Sweetener Composition

Abstract

Described herein are compounds useful as sweet flavor modifiers. Also described are ingestible compositions that include one or more of these compounds in combination with natural or artificial sweeteners.

Description

[Technical field]

[0001] The present disclosure relates to the field of chemical and flavor modifying compounds and sweeteners in food, beverages, animal feed, pharmaceuticals and other ingestible compositions.More specifically, the present disclosure relates to product combinations comprising one or more sweetening compounds and one or more flavor modifying compounds. [Background technology]

[0002] The taste system provides sensory information about the chemical composition of the external world. Gustatory transduction is one of the most sophisticated forms of chemically triggered sensation in animals. Taste signaling is found throughout the animal kingdom, from the simplest metazoans to the most complex vertebrates. Mammals are thought to have five basic taste modalities: sweet, bitter, sour, salty and umami (the taste of monosodium glutamate, also known as savory taste).

[0003] Obesity, diabetes and cardiovascular disease are growing health concerns worldwide, but at an alarming rate in the United States. Sugar and calories are key ingredients that can be limited to provide positive nutritional benefits to health. High-intensity sweeteners can provide the sweetness of sugar in a variety of taste qualities. Because they are many times sweeter than sugar, much less sweetener is needed to replace sugar.

[0004] High-intensity sweeteners have a wide range of chemically distinct structures and therefore different properties, including but not limited to odor, flavor, texture and aftertaste. It is well known that these properties, especially flavor and aftertaste, change over the course of consumption, such that each temporal profile is sweetener-specific.

[0005] Sweeteners such as saccharin and 6-methyl-1,2,3-oxathiazin-4(3H)-one-2,2-dioxide potassium salt (acesulfame potassium) are generally characterized as having a bitter and / or metallic aftertaste. Products prepared with 2,4-dihydroxybenzoic acid are claimed to show a reduction in the undesirable aftertaste associated with the sweetener, and at concentrations below the per se perceptible taste. Also, high-intensity sweeteners such as sucralose and aspartame have been reported to have sweetness delivery problems, i.e., a slow onset of sweetness and a persistent sweetness.

[0006] There is a need for new compounds that can enhance the sweetness of sweeteners.

[0007] Summary of the Invention In certain aspects, the present disclosure provides a compound represented by formula (I)-(III): [ka] (wherein R2 and R4 are each independently hydrogen or C-glycosyl, and one or both of R2 and R4 are C-glycosyl; R1, R3, R5, R6, R7, R8, R9 and R 10 are each independently hydrogen, -OH, methyl, -OMe, or O-glycosyl. or a salt or stereoisomer thereof, for enhancing the sweetness of a sweetener, and use thereof.

[0008] In addition to the above features, additional features and variations will be readily apparent from the following description. It should be understood that the following description describes typical alternatives and is not intended to limit the scope. Although the present disclosure is described in various exemplary alternatives and implementations provided herein, it should be understood that the various features, aspects and functions described in one or more of the individual alternatives are not limited in their applicability to the particular alternatives described. Instead, they can be applied to one or more of the other alternatives, either alone or in various combinations, regardless of whether an alternative is described or whether a feature is presented as part of a described alternative. Thus, the breadth and scope of the present disclosure should not be limited by any exemplary alternatives described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The embodiments disclosed herein generally relate to flavor modifying compounds. In some embodiments, the flavor modifying compounds are sweetener enhancers. Some embodiments include compositions that include a flavor modifying compound and one or more sweeteners. In some embodiments, these compositions include non-caloric or low-caloric high-potency natural sweeteners. In some embodiments, the compositions include a combination of one or more sweeteners and one or more flavor modifying compounds that can activate sweet taste receptors in vitro and impart sweetness enhancement. The combination compositions can be used in a variety of ingestible or non-ingestible compositions. In some embodiments, the ingestible composition includes one or more flavor modifying compounds and one or more sweeteners that can be natural sweeteners, e.g., sucrose, or synthetic sweeteners, e.g., sucralose. In some embodiments, the natural or synthetic sweeteners are high-potency sweeteners. The present disclosure also relates to compositions that can improve the taste of non-caloric or low-caloric natural and / or synthetic high-potency sweeteners by imparting a more sugar-like taste or characteristics by utilizing natural sweeteners in conjunction with other natural or synthetic sweeteners. In some embodiments, the ingestible composition provides a more sugar-like temporal profile, including sweetness onset and sweetness lingering, and / or a more sugar-like flavor profile.

[0010] In some embodiments, the ingestible composition may be a food or beverage product.

[0011] In some embodiments, the beverage may be selected from fortified sparkling beverages, fruit juices, fruit-flavored juices, juice drinks, nectars, vegetable juices, vegetable-flavored juices, sports drinks, energy drinks, fortified water drinks, fortified waters with vitamins, near-water drinks, coconut water, tea-type drinks, coffee, cocoa drinks, beverages containing dairy ingredients, dairy substitute beverages, beverages containing cereal extracts, and smoothies.

[0012] In some embodiments, the composition may be an animal feed product or an animal feed ingredient.

[0013] In some embodiments, the ingestible composition may be a pharmaceutical product, a nutritional product, a dietary supplement, or an over-the-counter drug. In some embodiments, the non-ingestible composition may be an oral care product, a hygiene product, or a cosmetic product.

[0014] These and other embodiments, advantages and features of the present disclosure will be set forth in part in the following description, and in part will be apparent from the description, or may be learned by practice of the embodiments disclosed herein. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the embodiments described.

[0015] compound Some embodiments have the following structure: [ka] (In the formula, R2 and R4 are each independently hydrogen or C-glycosyl, and one or both of R2 and R4 are C-glycosyl; R1, R3, R5, R6, R7, R8, R9 and R 10 are each independently hydrogen, -OH, methyl, -OMe, or O-glycosyl. or a salt or stereoisomer thereof.

[0016] In some embodiments of Formula (II), R 10 In another embodiment of formula (II), R 10 is O-glycosyl. In some embodiments of formula (II), R or R 10 is O-glycosyl, or both R2 and R4 are C-glycosyl and R7 is -OMe.

[0017] In some embodiments of formula (I), R4 is C-glycosyl, R7 is -OMe, R2 is C-glycosyl, R6 is -OMe, C-glycosyl is C-rhamnosyl, or each of R6, R7 and R8 is hydrogen.

[0018] In some embodiments, R1 is -OH. In some embodiments, R1 is O-glycosyl.

[0019] In some embodiments, R2 is hydrogen. In some embodiments, R2 is C-glycosyl.

[0020] In some embodiments, R3 is -OH. In some embodiments, R3 is O-glycosyl.

[0021] In some embodiments, R4 is hydrogen. In some embodiments, R4 is C-glycosyl.

[0022] In some embodiments, R5 is hydrogen.

[0023] In some embodiments, R6 is hydrogen. In some embodiments, R6 is -OH. In some embodiments, R6 is -OMe.

[0024] In some embodiments, R7 is -OH. In some embodiments, R7 is -OMe.

[0025] In some embodiments, R8 is hydrogen. In some embodiments, R8 is -OH. In some embodiments, R8 is -OMe.

[0026] In some embodiments, R9 is hydrogen.

[0027] In some embodiments, the compound is: [ka] [ka] [ka] [ka] or a salt or stereoisomer thereof.

[0028] In some embodiments, the compound is in pure, isolated form.

[0029] When the compounds disclosed herein have at least one chiral center, they may exist as individual enantiomers and diastereomers, or as mixtures of such isomers, including racemates. Separation of individual isomers or selective synthesis of individual isomers is achieved by applying various methods well known to those skilled in the art. Unless otherwise indicated (e.g., when the stereochemistry of the chiral center is explicitly indicated), all such isomers and mixtures thereof are included within the scope of the compounds disclosed herein. Furthermore, the compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included within the scope of the compounds disclosed herein, including any polymorphic forms. Furthermore, some of the compounds disclosed herein may form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise indicated, such solvates are included within the scope of the compounds disclosed herein.

[0030] Those skilled in the art will recognize that some structures described herein may be resonance forms or tautomers of compounds that may be significantly represented, even kinetically, by other chemical structures. Those skilled in the art will recognize that such structures may only represent a small portion of a sample of such compounds. Although such compounds are considered to be within the scope of the structures shown, such resonance forms or tautomers are not represented herein.

[0031] Isotopes may be present in the compounds described. Each chemical element represented in a compound structure may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference to a compound herein encompasses all possible isotopic forms, unless the context clearly indicates otherwise.

[0032] In some embodiments, the compounds disclosed herein can form acid salts and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto. Physiologically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Physiologically acceptable salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, bases containing sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like, with ammonium, potassium, sodium, calcium, and magnesium salts being particularly preferred. In some embodiments, treatment of the compounds disclosed herein with an inorganic base results in the loss of a labile hydrogen from the compound, forming Li + ,Na + ,K + ,Mg 2+ and Ca 2+Salt forms can be obtained with inorganic cations such as: Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine.

[0033] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs.All patents, applications, published applications and other publications are incorporated by reference in their entirety.If there are multiple definitions for terms in this specification, the definition in this section shall prevail unless otherwise stated.

[0034] The terms "a" and "an" do not denote a limitation of quantity, but rather the presence of at least one of the referenced items. The terms "or" or "and / or" are used as modifiers indicating that two words or expressions are to be interpreted together or separately. The terms "comprising," "having," "including," and "containing" are to be interpreted as open-ended terms (e.g., meaning "including, but not limited to"). The endpoints of all ranges directed to the same component or characteristic are inclusive and independently combinable.

[0035] Many types of plants are known for producing sweetening compounds and / or flavor modifying compounds, which are isolated and used as sweeteners and / or flavor modifying compounds. In some embodiments herein, the formulation of one or more sweeteners in combination with one or more flavor modifying compounds is obtained in whole or in part from a plant extract. By "extract" is meant a substance or mixture taken from a plant by at least one purification step or other processing step. As used herein, "plant" includes, but is not limited to, a whole plant, a plant part, a plant tissue, a plant cell, or a combination thereof. In some embodiments, the extract is obtained from a plant, a plant part, a plant tissue, or a plant cell. As used herein, "plant part" or "plant tissue" refers to any part of a plant. Examples of plant parts include, but are not limited to, leaves, stems, roots, tubers, seeds, branches, pubescence, nodules, rachises, flowers, pollen, stamens, pistils, petals, pedicels, petioles, stigmas, styles, bracts, fruits, stems, carpels, sepals, anthers, ovules, pedicels, needles, cones, rhizomes, spores, stalks, shoots, pericarp, endosperm, placenta, berries, stamens, sap, and leaf sheaths.

[0036] As used herein, the term "isolated" when referring to a compound means separated or isolated from other components, ingredients, or chemicals that are used or produced in the chemical or enzymatic synthesis of the compound of interest, or that are present with the compound of interest, whether or not the other components, ingredients, or chemicals are naturally present with the compound of interest in its natural state. In some embodiments, the term "isolated" means that the compound of interest is substantially or essentially free of components, ingredients, or chemicals that are normally associated with it in its natural state by at least one purification step or other processing step. Such isolated compounds may also be described as substantially pure. As used herein, the term "substantially pure" refers to a compound of interest that has been separated from components, ingredients, or chemicals that are naturally associated with it. In some embodiments, an isolated compound is substantially pure if at least about 50%, at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% (by volume, wet or dry weight, or by mole percent or mole fraction) of the total material is the compound of interest. Purity can be measured by any appropriate method, for example, by chromatography, gel electrophoresis, or HPLC analysis.

[0037] "Salt" refers to a salt of a compound that has the desired activity of the parent compound. Such salts include: (1) salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or salts formed with acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methyl ... or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or when coordinated with an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc.

[0038] "Solvate" refers to a compound formed by the interaction of a solvent with a compound described herein or a salt thereof. Suitable solvates are physiologically acceptable solvates, including hydrates.

[0039] As used herein, "sweetener," "sweet flavoring agent," "sweet flavorant," or "sweet compound" refers to a compound or a ingestibly acceptable salt thereof that induces a detectable sweet flavor in a subject, e.g., a compound that activates the T1R2 / T1R3 receptor in vitro.

[0040] The term "C-glycosyl" refers to a carbohydrate group that is attached to the remainder of the molecule through a carbon atom. Similarly, the term "O-glycosyl" refers to a carbohydrate group that is attached to the remainder of the molecule through an oxygen atom. As used herein, a C-glycosyl unit refers to a monosaccharide, disaccharide, oligosaccharide, or polysaccharide. A saccharide comprises at least one carbohydrate. Non-limiting examples of carbohydrates include sucrose, glyceraldehyde, dihydroxyacetone, erythrose, threose, erythrulose, arabinose, lyxose, ribose, xylose, ribulose, xylulose, allose, altrose, galactose, glucose, gulose, idose, mannose, talose, fructose, psicose, sorbose, tagatose, mannoheptulose, sedohetulose, octolose, fucose, rhamnose, arabinose, turanose, and sialose.

[0041] sweetener Sweeteners have a wide range of chemically distinct structures and therefore have a variety of properties, including, but not limited to, odor, flavor, texture and aftertaste. The compositions described herein contain any one or more sweeteners, including combinations of any one or more sweeteners disclosed herein.

[0042] Natural or artificial sweeteners for use in ingestible compositions comprising a sweetener in combination with a flavor enhancer include, but are not limited to, natural or synthetic carbohydrates or carbohydrate analogs, including monosaccharides, disaccharides, oligosaccharides and polysaccharides, including rare sugars or sugars in either the D- or L-configuration, such as sucrose, fructose, glucose, L-arabinose, L-fucose, L-glucose, L-ribose, D-arabino-hexulose, psicose, altrose, arabinose, turanose, abequose, allose, abrusoside A, aldotriose, threose, xylose, xylulose, xylo-oligosaccharides (e.g., xylotriose and xylobiose), lyxose, polydextrose, oligofructose, fucose, galacto-oligosaccharides, galactosamine, galactose, gentio-oligosaccharides (gentiobiose, gentiosyl). triose, gentiotetraose), dextrose, cellobiose, D-leucrose, D-psicose, D-ribose, D-tagatose, trehalose (mycose), neotrehalose, isotrehalose, raffinose, idose, tagatose, melibiose, mannan-oligosaccharides, rhamnose, ribose, ribulose, malto-oligosaccharides (e.g., maltotriose, maltotetraose, maltopentaose, maltohex ... sweeteners such as sucrose, maltoheptaose, maltose, sucrose acetate isobutyrate, dextrose, erythrose, erythrulose, deoxyribose, gulose, ketotriose, lactose, lactulose, kestose, nystose, mannose, sucralose, palatinose, polydextrose, sorbose, sugar idextrose (blended sugars) or talose, or a combination of any two or more of the foregoing sweeteners.

