• 专利附录
  • 专利说明
  • 权利要求
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    • 专利摘要:
    compounds described by formula i are provided: (i) wherein: r1 is a saturated or unsaturated, linear or branched aliphatic group having from 5 to 22 carbon atoms; r2 is selected from the group consisting of the functional groups: -nh2; and salts thereof; n is from 0 to 4; and R3 is a saturated or unsaturated, linear or branched aliphatic group having from 1 to 6 carbon atoms. Also provided are compositions comprising, and methods of using, compounds of the present invention.
    公开号:BR112017009601B1
    申请号:R112017009601-3
    申请日:2015-11-11
    公开日:2021-08-31
    发明作者:Robert J. Gambogi；Anthony R. Geonnotti Iii；Michael C. Giano；Latrisha Petersen
    申请人:Johnson & Johnson Consumer Inc；
    IPC主号:
    专利说明:

    REFERENCE REFERENCE TO RELATED REQUEST
    [0001] This application claims the benefit of provisional application of U.S. serial number 62/078,187, filed November 11, 2014. BACKGROUND
    [0002] A variety of amino acid derivatives are known in the art for a variety of uses. For example, US Patent No. 5,874,068, WO2003/013454 and US2010/0330136 disclose the use of L-arginine ethyl ester ("LAE"), and certain related compounds, for use in oral compositions. In addition, LAE is currently used in hydroalcoholic mouthwashes to prevent bacterial adhesion. However, applicants have recognized that LAE tends not to have sufficient stability to be useful in low-alcohol or non-alcoholic mouthwashes.
    [0003] Furthermore, other documents such as WO2008/137758A2 and WO2000/011022 disclose broad classes of compounds, which may include certain amino acid derivatives, for uses such as for drug application or anti-tumor end benefits, respectively. BRIEF DESCRIPTION OF THE DRAWINGS
    [0004] Figure 1 is a graph of high performance liquid chromatography (HPLC) and mass spectrometry graph of [amino({[4-dodecanamido-4-(ethyl carbamoyl)butyl]amino})methylidene]azanium .
    [0005] Figure 2 is a drawing of the chemical structure and mass spectrometry graph of [amino({[4-dodecanamido-4-(ethyl carbamoyl)butyl]amino})methylidene]azanium.
    [0006] Figure 3 is a 1H-NMR (nuclear magnetic resonance) graph of [amino({[4-dodecanamide-4-(ethyl carbamoyl)butyl]amino})methylidene]azanium. DESCRIPTION OF THE INVENTION
    [0007] The present invention relates to new amino acid derivatives developed by the applicants which are described by Formula I:
    wherein: R1 is a saturated or unsaturated, linear or branched aliphatic group having from 5 to 22 carbon atoms; R2 is selected from the group consisting of corresponding salt and free base forms of the functional groups:
    said salt versions having an X- anion, preferably selected from the group consisting of acetate, benzoate, besylate, bromide, chloride, chlorotheophyllinate, citrate, ethandisulfonate, fumarate, gluconate, hippurate, iodide, fluoride, lactate, lauryl sulfate, malate, lactate, mesylate, methylsulfate, napsylate, nitrate, octadecanoate, oxalate, pamoate, phosphate, polygalacturonate, succinate, sulfate, tartrate, and tosylate; n is 0 to 4; and R3 is a linear or branched, saturated or unsaturated aliphatic group having from 1 to 6 carbon atoms.
    The compositions of Formula I may have any suitable saturated or unsaturated, linear or branched aliphatic group having from 5 to 22 carbons for R1. Examples of suitable saturated or unsaturated aliphatic groups, linear or branched having from 5 to 22 carbons include C5 to C22 linear or branched alkyl groups such as pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, up to docosanyl, and the like; as well as C5 to C22 linear or branched alkylene groups such as myristolyl to docasanhexail, and the like.
    [0009] In certain embodiments, R1 is a linear or branched alkyl group having a carbon chain of 5 to 22 carbon atoms, including, for example, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl through docasonyl. In certain other embodiments, R1 is a linear or branched alkyl group having a carbon chain of 7 to 18 carbon atoms, including, for example, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl and octadecyl. In still other embodiments, R1 is a linear or branched alkyl group having a carbon chain of 9 to 14 carbon atoms, including, for example, decyl, undecyl, dodecyl through tetradecyl. In certain embodiments, R1 is an undecyl group. In certain embodiments, R1 is a heptyl group. In certain embodiments, R1 is a heptadecyl group.
    [0010] In certain embodiments, R1 is a linear or branched alkenyl group having a carbon chain of 5 to 22 carbon atoms, including, for example, 9-hexadecenyl, 9-octadecenyl, 11-decenyl, 9, 12- octadecandienyl, 9,12,15-octadecatrienyl, 6,9,12-octadecatrienyl, 9-eicosenyl, 5,8,11,14-eicosatetraenyl, 13-docosenyl and 4,7,10,13,16,19-docosa- heaenyl. In certain other embodiments, R1 is a linear or branched alkenyl group having a carbon chain of 16 to 20 carbon atoms, including, for example, 9-hexadecenyl, 9-octadecenyl, 11-decenyl, 9, 12-octadecandienyl, 9, 12,15-octadecatrienyl, and 6,9,12-octadecatrienyl.
    [0011] In certain embodiments, R1 is a branched alkyl group having a carbon chain of 5 to 22 carbon atoms, including, for example, 2-decylateddecanyl, 2-nonyltridecanyl, 2-octyltetradecanyl, 2-heptylpentadecanyl, 2-hexyl- hexadecanyl, 2-pentylheptadecanyl, 21-methylicosanyl, 18-ethylicosanyl, 16-propylnonadecyl, and 14-butyloctadecyl.
    [0012] The compositions of Formula I may comprise an R2 group which is an amine group in its free base form (-NH2) or a salt thereof, or a guanidinyl functional group in its free base form (-NH( CNH)NH2) or a salt thereof. Examples of suitable amine salts and guanidinyl salts include salts of such groups having an anion (X -) selected from the group consisting of acetate, benzoate, besylate, bromide, chloride, chlorotheophylinate, citrate, ethandisulfonate, fumarate, gluconate, hippurate, iodide, fluoride, lactate, lauryl sulfate, malate, laeate, mesylate, methylsulfate, napsylate, nitrate, octadecanoate, oxalate, pamoate, phosphate, polygalacturonate, succinate, sulfate, tartrate and tosylate. In certain embodiments, the composition of the present invention has an R2 group which is an amine group in its free base form (-NH2). In certain other embodiments, the composition of the present invention has an R2 group which is a guanidinyl group in its free base form (-NH(CNH)NH2). In certain embodiments, the composition of the present invention has an R2 group which is an amine salt having an anion selected from the group consisting of acetate, benzoate, besylate, bromide, chloride, chlorotheophyllinate, citrate, ethandisulphonate, fumarate, gluconate, hippurate, iodide, fluoride, lactate, lauryl sulfate, malate, laeate, mesylate, methylsulfate, napsylate, nitrate, octadecanoate, oxalate, pamoate, phosphate, polygalacturonate, succinate, sulfate, tartrate, and tosylate. In certain other embodiments, the R2 amine salt has an anion selected from the group consisting of acetate, benzoate, bromide, chloride, citrate, fumarate, gluconate, iodide, fluoride, lactate, malate, nitrate, oxalate, phosphate, sulfate , and in certain other embodiments, an anion selected from the group consisting of bromide, chloride, iodide, fluoride, oxalate and phosphate. Additionally, in certain embodiments, the composition of the present invention has an R2 group which is a guanidinyl salt having an anion selected from the group consisting of acetate, benzoate, besylate, bromide, chloride, chlorotheophylinate, citrate, ethandisulfonate, fumarate, gluconate, hippurate, iodide, fluoride, lactate, lauryl sulfate, malate, lacate, mesylate, methylsulfate, napsylate, nitrate, octadecanoate, oxalate, pamoate, phosphate, polygalacturonate, succinate, sulfate, tartrate, and tosylate. In certain other embodiments, the R2 guanidinyl salt has an anion selected from the group consisting of acetate, benzoate, bromide, chloride, citrate, fumarate, gluconate, iodide, fluoride, lactate, malate, nitrate, oxalate, phosphate, sulfate, and in certain other embodiments, an anion selected from the group consisting of bromide, chloride, iodide, fluoride, oxalate and phosphate.
    The compositions of Formula I may have any suitable saturated or unsaturated, linear or branched aliphatic group having from 1 to 6 carbons for R3. Examples of suitable saturated or unsaturated aliphatic groups, linear or branched having from 1 to 6 carbons include C1 to C6 linear or branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, neopentyl, isopentyl, hexyl, isohexyl, neohexyl; as well as linear or branched C2 to C6 alkenyl groups such as vinyl, allyl, propenyl, butenyl, pentenyl, hexenyl, and the like. In certain embodiments, R3 is a linear or branched alkyl group having a carbon chain of 1 to 4 carbon atoms, including, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl and tert-butyl. In certain other embodiments, R3 is a linear or branched alkyl group having a carbon chain of 1 to 3 carbon atoms, including, for example, methyl, ethyl, propyl and isopropyl. In some embodiments, R3 is an ethyl group.
    [0014] In certain embodiments, R3 is a linear or branched alkenyl group having a carbon chain of 2 to 6 carbon atoms, including, for example, vinyl, allyl, propenyl, butenyl, pentenyl, hexenyl, and the like, as well as mixture of them. In certain other embodiments, R3 is a linear or branched alkylene group having a carbon chain of 2 to 4 carbon atoms, including, for example, vinyl, allyl, propenyl and butenyl.
    [0015] In the compounds of Formula I, n can be from zero to four. In certain modes, n is 1 to 4, in certain modes, 2 to 4, in certain modes, 3 to 4. In certain specific modes, n is 0. In certain other modes, n is 1, in other modes , n is 2, in other modes, n is 3, and in other modes, n is 4.
    [0016] According to certain embodiments of the invention, compounds of Formula I are compounds wherein R2 is a guanidinyl functional group in its free base form (-NH(CNH)NH2) or a salt thereof; n is 3 or 4, preferably 3; R3 is an aliphatic group having a carbon chain of about 2 carbon atoms, for example an ethyl group; and R1 is an aliphatic group, linear or branched, saturated or unsaturated group, including, for example, an alkyl group, having from 9 to 16 carbon atoms, including from about 10 to about 16 carbon atoms, about 10 to about 15 carbon atoms, about 10 to about 14 carbon atoms, about 10 to about 13 carbon atoms, about 11 to about 14 carbon atoms, about 11 to about 15 carbon atoms , about 11 to about 16 carbon atoms, and about 11 and/or about 13 carbon atoms.
    [0017] In certain other embodiments, the compounds of Formula I are compounds wherein R2 is a guanidinyl functional group in its free base form (-NH(CNH)NH2) or a salt thereof; n is 3; R1 is a linear or branched, saturated or unsaturated aliphatic group, including, for example, an alkyl group, having about 11 carbon atoms; and R3 is a linear or branched, saturated or unsaturated aliphatic group, including, for example, an alkyl group, having a carbon chain length of about 1 to 11 carbon atoms, including about 2 to about 10 carbon atoms. carbon, about 2 to about 9 carbon atoms, about 2 to about 8 carbon atoms, about 3 to about 11 carbon atoms, about 3 to about 10 carbon atoms, about 3 to about 9 carbon atoms, about 3 to about 8 carbon atoms, and about 2, about 6 and/or about 8 carbon atoms.
    [0018] In certain other embodiments, the compounds of Formula I are compounds wherein R2 is a guanidinyl functional group in its free base form (-NH(CNH)NH2) or a salt thereof; n is 3; R1 is a linear or branched, saturated or unsaturated aliphatic group, including, for example, an alkyl group having about 7 carbon atoms; and R3 is a linear or branched, saturated or unsaturated aliphatic group, including, for example, an alkyl group, having a carbon chain length of about 7 to 16 carbon atoms, including about 7 to about 15 carbon atoms. carbon, about 7 to about 14 carbon atoms, about 7 to about 13 carbon atoms, about 7 to about 12 carbon atoms, about 7 to about 11 carbon atoms, and about 7 and/or about 11 carbon atoms.
    [0019] In certain other embodiments, compounds of Formula I are compounds wherein R2 is an amine group in its free base form (-NH2) or a salt thereof; and n is 1, 3 or 4. Examples of such compounds include those where n is 3; R1 is a linear or branched, saturated or unsaturated aliphatic group, including, for example, an alkyl group, having about 7 carbon atoms; and R3 is a linear or branched, saturated or unsaturated aliphatic group, including, for example, an alkyl group, having a carbon chain length of about 1 to 11 carbon atoms, including about 2 to about 10 carbon atoms. carbon, about 2 to about 9 carbon atoms, about 2 to about 8 carbon atoms, about 3 to about 11 carbon atoms, about 3 to about 10 carbon atoms, about 3 to about 9 carbon atoms, about 3 to about 8 carbon atoms, and about 8 and/or about 11 carbon atoms. Other examples include compounds where n is 3; R1 is a linear or branched, saturated or unsaturated aliphatic group, including, for example, an alkyl group, having about 11 carbon atoms; and R3 is a linear or branched, saturated or unsaturated aliphatic group, including, for example, an alkyl group, having a carbon chain length of about 1 to 11 carbon atoms, including from about 1 to about 10 carbon atoms, about 1 to about 9 carbon atoms, about 1 to about 8 carbon atoms, about 1 to about 7 carbon atoms, about 1 to about 6 carbon atoms, about 2 to about 11 carbon atoms, about 2 to about 10 carbon atoms, about 2 to about 9 carbon atoms, about 2 to about 8 carbon atoms, about 2 to about 7 atoms of carbon, about 2 to about 6 carbon atoms, and about 2 and/or about 6 carbon atoms.
    [0020] An example of a compound of Formula I of the present invention is [amino({[4-dodecanamide-4-(ethylcarbamoyl)butyl]amino})methylidene]azanium (compound 9) as shown below.

