Sweetener composition

Abstract

Described herein are compounds useful as sweet flavor modifiers. Also described are ingestible compositions comprising 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 chemistry and flavor modifying compounds and sweeteners in foods, beverages, animal feeds, pharmaceuticals and other ingestible compositions. More specifically, the present disclosure relates to product combinations including one or more sweetening compounds and one or more flavor modifying compounds. Background Art

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

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

[0004] High intensity sweeteners have a wide range of chemically different structures and therefore have different properties such as, but not limited to, aroma, flavor, mouthfeel and aftertaste. It is well known that these properties, especially flavor and aftertaste, vary over tasting time, so each temporal profile is unique to the sweetener.

[0005] Sweeteners such as saccharin and 6-methyl-1,2,3-oxathiazin-4(3H)-one-2,2-dioxide potassium salt (acesulfame potassium) are often characterized as having a bitter and / or metallic taste. Products prepared with 2,4-dihydroxybenzoic acid are said to show a reduction in the unpleasant aftertaste associated with sweeteners, and this is also true at concentrations below which their own taste is perceptible. In addition, high-intensity sweeteners such as sucralose and aspartame are reported to have sweetness delivery problems, namely delayed onset and lingering of the sweetness.

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

[0007] In certain forms, the present disclosure provides compounds and their use for enhancing the sweetness of sweeteners, wherein the compounds are compounds having structures of formula (I) to (III):

[0008]

[0009] or a salt or stereoisomer thereof, wherein:

[0010] R 2 and R 4 are each independently hydrogen or C-glycosyl, and R 2 and R 4 One or two of are C-sugar moieties; and

[0011] R 1 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 Each is independently hydrogen, -OH, methyl, -OMe or O-glycosyl.

[0012] In addition to the above features, additional features and variations can be easily seen 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 with various exemplary alternatives and embodiments provided herein, it should be understood that the various features, forms and functions described in one or more separate alternatives are not limited to their applicability to the specific alternatives describing them. On the contrary, they can be applied to one or more other alternatives individually or in various combinations, regardless of whether these alternatives are described or whether these features are presented as part of the alternatives. Therefore, the breadth and scope of the present disclosure should not be limited by any exemplary alternatives described herein. DETAILED DESCRIPTION

[0013] Embodiments disclosed herein generally relate to flavor modification compounds. In some embodiments, the flavor modification compound is a sweetener enhancer. Some embodiments include compositions comprising flavor modification compounds and one or more sweeteners. In some embodiments, these compositions include high-efficiency natural sweeteners that are calorie-free or low-calorie. In some embodiments, the composition includes a combination of one or more sweeteners and one or more flavor modification compounds, which can activate sweet taste receptors in vitro and impart sweetness enhancement. The composition of the combination can be used in various ingestible or non-ingestible compositions. In some embodiments, the ingestible composition includes one or more flavor modification compounds and one or more sweeteners, which can be natural sweeteners, such as sucrose; or synthetic sweeteners, such as sucralose. In some embodiments, natural or synthetic sweeteners are high-efficiency sweeteners. The present disclosure also relates to compositions that can improve the taste of calorie-free or low-calorie natural and / or synthetic high-efficiency sweeteners by combining natural sweeteners with other natural or synthetic sweeteners to impart a more sugar-like taste or characteristics. 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.

[0014] In some embodiments, the ingestible composition may be a food or beverage product.

[0015] In some embodiments, the beverage can be selected from the group consisting of enhanced sparkling beverages, fruit juices, fruit flavored juices, fruit drinks, nectar drinks, vegetable juices, vegetable flavored juices, sports drinks, energy drinks, fortified water drinks, vitamin-fortified waters, near-water drinks, coconut water, tea drinks, coffee, cocoa drinks, beverages containing milk ingredients, milk substitute beverages, beverages containing cereal extracts, and smoothies.

[0016] In some embodiments, the composition may be an animal feed product or an animal feed ingredient.

[0017] In some embodiments, the ingestible composition may be a pharmaceutical product, a nutritional product, a dietary supplement, or an over-the-counter medication. In some embodiments, the non-ingestible composition may be an oral care product, a hygiene product, or a beauty product.

[0018] These and other embodiments, advantages and features of the present disclosure are provided in part in the following description, and in part will become apparent from the description, or can be learned by practicing the embodiments disclosed herein. It should be understood that the foregoing general description and the following detailed description are only exemplary and explanatory, and are not limitations of the described embodiments.

[0019] Compound

[0020] Some embodiments include a flavor-modifying compound having one of the following structures:

[0021]

[0022] or a salt or stereoisomer thereof, wherein:

[0023] R 2 and R 4 are each independently hydrogen or C-glycosyl, and R 2 and R 4 One or two of are C-sugar moieties; and

[0024] R 1 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 Each is independently hydrogen, -OH, methyl, -OMe or O-glycosyl.

[0025] In some embodiments of Formula (II), R 10 In other embodiments of formula (II), R 10 In some embodiments of formula (II), R 3 or R 10 O-glycosyl, or R 2 and R 4 are all C-sugar groups, and R 7 It is -OMe.