[0043] The one or more sweeteners may also include, for example, one or more natural or synthetic carbohydrates, such as corn syrup, high fructose corn syrup, high maltose corn syrup, glucose syrup, sucralose syrup, hydrogenated glucose syrup (HGS), hydrogenated starch hydrolysates (HSH), or other syrups or sweetener concentrates derived from natural fruit and plant sources, or sweetener compositions including semi-synthetic "sugar alcohol" sweeteners, such as polyols. Non-limiting examples of polyols in some embodiments include erythritol, maltitol, mannitol, sorbitol, lactitol, xylitol, isomalt, propylene glycol, glycerol (glycerin), threitol, galactitol, palatinose, reduced isomalto-oligosaccharides, reduced xylo-oligosaccharides, reduced gentio-oligosaccharides, reduced maltose syrup, reduced glucose syrup, isomaltulose, maltodextrin, and the like, as well as sugar alcohols, or any other carbohydrates or combinations thereof that can be reduced and do not adversely affect the taste.

[0044] The one or more sweeteners may be agave inulin, agave nectar, agave syrup, amazake, brazzein, brown rice syrup, coconut crystals, coconut sugar, coconut syrup, date sugar, fructans (also called inulin fiber, fructo-oligosaccharides or oligo-fructose), green stevia powder, stevia rebaudiana (stevia rebaudiana), rebaudioside A, rebaudioside B, rebaudioside C, rebaudioside D, rebaudioside E, rebaudioside F, rebaudioside I, rebaudioside H, rebaudioside L, rebaudioside K, rebaudioside J, rebaudioside N, rebaudioside O, rebaudioside M and other sweet stevia glycosides, stevioside, stevioside, stevioside extract, honey, Jerusalem artichoke syrup, licorice root, Monk fruit (fruit, powder or extract), lucuma (fruit, powder or extract), maple sap (e.g., Acer saccharum, Acer nigrum, Acer rubrum, Acer saccharinum), saccharinum, Acer platanoides, Acer negundo, Acer macrophyllum, Acer grandidentatum, Acer glabrum, Acer mono), maple syrup, maple sugar, walnut sap (including sap extracted from, for example, Juglans cinerea, Juglans nigra, Juglans ailatifolia, Juglans regia), birch sap (including sap extracted from, for example, Betula papyrifera, Betula arganiensis, Betula alleghaniensis, Betula lenta, Betula nigra, Betula populifolia,including sap extracted from Betula pendula), sycamore sap (e.g., sap extracted from Platanus occidentalis), asada sap (e.g., sap extracted from Ostrya virginiana), virginiana), mascovado, molasses (e.g., blackstrap molasses), molasses sugar, monatin, monellin, cane sugar (also called natural sugar, unrefined cane sugar or sucrose), palm sugar, panocha, piloncillo, rapadura, raw sugar, rice syrup, sorghum, sorghum syrup, cassava syrup (also called tapioca syrup), thaumatin, yacon root, malt syrup, barley malt syrup, barley malt flour, beet sugar, cane sugar, crystallized fruit juice crystals, caramel , carbitol, carob syrup, castor sugar, hydrogenated starch aqueous extract, hydrolyzed canned juice, hydrolyzed starch, invert sugar, anethole, arabinogalactan, arop syrup, P-4000, acesulfame potassium (also called acesulfame K or ace K), alitame (also called acrème), advantame, aspartame, bayunoside, neotame, benzamide derivatives, bernadame, canderel, ca carrelame and other guanidine sweeteners, vegetable fibre, corn sugar, coupling sugar, curculin, cyclamate, cyclocaryoside I, demerara, dextran, dextrin, malt syrup, dulcin, sucrose, vulgin, dulcoside A, dulcoside B, emulin, enoxolone, maltodextrin, saccharin, estragole, ethyl maltol, glycine, gluconic acid, gluconolactone, glucosamine, glucoronic acid, glycerol, Glycine, glycyphyllin, glycyrrhizin, golden sugar, yellow sugar, golden syrup, granulated sugar, gynostemma, hernandalusine, isomerized liquid sugar, jalab, chicory root dietary fiber, kynurenine derivatives (including N'-formyl-kynurenine, N'-acetyl-kynurenine, 6-chloro-kynurenine), galactitol, litesse, ligicane, lycasin, ragduname, guanidine, falernum, mabinlin I,Mabinlin II, maltol, multisorb, maltodextrin, maltotriol, mannosamine, miraculin, starch syrup, mogrosides (including, for example, mogroside IV, mogroside V, and neomogroside), mukurodiosides, nanosugar, naringin dihydrochalcone, neohesperidin dihydrochalcone, nib sugar, nigero-oligosaccharides, norbu, olgate syrup, osladin, pekmez, pentadin, periandrin I, perillaldehyde, perillartine, petophyllum, phenylalanine, phlomisoside I, phlorogizin, phyllodulcin, polyglycitol syrup, polypodoside A, pterocaryoside A, pterocaryoside B, rebiana, refined syrup, rub syrup The sweetener may be a natural or synthetic sweetener, including, but not limited to, syrup, rubusoside, serigeain A, sugar (shugr), siamenoside I, Siraitia grosvenorii, soy oligosaccharides, splenda, SRI oxime V, steviol glycosides, steviolbioside, stevioside, strogin 1, 2 and 4 sucronates, sucrononate, sugar, suosan, phloridzin, super aspartame, tetrasaccharide, threitol, treacle, trilobtain, tryptophan and derivatives (6-trifluoromethyl-tryptophan, 6-chloro-D-tryptophan), vanilla sugar, volemitol, birch xylose, aspartame-acesulfame, asguline, and combinations or blends of any two or more thereof.

[0045] In yet other embodiments, one or more sweeteners may be chemically or enzymatically modified natural high-potency sweeteners. Modified natural high-potency sweeteners include glycosylated natural high-potency sweeteners, such as glycosyl-, galactosyl- or fructosyl-derivatives containing 1-50 glycoside residues. Glycosylated natural high-potency sweeteners may be prepared by enzymatic transglycosylation reactions catalyzed by various enzymes with transglycosylation activity. In some embodiments, modified sweeteners may be substituted or unsubstituted.

[0046] The additional sweetener also includes any combination of two or more of any of the aforementioned sweeteners. In some embodiments, the sweetener may include a combination of two, three, four or five sweeteners disclosed herein. In some embodiments, the sweetener may be a sugar. In some embodiments, the sweetener may be a combination of one or more sugars and other natural and artificial sweeteners.

[0047] Those skilled in the art will recognize that any one or more of any of the foregoing sweeteners can be combined in various ratios, amounts or concentrations to produce a single sweetener or a combination of two or more sweeteners which can then be combined with one or more flavor modifying compounds.

[0048] Those skilled in the art will recognize that the above sweeteners for use in formulations comprising one or more sweeteners and one or more taste modifying compounds are provided by way of example and are not intended to be limiting.

[0049] Flavor-modifying compounds In some embodiments, additional flavor modifying compounds may be combined with the compounds described herein. In some embodiments, one or more flavor modifying compounds are one or more flavor modifying compounds disclosed in U.S. Patent Application Publication No. 2005 / 0084506, entitled "Novel Flavors, Flavor Modifiers, Tastants, Taste Enhancers, Umami or Sweet Tastants, and / or Enhancers and Use Thereof," filed August 6, 2004, which is incorporated herein by reference in its entirety. In some embodiments, one or more flavor modifying compounds are one or more flavor modifying compounds disclosed in U.S. Patent Application Publication No. 2007 / 0003680, entitled "Bis-Aromatic Amides and Their Uses as Sweet Flavor Modifiers, Tastants, and Taste Enhancers," filed June 15, 2006, which is incorporated herein by reference in its entirety. In some embodiments, the one or more flavor modifying compounds are one or more flavor modifying compounds disclosed in U.S. Patent Application Publication No. 2008 / 0306093, entitled "Modulation of Chemosensory Receptors and Ligands Associated Therewith," filed June 8, 2007, which is incorporated herein by reference in its entirety. In some embodiments, the one or more flavor modifying compounds are one or more flavor modifying compounds disclosed in U.S. Patent Application Publication No. 2011 / 0224155, entitled "Modulation of Chemosensory Receptors and Ligands Associated Therewith," filed April 14, 2011, which is incorporated herein by reference in its entirety.In some embodiments, the one or more flavor modifying compounds are one or more flavor modifying compounds disclosed in U.S. Patent Application Publication No. 2011 / 0245353, entitled "Sweet Flavor Modifier," filed March 31, 2011, which is incorporated herein by reference in its entirety. In some embodiments, the one or more flavor modifying compounds are one or more flavor modifying compounds disclosed in U.S. Patent Application Publication No. 2013 / 0041046, entitled "Sweet Flavor Modifier," filed August 10, 2012, which is incorporated herein by reference in its entirety. In some embodiments, the one or more flavor modifying compounds are one or more flavor modifying compounds disclosed in U.S. Patent Application Publication No. 2014 / 0094453, entitled "Sweet flavor modifier," filed December 4, 2014, which is incorporated herein by reference in its entirety. In some embodiments, the one or more flavor modifying compounds are one or more flavor modifying compounds disclosed in U.S. Patent Application Publication No. 2014 / 0235624, entitled "Sweet flavor modifier", filed February 19, 2014, which is incorporated herein by reference in its entirety. In some embodiments, the one or more flavor modifying compounds are one or more flavor modifying compounds disclosed in U.S. Patent Application Publication No. 2015 / 0376176, entitled "Sweet flavor modifier", filed August 14, 2015, which is incorporated herein by reference in its entirety. In some embodiments, the one or more flavor modifying compounds are one or more flavor modifying compounds disclosed in U.S. Patent Application Publication No. 2016 / 0185727, entitled "Substituted 4-amino-5-(cyclohexyloxy)quinolone-3-carboxylic acids as Sweet Flavor Modifiers", filed October 28, 2015, which is incorporated herein by reference in its entirety.

[0050] In some embodiments, the one or more taste modifying compounds are compounds having a cyclic thiadiazine core.

[0051] Some embodiments include [ka] and any one or more of the flavor modifying compounds described or referenced herein.

[0052] Some embodiments include [ka] and any one or more of the flavor modifying compounds described or referenced herein.

[0053] Some embodiments include [ka] and any one or more of the flavor modifying compounds described or referenced herein.

[0054] Some embodiments include [ka] and any one or more of the flavor modifying compounds described or referenced herein.

[0055] Some embodiments include [ka] and any one or more of the flavor modifying compounds described or referenced herein.

[0056] Some embodiments include any combination of a flavor modifying compound described herein with any one or more sweeteners described herein.

[0057] In some embodiments, the one or more flavor modifying compounds are present in an amount of about 0.001 ppm to 500 ppm. Thus, in some alternatives, the amount of the one or more flavor modifying compounds is 0.001, 0.01, 0.1, 1, 5, 10, 20, 50, 100, 200, 300, 400 or 500 ppm, or a value within a range defined by any two of the foregoing values.

[0058] Compositions and Uses Some compositions herein relate to a formulation comprising one or more sweeteners disclosed herein in combination with one or more flavor modifying compounds described herein.Therefore, it is recognized that the combination of one or more sweeteners and one or more flavor modifying compounds disclosed herein is not limiting.In some embodiments, the formulation comprising one or more sweeteners and one or more flavor modifying compounds is used as a composition for ingestible or non-ingestible products.

[0059] Formulations comprising one or more sweeteners in combination with one or more flavor modifying compounds can be used to modulate chemosensory receptors and / or their ligands, including modulating the activity, structure, function, expression and / or modification of chemosensory receptors, as well as modulating, treating, or taking preventative measures against conditions, e.g., physiological or pathological conditions, associated with chemosensory receptors. Generally, physiological or pathological conditions associated with chemosensory receptors include conditions, diseases or disorders associated with chemosensory receptors and / or their ligands, e.g., gastrointestinal disorders, metabolic disorders, functional gastrointestinal disorders, and the like. In some embodiments, the formulations increase or enhance sweet flavor. In another embodiment, the formulations modulate sweet receptors and / or their ligands expressed in locations of the body other than taste buds, such as internal organs. Generally, the formulations of the present disclosure can be provided in a composition, e.g., an ingestible composition. In some embodiments, the formulations can impart a more sugar-like temporal and / or flavor profile to a sweetener composition by combining one or more flavor modifying compounds with one or more sweeteners in a combination formulation. In another embodiment, the present formulations can increase or enhance the sweetness of a composition by contacting the composition with one or more of the present formulations to form a modified composition. In another embodiment, the present formulations can be present in a composition that modulates sweet receptors and / or their ligands expressed in the body other than taste buds.

[0060] In some embodiments, the formulations have sucrose-modifying and / or sweet agonist behavior in vitro and / or in vivo (e.g., as shown by sensory testing). In some embodiments, the formulations exhibit a favorable minor taste profile in vivo.

[0061] Whether a formulation exhibits a sweetness-modifying / agonist effect can be determined by any suitable test method. For example, a formulation that includes one or more sweeteners in combination with one or more flavor-modifying compounds can be evaluated in a sensory test using a human taste panel.

[0062] In some embodiments, the formulation may be diluted before being tested, hi some embodiments, the formulation is diluted about 2-fold, about 5-fold, about 10-fold, about 50-fold, about 100-fold, about 200-fold, about 300-fold, about 400-fold, about 500-fold, about 1000-fold or more before being tested.