    [0021] As shown in the Formula above, compound 9 represents a compound of Formula I wherein R1 is an undecyl group, R2 is a guanidinyl group in its free base form, R3 is an ethyl group, and n is 3.
    [0022] Other examples of compounds of the present invention include, but are not limited to compounds described by the formulas:







    [0023] Any one of a variety of methods suitable for synthesizing the compounds of the present invention can be used. For example, in the specific method for synthesizing [amino({[4-dodecanamido-4-(ethyl carbamoyl)butyl]amino})methylidene]azanium is described in Example 1. As will be recognized by those skilled in the art, other similar compounds of the Formula I can be synthesized in a similar manner using the appropriate starting materials to obtain the proper R1, R2, R3 and n substitution in the molecule without undue experimentation.
    Applicants have recognized that the compounds of the present invention provide a wide variety of benefits, including, for example, in compositions for use in healthcare applications. Accordingly, in certain embodiments, the present invention is directed to healthcare compositions comprising at least one compound of Formula I. Such healthcare compositions may be in any form suitable for use as, in, or in care. personal care, cosmetics, pharmaceuticals, medical device products, and the like. In certain preferred embodiments, the compositions of the present invention are oral care compositions, including, for example, oral care compositions in the form of a solution, mouthwash, mouthwash, mouth spray, toothpaste, dental gel, subgingival gel, mousse , foam, denture care product, dentifrice, lozenge, chewable tablet, dissolvable tablet, dry powder and the like. The oral care composition may also be incorporated into dental floss, strips or dissolvable films or be integrated into or over an oral device or applicator.
    In certain embodiments, the compositions of the invention comprise at least one composition of Formula I and a carrier. Any acceptable carrier can be used in the compositions of the present invention. Preferably, the vehicle is selected from the group consisting of cosmetically acceptable and pharmaceutically acceptable vehicles. As used herein, "cosmetically acceptable" and "pharmaceutically acceptable" carriers are liquids, solids or other ingredients suitable for use as carriers in products for mammals, including humans, without causing undue toxicity, incompatibility, instability, irritation, allergic response, and similar.
    For liquid compositions, the vehicle may be any suitable aqueous or non-aqueous liquid vehicle. In certain embodiments, the liquid vehicle comprises water. For example, in many compositions, as those skilled in the art will understand, water is added up to q.s. (Quantum Sufficit, Latin for "as much as necessary") of the composition. In certain embodiments, the composition comprises from about 60% to about 99.99% water, including from about 70% to about 95% water, from about 80% to 95% water, from about 60% to about 90% water, from about 60% to about 80% water, or from about 60% to about 75% water.
    [0027] In certain modalities, alcohol may be added to the composition. Any one of a variety of alcohols represented by the Formula R4-OH, where R4 is an alkyl group having from 2 to 6 carbons, can be used in the present invention. Examples of suitable alcohols of the formula R4-OH include ethanol; n-propanol, iso-propanol; butanols; pentanols; hexonols, and combinations of two or more of them, and the like. In certain embodiments, alcohol is or comprises ethanol.
    [0028] In some embodiments, alcohol may be present in the composition in an amount of at least about 10.0% v/v of the total composition, or from about 10% to about 35% v/v of the total composition. composition, or from about 15% to about 30% v/v of the total composition, and may be from about 20% to about 25% v/v of the total composition.
    Applicants have found that the compounds of the present invention exhibit greater stability in low-alcohol or alcohol-free formulations while retaining other oral care benefits compared to compounds derived from known amino acids. Consequently, in some embodiments, the composition can comprise a reduced alcohol content. The phrase "reduced alcohol content" means an amount of an alcohol R4-OH of about 10% v/v or less, optionally about 5% v/v or less, optionally about 1% v/v or less, optionally about 0.1% v/v or less by volume of the total composition. In certain embodiments, the compositions of the present invention are free of R4-OH alcohols.
    [0030] Alternatively, the compositions of the present invention may be formulated in the form of a dissolvable tablet, dry powder, chewing gum, film, semi-solid, solid or liquid concentrated form. In such embodiments, for example, water is added to qs as needed in the case of dissolvable tablet, liquid or powder concentrate formulations, or water can be removed using conventional evaporation procedures known in the art to produce a composition. in the form of a dry powder. Evaporated or freeze-dried forms are advantageous for storage and transport.
    Any suitable amounts of one or more compounds of Formula I may be used in the compositions of the present invention. In certain embodiments, the compositions comprise a total amount of compounds of Formula I (whether the composition comprises only one compound of Formula I or a combination of two or more thereof) of from about 0.0001% to about 50%, by weight, of the active/solid amount of total compounds of Formula I, based on the total weight of the composition. In certain embodiments, the percentage of total compound(s) of Formula I is from about 0.001% to about 10%, or from about 0.01% to about 1%, or from about 0. 05% to about 0.5% by weight of the active/solid amount of total compounds of Formula I based on the total weight of the composition.
    In certain embodiments, as will be recognized by those skilled in the art, compounds made in accordance with the present invention may be purified and/or may comprise a mixture of two or more compounds of Formula I. In certain embodiments, compositions of The present invention comprises a combination of at least two compounds of Formula I. In certain embodiments, compositions of the present invention comprise a combination of at least three compounds of Formula I.
    [0033] The compositions of the present invention may further comprise any of a variety of optional ingredients, including, but not limited to, oily components, active ingredients, additional surfactants, humectants, solvents, flavorings, sweeteners, colorants, preservatives, oil adjusters. pH, pH buffers, and the like.
    [0034] Any of a variety of oily components can be used in the present compositions. The oily component can comprise any one or more oils, or other materials that are insoluble in water, or substantially insoluble in water, meaning that its solubility is less than about 1%, by weight, in water at 25°C or optionally , less than about 0.1%. In certain embodiments, the oily component of the present invention comprises, consists essentially of, or consists of at least one essential oil, i.e., a concentrated natural or synthetic hydrophobic material (or combination thereof) of plant origin, generally containing compounds volatiles, at least one flavoring oil, or a combination of two or more of them. Examples of suitable essential oils, flavoring oils, and their amounts are described below. In certain embodiments, the composition comprises a total amount of oil component of about 0.05%, by weight, or more, about 0.1%, by weight, or more, or about 0.2%, by weight. , or more of oily component.
    In certain embodiments, the compositions of the present invention comprise essential oils. Essential oils are volatile aromatic oils that can be synthetic or can be derived from plants by distillation, expression or extraction, and which generally carry the aroma or flavor of the plant from which they are obtained. Helpful essential oils can provide antiseptic activity. Some of these essential oils also act as flavoring agents. Useful essential oils include, but are not limited to, citra, thymol, menthol, methyl salicylate (oil of wintergreen), eucalyptol, carvacrol, camphor, anethole, carvone, eugenol, isoeugenol, limonene, osimen, n-decyl alcohol , citronel, a-salpineol, methyl acetate, citronyl acetate, methyl eugenol, cineol, linalool, ethyl linalool, safrole vanillin, mint oil, peppermint oil, oil of orange oil, lemon oil, rosemary oil, cinnamon oil, pepper oil, laurel oil, cedar leaf oil, gerianol, verbenone, anise oil, Indian laurel oil, benzaldehyde, bergamot oil, bitter almond, chlorothymol, cinnamic aldehyde , citronella oil, clove oil, coal tar, eucalyptus oil, guaiacol, tropolone derivatives such as hinokitiol, lavender oil, mustard oil, phenol, phenyl salicylate, pine oil, pine needle oil, oil of sassafras, latifolia lavender oil, storax, thyme oil, tolu balm, turpentine oil , oil of cloves, and combinations thereof.
    [0036] In certain modalities, essential oils are selected from the group consisting of thymol ((CH3)2CHC6H3(CH3)OH, also known as isopropyl-m-cresol), eucalyptol (C10H18O, also known as cineol), menthol (CH3C6H9(C3H7)OH), also known as hexahydrothymol), methyl salicylate (C6H4OHCOOCH3, also known as oil of wintergreen), isomers of each of these compounds, and combinations of two or more of them. In certain embodiments, the compositions of the present invention contain thymol. In certain embodiments, the compositions of the present invention contain menthol. In certain modalities, the composition contains all four of these essential oils.
    [0037] In certain embodiments, thymol is employed in amounts of from about 0.0001% to about 0.6%, by weight per volume, or from about 0.005% to about 0.07%, by weight per volume, of the composition. In certain embodiments, eucalyptol can be employed in amounts of from about 0.0001% to about 0.51%, by weight per volume, or from about 0.0085% to about 0.10%, by weight per volume, of the composition. In certain embodiments, menthol is employed in amounts of from about 0.0001% to about 0.25%, weight to volume, or from about 0.0035% to about 0.05%, weight to volume. , of the composition. In certain embodiments, methyl salicylate is employed in amounts of from about 0.0001% to about 0.28%, by weight to volume, or from about 0.004% to about 0.07%, by weight to volume. , of the composition. In certain embodiments, the total amount of all such essential oils present in the disclosed compositions can be from about 0.0004% to about 1.64%, by weight to volume, or from about 0.0165% to about 0 .49%, by weight by volume, of the composition.
