and vinylite resins desirably with conventional plasticizers or softeners, sugar or other sweeteners or carbohydrates such as glucose, sorbitol and the like. The vehicle or carrier in a tablet or lozenge is a non-cariogenic solid water-soluble polyhydric alcohol (polyol) such as mannitol, xylitol, sorbitol, malitol, a hydrogenated starch hydrolysate hydrogenated glucose, hydrogenated disaccharides or hydrogenated polysaccharides, in an amount of about 90 to 98% by weight of the total composition. Salts such as sodium bicarbonate, sodium chloride, potassium bicarbonate or potassium chloride may totally or partially replace the polyol carrier. Tableting lubricants, in minor amounts of about 0.1 to 5% by weight, may be incorporated into the tablet or lozenge formulation to facilitate the preparation of both the tablets and lozenges. Suitable lubricants include vegetable oils such as coconut oil, magnesium stearate, and aluminum stearate. Lozenge formulations contain about 2% gum as a barrier agent to provide a shiny surface as opposed to a tablet which has a smooth finish. Suitable non-cariogenic gums include kappa carrageenan, carboxymethyl cellulose, and hydroxyethyl cellulose. |
| PATENT EXAMPLES | This data is not available for free |
| PATENT PHOTOCOPY | Available on request |
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