[0063] Testing can be done with or without additives. In some embodiments, the formulation is tested to evaluate the sweetness enhancement to one or more additives. In the test, participants can provide their impressions of the similarity of the characteristics of the sweetener composition with and / or without additives to the characteristics of the sweetener composition with sugar. A suitable procedure for determining whether a composition has a more sugar-like taste is by using a panel of evaluators to measure the sweetness of the formulation.

[0064] One embodiment provides a formulation for use in a method for preparing a ready-to-use composition, such as a final food or beverage product, or an animal feed product, comprising contacting a first composition, such as a first food or beverage product, which may contain one or more sweeteners as described herein, with a flavor concentrate composition or formulation (e.g., solid or liquid) comprising one or more flavor modifying compounds to form a ready-to-use composition.

[0065] In some embodiments, the ingestible composition may be a beverage. In some embodiments, the beverage may be selected from the group consisting of enhanced sparkling beverages, cola, lemon-lime flavored sparkling beverages, orange flavored sparkling beverages, grape flavored sparkling beverages, strawberry flavored sparkling beverages, pineapple flavored sparkling beverages, ginger ale, root beer, fruit juice, fruit flavored juice, juice drink, nectar, vegetable juice, vegetable flavored juice, sports drink, energy drink, enhanced water drink, enhanced water with vitamins, near water drink, coconut water, tea type drink, coffee, cocoa drink, beverage containing dairy ingredients, chocolate milk, dairy only flavored milk beverage, fruit juice flavored milk beverage, milk substitute beverage, such as rice milk, almond milk, cashew milk, coconut milk, hazelnut milk, hemp milk, pistachio milk, oat milk, wheat milk, barley milk, millet milk, spelt milk, triticale milk and soy milk, sour milk drink, fermented dairy drink, kefir, beverage containing cereal extract and smoothie. In some embodiments, the beverage may be a soft drink.

[0066] In some embodiments, one or more flavor modifying compounds described herein and one or more sweeteners described herein may be included in a food or beverage product, wherein the food or beverage product comprises one or more of the following:

[0067] Acids, including for example citric acid, phosphoric acid, ascorbic acid, sodium bisulfate, lactic acid or tartaric acid;

[0068] bitter ingredients, such as caffeine, quinine, green tea, catechins, polyphenols, green robusta coffee extract, green coffee extract, whey protein isolate or potassium chloride;

[0069] Colourants such as caramel colour, Red No. 40, Yellow No. 5, Yellow No. 6, Blue No. 1, Red No. 3, purple carrot, black carrot juice, purple sweet potato, vegetable juice, fruit juice, beta carotene, turmeric curcumin or titanium dioxide;

[0070] preservatives, such as sodium benzoate, potassium benzoate, potassium sorbate, sodium metabisulfate, sorbic acid or benzoic acid;

[0071] antioxidants, such as ascorbic acid, disodium calcium EDTA, alpha tocopherol, mixed tocopherols, rosemary extract, grape seed extract, resveratrol or sodium hexametaphosphate;

[0072] For example, resveratrol, Co-Q10, omega-3 fatty acids, theanine, choline chloride (cytocholine), Fibersol, inulin (chicory root), taurine, ginseng extract, guanana extract, ginger extract, L-phenylalanine, L-carnitine, L-tartrate, D-glucoronolactone, inositol, bioflavonoids, echinacea, ginkgo biloba, yerba mate, flaxseed oil, garcinia cambogia vitamins or functional ingredients including cambogia (safflower) peel extract, white tea extract, ribose, milk thistle extract, grape seed extract, pyrodixine HCl (vitamin B6), cyanoobalamin (vitamin B12), niacinamide (vitamin B3), biotin, calcium lactate, calcium pantothenate (pantothenic acid), calcium phosphate, calcium carbonate, chromium chloride, chromium polynicotinate, cupric sulfate, folic acid, ferric pyrophosphate, iron, magnesium lactate, magnesium carbonate, magnesium sulfate, monopotassium phosphate, monosodium phosphate, phosphorus, potassium iodide, potassium phosphate, riboflavin, sodium sulfate, sodium gluconate, sodium polyphosphate, sodium bicarbonate, thiamine nitrate, vitamin D3, vitamin A palmitate, zinc gluconate, zinc lactate or zinc sulfate;

[0073] Opacifiers including, for example, ester gun, brominated vegetable oil (BVO) or sucrose acetate isobutyrate (SAIB);

[0074] buffers containing, for example, sodium citrate, potassium citrate or salts;

[0075] For example, propylene glycol, ethyl alcohol, glycerin, gum arabic (gum acacia), maltodextrin, modified corn starch, dextrose, natural flavors, natural flavors including other natural flavors (natural flavors WONF), natural and artificial flavors, artificial flavors, flavors including silicon dioxide, magnesium carbonate, or tricalcium phosphate; and

[0076] Additional stabilizers may be included including, for example, pectin, xanthan gum, carboxymethylcellulose (CMC), polysorbate 60, polysorbate 80, medium chain triglycerides, cellulose gel, cellulose gum, sodium caseinate, modified food starch, gum arabic (acacia gum) or carrageenan.

[0077] Some embodiments provide supplements, nutraceuticals, functional foods (e.g., any fresh or processed food that is claimed to have health-promoting and / or disease-preventing properties beyond the basic nutritional function of providing nutrients), animal feed products, pharmaceutical products, over-the-counter (OTC) products, oral care products, cosmetic products such as sweetened lip balms, and other personal care products that comprise one or more flavor-modifying compounds described herein and a sweetener described herein.

[0078] In general, over-the-counter (OTC) products and oral care products generally refer to products for home and / or personal use that can be sold without a prescription and / or without a medical professional visit. Examples of OTC products include, but are not limited to, vitamins and dietary supplements; topical pain relievers and / or anesthetics; cough, cold and allergy remedies; antihistamines and / or allergy remedies; and combinations thereof. Vitamins and dietary supplements include, but are not limited to, vitamins, dietary supplements, tonics / bottled nutritional drinks, children's vitamins, dietary supplements, any other nutritional products, nutrition-related or nutrition-providing products, and combinations thereof. Topical pain relievers and / or anesthetics include any topical creams / ointments / gels used to relieve superficial or deep pain and pain, such as muscle pain; gels for toothache; patches containing pain-relieving ingredients; and combinations thereof. Cough, cold and allergy remedies include, but are not limited to, decongestants, cough suppressants, throat preparations, medicated confectionery, antihistamines and children's cough, cold and allergy remedies; and combination products.Antihistamines and / or allergy remedies include, but are not limited to, any systemic treatment for hay fever, nasal allergies, insect bites and stings.Examples of oral care products include, but are not limited to, mouthwash strips, toothpaste, toothbrushes, mouthwash / dental rinses, denture care products, breath fresheners, home whitening toothpastes, tooth powders and dental floss.

[0079] In some embodiments, one or more flavor modifying compounds as described herein and one or more sweeteners as described herein can be included in food or beverage products or formulations.Examples of food and beverage products or formulations include, but are not limited to, sweetened coatings, frostings or glazes for ingestible products or any products that are included in soup category, dry processed food category, beverage category, ready meal category, canned or preserved food category, frozen processed food category, chilled processed food category, snack food category, baked goods category, confectionery category, dairy category, ice cream category, meal replacement category, pasta and noodle category, and sauce, dressing, condiment category, baby food category, and / or spread category.

[0080] In general, the soup category refers to canned / preserved, dehydrated, instant, chilled, UHT and frozen soups. For the purposes of this definition, soup means food prepared from meat, poultry, fish, vegetables, grains, fruits and other ingredients, cooked in a liquid that may contain some or all visible portions of these ingredients. Soups may be clear (as broths) or thick (as chowders), smooth, pureed or chunky, ready to serve, semi-condensed or condensed, and may be served hot or cold, as a first course or as the main course of a meal, or as a snack between meals (sipped in small portions like a beverage). Soups may be used as an ingredient for cooking other meal ingredients and may range from broths (consomme) to sauces (cream or cheese-based soups).

[0081] The dehydrated and prepared foods category generally refers to: (i) cooking aid products, such as powders, granules, pastes, concentrated liquid products, such as concentrated bouillons, bouillons and bouillon-like products in compressed cubes, tablets, powders or granules form, sold separately (regardless of technology) as finished products or as ingredients in products, sauces and recipe mixes; (ii) dietary solution products, such as dehydrated and freeze-dried soups, such as dehydrated soup mixes, dehydrated instant soups, dehydrated semi-cooked soups, dehydrated or packaged ready-made staples and single-serving main dishes including pasta, potato and rice dishes; (iii) meal accompaniment products, such as condiments, marinades, salad dressings, salad toppings, dips, bread crumbs, batter mixes, shelf stable spreads, barbecue sauces, liquid recipe mixes, concentrates, sauces or sauce mixes, such as salad recipe mixes, sold in dehydrated, liquid or frozen state, either as finished products or as ingredients in products.

[0082] The beverage category generally refers to beverages, beverage mixes and concentrates, including but not limited to carbonated and non-carbonated beverages, alcoholic and non-alcoholic beverages, ready-to-drink beverages, liquid concentrate formulations for producing beverages such as sodas, and dry powdered beverage pre-mixes. The beverage category also includes alcoholic drinks, soft drinks, sports drinks, isotonic drinks and hot drinks. Alcoholic drinks include but are not limited to beer, cider / perry, flavored alcoholic drinks, wine and spirits. Soft drinks include carbonated, e.g. cola and non-cola carbonated; fruit juices, e.g. juice, nectar, juice drinks and fruit flavored drinks; bottled waters, e.g. sparkling water, spring water and purified water / table water, and vitamin water; functional drinks, e.g. which may be carbonated or non-carbonated and include sports drinks, energy drinks or elixir drinks; concentrates, e.g. ready-to-drink measured liquid and powder concentrates, but are not limited to them. Hot or cold drinks include, but are not limited to, coffee or iced coffee, such as brewed, instant and combination coffees; tea or iced tea, such as black tea, green tea, white tea, oolong tea and flavored teas; and other beverages, including flavored, malt or plant-based powders, granules, blocks or tablets mixed with milk or water.

[0083] The snack food category generally refers to any food that can be a light informal meal, including but not limited to sweet and savory snacks and snack bars. Examples of snack foods include, but are not limited to, fruit snacks, chips / crisps, extruded snacks, tortilla / corn chips, popcorn, pretzels, nuts, and other sweet and savory snacks. Examples of snack bars include, but are not limited to, granola / muesli bars, breakfast bars, energy bars, fruit bars, and other snack bars.

[0084] The baked goods category generally refers to any edible product that undergoes a cooking process that includes exposure to heat or excessive sunlight. Examples of baked goods include, but are not limited to, bread, buns, cookies, muffins, cereals, toaster pastries, pastries, waffles, tortillas, biscuits, pies, bagels, tarts, quiches, cakes, any baked food product, and any combination thereof.

[0085] The ice cream category generally refers to frozen desserts that contain cream and sugar and flavorings. Examples of ice cream include, but are not limited to, impulse ice cream; takeaway ice cream; frozen yogurt and artisanal ice cream; gelato; sorbet; sherbet; soy, oat, bean (e.g., red and mung bean), coconut, nut, and rice-based ice cream.

[0086] The confectionery category generally refers to sweet tasting edible products. Examples of confectionery include, but are not limited to, candy, gelatin, chocolate confectionery, sugar confectionery, gum, and the like, and any combination products.

[0087] The meal replacement category generally refers to any food product intended to replace a regular meal, especially for people with health or fitness concerns. Examples of meal replacements include, but are not limited to, slimming products and recovery products.

[0088] The ready meal category generally refers to any food that can be served as a meal without extensive cooking or processing. Ready meals include products to which recipe "skill" has been added by the manufacturer, resulting in a high degree of preparation, completion and convenience. Examples of ready meals include, but are not limited to, canned / preserved, frozen, dried, chilled ready meals; dinner mixes; frozen pizza; chilled pizza; and pre-prepared salads.

[0089] The pasta and noodles category includes any pasta and / or noodles, including but not limited to canned, dried and chilled / fresh pasta; regular, instant, chilled, frozen and snack noodles.

[0090] The canned / preserved foods category includes, but is not limited to, canned / preserved meat and meat products, fish / seafood, vegetables, tomatoes, beans, fruit, ready meals, soups, pasta and other canned / preserved foods.

[0091] The frozen processed foods category includes, but is not limited to, frozen processed red meat, processed poultry, processed fish / seafood, processed vegetables, meat substitutes, processed potatoes, bakery products, desserts, ready meals, pizza, soups, noodles and other frozen foods.

[0092] The dry processed food category includes, but is not limited to, rice, dessert mixes, dry ready meals, dehydrated soups, instant soups, dry pasta, regular noodles and instant noodles. The chilled processed food category includes, but is not limited to, chilled processed meats, processed fish / seafood products, lunch kits, fresh cut fruit, ready meals, pizza, prepared salads, soups, fresh pasta and noodles.

[0093] The sauces, dressings and condiments category includes, but is not limited to, tomato paste and purees, bouillon / stock cubes, herbs and spices, monosodium glutamate (MSG), table sauces, soy-based sauces, pasta sauces, wet / cooking sauces, dry sauces / powder mixes, ketchup, mayonnaise, mustard, salad dressings, vinaigrettes, dips, pickle products and other sauces, dressings and condiments.

[0094] Baby food categories include, but are not limited to, milk or soy-based formulas; cooked, dried and other baby foods.

[0095] Spread categories include, but are not limited to, jams and preserves, honey, chocolate spreads, nut-based spreads, speculoos spreads, butter, flavored butter, margarine, edible oil spreads, Oreo, cheese or cream cheese spreads, savory spreads, and yeast-based spreads.

[0096] The dairy category generally refers to edible products produced from mammalian milk. Examples of dairy products include, but are not limited to, drinking dairy products, cheese, yogurt and sour milk drinks, and other dairy products.