    In certain embodiments, fluoride-providing compounds may be present in the mouthwash compositions of the present invention. These compounds can be slightly soluble in water or can be completely soluble in water, and are characterized by their ability to release fluoride ions or fluoride-containing ions into water. Typical fluoride-providing compounds are inorganic fluoride salts such as soluble alkali metal alkaline earth metal and heavy metal salts, for example sodium fluoride, potassium fluoride, ammonium fluoride, cupric fluoride, zinc fluoride, stannic fluoride , stannous fluoride, barium fluoride, sodium hexafluorosilicate, ammonium hexafluorosilicate, sodium fluorozirconate, sodium monofluorophosphate, aluminum mono and difluorophosphate, and fluorinated sodium calcium pyrophosphate. Amine fluorides such as N'-octadecyl trimethylene diamine-N,N,N'-tris(2-ethanol)-dihydrofluoride and 9-octadecenyl amine-hydrofluoride) can also be used. In certain embodiments, the fluoride-providing compound is generally present in an amount sufficient to release up to about 5%, or from about 0.001% to about 2%, or from about 0.005% to about 1.5% of fluoride by weight of the composition.
    [0039] In certain embodiments, sensitivity reducing agents such as potassium salts of nitrate and oxalate in an amount of from about 0.1% to about 5.0%, by weight by volume, of the composition, can be incorporated in the present invention. Other potassium releasing compounds can also be used (eg KCl). High concentrations of calcium phosphates can also provide some additional relief from sensitivity. These agents are believed to work either by forming an occlusive mineral deposit on the tooth surface or by supplying potassium to nerves within the teeth to depolarize said nerves. A more detailed discussion of suitable sensitivity reducing agents can be found in US 2006/0013778, to Hodosh, and in US patent 6,416,745, to Markowitz et al., both of which are incorporated herein by reference in their entirety.
    In certain embodiments, compounds with anticalculus benefits (eg, various carboxylates, polyaspartic acid, etc.) can be incorporated into the present invention. Anionic polymeric polycarboxylates are also useful as an anticalculus agent. Such materials are well known in the art, being employed in the form of their free acids, or partially or preferably fully neutralized water-soluble alkali metal salts (eg, potassium and preferably sodium), or salts of ammonium. Copolymers of 1:4 to 4:1 by weight of maleic acid anhydride or maleic acid with another polymerizable ethylenically unsaturated monomer, preferably methyl vinyl ether (ethylene methoxy) having a molecular weight (MW) of from about 30,000 to about of 1,000,000. Such copolymers are available, for example, as Gantrez 25 AN 139 (molecular weight 500,000), AN 119 (molecular weight 250,000) and preferably S-97 Pharmaceutical Grade molecular weight 70,000) from GAF Chemicals Corporation.
    [0041] Additional anticalculus agents may be selected from the group consisting of polyphosphates (including pyrophosphates), and salts thereof, polyamino propane sulfonic acid (AMPS) and salts thereof; polyolefin sulfonates as well as salts of these substances, polyvinyl phosphates as well as salts of these substances, polyolefin phosphates as well as salts of these substances, diphosphonates as well as salts of these substances, phosphonoalkane carboxylic acid as well as salts of these substances, polyphosphonates as well as salts of these substances, polyvinyl phosphonates as well as salts of these substances, polyolefin phosphonates as well as salts of these substances, polypeptides as well as mixtures thereof: carboxy-substituted polymers, and mixtures thereof. In one embodiment, the salts are alkali metal or ammonium salts. Polyphosphates are generally used in the form of their water-soluble, fully or partially neutralized alkali metal salts such as potassium, sodium, ammonium salt and mixtures of these items. Inorganic polyphosphate salts include alkali metal tripolyphosphate or tetrapolyphosphate (eg sodium), metal dialkyl diacid (eg disodium), metal trialkyl monoacid (eg trisodium), potassium hydrogen phosphate, sodium hydrogen phosphate, alkali metal hexametaphosphate (eg sodium) and mixtures thereof. Polyphosphates larger than tetrapolyphosphate usually occur as amorphous glassy materials. In one embodiment, polyphosphates are those produced by the FMC Corporation, which are known commercially under the trade names Sodaphos (n~6), Hexaphos (n~13) and Glass H (n~21, sodium hexametaphosphate), and mixtures thereof. Pyrophosphate salts useful in the present invention include: alkali metal pyrophosphates, di, tri and monopotassium or sodium pyrophosphates, metal dialkali pyrophosphate salts, metal tetraalkali pyrophosphate salts, and mixtures thereof. In one embodiment, the pyrophosphate salt is selected from the group consisting of trisodium pyrophosphate, disodium dihydrogen pyrophosphate (Na2H2P2O7), dipotassium pyrophosphate, tetrasodium pyrophosphate (Na4P2O7), tetrapotassium pyrophosphate (K4P2O7), and mixtures thereof. Polyolefin sulfonates include those in which the olefin group contains 2 or more carbon atoms, as well as their salts. Polyolefin phosphonates include those in which the olefin group contains 2 or more carbon atoms. Polyvinyl phosphonates include polyvinyl phosphonic acid. Diphosphonates and salts of these substances include azocycloalkane-2,2-diphosphonic acids and their salts, azocycloalkane-2,2-diphosphonic acid ions and their salts, azacyclohexane-2,2-diphosphonic acid, azacyclopentane-2,2- diphosphonic acid, N-methyl-azacyclopentane-2,3-diphosphonic acid, EHDP (ethane-1-hydroxy-1,1,-diphosphonic acid), AHP (azacycloheptane-2,2-diphosphonic acid), ethane-1- amino-1,1-diphosphonate, dichloromethane-diphosphonate, etc. Phosphonoalkane carboxylic acid or its alkali metal salts include PPTA (phosphonopropane tricarboxylic acid), PBTA (phosphonobutane-1,2,4-tricarboxylic acid), each as alkali metal acid or salts. Polyolefin phosphates include those in which the olefin group contains 2 or more carbon atoms. Polypeptides include polyaspartic and polyglutamic acids.
    [0042] In certain embodiments, zinc salts such as zinc chloride, zinc acetate or zinc citrate may be added as an astringent for an "antiseptic clean" feel, as an enhancer of breath protection, or as an antiseptic agent. - calculated in an amount from about 0.0025%, by weight to volume, to about 0.75%, by weight to volume, of the composition.
    [0043] Any one of a variety of additional surfactants can be used in the present invention. Suitable surfactants can include anionic, nonionic, cationic, amphoteric, zwitterionic, and combinations of two or more of the same. Examples of suitable surfactants are disclosed, for example, in U.S. Patent No. 7,417,020, to Fevola, et al, which is incorporated herein by reference in its entirety.
    [0044] In certain embodiments, the compositions of the present invention comprise a non-ionic surfactant. Those skilled in the art will understand that any of a variety of one or more nonionic surfactants include, but are not limited to, compounds produced by the condensation of alkylene oxide groups (hydrophilic in nature) with an organic hydrophobic compound which may be in nature aliphatic or alkyl aromatic. Examples of suitable nonionic surfactants include, but are not limited to, alkyl polyglycosides; alkyl glucose amines, block copolymers such as ethylene oxide and propylene oxide copolymers, for example poloxamers; commercially available ethoxylated hydrogenated castor oils, for example, under the trade name CRODURET (Croda Inc., Edison, NJ, USA); alkyl poly(ethylene oxide), for example polysorbates and/or; fatty alcohol ethoxylates; poly(ethylene oxide) condensates of alkylphenols; products derived from the condensation of ethylene oxide with the reaction product of propylene oxide and ethylenediamine; ethylene oxide condensates of aliphatic alcohols; long-chain tertiary amine oxides; long-chain tertiary phosphine oxides; long-chain dialkylsulfoxides; and mixtures thereof.
    [0045] Exemplary nonionic surfactants are selected from the group known as poly(oxyethylene)-poly(oxypropylene) block copolymers. These copolymers are commercially known as poloxamers and are produced in a wide range of structures and molecular weights with varying ethylene oxide contents. These non-ionic poloxamers are non-toxic and are acceptable as direct food additives. They are stable and readily dispersible in aqueous systems and are compatible with a wide variety of formulations and other ingredients for oral preparations. Such surfactants should have an HLE (hydrophilic-lipophilic balance) of between about 10 and about 30, and preferably between about 10 and about 25. By way of example, nonionic surfactants useful in the present invention include poloxamers identified as poloxamers 105, 108, 124, 184, 185, 188, 215, 217, 234, 235, 237, 238, 284, 288, 333, 334, 335, 338, 407, and combinations of two or more of the same. In certain preferred embodiments, the composition comprises poloxamer 407.
    [0046] In certain embodiments, the compositions of the claimed invention comprise less than about 9% nonionic surfactant, less than 5%, or less than 1.5%, or less than 1%, or less than 0.8 , less than 0.5%, less than 0.4%, or less than 3% of nonionic surfactants. In certain embodiments, the composition of the present invention is free of nonionic surfactants.
    In certain embodiments, the compositions of the present invention also contain at least one alkyl sulfate based surfactant. In certain embodiments, suitable alkyl sulfate based surfactants include, but are not limited to, alcohols with carbon chain length in even numbers, from C8 to C18, sulfated, optionally from C10 to C16. sulfated, neutralized with a suitable base salt such as sodium carbonate or sodium hydroxide and mixtures thereof so that the alkyl sulfate based surfactant has an even numbered chain length from C8 to C18, optionally C10 to C16. In certain embodiments, the alkyl sulfate is selected from the group consisting of sodium lauryl sulfate, sodium hexadecyl sulfate and mixtures thereof. In certain embodiments, commercially available mixtures of alkyl sulfates are used. A typical percentage distribution of alkyl sulfates by alkyl chain length of commercially available sodium lauryl sulfate (LSS) is as follows:

    [0048] In certain embodiments, the alkyl sulfate based surfactant is present in the composition from about 0.001% to about 6.0%, weight to volume, or optionally, from about 0.1% to about 0.5%, by weight by volume, of the composition.
    [0049] Another suitable surfactant is selected from the group consisting of sarcosinate based surfactants, isethionate based surfactants and taurate based surfactants. Preferred for use in the present invention are the alkali metal or ammonium salts of such surfactants, such as the sodium and potassium salts of the following: lauroyl sarcosinate, myristoyl sarcosinate, palmitoyl sarcosinate, stearoyl sarcosinate and sarcosinate of oil. Sarcosinate surfactant can be present in the compositions of the present invention in amounts of from about 0.1% to about 2.5%, or from about 0.5% to about 2.0%, by weight of the total of the composition.
    [0050] Synthetic zwitterionic surfactants useful in the present invention include aliphatic quaternary ammonium derivatives, phosphonium and sulfonium-based compounds, in which the aliphatic radicals may be straight-chain or branched, and in which one of the aliphatic substituents contains of about 8 to 18 carbon atoms and one contains an anionic water-solubilizing group, for example, carboxy, sulfonate, sulfate, phosphate or phosphonate.
    Amphoteric surfactants useful in the present invention include, but are not limited to, secondary and tertiary aliphatic amine derivatives, wherein the aliphatic radical may be a straight or branched chain, and wherein one of the aliphatic substituents contains about from 8 to about 18 carbon atoms, and one contains an anionic water-solubilizing group, for example carboxylate, sulfonate, sulfate, phosphate or phosphonate. Examples of suitable amphoteric surfactants include, but are not limited to, alkylimino-dipropionates, alkylamphoglycinates (mono- or di-), alkylamphopropionates (mono- or di), alkylamphoacetates (mono- or di-), N-alkyl acids [3-acids]. aminopropionics, alkylpolyamino carboxylates, phosphorylated imidazolines, alkylbetaines, alkylamidobetaines, alkylamidopropylbetaines, alkylsultains, alkylamidosultaines and mixtures thereof. In certain embodiments, the amphoteric surfactant is selected from the group consisting of alkylamidopropylbetaines, amphoacetates such as sodium auroamphoacetate and mixtures thereof. Mixtures of any of the above mentioned surfactants can also be used. A more detailed discussion of anionic, nonionic, and amphoteric surfactants can be found in Lennon's US Patent No. 7,087,650; US Patent No. 7,084,104, to Martin et al.; US Patent No. 5,190,747, to Sekiguchi et al.; and US Patent No. 4,051,234, to Gieske, et al., each of which is incorporated herein by reference in its entirety.
    In certain embodiments, the compositions of the claimed invention comprise less than about 9% amphoteric surfactant, less than 5%, or less than 1.5%, or less than 1%, or less than 0 .8, less than 0.5%, less than 0.4%, or less than 0.3% of amphoteric surfactants. In certain embodiments, the composition of the present invention is free of amphoteric surfactants.
    [0053] Additional surfactants can be added with the surfactant based on alkyl sulfate to aid in the solubilization of essential oils, provided that these surfactants do not affect the bioavailability of essential oils. Suitable examples include anionic surfactants, nonionic surfactants and additional amphoteric surfactants, as well as mixtures thereof. However, in certain embodiments, the total concentration of surfactant (including the alkyl sulfate based surfactant alone or in combination with other surfactants) for mouthwashes of the present invention should not exceed or should be about 9% or less, optionally, the total concentration of surfactant should be about 5% or less, optionally, about 1% or less, optionally, about 0.5% or less, by weight, of the active surfactant by weight of the composition.
    [0054] In certain embodiments, a sugar alcohol (humectant) is also added to the buccal compositions of the present invention. The one or more sugar alcohol-based solvents can be selected from those multi-hydroxy-functional compounds that are conventionally used in oral and ingestible products. In certain embodiments, the sugar alcohol or alcohols must be non-metabolizable and non-fermentable sugar alcohol or alcohols. In specific embodiments, sugar alcohols include, but are not limited to sorbitol, glycerol, xylitol, mannitol, maltitol, inositol, allitol, altritol, dulcitol, galactitol, glucitol, hexitol, iditol, pentitol, ribitol, erythritol, and mixtures of the same. Optionally, the sugar alcohol is selected from the group consisting of sorbitol and xylitol, or mixtures thereof. In some embodiments, the sugar alcohol is sorbitol. In certain embodiments, the total amount of alcohol or sugar alcohols that is added to effectively aid in dispersing or dissolving the mouthwash or other ingredients should not exceed 50% by weight of the total composition. Optionally, the total amount of sugar alcohol should not exceed about 30%, by weight by volume, of the total composition. Or, the total amount of sugar alcohol should not exceed 25%, by weight by volume, of the total composition. The sugar alcohol can be present in an amount of from about 1.0% to about 24%, by weight to volume, or from about 1.5% to about 22%, by weight to volume, or from about from 2.5% to about 20%, by weight by volume, of the total composition.
    [0055] In certain embodiments, a polyol-based solvent is added to the composition. The polyol-based solvent comprises a polyol or polyhydric alcohol selected from the group consisting of polyhydric alkanes (such as propylene glycol, glycerin, butylene glycol, hexylene glycol, 1,3-propanediol); polyhydric alkane esters (dipropylene glycol, ethoxy diglycol); polyalkene glycols (such as polyethylene glycol, polypropylene glycol) and mixtures thereof. In certain embodiments, the polyol-based solvent can be present in an amount of from 0% to about 40%, by weight to volume, or from about 0.5% to about 20%, by weight to volume or of about 1.0% to about 10%, by weight by volume, of the composition.
    In certain embodiments, the compositions of the present invention have a pH of about 11 or less. In some embodiments, the compositions have a pH of from about 3 to about 7, at or about 3.5 to about 6.5, or from about 3.5 to about 5.0.
    [0057] As will be recognized by those skilled in the art, the pH of the composition may be adjusted or maintained with the use of a buffer in an amount effective to provide the composition with a pH equal to or less than 11. The composition may optionally comprise at least one pH modifying agent, including among those useful in the present invention, acidifying agents to reduce pH, basifying agents to increase pH, and buffering agents to maintain the pH within a desired range. For example, one or more compounds selected from acidifying, basifying, and buffering agents can be included to provide a pH of from about 2 to about 7, or in various embodiments from about 3 to about 6, or from about 4 to about 5. Any orally acceptable pH modifying agent can be used including, without limitation, hydrochloric, carboxylic and sulfonic acids, acid salts (eg, monosodium citrate, disodium citrate, monosodium malate, etc.), alkali metal hydroxides such as sodium hydroxide, borates, silicates, imidazole and mixtures thereof. One or more pH modifying agents are optionally present in a total amount effective to maintain the composition within an orally acceptable pH range. In certain embodiments, inorganic acids can be used as the buffer added to the composition.
    [0058] In certain embodiments, organic acids can be used as the buffer added to the composition. Suitable organic acids for use in the compositions of the present invention include, but are not limited to, ascorbic acid, sorbic acid, citric acid, glycolic acid, lactic acid and acetic acid, benzoic acid, salicylic acid, phthalic acid, phenol sulfonic acid and mixtures thereof wherein, optionally, the organic acid is selected from the group consisting of benzoic acid, sorbic acid, citric acid and mixtures thereof or, optionally, the organic acid is benzoic acid.
    In general, the amount of buffering compound is from about 0.001% to about 20.0% of the composition. In one embodiment, the organic acid buffer is present in amounts of from about 0.001% to about 10%, by weight by volume of the composition, or from about 0.01% to about 1% of the composition.
    [0060] In certain embodiments, additional conventional components may be added, such as in prior art mouthwashes. Although some alcohol-containing mouthwashes have a pH of about 7.0, reducing the alcohol content may require the addition of acidic preservatives, such as sorbic acid or benzoic acid, which lower the pH levels. Buffer systems are then needed to control the pH of the composition to optimal levels. This is usually accomplished by adding a weak acid and its salt, or a weak base and its salt. In some embodiments, useful systems have been found to be sodium benzoate and benzoic acid in amounts of 0.01% (or about 0.01%, weight to volume) to 1.0%, weight to volume (or about 1.0%, by weight to volume), of the composition, sodium citrate and citric acid in amounts of 0.001% (or about 0.001%, by weight to volume) to 1.0%, by weight to volume ( or about 1.0%, by weight by volume) of the composition, phosphoric acid and sodium/potassium phosphate in amounts of 0.01% (or about 0.01%) to 1.0% (or about 1.0 %), by weight of the composition. In certain embodiments, the buffers are incorporated in amounts that maintain the pH at levels from 3.0 (or about 3.0) to 8.0 (or about 8.0), optionally from 3.5 (or about 3.5) to 6.5 (or about 6.5), optionally from 3.5 (or about 3.5) to 5.0 (or about 5.0).
    [0061] Buffering agents include alkali metal hydroxides, ammonium hydroxide, organic ammonium compounds, carbonates, sesquicarbonates, borates, silicates, phosphates, imidazole, and mixtures thereof. Specific buffering agents include monosodium phosphate, trisodium phosphate, sodium hydroxide, potassium hydroxide, alkali metal carbonate salts, sodium carbonate, imidazole, pyrophosphate salts, sodium gluconate, sodium lactate, citric acid, and citrate of sodium.
    [0062] Sweeteners such as aspartame, sodium saccharin (saccharin), sucralose, stevia, acesulfame-K and the like can be added to improve flavor in amounts from about 0.0001%, weight to volume, to about 1.0 % by weight by volume. In certain preferred embodiments, the sweetener comprises sucralose.
    [0063] In certain embodiments, the composition additionally comprises flavoring or flavoring to modify or enhance the flavor of the composition or to reduce or mask the strong "stinging" or "burning" of ingredients such as thymol. Suitable flavorings include, but are not limited to, flavoring oils such as aniseed oil, anethole, benzyl alcohol, peppermint oil, citrus oils, vanillin and the like can be incorporated. Other flavorings such as citrus oils, vanillin and the like can be incorporated to provide more flavor variations. In such embodiments, the amount of flavoring oil added to the composition can be from about 0.001% to about 5%, by weight to volume, or from about 0.01% to about 0.3%, by weight to volume. of the total composition. The specific flavorings or flavorings and other flavor enhancing ingredients employed will vary depending on the specific taste and feel desired. Those skilled in the art can select and customize these types of ingredients to get the desired results.