[0097] Additional examples of ingestible compositions, particularly food and beverage products or formulations, are provided below. Exemplary ingestible compositions include one or more of confectionery, chocolate confectionery, tablets, countlines, bagged selflines / softlines, boxed assortments, standard boxed assortments, twist wrapped miniatures, and the like. miniatures, seasonal chocolates, chocolates with toys, alfajores, other chocolate confectionery, mints, standard mints, power mints, boiled sweets, pastilles, gums, jellies and chews, toffees, caramel and nougat, medicated confectionery, lollipops, liquorice, other sugar confectionery, bread, packaged / industrial bread, unpackaged / artisan bread, pastries, cakes, packaged / industrial cakes, unpackaged / artisan cakes, cookies, chocolate coated biscuits, sandwich biscuits, filled biscuits, savoury biscuits and crackers, bread substitutes, breakfast cereals, rte cereals, family breakfast cereals, flakes, muesli, other cereals, children's breakfast cereals, hot cereals, ice cream, impulse ice cream, single portion dairy ice cream, single portion water ice cream, multipack dairy ice cream, Water ice cream in multipacks, Take away ice cream, Take away dairy ice cream, Ice cream desserts, Bulk ice cream, Take away water ice cream, Frozen yogurt, Artisanal ice cream, Dairy products, Milk, Raw milk / Pasteurized milk, Whole fat raw milk / Pasteurized milk, Semi skimmed milk / Pasteurized milk, Long life / uht milk, Whole fat long life / uht milk, Semi skimmed long life / uht milk, Fat free long life / uht milk, Goat milk, Condensed milk / Evaporated milk, Plain condensed milk / Evaporated milk, Flavoured, Functional and other condensed milk, Flavoured milk beverages, Chocolate milk, Dairy only flavoured milk beverages, Flavoured milk beverages with fruit juice, Milk alternative beverages e.g. Rice milk, Almond milk, Cashew milk, Coconut milk, Hazelnut milk, Hemp milk, Pistachio milk, Oat milk, Wheat milk, Barley milk, Millet milk,Spelt milk, triticale milk and soy milk etc, Sour milk drinks, Fermented dairy drinks, Kefir, Coffee whitener, Powdered milk, Flavoured powdered milk drinks, Cream, Cheese, Processed cheese, Spreadable processed cheese, Non-spreadable processed cheese, Raw cheese, Spreadable raw cheese, Hard cheese, Packaged hard cheese, Unpackaged hard cheese, Yogurt, Plain yogurt / natural yogurt, Flavoured yogurt, Fruit yogurt, Probiotic yogurt, Drinking yogurt, Regular drinking yogurt, Probiotic drinking yogurt, Refrigerated shelf stable desserts, Dairy based desserts, Soy based desserts, Chilled snacks, Fromage frais and quark, Plain fromage frais and quark, Flavoured fromage frais and quark, Savory fromage frais and quark, Sweet and savoury snacks, Fruit snacks, Chips / crisps, Extruded snacks, Tortilla / corn chips, Popcorn, Pretzels, Nuts, Other sweet and savoury snacks, Snack bars, Granola bars, Breakfast snacks Food bars, energy bars, fruit bars, other snack bars, meal replacement products, slimming products, recovery drinks, ready meals, canned ready meals, frozen ready meals, dried ready meals, chilled ready meals, dinner mixes, frozen pizza, chilled pizza, soup, canned soup, dehydrated soup, instant soup, chilled soup, hot soup, frozen soup, pasta, canned pasta, dried pasta, chilled / fresh pasta, noodles, regular noodles, instant noodles, cup / bowl instant noodles, pouch instant noodles, chilled noodles, snack noodles, canned food, canned meat and meat products, canned fish / seafood, canned vegetables, canned tomatoes, canned beans, canned fruit, canned ready meals, canned soups, canned pasta, other canned foods, frozen foods, frozen processed red meat, frozen processed poultry, frozen processed fish / seafood, frozen processed vegetables, frozen meat substitutes, frozen potatoes, oven baked potato chips, other oven baked potato products, non-oven frozen potatoes, frozen bakery products, frozen desserts, frozen ready meals, frozen pizza, frozen soups, frozen noodles, other frozen foods, dehydrated foods, dessert mixes, dehydrated ready meals, dehydrated soups, instant soups, dehydrated pasta, regular noodles,Instant Noodles, Cup / Bowl Instant Noodles, Pouch Instant Noodles, Chilled Food, Chilled Processed Meat, Chilled Fish / Seafood Products, Chilled Processed Fish, Chilled Coated Fish, Chilled Smoked Fish, Chilled Lunch Kits, Chilled Ready Meals, Chilled Pizza, Chilled Soup, Chilled / Fresh Pasta, Chilled Noodles, Oils & Fats, Olive Oil, Vegetable Seed Oils, Cooking Oils & Fats, Butter, Margarine, Spreadable Oils & Fats, Functional Spreadable Oils & Fats, Sauces, Dressings & Condiments, Tomato Paste & Puree, Bouillon / Stock Cubes, Stock Cubes, Gravy Granules, Liquid Stocks & Fonds, Herbs & Spices, Fermented Sauces, Soy Based Sauces, Pasta Sauces, Wet Sauces, Dry Sauces / Powder Mixes, Ketchup The compositions include, but are not limited to, mayonnaise, regular mayonnaise, mustard, salad dressing, regular salad dressing, low fat salad dressing, vinaigrettes, dips, pickle products, other sauces, dressings and condiments, baby foods, formulas, standard formulas, follow-on formulas, toddler formulas, hypoallergenic formulas, prepared baby foods, dry baby foods, other baby foods, spreads, jams and preserves, honey, chocolate spreads, nut-based spreads, speculoos spreads, butter, flavored butters, margarines, edible oil spreads, Oreos, cheese or cream cheese spreads, savory spreads, and yeast-based spreads. Exemplary ingestible compositions include confectionery, bakery products, ice cream, dairy products, sweet and savory snacks, snack bars, meal replacement products, ready meals, soups, pastas, noodles, canned foods, frozen foods, dried foods, chilled foods, fats and oils, baby foods or spreads, or mixtures thereof. Exemplary ingestible compositions also include solid or liquid concentrate compositions for producing breakfast cereals, sweetened drinks, or beverages, ideally allowing for reduced concentrations of previously known sugar or artificial sweeteners.

[0098] Some embodiments provide chewable compositions that may or may not be intended to be swallowed. In some embodiments, the chewable composition may be a gum, chewing gum, sugar-coated gum, sugar-free gum, functional gum, bubble gum, which comprises one or more taste-modifying compounds as described herein and a sweetener as described herein.

[0099] In some embodiments, one or more flavor modifying compounds described herein and one or more sweeteners described herein may be provided in a flavor concentrate formulation, e.g., suitable for subsequent processing to produce a ready-to-use (e.g., ready-to-serve) product. By "flavor concentrate formulation" is meant a formulation to be reconstituted with one or more dilution media to become a ready-to-use composition. The term "ready-to-use composition" is used interchangeably herein with "ingestible composition," which refers to any substance that can be taken by mouth, whether or not it is intended for consumption, alone or together with another substance. In one embodiment, a ready-to-use composition includes a composition that can be directly consumed by a human or animal. A flavor concentrate formulation is typically used by mixing with or diluting with one or more dilution media, e.g., any consumable or ingestible ingredient or product, to impart or modify one or more flavors to the dilution medium. Such a process of use is often referred to as reconstitution. Reconstitution can be carried out in a domestic or industrial environment. For example, a frozen fruit juice concentrate can be reconstituted with water or other aqueous medium by a consumer in the kitchen to obtain a ready-to-use fruit juice beverage. In another example, soft drink syrup concentrates can be reconstituted with water or other aqueous media by manufacturers on a large industrial scale to produce ready-to-use soft drinks. Because flavor concentrate formulations have higher concentrations of flavoring agents or flavor modifiers than ready-to-use compositions, flavor concentrate formulations are typically not suitable for direct consumption without reconstitution. There are many benefits to the use and manufacture of flavor concentrate formulations. For example, one benefit is that flavor concentrate formulations can be reconstituted at the time of use by adding a suitable solvent, solid or liquid, thus reducing the weight and volume of shipping.

[0100] In one embodiment, the flavor concentrate formulation comprises i) one or more flavor modifying compounds as described herein, ii) a carrier, and iii) optionally at least one adjuvant. The term "carrier" refers to a normally inert accessory substance, such as a solvent, binder, or other inert medium, that is used in combination with one or more flavor modifying compounds and one or more optional adjuvants to form a formulation. For example, water or starch can be a carrier for the flavor concentrate formulation. In some embodiments, the carrier is the same as the dilution medium for reconstituting the flavor concentrate formulation, and in other embodiments, the carrier is different from the dilution medium. The term "carrier" as used herein includes, but is not limited to, ingestibly acceptable carriers.

[0101] The term "adjuvant" refers to an additive that supplements, stabilizes, maintains or enhances the intended function or effectiveness of an active ingredient, such as a compound of the present disclosure. In one embodiment, the at least one adjuvant includes one or more flavoring agents. The flavoring agents may be of any flavor known to the artisan or consumer, such as flavors of chocolate, coffee, tea, mocha, French vanilla, peanut butter, chai, or combinations thereof. In another embodiment, the at least one adjuvant includes one or more sweeteners. The one or more sweeteners may be any of the sweeteners described above. In another embodiment, the at least one adjuvant includes one or more ingredient components selected from the group consisting of emulsifiers, stabilizers, antimicrobial preservatives, antioxidants, vitamins, minerals, fats, starches, protein concentrates and isolates, salts, and combinations thereof. Examples of emulsifiers, stabilizers, antimicrobial preservatives, antioxidants, vitamins, minerals, fats, starches, protein concentrates and isolates, and salts are described in U.S. Pat. No. 6,468,576, the contents of which are incorporated herein by reference in their entirety for all purposes.

[0102] In one embodiment, the flavor concentrate formulation may be in a form selected from the group consisting of liquids, including solutions and suspensions, solids, foamy materials, pastes, gels, creams, and combinations thereof, such as liquids containing a certain amount of solids. In one embodiment, the flavor concentrate formulation is in the form of a liquid, including aqueous and non-aqueous. In some embodiments, the flavor concentrate formulation may be carbonated or non-carbonated.

[0103] The flavor concentrate formulation may further include a freezing point depressant, a nucleating agent, or both as at least one adjuvant. A freezing point depressant is a ingestibly acceptable compound or agent that can depress the freezing point of a liquid or solvent to which the compound or agent is added. That is, a liquid or solution containing a freezing point depressant has a lower freezing point than a liquid or solvent without the freezing point depressant. In addition to depressing the starting freezing point, the freezing point depressant can also reduce the water activity of the flavor concentrate formulation. Examples of freezing point depressants include, but are not limited to, carbohydrates, oils, ethyl alcohol, polyols such as glycerol, and combinations thereof. A nucleating agent refers to a ingestibly acceptable compound or agent that can promote nucleation. The presence of a nucleating agent in the flavor concentrate formulation can improve the texture of the frozen blushes of the frozen slush and help maintain the physical properties and performance of the slush at freezing temperatures by increasing the number of desirable ice crystallization centers. Examples of nucleating agents include, but are not limited to, calcium silicate, calcium carbonate, titanium dioxide, and combinations thereof.

[0104] In one embodiment, the flavor concentrate formulation is formulated to have a low water activity to extend shelf life. Water activity is the ratio of the vapor pressure of water in the formulation to the vapor pressure of pure water at the same temperature. In one embodiment, the flavor concentrate formulation has a water activity of less than about 0.85. In another embodiment, the flavor concentrate formulation has a water activity of less than about 0.80. In another embodiment, the flavor concentrate formulation has a water activity of less than about 0.75.

[0105] In one embodiment, the flavor concentrate formulation comprises one or more flavor modifying compounds at a concentration of at least 2 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation comprises one or more flavor modifying compounds at a concentration of at least 5 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation comprises one or more flavor modifying compounds at a concentration of at least 10 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation comprises one or more flavor modifying compounds at a concentration of at least 15 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation comprises one or more flavor modifying compounds at a concentration of at least 20 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation comprises one or more flavor modifying compounds at a concentration of at least 30 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation comprises one or more flavor modifying compounds at a concentration of at least 40 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation comprises one or more flavor modifying compounds at a concentration of at least 50 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation comprises one or more flavor modifying compounds at a concentration of at least 60 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation comprises one or more flavor modifying compounds at a concentration of up to 100 times the concentration of the compound in the ready-to-use composition.

[0106] Ingestible Composition In some embodiments, the compounds disclosed and described herein can be used individually or in combination in one or more methods, such as modifying receptor function associated with chemosensory or chemosensory-related sensations or responses. Some embodiments provide methods for modulating chemosensory receptors, including modulating the activity, structure, function, and / or modification of chemosensory receptors, as well as modulating, treating, or taking preventative measures for conditions, such as physiological or pathological conditions, associated with chemosensory receptors. In general, physiological or pathological conditions associated with chemosensory receptors include conditions, diseases, or disorders associated with chemosensory receptors and / or their ligands, such as gastrointestinal disorders, metabolic disorders, functional gastrointestinal disorders, and the like. In one embodiment, the method includes increasing or enhancing sweet flavor. In another embodiment, the method includes modulating sweet receptors and / or their ligands expressed in body locations other than taste buds, such as internal organs.

[0107] In general, the compounds disclosed and described herein can be provided individually or in combination in a composition, such as an ingestible composition. In one embodiment, the compounds disclosed and described herein can be provided individually or in combination in a sweetener composition by combining one or more of the compounds disclosed and described herein with one or more sweeteners in the sweetener composition to impart a sugar-like temporal profile and / or flavor profile. In another embodiment, the compounds disclosed and described herein can be provided individually or in combination in a composition to increase or enhance the sweetness of the composition by contacting the composition with a compound disclosed and described herein to form a modified composition. In another embodiment, the compounds disclosed and described herein can be provided individually or in combination in a composition that modulates sweet receptors and / or their ligands expressed in the body other than taste buds.

[0108] Some embodiments provide an ingestible composition comprising a compound of any one of formulas (I), (II) or (III) and a sweetener. In some embodiments, the composition further comprises a vehicle. In some embodiments, the vehicle is water. In some embodiments, the compound may be present at a concentration below its sweetness perception threshold. In some embodiments, the sweetener is present in an amount of about 0.1% to about 12% by weight. In some embodiments, the sweetener is present in an amount of about 0.2% to about 10% by weight. In some embodiments, the sweetener is present in an amount of about 0.3% to about 8% by weight. In some embodiments, the sweetener is present in an amount of about 0.4% to about 6% by weight. In some embodiments, the sweetener is present in an amount of about 0.5% to about 5% by weight. In some embodiments, the sweetener is present in an amount of about 1% to about 2% by weight. In some embodiments, the sweetener is present in an amount of about 0.1% to about 5% by weight. In some embodiments, the sweetener is present in an amount of about 0.1% to about 4% by weight. In some embodiments, the sweetener is present in an amount of about 0.1% to about 3% by weight. In some embodiments, the sweetener is present in an amount of about 0.1% to about 2% by weight. In some embodiments, the sweetener is present in an amount of about 0.1% to about 1% by weight. In some embodiments, the sweetener is present in an amount of about 0.1% to about 0.5% by weight. In some embodiments, the sweetener is present in an amount of about 0.5% to about 10% by weight. In some embodiments, the sweetener is present in an amount of about 2% to about 8% by weight.In some embodiments, the sweetener may be a sweetener composition including common carbohydrate sweeteners such as sucrose, fructose, glucose, and natural sugars such as corn syrup (including high fructose corn syrup) or other syrups or sweetener concentrates derived from natural fruit and plant sources; rare natural sugars including D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-albinose, D-turanose, D-leucrose; semi-synthetic "sugar alcohol" sweeteners such as erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, maltodextrin; and artificial sweeteners such as aspartame, saccharin, acesulfame-K, cyclamate, sucralose, and alitame. In some embodiments, the sweetener may be selected from the group consisting of cyclamic acid, mogrosides, tagatose, maltose, galactose, mannose, sucrose, fructose, lactose, neotame and other aspartame derivatives, glucose, D-tryptophan, glycine, maltitol, lactitol, isomalt, hydrogenated glucose syrup (HGS), hydrogenated starch hydrolysates (HSH), stevioside, rebaudioside A, other sweet stevia-based glycosides, carreme and other guanidine-based sweeteners. In some embodiments, the sweetener may be a combination of two or more sweeteners disclosed herein. In some embodiments, the sweetener may be a combination of two, three, four or five sweeteners disclosed herein. In some embodiments, the sweetener may be a sugar. In some embodiments, the sweetener may be a combination of one or more sugars with other natural and artificial sweeteners. In some embodiments, the sweetener is a sugar. In some embodiments, the sugar is cane sugar. In some embodiments, the sugar is beet sugar. In some embodiments, the sugar may be sucrose, fructose, glucose or a combination thereof. In some embodiments, the sugar may be sucrose. In some embodiments, the sugar may be a combination of fructose and glucose. In some embodiments, the sugar may be a combination of about 55% fructose and about 42% glucose.In some embodiments, the sugar may be a combination of about 42% fructose and about 53% glucose. In some embodiments, the sugar may be a combination of about 90% fructose and about 10% glucose. In some embodiments, the sweetener may be a rare sugar. In some embodiments, the rare sugar is selected from the group consisting of D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-albinose, D-turanose, D-leucrose, and combinations thereof. In some embodiments, the rare sugar is D-psicose. In some embodiments, the rare sugar is D-tagatose. In some embodiments, the sweetener is an artificial sweetener. In some embodiments, the artificial sweetener may be sucralose.

[0109] In some embodiments, the ingestible composition may be a beverage. In some embodiments, the beverage may be selected from the group consisting of enhanced sparkling beverages, cola, lemon-lime flavored sparkling beverages, orange flavored sparkling beverages, grape flavored sparkling beverages, strawberry flavored sparkling beverages, pineapple flavored sparkling beverages, ginger ale, root beer, fruit juice, fruit flavored juice, juice drink, nectar, vegetable juice, vegetable flavored juice, sports drink, energy drink, enhanced water drink, enhanced water with vitamins, near water drink, coconut water, tea type drink, coffee, cocoa drink, beverage containing dairy ingredients, beverage containing cereal extract, and smoothie. In some embodiments, the beverage may be a soft drink.

[0110] In one embodiment, the compounds disclosed and described herein can be used in combination with one or more known sweeteners, natural or artificial, at their ligand-enhancing concentrations, e.g., very low concentrations on the order of parts per million, either individually or in combination, to reduce the concentration of the known sweetener required to prepare an ingestible composition having a desired degree of sweetness.

[0111] In one embodiment, the compounds disclosed and described herein, individually or in combination, can enhance the sweetness of a sweetener under a wide range of pH, for example, from lower to neutral pH. Lower and neutral pH include, but are not limited to, pH from about 2.5 to about 8.5; from about 3.0 to about 8.0; from about 3.5 to about 7.5; from about 4.0 to about 7. In certain embodiments, the compounds disclosed and described herein, individually or in combination, can enhance the perceived sweetness of a certain concentration of sweetener in a taste test at a compound concentration of about 50 μM, 40 μM, 30 μM, 20 μM, or 10 μM, both from low to neutral pH values. In certain embodiments, the enhancement factor of the compounds disclosed and described herein, individually or in combination, at lower pH is substantially similar to the enhancement factor of the compounds at neutral pH. Such consistent sweetness enhancing properties under a wide range of pH allow the compounds disclosed and described herein to be widely used individually or in combination in a wide variety of foods and beverages.In some embodiments, the sweetener may be a sweetener composition that includes common carbohydrate sweeteners, such as sucrose, fructose, glucose, and natural sugars, such as corn syrup (including high fructose corn syrup) or other syrups or sweetener concentrates that are derived from natural fruit and plant sources; rare natural sugars, including D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-albinose, D-turanose, D-leucrose; semi-synthetic "sugar alcohol" sweeteners, such as erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, maltodextrin; and artificial sweeteners, such as aspartame, saccharin, acesulfame-K, cyclamate, sucralose and alitame.In some embodiments, the sweetener may be selected from the group consisting of cyclamic acid, mogrosides, tagatose, maltose, galactose, mannose, sucrose, fructose, lactose, neotame and other aspartame derivatives, glucose, D-tryptophan, glycine, maltitol, lactitol, isomalt, hydrogenated glucose syrup (HGS), hydrogenated starch hydrolysates (HSH), stevioside, rebaudioside A, other sweet stevia-based glycosides, carreme and other guanidine-based sweeteners. In some embodiments, the sweetener may be a combination of two or more sweeteners disclosed herein. In some embodiments, the sweetener may be a combination of two, three, four or five sweeteners disclosed herein. In some embodiments, the sweetener may be a sugar. In some embodiments, the sweetener may be a combination of one or more sugars and other natural and artificial sweeteners. In some embodiments, the sweetener may be a sugar. In some embodiments, the sugar is cane sugar. In some embodiments, the sugar is beet sugar. In some embodiments, the sweetener may be a combination of one or more sugars with other natural and artificial sweeteners. In some embodiments, the sugar may be sucrose, fructose, glucose or a combination thereof (e.g., high fructose corn syrup). In some embodiments, the sugar may be sucrose. In some embodiments, the sugar may be a combination of fructose and glucose. In some embodiments, the sugar may be a combination of about 55% fructose and about 42% glucose. In some embodiments, the sugar may be a combination of about 42% fructose and about 53% glucose. In some embodiments, the sugar may be a combination of about 90% fructose and about 10% glucose. In some embodiments, the sweetener may be a rare sugar. In some embodiments, the rare sugar is selected from the group consisting of D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-albinose, D-turanose, D-leucrose, and combinations thereof. In some embodiments, the rare sugar is D-psicose.In some embodiments, the rare sugar is D-tagatose. In some embodiments, the sweetener is an artificial sweetener. In some embodiments, the artificial sweetener is sucralose.

[0112] Typically, at least a sweet receptor modulating amount, a sweet receptor ligand modulating amount, a sweet flavor modulating amount, a sweet flavor enhancer amount, or a therapeutically effective amount of one or more of the present compounds, optionally in the presence of a sweetener, is added to an ingestible composition such that the sweet flavor modified ingestible composition has an increased sweetness as judged, generally by a human or animal via procedures commonly known in the art, or, in the case of formulation testing, by a majority of a panel of at least eight human taste testers, compared to an ingestible composition prepared without the compounds of the present invention.

[0113] In some embodiments, the compounds disclosed and described herein, individually or in combination, modulate the sweetness or other taste characteristics of other natural or synthetic sweeteners and ingestible compositions made therefrom. In one embodiment, the compounds disclosed and described herein, individually or in combination, may be used or provided at their ligand-enhanced concentrations. For example, the compounds disclosed and described herein, individually or in combination, may be present in an amount of about 0.001 ppm to about 100 ppm, or in narrower alternative ranges, about 0.1 ppm to about 10 ppm, about 0.01 ppm to about 30 ppm, about 0.05 ppm to about 10 ppm, about 0.01 ppm to about 5 ppm, or about 0.02 ppm to about 2 ppm, or about 0.01 ppm to about 1 ppm.

[0114] Some embodiments provide a sweetness enhancing composition comprising a sweet flavor enhancing amount of a compound of the present invention in combination with a first amount of a sweetener, the sweetness being greater than the sweetness provided by the first amount of the sweetener without the compound. In some embodiments, the sweetener may be a sweetener composition including common carbohydrate sweeteners such as sucrose, fructose, glucose, and natural sugars such as corn syrup (including high fructose corn syrup) or other syrups or sweetener concentrates derived from natural fruit and plant sources; rare natural sugars including D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-albinose, D-turanose, D-leucrose; semi-synthetic "sugar alcohol" sweeteners such as erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, maltodextrin; and artificial sweeteners such as aspartame, saccharin, acesulfame-K, cyclamate, sucralose, and alitame. In some embodiments, the sweetener may be selected from the group consisting of cyclamic acid, mogrosides, tagatose, maltose, galactose, mannose, sucrose, fructose, lactose, neotame and other aspartame derivatives, glucose, D-tryptophan, glycine, maltitol, lactitol, isomalt, hydrogenated glucose syrup (HGS), hydrogenated starch hydrolysates (HSH), stevioside, rebaudioside A, other sweet stevia-based glycosides, carreme and other guanidine-based sweeteners. In some embodiments, the sweetener may be a combination of two or more sweeteners disclosed herein. In some embodiments, the sweetener may be a combination of two, three, four or five sweeteners disclosed herein. In some embodiments, the sweetener may be a sugar. In some embodiments, the sweetener may be a combination of one or more sugars and other natural and artificial sweeteners. In some embodiments, the sweetener may be a sugar. In some embodiments, the sugar is cane sugar. In some embodiments, the sugar is beet sugar. In some embodiments, the sweetener may be a combination of one or more sugars with other natural and artificial sweeteners.In some embodiments, the sugar may be sucrose, fructose, glucose or a combination thereof (e.g., high fructose corn syrup). In some embodiments, the sugar may be sucrose. In some embodiments, the sugar may be a combination of fructose and glucose. In some embodiments, the sugar may be a combination of about 55% fructose and about 42% glucose. In some embodiments, the sugar may be a combination of about 42% fructose and about 53% glucose. In some embodiments, the sugar may be a combination of about 90% fructose and about 10% glucose. In some embodiments, the sweetener may be a rare sugar. In some embodiments, the rare sugar is selected from the group consisting of D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-albinose, D-turanose, D-leucrose and combinations thereof. In some embodiments, the rare sugar is D-psicose. In some embodiments, the rare sugar is D-tagatose. In some embodiments, the sweetener is an artificial sweetener. In some embodiments, the artificial sweetener may be sucralose.

[0115] In some embodiments, the compounds disclosed and described herein, individually or in combination, are effective in reducing the EC of sweeteners with and without the compounds described herein. 50In some embodiments, the compounds disclosed and described herein, individually or in combination, provide an enhancement ratio of greater than 1 and less than 10. In some embodiments, the compounds disclosed and described herein, individually or in combination, provide an enhancement ratio of 10-20. In some embodiments, the compounds disclosed and described herein, individually or in combination, provide an enhancement ratio of greater than 20. In some embodiments, the sweetener may be a sweetener composition including common carbohydrate sweeteners such as sucrose, fructose, glucose, and natural sugars such as corn syrup (including high fructose corn syrup) or other syrups or sweetener concentrates derived from natural fruit and plant sources; rare natural sugars including D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-albinose, D-turanose, D-leucrose; semi-synthetic "sugar alcohol" sweeteners such as erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, maltodextrin; and artificial sweeteners such as aspartame, saccharin, acesulfame-K, cyclamate, sucralose, and alitame. In some embodiments, the sweetener may be selected from the group consisting of cyclamic acid, mogrosides, tagatose, maltose, galactose, mannose, sucrose, fructose, lactose, neotame and other aspartame derivatives, glucose, D-tryptophan, glycine, maltitol, lactitol, isomalt, hydrogenated glucose syrup (HGS), hydrogenated starch hydrolysates (HSH), stevioside, rebaudioside A, other sweet stevia-based glycosides, carreme and other guanidine-based sweeteners. In some embodiments, the sweetener may be a combination of two or more sweeteners disclosed herein. In some embodiments, the sweetener may be a combination of two, three, four or five sweeteners disclosed herein. In some embodiments, the sweetener may be a sugar. In some embodiments, the sweetener may be a combination of one or more sugars with other natural and artificial sweeteners.In some embodiments, the sweetener may be a sugar. In some embodiments, the sweetener may be a combination of one or more sugars and other natural and artificial sweeteners. In some embodiments, the sugar may be sucrose, fructose, glucose, or a combination thereof (e.g., high fructose corn syrup). In some embodiments, the sugar may be sucrose. In some embodiments, the sugar may be a combination of fructose and glucose. In some embodiments, the sugar may be a combination of about 55% fructose and about 42% glucose. In some embodiments, the sugar may be a combination of about 42% fructose and about 53% glucose. In some embodiments, the sugar may be a combination of about 90% fructose and about 10% glucose. In some embodiments, the sweetener may be a rare sugar. In some embodiments, the rare sugar is selected from the group consisting of D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-albinose, D-turanose, D-leucrose, and combinations thereof. In some embodiments, the rare sugar is D-psicose. In some embodiments, the rare sugar is D-tagatose. In some embodiments, the sweetener is an artificial sweetener. In some embodiments, the artificial sweetener may be sucralose.