    [0064] In certain embodiments, acceptable approved food colorings may be used to impart a pleasing color to the compositions of the invention. These can be selected from, but not limited to, a long list of acceptable food colors. Dyes suitable for this purpose include FD&C Yellow #5, FD&C Yellow #10, FD&C Blue #1 and FD&C Green #3. These are added in conventional amounts, typically in individual amounts from about 0.00001%, weight to volume, to about 0.0008%, weight to volume, or about 0.000035%, weight to volume, to about 0.0005%, by weight to volume, of the composition.
    [0065] Other conventional ingredients may be used in the liquid or mouthwash compositions of the present invention, including those known and used in the art. Examples of such ingredients include thickeners, suspending agents and softeners. Thickeners and suspending agents useful in the compositions of the present invention can be found in U.S. Patent No. 5,328,682, to Pullen et al., hereby incorporated by reference in its entirety. In certain embodiments, these are incorporated in amounts from about 0.1%, by weight to volume, to about 0.6%, by weight to volume, or about 0.5%, by weight to volume, of the composition. .
    [0066] In certain embodiments, antimicrobial preservatives can be added to the composition. Some antimicrobial preservatives that can be used include, but are not limited to, cationic bactericides such as sodium benzoate, polycationic polyquaternium polymers (ie, polyquaternium-42: Poly[oxyethylene(dimethyl imino)ethylene(dimethyl imino) )ethylene dichloride]), quaternary ammonium salts or quaternary ammonium compounds, parabens (i.e., para-hydroxybenzoates or para-hydroxybenzoic acid esters), hydroxy acetophenone, 1,2-hexane diol, caprylic glycol, chlorhexidine, alexidine, hexetidine, benzalkonium chloride, domiphene bromide, cetylpyridinium chloride (CPC), tetradecylpyridinium chloride (TPC), N-tetradecyl-4-ethylpyridinium chloride (TDEPC), octenidine, bisbiguanides, zinc or tin ionic agents, extract of grapefruit, and mixtures thereof. Other antibacterial and antimicrobial agents include, but are not limited to: 5-chloro-2-(2,4-dichlorophenoxy)-phenol, commonly referred to as triclosan; 8-hydroxy quinoline and its salts, copper II compounds, including but not limited to copper(II) chloride, copper(II) sulfate, copper(II) chloride, copper(II) fluoride and hydroxide copper(II); phthalic acid and its salts including, but not limited to, those disclosed in US Patent No. 4,994,262, including magnesium mono-potassium phthalate; sanguinarine, salicylanilide, iodine, sulfonamides, phenolics, delmopinol, octapinol and other piperidine derivatives, niacin preparations, nystatin, apple extract, thyme oil, thymol, antibiotics such as aumentin, amoxicillin, tetracycline, doxycycline, minocycline, metronidazole, neomycin, kanamycin, cetylpyridinium chloride and clindamycin; analogues and salts of the foregoing, methyl salicylate, hydrogen peroxide, metal chlorite salts, pyrrolidone ethyl cocoyl arginate, lauroyl ethyl arginate monohydrochloride, and mixtures of all the aforementioned items. In another embodiment, the composition comprises phenolic microbicide compounds and mixtures thereof. The microbicide components can be present in an amount of from about 0.001% to about 20%, by weight of the oral care composition. In another embodiment, microbicidal agents generally comprise from about 0.1% to about 5%, by weight, of the oral care compositions of the present invention.
    [0067] Other bactericidal agents can be basic amino acids and salts. Other modalities can comprise arginine.
    [0068] Other active and/or inactive ingredients useful for oral treatment, and other examples thereof, can be found in US patents No. 6,682,722 to Majeti et al. and 6,121,315 to Nair et al., each of which is incorporated herein by reference in its entirety.
    The compositions of the present invention can be produced according to any of a variety of methods disclosed herein and known in the art. In particular, Applicants have found, for certain oral care compositions, that the present compounds can be incorporated into oral care compositions to produce compositions that tend to be relatively more stable than prior compositions, including, for example, similar compositions comprising ester. ethyl L-arginine ("LAE").
    According to certain embodiments, the compositions of the present invention can be produced according to the following method(s).
    [0071] The compounds and compositions of the present invention can be used in a variety of methods for treating the body of a mammal. These methods, in general, comprise introducing a compound or composition of the present invention into or onto the body of a mammal to be treated. For example, certain methods of the present invention comprise treating a condition or disease of the skin, mucous membrane, hair, eyes, or other body part of a mammal by applying it to the skin, mucous membranes, hair, eyes, or other. part of the body, respectively, or injection into the body of a mammal, of a compound or composition of the claimed invention. Certain methods of the present invention comprise treating a disease or condition of the oral cavity, including teeth, mucous/gum membranes, and the like, by applying to the oral cavity, or injecting into the oral cavity or body of a mammal, a compound or composition of the claimed invention.
    [0072] The compounds and compositions of the present invention can be used in a variety of methods for treating a mammalian body, in particular, for the disruption of a biofilm on a surface of the oral cavity. In certain embodiments, the present invention comprises disrupting biofilm on a surface by contacting the surface comprising biofilm with a composition of the present invention. In certain embodiments, the present invention comprises removing biofilm from a surface by contacting the surface comprising biofilm with a composition of the present invention. In certain embodiments, the present invention comprises reducing bacterial adhesion to a surface comprising contacting the surface with a composition of the present invention. In certain embodiments, the present method comprises inhibiting plaque by contacting the surface of the oral cavity with a compound or composition of the present invention.
    [0073] Any suitable surface of the oral cavity may be in contact in accordance with the methods of the present invention, including one or more surfaces selected from the group consisting of surfaces of one or more teeth, the surfaces of the gums, combinations of two or more of the same, and the like.
    [0074] In each of the above methods, the composition of the claimed method may be introduced to the surface to be contacted by any of a variety of methods. In certain embodiments, the composition is introduced into the oral cavity and applied to the surface by a user as a mouthwash or mouthwash. In certain embodiments, the composition is introduced into the oral cavity and applied to the surface as a toothpaste in a tooth cleaning article, eg, a toothbrush. The compositions of the present invention can additionally be introduced through the mouth and applied to the surface as a gum, lozenge, dissolvable strip, or the like.
    [0075] In addition, the contacting step of the methods of the present invention may comprise contacting the surface with the composition for any suitable amount of time. In certain embodiments, the contact step comprises contacting the surface for less than thirty seconds. In certain embodiments, the contacting step comprises contacting the surface with the composition for thirty seconds or more, for example, for about thirty seconds, for about 40 seconds, for about one minute, or for more than one minute. Examples Example 1: Synthesis of [amino({[4-dodecanamido-4-(ethyl carbamoyl)butyl]amino})methylidene]azanium(compound 9) Reaction scheme employed for the synthesis of compound 9
    [0076] [amino({[4-dodecanamido-4-(ethyl carbamoyl)butyl]amino})methylidene] azanium was synthesized according to the following procedure:
    [0077] Ethylamine-protected arginine condensation: A mass of 19.72 g of N-α-(9-fluorenylmethyloxycarbonyl)-N-w',Nw"-bis-ter-butyloxycarbonyl-L-argin (Fmoc-Arg(Boc) )2-OH; 0.033050; 1.0 equivalent) and 12.80 g of 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxid hexafluorophosphate (HATU; 0.033663 mol; 1.0 equivalent) were dissolved in 120 ml of dichloromethane (DCM), to which 19.0 ml (0.038000 mol; 1.1 equivalent) of 2.0 M ethylamine in tetrahydrofuran, (THF) were added to the reaction mixture. To promote the condensation reaction, 18.0 mL diisopropylethylamine (DIEA; 0.10334 mol; 3.0 equivalents) was added to the reaction mixture and left stirring for 24 hours at room temperature, under argon gas (Ar(g)). The reaction was followed by thin layer chromatography, monitoring the consumption of reagents and the production of product 1. At the end, the reaction mixture was concentrated under vacuum and the product 1 was purified on silica using a g. methanol radiant (MeOH) with DCM. The purified mass of product 1 was 16.5 g, 80% yield.
    [0078] Deprotection of the Fmoc of Product 1: A mass of 16.5 g of product 1 (0.026453 mol; 1.0 equivalent) was dissolved in 80 ml of DCM. Period after which 20 mL of piperidine (0.23488 mol; 8.9 equivalents) was added to the reaction mixture and allowed to stir at room temperature under Ar(g). The reaction was monitored by CCF until completion. Product 2 was concentrated in vacuo and purification was experimented on silica. The crude mass of product 2 was 10.83 g.
    [0079] Condensation of product 2 with lauric acid: A mass of 10.83 g of product 2 (0.026973 mol; 1.0 equivalent) and 11.29 g of HATU (0.029692 mol; 1.1 equivalent) was dissolved in 120 ml of DCM. To that mass of 5.95 g of lauric acid (0.029702 mol; 1.1 equivalent) was added to the reaction mixture. To promote the condensation reaction, 14.0 mL of DIEA (0.080377 mol; 3.0 equivalents) was added to the reaction mixture and left to stir for 24 hours at room temperature under Ar(g). The reaction was followed by thin layer chromatography, monitoring the consumption of reagents and the production of product 3. At the end, the reaction mixture was concentrated in vacuo and product 3 was purified on silica using an ethyl acetate (EtOAc) gradient with heptane. The purified mass of product 3 was 7.0 g, a 44% yield.
    [0080] Deprotection of the Boc group of Product 3: A mass of 7.0 g of product 3 (0.011990 mol; 1.0 equivalent) was dissolved in dioxane. At this, 50 mL of 12.1 M concentration of hydrochloric acid (HCl; 0.60500 mol; 50.1 equivalents) were added to the reaction mixture. The reaction mixture was stirred for 2 hours at room temperature under Ar(g). At the end of the reaction, a significant amount of product 3 remained with respect to product 4. Therefore, the reaction mixture was concentrated and the reaction was repeated for 30 minutes to ensure complete conversion of product 3 to product 4. if conversion nearly complete, the reaction was concentrated in vacuo and purified over silica using a MeOH gradient with DCM. The final purified mass of product 4, the desired product, was 2.77 g, a 60% yield. Full 1H-NMR, CL/MS and ESI-MS (Electrospray Ionization Mass Spectrometry) in positive flow injection mode were performed to confirm product identity.
    [0081] In general, the reaction scheme that can be employed is shown below. Here, the Fmoc-protected amino acid can be paired with any primary (or secondary) amine with any of several coupling agents to amidate the carboxylic acid. After deprotection of the Fmoc group with piperidine, the amine in the amino acid can be acetylated with any carboxylic acid using any one of a multitude of coupling agents. Finally, deprotection of any side chain protecting groups can be carried out using a strong acid. Generalized Amino Acid Surfactant Reaction Scheme