[0116] In one embodiment, the flavor concentrate formulation may be in a form selected from the group consisting of liquids, including solutions and suspensions, solids, foamy materials, pastes, gels, creams, and combinations thereof, such as liquids containing a certain amount of solids. In one embodiment, the flavor concentrate formulation is in the form of a liquid, including aqueous and non-aqueous. In some embodiments, the flavor concentrate formulation may be carbonated or non-carbonated.

[0117] In one embodiment, the flavor concentrate formulation has the compound at a concentration at least twice as high as the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation has the compound at a concentration at least 5 times as high as the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation has the compound at a concentration at least 10 times as high as the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation has the compound at a concentration at least 15 times as high as the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation has the compound at a concentration at least 20 times as high as the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation has the compound at a concentration at least 30 times as high as the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation has the compound at a concentration at least 40 times as high as the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation has the compound at a concentration at least 50 times as high as the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation has the compound at a concentration of at least 60 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation has the compound at a concentration of up to 100 times the concentration of the compound in the ready-to-use composition.

[0118] Therapeutic utility In some embodiments, the compounds disclosed and described herein can be used individually or in combination for therapeutic purposes, such as modulating chemosensory receptors and / or their ligands to achieve a therapeutic effect. For example, therapeutic purposes can include modulating chemosensory receptors and / or their ligands expressed in the body other than taste buds.

[0119] In some embodiments, the method of modulating a chemosensory receptor and / or its ligand comprises modulating the expression, secretion and / or function level of T1R expressing cells associated with hormone, peptide, enzyme production by administering the compounds disclosed and described herein, individually or in combination, to an individual in need thereof. In one example, the method of the present invention comprises modulating the level of glucose, for example, using an inhibitor or modulator of a chemosensory receptor such as T1R2 / T1R3, to reduce the level of glucose (e.g., glucose absorption) in a subject by administering the compounds disclosed and described herein, individually or in combination, to an individual in need thereof. In some embodiments, the method comprises modulating the level of incretin, for example, using an agonist or enhancer of a chemosensory receptor such as T1R2 / T1R3, to increase glucagon-like peptide 1 (GLP-1), and thus increase the production of insulin, by administering the compounds disclosed and described herein, individually or in combination, to an individual in need thereof. In some embodiments, the method comprises modulating the expression, secretion and / or activity levels of hormones or peptides produced by T1R expressing cells or gastrointestinal hormone producing cells, such as ligands for 5HT receptors (e.g., serotonin), incretins (e.g., GLP-1 and glucose-dependent insulinotropic polypeptide (GIP)), gastrin, secretin, pepsin, cholecystokinin, amylase, ghrelin, leptin, somatostatin, etc., by administering to an individual in need thereof a compound disclosed and described herein, either individually or in combination. In some embodiments, the method comprises modulating pathways associated with hormones, peptides and / or enzymes secreted by T1R expressing cells, by administering to an individual in need thereof a compound disclosed and described herein, either individually or in combination.

[0120] In some embodiments, the method comprises administering the compounds disclosed and described herein, individually or in combination, to an individual in need thereof to induce or inhibit T1R (e.g., T1R1, T1R2, or T1R3) expressing cells, such as liver cells (e.g., hepatocytes, endothelial cells, Kupffer cells, stellate cells, bile duct epithelial cells, etc.), cardiac cells (e.g., endothelial cells, cardiac cells and smooth muscle cells, etc.), pancreatic cells (e.g., alpha cells, beta cells, delta cells, neurosecretory PP cells, D1 cells, etc.), cells within the papilla (e.g., ductal epithelial cells, etc.), gastric cells (e.g., mucous cells, parietal cells, chief cells, G cells, P / D1 cells), intestinal cells (e.g., ductal epithelial cells, etc.), and / or endothelial cells (e.g., ductal epithelial cells, etc.). The present invention includes regulating the activity of T1R-expressing cells, such as enteroendocrine cells, brush cells, salivary gland cells, such as serous cells, mucous cells, myoepithelial cells, interstitial duct cells, striated duct cells, L cells, such as expression of GLP-1, enterochromaffin cells, such as expression of serotonin, enterochromaffin-like cells, G cells, such as expression of gastrin, D cells, such as delta cells, such as expression of somatostatin, I cells, such as expression of cholecystokinin (CCK), K cells, such as expression of gastric inhibitory polypeptide, P / D1 cells, such as expression of ghrelin, chief cells, such as expression of pepsin, and S cells, such as expression of secretin. In some embodiments, the method includes increasing the expression level of T1R in T1R-expressing cells by administering a compound disclosed and described herein, individually or in combination, to an individual in need thereof. In some embodiments, the method comprises increasing secretion levels of T1R-expressing cells by administering, individually or in combination, the compounds disclosed and described herein to an individual in need thereof.

[0121] In some embodiments, the method provides for the treatment of conditions associated with esophageal motility (e.g., cricopharyngeal achalasia, globus hystericus, achalasia, diffuse esophageal spasms and related motility disorders, scleroderma involving the esophagus, etc.), inflammatory disorders (e.g., gastroesophageal reflux and esophagitis, infectious esophagitis, etc.), peptic ulcer, duodenal ulcer, gastric ulcer, gastrinoma, stress ulcers and erosions, drug-related ulcers and erosions, gastritis, esophageal cancer, gastric tumors, absorption disorders (e.g., absorption of carbohydrates, proteins, amino acids, fats, cholesterol and fat-soluble vitamins, water and certain nutrients such as sodium, calcium, iron, water-soluble vitamins), malabsorption disorders, defects in mucosal function (e.g., inflammatory or infiltrative disorders, biochemical or genetic abnormalities, endocrine disorders, and the like). and / or to regulate, treat and / or prevent conditions related to the gastrointestinal system, including, but not limited to, metabolic disorders, protein losing enteropathy, etc., autoimmune diseases of the gastrointestinal tract (e.g., celiac disease, Crohn's disease, ulcerative colitis, etc.), irritable bowel syndrome, inflammatory bowel disease, complications of inflammatory bowel disease, extraintestinal manifestations of inflammatory bowel disease, intestinal motility disorders, intestinal vascular disorders, anorectal disorders (e.g., hemorrhoids, anal inflammation, etc.), colorectal cancer, small intestinal tumors, anal cancer, liver metabolic disorders, hyperbilirubinemia, hepatitis, alcoholic liver disease and cirrhosis, biliary cirrhosis, liver neoplasms, invasive and metabolic diseases affecting the liver (e.g., fatty liver, Reye's syndrome, diabetic glycogen storage disease, glycogen storage disease, Wilson's disease, hemochromatosis), diseases of the gallbladder and bile ducts, disorders of the pancreas (e.g., pancreatitis, exocrine pancreatic insufficiency, pancreatic cancer, etc.), endocrine tumors of the gastrointestinal tract and pancreas, and the like.

[0122] In some embodiments, the methods include regulating, treating and / or preventing conditions associated with metabolic disorders, such as appetite, body weight, food or liquid intake or a subject's response to food or liquid intake, or satiety or a subject's perception of satiety, nutrient intake and regulation (e.g., protein-energy malnutrition, physiological disorders associated with protein-energy malnutrition, etc.), obesity, secondary obesity (e.g., hypothyroidism, Cushing's disease, insulinoma, hypothalamic disorders, etc.), eating disorders (e.g., anorexia nervosa, bulimia, etc.), vitamin deficiency and excess, insulin metabolism, diabetes (types I and II) and its complications (e.g., circulatory abnormalities, retinopathy, diabetic nephropathy, diabetic neuropathy, diabetic foot ulcers, etc.), glucose metabolism, fat metabolism, hypoglycemia, hyperglycemia, hyperlipoproteinemia, etc., by administering the compounds disclosed and described herein, individually or in combination, to an individual in need thereof.

[0123] In some embodiments, the method includes regulating, treating and / or preventing a condition associated with a functional gastrointestinal disorder, e.g., in the absence of a specific pathological condition such as peptic ulcer and cancer, in which a subject has abdominal indigestion, e.g., abdominal bloating, nausea, vomiting, abdominal pain, loss of appetite, acid reflux, or abnormal bowel movements (constipation, diarrhea, etc.), optionally based on retention of contents in the gastrointestinal tract, particularly in the stomach. In one example, a functional gastrointestinal disorder includes a condition that is not accompanied by organic disease of the gastrointestinal tract but has one or more reproducible gastrointestinal symptoms and affects the quality of life of a subject, e.g., a human, by administering the compounds disclosed and described herein, individually or in combination, to an individual in need thereof.

[0124] Exemplary functional gastrointestinal disorders include, but are not limited to, functional dyspepsia, gastroesophageal reflux disease, diabetic gastroparesis, reflux esophagitis, postoperative gastrointestinal dysfunction, nausea, vomiting, retching, heartburn, abdominal bloating, heavy stomach, burping, chest nausea, chest pain, stomach discomfort, loss of appetite, dysphagia, acid reflux, abdominal pain, constipation, diarrhea, shortness of breath, feeling of being short of breath, loss of motivation or energy, feeling of obstruction in the pharynx, foreign body sensation, fatigue, stiff shoulders, muscle tension, dry mouth (dry mouth, dry throat, etc.), tachypnea, burning sensation in the digestive tract, cold extremities, difficulty concentrating, restlessness, sleep disorders, headache, general malaise, palpitations, night sweats, anxiety, dizziness, lightheadedness, hot flashes, excessive sweating, depression, and the like.

[0125] In some embodiments, the methods include increasing or promoting digestion, absorption, blood nutrient levels and / or gastrointestinal motility in a subject, for example, promoting gastric emptying (e.g., clearance of gastric contents), reducing abdominal bloating during the early postprandial period, ameliorating anorexia, etc., by administering the compounds disclosed and described herein, either individually or in combination, to an individual in need thereof. Generally, such promotion can be achieved directly or by increasing the secretion of regulatory entities, such as hormones, by administering the compounds disclosed and described herein, either individually or in combination, to an individual in need thereof.

[0126] In some embodiments, the methods include increasing one or more gastrointestinal functions in a subject, e.g., to improve the quality of life or health of an individual, by administering, individually or in combination, the compounds disclosed and described herein.

[0127] Some embodiments provide a method of treating a respiratory tract infection, comprising administering a compound disclosed and described herein, either individually or in combination, to an individual in need thereof. In some embodiments, the compounds disclosed and described herein, either individually or in combination, can be used to inhibit a respiratory tract infection. Some embodiments provide a method of treating infertility, comprising administering a compound disclosed and described herein, either individually or in combination, to an individual in need thereof.

[0128] Some embodiments provide pharmaceutical compositions containing a therapeutically effective amount of one or more compounds disclosed and described herein, or salts, solvates and / or prodrugs thereof, optionally including a suitable amount of a pharma- ceutically acceptable vehicle. In another embodiment, the pharmaceutical composition comprises a therapeutically effective amount of one or more compounds disclosed and described herein, or salts, solvates and / or prodrugs thereof, and a suitable amount of a pharma- ceutically acceptable vehicle to provide the form for proper administration to a patient.

[0129] In one embodiment, when administered to a patient, the compounds disclosed and described herein and optional pharma-ceutically acceptable vehicles are sterile. In one embodiment, when the compounds disclosed and described herein are administered intravenously, water is the preferred vehicle. Physiological saline and aqueous dextrose and glycerol solutions can also be used as liquid vehicles, especially for injectable solutions. Suitable pharmaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, etc. The pharmaceutical composition can also contain small amounts of wetting or emulsifying agents or pH buffering agents, if desired. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents may be used.

[0130] The pharmaceutical composition comprising the compound disclosed and described herein can be prepared by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, encapsulating or lyophilizing process.The pharmaceutical composition can be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliary agents, which facilitate the processing of the compound of the present invention into a medicament that can be used pharmaceutical.The suitable formulation depends on the administration route selected.

[0131] In some embodiments, pharmaceutical composition can be in the form of solution, suspension, emulsion, tablet, pill, pellet, capsule, capsule containing liquid, powder, sustained release formulation, suppository, emulsion, aerosol, spray, suspension, or any other form suitable for use.In some embodiments, the pharmaceutically acceptable vehicle is a capsule (see, for example, Grosswald et al., U.S. Pat. No. 5,698,155).Other examples of suitable pharmaceutical vehicles are described in the art (see Remington: The Science and Practice of Pharmacy, Philadelphia College of Pharmacy and Science, 20th Edition, 2000).

[0132] For topical administration, the compounds disclosed and described herein can be formulated as solutions, gels, ointments, creams, suspensions, etc., as is well known in the art.

[0133] Systemic formulations include those designed for administration by injection, such as subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or pulmonary administration.Systemic formulations may be made in combination with additional active agents that improve the mucociliary clearance of airway mucus or reduce mucus viscosity.These active agents include, but are not limited to, sodium channel blockers, antibiotics, N-acetylcysteine, homocysteine ​​and phospholipids.

[0134] In some embodiments, the compounds disclosed and described herein may be formulated in a conventional manner as pharmaceutical compositions adapted for intravenous administration to humans. Typically, compounds for intravenous administration are solutions in sterile isotonic aqueous buffers. For injection, compounds may be formulated in aqueous solutions, preferably in physiologically compatible buffers, such as Hanks' solution, Ringer's solution or physiological saline buffer. The solutions may contain formulating agents, such as suspending agents, stabilizing agents and / or dispersing agents. If necessary, pharmaceutical compositions may also contain solubilizing agents.

[0135] Pharmaceutical compositions for intravenous administration may optionally include a local anesthetic, such as lignocaine, to ease pain at the site of the injection. Generally, the ingredients are supplied separately or mixed together in unit dosage form, for example as a lyophilized powder or water-free concentrate in a sealed container, such as an ampoule or sachet indicating the quantity of active agent. When the compound is administered by infusion, the compound can be dispensed, for example, in an infusion bottle containing sterile pharmaceutical grade water or saline. In some embodiments, when the compound is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.

[0136] For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0137] The pharmaceutical composition for oral delivery may be in the form of, for example, tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups or elixirs.The pharmaceutical composition for oral administration may contain one or more optional agents, for example, sweeteners, such as fructose, aspartame or saccharin; flavorings, such as peppermint, wintergreen oil or cherry colorings, and preservatives, to provide a medicament that is pharmacologic and palatable.

[0138] Additionally, in tablet or pill form, the pharmaceutical composition can be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over an extended period of time. Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for the orally administered compounds of the present invention. In these latter platforms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells and displaces the drug or drug composition through an opening. These delivery platforms can provide an essentially zero order delivery profile, as opposed to the spiked profiles of immediate release formulations. Time-delay materials such as glycerol monostearate or glycerol stearate can also be used. Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Such vehicles are preferably of pharmaceutical grade.

[0139] In the case of oral liquid preparations, such as suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, physiological saline, alkylene glycols (e.g., propylene glycol), polyalkylene glycols (e.g., polyethylene glycol), oils, alcohol, weakly acidic buffer solutions of pH 4 to pH 6 (e.g., about 5 mM to about 50 mM acetate, citrate, ascorbate), etc. Furthermore, flavoring agents, preservatives, coloring agents, bile salts, acylcarnitines, etc. may be added.

[0140] For buccal administration, the pharmaceutical compositions may take the form of tablets, lozenges, etc. formulated in conventional manner.

[0141] Liquid drug formulations suitable for use in nebulizers and liquid spray devices and EHD aerosol devices typically contain the compounds of the present invention together with a pharma- ceutically acceptable vehicle.Preferably, the pharma- ceutically acceptable vehicle is a liquid such as alcohol, water, polyethylene glycol or perfluorocarbon.Optionally, another material may be added to change the aerosol properties of the solution or suspension of the compounds of the present invention.Preferably, this material is a liquid such as alcohol, glycol, polyglycol or fatty acid.Other methods of formulating liquid drug solutions or suspensions suitable for use in aerosol devices are known to those skilled in the art (see, for example, Biesalski, U.S. Pat. No. 5,112,598; Biesalski, U.S. Pat. No. 5,556,611).

[0142] In some embodiments, the compounds disclosed and described herein may also be formulated into rectal or vaginal pharmaceutical compositions such as suppositories or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides.

[0143] In addition to the above-mentioned preparation, the compound disclosed and described herein can also be formulated as depot preparation.Such long-acting preparation can be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection.Thus, for example, the compound of the present invention can be formulated with suitable polymer or hydrophobic material (e.g., as emulsion in acceptable oil) or ion exchange resin, or as sparingly soluble derivative, for example, as sparingly soluble salt.

[0144] The compounds and / or pharmaceutical compositions disclosed and described herein are generally used in an amount effective to achieve the intended purpose.When used to treat or prevent a disease or disorder, the compounds and / or pharmaceutical compositions disclosed and described herein are administered or applied in a therapeutically effective amount.

[0145] In some embodiments, the dosage may be delivered in the pharmaceutical composition by single administration, multiple application or controlled release.In some embodiments, the compounds disclosed and described herein may be delivered by oral sustained release administration.Administration may be repeated intermittently, may be provided alone or in combination with other drugs, and may continue as long as necessary for effective treatment of disease state or disorder.

[0146] Suitable dosage ranges for oral administration depend on potency, but are generally about 0.001 mg to about 200 mg of a compound disclosed and described herein per kilogram of body weight.

[0147] Suitable dosage ranges for intravenous (iv) administration are about 0.01 mg to about 100 mg per kilogram of body weight. Suitable dosage ranges for intranasal administration are generally about 0.01 mg per kilogram of body weight to about 1 mg per kilogram of body weight. Suppositories generally contain about 0.01 milligrams to about 50 milligrams of the compound of the invention per kilogram of body weight, with active ingredient in the range of about 0.5% to about 10% by weight. Recommended dosages for intradermal, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual or intracerebral administration are in the range of about 0.001 mg to about 200 mg per kilogram of body weight. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0148] In some embodiments, the dosage of the compounds described herein lies preferably within a range of circulating concentrations that include the effective dose with little or no toxicity.

[0149] In certain embodiments, the compounds and / or pharmaceutical compositions disclosed and described herein can be used in combination therapy with at least one other agent. In some embodiments, the compounds and / or pharmaceutical compositions disclosed and described herein are administered simultaneously with the administration of another agent, which may be part of the same pharmaceutical composition as the compound of the present invention or may be a different pharmaceutical composition. In other embodiments, the pharmaceutical composition of the present invention is administered before or after the administration of another agent.

[0150] Preparation method The compounds disclosed herein can be synthesized by the methods described below or by modification of these methods. Methods for modifying this methodology include, among others, temperature, solvent, reagents, etc., known to those skilled in the art. In general, during any of the processes for preparing the compounds disclosed herein, it may be necessary and / or desirable to protect any sensitive or reactive groups of the molecules involved. This can be achieved by conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. J.F.W.MacOmie, Plenum Press, 1973); and P.G.M.Green, T.W.Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999), all of which are incorporated herein by reference in their entirety. Protecting groups can be removed at a convenient subsequent stage using methods known in the art. Synthetic chemical transformations useful for synthesizing applicable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995, both of which are incorporated herein by reference in their entirety. The routes shown and described herein are exemplary only and are not intended or construed to limit the scope of the claims in any manner. Those skilled in the art will recognize modifications of the disclosed syntheses and can devise alternative routes based on the disclosure herein, and all such modifications and alternative routes are within the scope of the claims.

[0151] The general synthesis procedure for the flavonoid-C-glycosides described herein is as follows: A solution of flavanone / DHC (1 eq.) and D-glucose (2 eq.) in a sealed tube with 2:1 CH3CN-H2O is refluxed in an oil bath in the presence of Sc(OTf)3 (0.2 eq.) for 24 h. The reaction mixture is then concentrated and passed through a column of MCI GEL (80 g) packed with water. The column is washed with water and eluted with 30% aqueous ethanol and 100% ethanol. The combined eluate is concentrated and purified by preparative LC equipped with a Luna C18(2) column (Phenomenex, 250*21.20 mm*5 μm) and lyophilized. References: [Carbohydrate Research 345(2010)1825-1830]; [Carbohydrate Research 341(2006)964-970]; [Eur. J. Org. Chem. 2013, 1441-1447], all of which are incorporated by reference in their entireties. EXAMPLES

[0152] The following examples are included to further illustrate the present invention. The examples should not be construed as specifically limiting the present invention. Variations of these examples within the scope of the claims are within the scope of the skilled artisan and are considered to be within the scope of the invention described and claimed herein. The reader will recognize that the skilled artisan, armed with this disclosure, can prepare and use the present invention without the exhaustive examples.

[0153] Example 1: Synthesis of Compounds 1, 2 and 3 [ka]

[0154] A solution of naringenin (3 g, 11.0 mmol) and D-glucose (3.9 g, 21.6 mmol) in 2:1 CH3CN-H2O (42 mL) in a 100 mL sealed tube was refluxed in an oil bath for 24 h in the presence of Sc(OTf)3 (1.2 g, 2.44 mmol). The reaction mixture was then concentrated and passed through a column of MCI GEL (80 g) preconditioned with water. The column was washed with 1000 mL of water and eluted with 750 mL of 30% aqueous ethanol and 100% ethanol. The combined 30% aqueous ethanol fraction was concentrated and determined by UHPLC-UV-HRMS. LC HRMS analysis was used to confirm the three compounds (1, 2, 3). This fraction was then purified by preparative LC equipped with a Luna C18(2) column (Phenomenex, 250*21.20 mm*5 μm). After lyophilization, two white amorphous powders were obtained as Compound 1 (620 mg) and Compound 2 (25 mg). The structures of Compound 1 and Compound 2 are shown below. 1 H and 13 The structure of compound 3 was determined as naringenin 6-C-β-D glucoside and naringenin 8-C-β-D glucoside by C NMR and HR-ESI-MS spectroscopy. The structure of compound 3 was determined as naringenin 6,8-di-C-β-D glucoside by HR-ESI-MS spectroscopy.

[0155] Example 2: Synthesis of Compounds 4, 5 and 6 [ka]

[0156] A solution of eriodictyol (1.6 g, 5.5 mmol) and D-glucose (4 g, 22.2 mmol) in 2:1 CH3CN-H2O (36 mL) in a 100 mL sealed tube was refluxed in an oil bath for 24 h in the presence of Sc(OTf)3 (0.5 g, 1 mmol). The reaction mixture was then concentrated and passed through a column of MCI GEL (80 g) preconditioned with water. The column was washed with water and eluted with 40% aqueous ethanol and 100% ethanol. The combined 40% aqueous ethanol fraction was concentrated and examined by U(H)PLC-UV-HRMS. Three compounds (4, 5, 6) were detected using LC HRMS analysis. This fraction was then purified by preparative LC equipped with a Luna C18(2) column (Phenomenex, 250*21.20 mm*5 μm). After lyophilization, two white amorphous powders were obtained as Compound 4 (620 mg) and Compound 5 (3 mg). The structures of Compound 4 and Compound 5 are shown below. 1 H and 13 The structure of compound 6 was determined by 1C NMR and HR-ESI-MS spectroscopy as eriodictyol 6-C-β-D glucoside and eriodictyol 8-C-β-D glucoside. The structure of compound 6 was determined by HR-ESI-MS spectroscopy as eriodictyol 6,8-di-C-β-D glucoside.

[0157] Example 3: Synthesis of Compounds 7, 8 and 9 [ka]

[0158] A solution of hesperetin (2 g, 6.6 mmol) and D-glucose (5 g, 27.7 mmol) in 2:1 CH3CN-H2O (45 mL) in a 100 mL sealed tube was refluxed in an oil bath for 48 h in the presence of Sc(OTf)3 (1.6 g, 3.3 mmol). The reaction mixture was then concentrated and passed through a column of MCI GEL (80 g) preconditioned with 5% aqueous ethanol. The column was washed with 250 mL of 10% aqueous ethanol and eluted successively with 750 mL of 15% aqueous ethanol and 1000 mL of 40% aqueous ethanol. The fractions were examined by UHPLC-UV-HRMS. Three compounds (7, 8, 9) were detected using LC HRMS analysis.

[0159] The combined 15% aqueous ethanol fractions containing compound 9 were concentrated and purified by preparative LC equipped with a Luna C18(2) column (Phenomenex, 250*21.20mm*5μm). After lyophilization, 170mg of hesperetin-6,8-di-C-glucoside (compound 9) was obtained as a white amorphous powder.

[0160] The combined 40% aqueous ethanol fractions containing compound 7 and compound 8 were concentrated and purified by preparative LC equipped with a Luna C18(2) column (Phenomenex, 250*21.20mm*5μm). After lyophilization, 420mg of hesperetin-6-C-β-D-glucoside (compound 7) was obtained as a white amorphous powder. The structures of compound 7 and compound 9 are shown below. 1 H and 13 The structure of compound 8 was determined by 1C NMR and HR-ESI-MS spectroscopy as hesperetin 6-C-β-D glucoside and hesperetin 6,8-di-C-β-D glucoside. The structure of compound 8 was determined by HR-ESI-MS spectroscopy as hesperetin 8-C-β-D glucoside.

[0161] Example 4: Synthesis of Compounds 10, 11 and 12 [ka]

[0162] A solution of homoeriodictyol (0.3 g, 1.0 mmol) and D-glucose (0.35 g, 1.9 mmol) in 2:1 CH3CN-H2O (4 mL) in a 15 mL sealed tube was refluxed in an oil bath for 24 h in the presence of Sc(OTf)3 (0.11 g, 0.2 mmol). The reaction mixture was then concentrated and passed through a column of MCI GEL (80 g) preconditioned with water. The column was washed with water and eluted with 40% aqueous ethanol and 100% ethanol. The combined 40% aqueous ethanol fraction was concentrated and examined by UHPLC-UV-HRMS. Three compounds (10, 11, 12) were detected using LC HRMS analysis. This fraction was then purified by preparative LC equipped with a Luna C18(2) column (Phenomenex, 250*21.20 mm*5 μm). After lyophilization, two white amorphous powders were obtained as Compound 10 (105 mg) and Compound 12 (5 mg). The structures of Compound 10 and Compound 12 are shown below. 1 H and 13 The structure of 11 was determined by 1C NMR and HR-ESI-MS spectroscopy as homoeriodictyol 6-C-β-D glucoside and homoeriodictyol 6,8-di-C-β-D glucoside. The structure of 12 was determined by HR-ESI-MS spectroscopy as homoeriodictyol 8-C-β-D glucoside.

[0163] Example 5: Synthesis of Compound 13 [ka]

[0164] A solution of trilobatin (0.9 g, 1.9 mmol) and D-glucose (1.36 g, 7.5 mmol) in 2:1 CH3CN-H2O (7.3 mL) in a 15 mL sealed tube was refluxed in an oil bath for 24 h in the presence of Sc(OTf)3 (0.41 g, 0.83 mmol). The reaction mixture was then concentrated and passed through a column of MCI GEL (80 g) preconditioned with water. The column was washed with water and eluted with 40% aqueous ethanol and 100% ethanol. The combined 40% aqueous ethanol fraction was concentrated and examined by UHPLC-UV-HRMS. The new compound 13 was detected by HRMS spectrum. This fraction was then purified by preparative LC equipped with a Luna C18(2) column (Phenomenex, 250*21.20 mm*5 μm). After lyophilization, a white amorphous powder was obtained as compound 13 (200 mg). The structure of compound 13 is 1 H and 13 The identity of this compound was determined to be trilobatin 3'-C-β-D-glucoside by C NMR and HR-ESI-MS spectroscopy.