    [0082] As further illustrated in Figures 1-3, the resulting purified product was measured using absorbance monitoring HPLC at 220 nm wavelength, mass spectrometry, and proton NMR in D2O using a Bruker 400 MHz instrument with 16 scans and identified as [amino({[4-dodecanamido-4-(ethyl carbamoyl)butyl]amino})methylidene]azanium. Figure 1 shows the LC/MS of purified compound 9. (A) Absorbance monitoring from HPLC chromatogram at 220 nm wavelength. (B) The corresponding positive-mode electrospray ionization mass spectrometry of the primary peak highlighted in the red dotted line box. The calculated m/z for the [M+H]+ of compound 9 is calculated to be 384.58727. Shown in Figure 2: (A) The chemical structure at /z [M+H]+ corresponding to compound 9. (B) ESIMS in positive mode of the final product of compound 9. Shown in Figure 3: 1H-NMR of compound 9 in D2O on the Bruker400 MHz instrument with 16 scans. Example 2: Dose-response of compound 9 in preventing bacterial adhesion
    [0083] AF compositions comprising different concentrations of compound 9 in water are shown in Table 1. Table 1: Formulation compositions used in Example 2

    [0084] Initial studies evaluated the effect of concentration of compound 9 in a simple aqueous solution (compositions in Table 1) in preventing bacterial adhesion to film-coated HA plates. Compound 9 in water demonstrated a dose-dependent response and the most effective concentration was identified as 0.3% by weight (Table 2). However, 0.15% by weight of compound 9 also demonstrated efficacy in preventing bacterial adhesion and was further evaluated at that concentration to correlate with the concentration of LAE in the current commercial product, Listerine Advanced Defense Gum Health (positive control). 2: Prevention trial efficacy results for compositions in Table 1
    Example 3: Compound 9 prevents bacterial adhesion equivalent to LAE
    [0085] The best concentration of compound 9 (0.15% by weight) was compared with the same concentration of LAE for bacterial adhesion prevention when formulated in a simple solution of water or alcohol (Table 3).Table 3: Compositions of the formulation used in Example 3


    [0086] Table 4 suggests that compound 9 (0.15% by weight) is as effective as LAE (0.15% by weight) in preventing bacterial adhesion in both a 21.6% base solution of alcohol and water. The concentration of LAE in Listerine Advanced Defense Gum Treatment (LAGDT) is 0.15% by weight, which was the positive control with water as the negative control.Table 4. Comparison between LAE and compound 9 in preventing bacterial adhesion
    Example 4: Compound 9 prevents bacterial adhesion to full formula
    [0087] After confirming that LAE prevents bacterial adhesion to the same degree as LAE by the same mechanism of action, complete formulas with compound 9 were optimized. Compositions KR of compound 9 include 0.15% by weight of compound 9 in alcohol free base (Table 5). Table 5: Formulation compositions used in Example 3.


    [0088] The results in Table 6 suggest that the presence of essential oils (EOs) has no effect on compound 9 (0.15% by weight) for preventing bacterial adhesion. However, the surfactant has an important effect with 0.645% by weight of Mackam and no surfactant provides the best adhesion prevention. The concentration of LAE in Listerine Advanced Defense Gum Treatment (LAGDT) is 0.15% by weight, which is the positive control with water as the negative control.Table 6: Prevention Effectiveness of Formulations in Table 5.
    Example 5: Compound 9 maintains stability in an alcohol-free formulation whereas LAE does not
    [0089] Selected formulations (Table 7) were further evaluated to ascertain stability after incubation at 50°C for 4 weeks by HPLC. Table 7: Formulation Compositions for Example 5.


    [0090] Table 8 shows that compound 9 contains formulations that are able to maintain at least 90% of compound 9 for 8 weeks when stored at 50°C as opposed to LAE which shows only 46 and 73% stability of the molecule after shelf life (determined by HPLC).Table 9. Compound 9 is stable in alcohol-free formulation compositions.
    Example 6: Compounds 1, 2, 3, 4, 6, 9, 11, 12, 16, 17, 18, 19, 20, 21,22, 23, 24, 25 and 26 prevent bacterial adhesion.
    [0091] A broader set of compounds (compounds 1-26) was evaluated for their ability to prevent bacterial adhesion in a bacterial film fixation on hydroxy apatite coated film plates. The results in Table 10 suggest that compounds 1, 2, 3, 4, 6, 9, 11, 12, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 and 26 have the ability to avoid bacterial adhesion with compounds 1, 2, 3, 6, 9, 12, 17, 18, 19, 21, 22 and 26, better preventing bacterial adhesion. All tests were performed on single-solution solvent-based formulas (Table 11). Listerine Advanced Defense Gum Treatment (LAGDT) is the positive control with water as the negative control.
    Table 11: Formulation compositions used in Example 6.

    Example 7: Compounds 1 and 3-13 are stable in single solution formulations (Table 13) and compounds 1, 2, 3, 4, 6, 7, 9, 11 and 12 do not result in more than one logarithmic reduction in S. mutans
    Compounds 1, 2, 3, 4, 6, 7, 9, 11 and 12 were evaluated in an in-vitro biofilm model with a single species of S. mutans (Table 12 row 2). All compounds tested do not result in more than one logarithmic reduction of S. mutans. Listerine Cool Mint was the positive control with water as the negative control. Compounds 1-13 were evaluated for structural stability by HPLC after storage at 50°C for 4 and 8 weeks (Table 12, lanes 3 and 4). All tested compounds maintained stability with only compound 2 showing a significant decrease in peak area. All tests were performed on single-solution solvent-based formulas (Table 13). Table 12: Efficacy of S. mutans biofilm (row 2), compound stability after 4 weeks storage at 50°C (row 3) , and compound stability after 8 weeks storage at 50°C (row 4) of the formulations in Table 13. NT = composition not tested
    Table 13: Formulation compositions used in Example 7.

    Example 8: Compounds 1, 2, 3, 6, 9, 11 and 12 prevent bacterial adhesion when tested in alcohol-free complete formulations (Table 15).
    [0093] Some of the leading candidates for bacterial adhesion prevention have been further optimized in alcohol-free complete formulations with water as the sole solvent (Table 15), due to their ability to prevent bacterial adhesion, with and without essential oils (OEs). ) (Table 14: J2-Q2 without OEs and Q2-W2 with OEs). All tested formulations better prevent bacterial adhesion when formulated with EOs. Listerine Advanced Defense Gum Treatment (LAGDT) is the positive control with water as the negative control.
    Table 15: Formulation compositions used in Example 8.

    Table 15, continued: Formulation compositions used in Example 8.

    Example 9: Compounds 1, 2, 3, 6, 9, 11 and 12 prevent bacterial adhesion when tested in alcohol-free complete formulations (Table 17).
    [0094] The main candidates for bacterial adhesion prevention were further optimized in alcohol-free complete formulations with water and propylene glycol as the solvents (Table 17), due to their ability to prevent bacterial adhesion, with and without essential oils ( OEs) (Table 16: X2-D3 without OEs and E3-K3 with OEs). All tested formulations better prevent bacterial adhesion when formulated with EOs. Listerine Advanced Defense Gum Treatment (LAGDT) is the positive control with water as the negative control.
    Table 17: Formulation compositions used in Example 9.