[0165] Example 6: Synthesis of Compound 14 [ka]

[0166] A solution of hesperetin dihydrochalcone 4'-O-β-D-glucoside (0.5 g, 1.1 mmol) and D-glucose (0.4 g, 2.2 mmol) in 2:1 CH3CN-H2O (7.5 mL) in a 15 mL sealed tube was refluxed in an oil bath for 24 h in the presence of Sc(OTf)3 (0.3 g, 0.61 mmol). The reaction mixture was then concentrated and passed through a column of MCI GEL (80 g) preconditioned with water. The column was washed with water and eluted with 40% aqueous ethanol and 100% ethanol. The combined 40% aqueous ethanol fraction was concentrated and examined by UHPLC-UV-HRMS. A new compound 14 was detected by both HRMS spectra. This fraction was then purified by preparative LC equipped with a Luna C18(2) column (Phenomenex, 250*21.20 mm*5 μm). After lyophilization, a white amorphous powder was obtained as compound 14 (120 mg). The structure of compound 14 was determined as hesperetin dihydrochalcone 4'-O-β-D glucopyranosyl-3'-C-β-D glucoside by 1H and 13C NMR and HR-ESI-MS spectroscopy.

[0167] Example 7: Synthesis of Compounds 15-16 [ka]

[0168] A solution of naringenin (2 g, 7.4 mmol) and L-rhamnose (5 g, 30.5 mmol) in 2:1 CH3CN-H2O (28 mL) in a 100 mL sealed tube was refluxed in an oil bath for 24 h in the presence of Sc(OTf)3 (1.6 g, 3.3 mmol). The reaction mixture was then concentrated and passed through a column of MCI GEL (80 g) preconditioned with water. The column was washed with water and eluted with 60% aqueous ethanol and 100% ethanol. The combined 60% aqueous ethanol fraction was concentrated and examined by UHPLC-UV-HRMS. Compounds 15 and 16 were detected by both UV and HRMS spectra. This fraction was then purified by preparative LC equipped with a Luna C18(2) column (Phenomenex, 250*21.20 mm*5 μm). After lyophilization, a white amorphous powder was obtained as Composition 1 (200 mg). Composition 1 contained Compound 15 and Compound 16 in a ratio of 2.7 to 1. The structures of Compounds 15 and 16 are shown below. 1 H and 13 The compounds were determined as naringenin 6-C-rhamnoside and naringenin 6-C-rhamnoside by C NMR and HR-ESI-MS spectroscopy.

[0169] Example 8: Isolation of Compounds 4, 17, 18 and 19 [ka]

[0170] 300 grams of fermented rooibos tea was extracted five times with 50% aqueous ethanol. The solution was concentrated under reduced pressure by rotary evaporator. The aqueous solution was extracted successively with cyclohexane, ethyl acetate and butanol. The combined butanol extracts were concentrated. The dried extracts were first fractionated by silica gel chromatography on a flash chromatography system (DCM:MeOH 10:1 to 2:1). The fractions containing flavonoid C-glucosides were combined and dried. Chemical separation was achieved by using a C18 column (Phenomenex Luna C18(2) column (5 μm, 250 × 21.20 mm, 100A) in a Prep-LC system. The column was eluted with water and acetonitrile (ACN) at 30 °C with a gradient (10% ACN-30% ACN). After drying, 300 mg of eriodictyol-6-C-β-D-glucoside (compound 4) was obtained. Isoorientin (compound 17, 220 mg), orientin (compound 18, 123 mg) and isovitexin (19, 9 mg) were also obtained using the same preparative LC chromatography. The structures of compounds 4, 17–19 are shown in Table 1. 1 H and 13 The structure was determined by C NMR and HR-ESI-MS spectroscopy.

[0171] Example 9: Isolation of Compounds 20 and 21 [ka]

[0172] 70 grams of unfermented (green) rooibos tea powder was extracted three times with 50% aqueous ethanol. The solution was concentrated under reduced pressure by rotary evaporator to remove the solvent. The aqueous solution was first extracted three times with cyclohexane to remove volatiles, then extracted four times with ethyl acetate. The combined organic extracts were concentrated. The dried extract was pre-diluted with ethanol and loaded onto an MCI gel column. The column was eluted with solvent A (MeOH:H2O:FA 5:95:0.1) and solvent B (MeOH:H2O:FA 75:25:0.1) in a gradient in a flash chromatography system. Partial fractions were further purified by preparative LC chromatography to obtain aspalathin (compound 20, 1000 mg) and nothofagin (compound 21, 100 mg). The structures of compounds 20-21 were determined by 1H and 13C NMR and HR-ESI-MS spectroscopy.

[0173] Example 10: Isolation of Compound 22 [ka]

[0174] 1774 grams of kumquat fruit was extracted three times with 2 L of 50% aqueous ethanol. The solution was concentrated under reduced pressure by rotary evaporator. The concentrated solution was loaded onto an MCI column connected to a flash chromatography system. The column was first washed with water and successively eluted with 50% ethanol and 80% ethanol. The 50% ethanol solution was collected for further reversed-phase ODS column chromatography. The system was eluted with solvent A (water) and solvent B (ethanol) in a gradient of 9:1 to 1:1 in the flash chromatography system. The fractions containing flavonoid C-glucosides were combined, concentrated, and fractionated by silica gel chromatography (DCM:MeOH 5:1 to 3:1). Compound 22 (1.9434 g) was finally obtained by using a C18 column (Phenomenex Luna C18(2) column (5 μm, 250×21.20 mm, 100A) on a Prep-LC system. The column was eluted with water and acetonitrile (ACN) at 30° C. with a gradient (10% ACN-30% ACN). The structure was confirmed as phloretin-3',5'-di-C-β-D-glucoside (compound 22) based on NMR analysis.

[0175] Compound 23 was purchased. [ka]

[0176] Example 11: Synthesis of Compounds 24, 25 and 26 [ka]

[0177] A solution of pinocembrin (0.5 g, 1.9 mmol) and D-glucose (0.7 g, 3.8 mmol) in 2:1 CH3CN-H2O (7.5 mL) in a 15 mL sealed tube was refluxed in an oil bath for 24 h in the presence of Sc(OTf)3 (0.22 g, 0.4 mmol). The reaction mixture was then concentrated and passed through a column of MCI GEL (80 g) preconditioned with water. The column was washed with water and eluted with 50% aqueous ethanol and 100% ethanol. The combined 50% aqueous ethanol fraction was concentrated and examined by UHPLC-UV-HRMS. Three compounds (24, 25, 26) were detected by both UV and HRMS spectra. This fraction was then purified by preparative LC equipped with a Luna C18(2) column (Phenomenex, 250*21.20 mm*5 μm). After lyophilization, two white amorphous powders were obtained as compound 24 (80 mg) and compound 26 (10 mg). The structure of compound 25 was determined by HR-ESI-MS spectroscopy as pinocembrin 8-C-β-D-glucoside. The structures of compounds 24 and 26 were 1 H and 13 It was determined as pinocembrin 6-C-β-D-glucoside and pinocembrin 6,8-di-C-β-D-glucoside by C NMR and HR-ESI-MS spectroscopy.

[0178] Example 12: Synthesis of Compounds 27 and 28 [ka]

[0179] A solution of hesperetin dihydrochalcone (50 mg, 0.16 mmol) and D-glucose (50 mg, 0.28 mmol) in 2 mL sealed vials with 2:1 CH3CN-H2O (0.5 mL) was refluxed at 80 degrees in a parallel reactor in the presence of Sc(OTf)3 (20 mg, 0.04 mmol). The reaction was monitored by UHPLC-UV-HRMS. After the reaction was completed and cooled to room temperature, the reaction mixture was diluted with ethanol, filtered through a 0.2 μm PTFE filter, and examined by UHPLC-UV-HRMS. New compounds 27 and 28 were detected by both UV and HRMS spectra. The structure of compound 27 was determined as hesperetin dihydrochalcone 3'-C-β-D-glucoside and the structure of compound 28 was determined as hesperetin dihydrochalcone 3',5'-di-C-β-D-glucoside by HR-ESI-MS spectroscopy.

[0180] Example 13: Synthesis of Compounds 21, 29, and 30 [ka]

[0181] A solution of phlorizin (50 mg, 0.11 mmol) and D-glucose (40 mg, 0.22 mmol) in 2 mL sealed vials with 2:1 CH3CN-H2O (0.5 mL) was refluxed at 80 degrees in a parallel reactor in the presence of Sc(OTf)3 (20 mg, 0.04 mmol). The reaction was monitored by UHPLC-UV-HRMS. After the reaction was completed and cooled to room temperature, the reaction mixture was diluted with ethanol, filtered through a 0.2 μm PTFE filter, and examined by UHPLC-UV-HRMS. Compounds 21, 29, and 30 were detected by both UV and HRMS spectra. The structure of compound 21 was determined as phloretin 3'-C-β-D-glucoside corresponding to a standard using HR-ESI-MS spectroscopy. The structure of compound 29 was determined as phlorizin 3'-C-β-D-glucoside and the structure of compound 30 was determined as phlorizin 5'-C-β-D-glucoside by HR-ESI-MS spectroscopy.

[0182] Sensory Experiment Methods: A panel of 8-25 trained panelists rated the taste attributes (sweetness and / or sweet off-taste, e.g. duration) of samples on a scale of -5 to 5 (-5 indicating a strong masking effect, 5 indicating a strong enhancing effect, and 0 being the strength of a reference aqueous solution containing 4% sucrose or 0.02% SG95 stevia product).

[0183] The results of these experiments are shown in Tables 1-12. Compounds 1, 4, 7, 21, 13, 20, 23 and 18 show significant sweetness enhancing effects on sucrose solutions. Compounds 9, 22, 15, 16 and 17 show sweetness enhancing effects on sucrose solutions. Compound 21 shows sweetness enhancing effects on SG95 stevia product solutions. Compound 22 shows sweetness enhancing effects on SG95 stevia product solutions and an off masking taste effect that sustains the masking. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12]

[0184] The foregoing detailed description has been given for clarity of understanding only, and no unnecessary limitations should be understood therefrom, as modifications will be apparent to those skilled in the art. No admission is made that any of the information provided herein is prior art or relevant to the embodiments claimed herein, or that any publication specifically or implicitly referenced is prior art.

Claims

1. Formulas (I) to (III): 【Chemistry 1】 (In the formula, R ２ and R ４ are each independently hydrogen or C-glycosyl; R ２ and R ４ one or both of are C-glycosyl; R １ , R ３ , R ５ , R ６ , R ７ , R ８ , R ９ and R １０ are each independently hydrogen, —OH, methyl, —OMe, or O-glycosyl. Use of a compound having the structure: or a salt or stereoisomer thereof for enhancing the sweetness of a sweetener.

2. Formula (II): 【Chemistry 2】 2. The compound of claim 1, or a salt or stereoisomer thereof, having the structure:

3. R １０ The compound of claim 1 , wherein is —OH.

4. R ３ Or R １０ is O-glycosyl, or R ２ and R ４ and both of R ７ The compound of claim 1, wherein is -OMe.

5. Formula (I): 【Transformation 3】 2. The compound of claim 1, or a salt or stereoisomer thereof, having the structure:

6. R ４ is C-glycosyl and R ７ is -OMe, and R ２ is C-glycosyl and R ６ is -OMe and the C-glycosyl is C-rhamnosyl, or R ６ , R ７ and R ８ 6. The compound of claim 5, wherein each of is hydrogen.

7. Formula (III): 【Chemistry 4】 2. The compound of claim 1, or a salt or stereoisomer thereof, having the structure:

8. R １ The compound of claim 1 , wherein is —OH.

9. R １ The compound of claim 1, wherein is O-glycosyl.

10. R ２ The compound of claim 1 , wherein is hydrogen.

11. R ２ The compound of claim 1, wherein is C-glycosyl.

12. R ３ The compound of claim 1 , wherein is —OH.

13. R ３ The compound of claim 1, wherein is O-glycosyl.

14. R ４ The compound of claim 1 , wherein is hydrogen.

15. R ４ The compound of claim 1, wherein is C-glycosyl.

16. R ５ The compound of claim 1 , wherein is hydrogen.

17. R ６ The compound of claim 1 , wherein is hydrogen.

18. R ６ The compound of claim 1 , wherein is —OH.

19. R ６ The compound of claim 1, wherein is -OMe.

20. R ７ The compound of claim 1 , wherein is —OH.

21. R ７ The compound of claim 1, wherein is -OMe.

22. R ８ The compound of claim 1 , wherein is hydrogen.

23. R ８ The compound of claim 1 , wherein is —OH.

24. R ８ The compound of claim 1, wherein is -OMe.

25. R ９ The compound of claim 1 , wherein is hydrogen.

26. The compound is 【Chemistry 5-1】 【Chemistry 5-2】 【Chemistry 5-3】 2. The compound of claim 1, selected from the group consisting of: or a salt or stereoisomer thereof. 【Request Item 27】 【Chemistry 6-1】 【Chemistry 6-2】 A compound having a structure selected from the group consisting of: 【Request Item 28】 【Chemistry 7】 or a salt or stereoisomer thereof.

29. A compound according to any one of claims 1 to 28 in pure and isolated form.

30. 29. An ingestible composition comprising a compound according to any one of claims 1 to 28 and one or more sweeteners.

31. 31. The ingestible composition of claim 30, wherein the sweetener is a sugar.

32. 32. The ingestible composition of claim 31, wherein the sweetener is sucrose.

33. 32. The ingestible composition of claim 31, wherein the sweetener comprises a combination of fructose and glucose.

34. 31. The ingestible composition of claim 30, wherein the sweetener is sucralose.

35. 31. The ingestible composition of claim 30, wherein the sweetener is high fructose corn syrup.

36. 29. A method for enhancing the sweetness of a sweetener, comprising combining a compound according to any one of claims 1 to 28 with said sweetener.

37. 37. The method of claim 36, wherein the sweetener is a sugar.

38. 38. The method of claim 37, wherein the sweetener is sucrose.

39. 38. The method of claim 37, wherein the sweetener comprises a combination of fructose and glucose.

40. 37. The method of claim 36, wherein the sweetener is sucralose.

41. 37. The method of claim 36, wherein the sweetener is high fructose corn syrup.

42. 37. The method of claim 36, wherein the compound is present at a concentration of 0.001 to 1000 ppm.

43. 37. The method of claim 36, wherein the compound is present at a concentration of 0.1 to 500 ppm.

44. 37. The method of claim 36, wherein the compound is present at a concentration of 0.1 to 100 ppm.

45. 28. The compound of claim 27 for use in enhancing the sweetness of a sweetener.

46. 28. Use of the compound according to claim 27 to enhance the sweetness of a sweetener.

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