    Table 17, continued: Compositions of the formation used in Example 9.

    Methods Formulation preparation
    [0095] The formulations in Examples 2 to 9 were prepared using conventional mixing technology. Briefly, benzoic acid and sodium benzoate were dissolved in propylene glycol or water. Flavoring and essential oils were dissolved in propylene glycol or in surfactant and water (in some compositions no essential oils or flavoring were added). Sucralose was dissolved in water. Surfactant was dissolved/mixed in water. The solution containing sodium benzoate and benzoic acid was added to the mixer container followed by essential oil and flavoring solutions, and then the surfactant and sorbitol solution. This was followed by addition of the solid compound. Sonication or temperature increase may or may not be used to accelerate the dissolution of compounds. The pH of the formulations was adjusted to about pH 4.2 with sodium hydroxide or hydrochloric acid, and then water was added until q.s. of makeup. Prevention trial method
    [0096] The formulations in test examples 2-4, 6, 8 and 9 were prepared and tested for the prevention of bacterial adhesion using the prevention assay. In this assay, a plate with polystyrene pins coated with hydroxy apatite (96 pins, N=8 per group) was exposed to saliva for one minute to form a film at a temperature of 35C. Then, for each formulation, eight pins (N=8) were pretreated for ten minutes with the formulation using an orbital shaker set at 500 rpm at room temperature. As a negative control, eight pins (N=8) were pretreated for ten minutes with sterile water. Then, a 16-hour salivary biofilm was cultured on these polystyrene pin plates at a temperature of 35°C.
    [0097] After completion of all treatments, the biofilm of each post was neutralized and rinsed. Biofilm was harvested via sonication using a Q-Sonica Q700 ultrasonic liquid processor with a 431MP4-00 Damper microplate horn and a 0.5:1 reverse gain booster (Q-Sonica, Newtown, CT). Using a Celsis Rapid Detection RapiScreen Rapid Detection Kit (Celsis International PLC, Chicago, IL, USA), the bacteria were lysed with Celsis Luminex and then the adenosine triphosphate (ATP) of the lysed bacteria was measured using the Celsis LuminATE bioluminescence marker and a Centro LB 960 microplate luminometer supplied by Ber-thold Technologies (Wildbad, Germany). Data were reported in log URLs (relative light units) where the reduction in log URLs indicated a smaller amount of bacteria remaining in the biofilm substrate. The log URLs for the prevention test are shown in Tables 2, 4, 6, 10, 14 and 16. Tests to exterminate unique species of S. mutans
    The formulations shown in Example 7 were prepared and tested using an in-vitro biofilm model with a single species of S. mutans. A 24-hour S. mutans biofilm is grown on a plate with polystyrene pins (96 pins, N=6 per test group). The pins were subsequently treated for thirty seconds with each of formulations H and I, as well as the positive and negative controls. The treatment is applied as a single treatment of thirty (30) seconds. The positive control is a commercially available essential oil-based mouthwash. The negative control is sterile water. After treatment, the biofilm was neutralized and rinsed. Biofilm is harvested via sonication using a Misonix ultrasonic liquid processor (Farmingdale, NY, USA). Using a Celsis Rapid Detection RapiScreen Rapid Detection Kit (Celsis International PLC, Chicago, USA), the bacteria were lysed with Celsis Luminex and then the adenosine triphosphate (ATP) of the lysed bacteria is measured using the lysed bacteria marker. bioluminescence microplate luminometer LB960 supplied from Berthol (Wildbad, Germany). Data were reported in log URLs (relative light units) where the reduction in log URLs indicates a smaller amount of bacteria remaining in the biofilm substrate. Quantification of compounds by HPLC
    [0099] Briefly, formulations containing both LAE and any of the 26 compounds and standards are diluted in a solution of 50% acetonitrile and 50% water. They are evaluated in an Agilent High Performance Liquid Chromatography using a Zorbax ion exchange column. In the method, 10 µl of the sample is taken and subjected to HPLC with a mobile phase of 40% potassium phosphate (molarity at pH 3.0) 60% acetonitrile. Sample retention time varies between 4 and 12 minutes, depending on the molecule. The peak of the molecule is self-integrated using Agilent Online HPLC software. Comparisons are made to the standard to identify % compound remaining after storage.
    权利要求:
    Claims (14)
    [0001]
    1. Compound, characterized by the fact that it is described by Formula I:
    [0002]
    2. Compound according to claim 1, characterized in that R3 is a C1-C6 alkyl group.
    [0003]
    3. Compound according to claim 1, characterized in that it is selected from the group consisting of:
    [0004]
    4. Compound, according to claim 3, characterized in that it has the formula:
    [0005]
    5. Compound according to claim 1, characterized in that R2 is a guanidinyl functional group in its free base form or a salt thereof; n is 3 or 4; R3 is an ethyl group; R1 is an alkyl group having 9 to 16 carbon atoms.
    [0006]
    6. Compound according to claim 5, characterized in that n is 3 and R1 is an alkyl group having 11 to 13 carbon atoms.
    [0007]
    7. Compound according to claim 1, characterized in that it is described by Formula I:
    [0008]
    8. Compound according to claim 7, characterized in that R3 is an alkyl group having a carbon chain length of 2 to 8 carbon atoms.
    [0009]
    9. Compound according to claim 1, characterized in that it is described by Formula I:
    [0010]
    10. Compound according to claim 9, characterized in that R3 is an alkyl group having a carbon chain length of 7 to 11 carbon atoms.
    [0011]
    11. Composition, characterized in that it comprises a compound as defined in any one of claims 1 to 10 and a vehicle, wherein said composition is in a form selected from the group consisting of a mouthwash, mouthwash, mouthwash, toothpaste, toothpaste, subgingival gel, mousse, foam, denture care product, dentifrice, lozenge and chewable tablet.
    [0012]
    12. Composition according to claim 11, characterized in that said composition is a mouthwash comprising a compound as defined in claim 3; a vehicle comprising water; and at least one surfactant selected from the group consisting of anionic, nonionic surfactants, betaine surfactants, and combinations of two or more thereof.
    [0013]
    13. Composition according to claim 12, characterized in that it additionally comprises at least one essential oil selected from the group consisting of menthol, thymol, eucalyptol, methyl salicylate, and combinations of two or more thereof.
    [0014]
    14. Compound according to claim 1, characterized in that it is described by Formula I: wherein: R1 is a C1-C17 alkyl group; R2 is selected from the group consisting of the functional groups: and salts thereof, said salts having an X- anion, preferably selected from the group consisting of acetate, benzoate, besylate, bromide, chloride, chlorotheophyllinate, citrate, ethanedisulfonate, fumarate, gluconate, hippurate, iodide, fluoride, lactate, lauryl sulfate, malate, lacate, mesylate, methylsulfate, napsylate, nitrate, octadecanoate, oxalate, pamoate, phosphate, polygalacturonate, succinate, sulfate, tartrate, and tosylate; n is 1 to 4; eR3 is a linear or branched, saturated or unsaturated aliphatic group having 1 to 6 carbon atoms for use in inhibiting plaque in the cavity in the oral cavity which comprises contacting a surface of the oral cavity with the compound.
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    同族专利:
    公开号 | 公开日
    RU2020125263A|2020-08-10|
    US11046643B2|2021-06-29|
    US9975847B2|2018-05-22|
    RU2730515C2|2020-08-24|
    AU2021240334A1|2021-10-28|
    WO2016077464A8|2017-05-11|
    US20160145203A1|2016-05-26|
    CA2967332A1|2016-05-19|
    RU2017120177A3|2019-04-11|
    RU2017120177A|2018-12-13|
    JP6643335B2|2020-02-12|
    JP2017535544A|2017-11-30|
    AU2020203887A1|2020-07-02|
    BR112017009601A2|2017-12-19|
    RU2020125263A3|2021-02-19|
    US20180230089A1|2018-08-16|
    WO2016077464A1|2016-05-19|
    US20200115331A1|2020-04-16|
    AU2015346374A1|2017-04-27|
    US20210284604A1|2021-09-16|
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    法律状态:
    2019-09-03| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2020-11-17| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|
    2021-03-23| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|
    2021-07-13| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-08-31| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 11/11/2015, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    US201462078187P| true| 2014-11-11|2014-11-11|
    US62/078,187|2014-11-11|
    US14/938,334|2015-11-11|
    PCT/US2015/060166|WO2016077464A1|2014-11-11|2015-11-11|Amino acid derivatives and their uses|
    US14/938,334|US9975847B2|2014-11-11|2015-11-11|Amino acid derivatives and their uses|
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