[0026] In some embodiments of Formula (I), R 4 is a C-sugar group and R 7 For -OMe, R 2 is a C-sugar group and R 6 is -OMe, the C-sugar group is C-rhamnosyl, or R 6 , R 7 and R 8 Each of them is hydrogen.

[0027] In some embodiments, R 1 In some embodiments, R 1 It is an O-glycosyl group.

[0028] In some embodiments, R 2 In some embodiments, R 2 It is a C-sugar group.

[0029] In some embodiments, R 3In some embodiments, R 3 It is an O-glycosyl group.

[0030] In some embodiments, R 4 In some embodiments, R 4 It is a C-sugar group.

[0031] In some embodiments, R 5 For hydrogen.

[0032] In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 It is -OMe.

[0033] In some embodiments, R 7 In some embodiments, R 7 It is -OMe.

[0034] In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 It is -OMe.

[0035] In some embodiments, R 9 For hydrogen.

[0036] In some embodiments, the compound is selected from the group consisting of:

[0037]

[0038]

[0039]

[0040]

[0041] or a salt or a stereoisomer thereof.

[0042] In some embodiments, the compounds are in pure and isolated form.

[0043] When the compounds disclosed herein have at least one chiral center, they can exist as individual enantiomers and diastereomers or as mixtures of such isomers (including racemates). The separation of each isomer or the selective synthesis of each isomer is completed by applying various methods well known to those skilled in the art. Unless otherwise specified (for example, in the case of clearly showing the stereochemistry of the chiral center), all such isomers and mixtures thereof are included in the scope of the compounds disclosed herein. In addition, the compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise specified, all of these forms are included in the scope of the compounds disclosed herein, including any polymorphic form. In addition, some compounds disclosed herein can form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise specified, such solvates are included in the scope of the compounds disclosed herein.

[0044] Those skilled in the art will recognize that some of the structures described herein may be resonance forms or tautomers of compounds that can be reasonably represented by other chemical structures, even kinetically; the skilled artisan recognizes that such structures may represent only a small fraction of such compound samples. Although such resonance forms or tautomers are not shown herein, such compounds are still considered to be within the scope of the structures shown.

[0045] Isotopes may be present in the described compounds. Each chemical element represented in the compound structure may include any isotope of the element. For example, in the compound structure, a hydrogen atom may be explicitly disclosed or understood to be present in the compound. In any position where a hydrogen atom may be present in the compound, the hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Therefore, the compounds mentioned herein encompass all possible isotopic forms unless the context clearly indicates otherwise.

[0046] In some embodiments, the compounds disclosed herein are capable of forming acidic and / or basic 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; particularly preferred are ammonium, potassium, sodium, calcium, and magnesium salts. In some embodiments, treatment of the compounds disclosed herein with an inorganic base causes the compound to lose unstable hydrogen, thereby obtaining an inorganic cation such as Li + 、Na + , K + Mg 2+ and Ca 2 + 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, in particular isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine.

[0047] definition

[0048] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications, and other publications are incorporated herein by reference in their entirety. If a term is defined in multiple ways herein, the definition in this section shall prevail unless otherwise stated.

[0049] The terms "a" and "an" do not indicate a quantitative limitation, but rather indicate the presence of at least one of the items mentioned. The terms "or" or "and / or" are used as function words to indicate that two words or expressions are used together or alone. The terms "comprising", "having", "including" and "containing" should be interpreted as open-ended terms (e.g., meaning "including but not limited to"). The endpoints of all ranges involving the same component or property are included and independently combinable.

[0050] Many types of plants are known to produce sweet compounds and / or flavor-modifying compounds, and these compounds have been isolated and used as sweeteners and / or flavor-modifying compounds. In some embodiments herein, formulations of a combination of one or more sweeteners and one or more flavor-modifying compounds are obtained in whole or in part from plant extracts. "Extract" refers to a substance or mixture extracted from a plant by at least one purification or other processing step. As used herein, "plant" includes but is not limited to whole plants, plant parts, plant tissues, plant cells, or combinations 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, leaf axils, flowers, pollen, stamens, pistils, petals, peduncles, petioles, stigmas, styles, bracts, fruits, trunks, carpels, sepals, anthers, ovules, pedicels, needles, cones, rhizomes, spores, runners, buds, pericarp, endosperm, placenta, berries, stamens, sap, and sheaths.

[0051] As used herein, the term "isolated" when referring to a compound refers to being separated or isolated from other components, ingredients or chemicals that coexist with the target compound, whether or not other components, ingredients or chemicals are used or produced when the target compound is chemically or enzymatically synthesized, and whether or not other components, ingredients or chemicals exist naturally with the target compound in its native state. In some embodiments, the term "isolated" refers to a target compound that is substantially or substantially freed from components, ingredients or chemicals that normally accompany it in its native state by at least one purification or other processing step. Such isolated compounds may also be described as substantially pure. As used herein, the term "substantially pure" describes a target compound that has been separated from components, ingredients or chemicals that naturally accompany it. In some embodiments, an isolated compound is substantially pure when 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, by wet weight or dry weight, or by mole percentage or mole fraction) of the total material is the target compound. Purity can be measured by any appropriate method, such as by chromatography, gel electrophoresis, or HPLC analysis.

[0052] "Salt" refers to a salt of a compound that has the desired activity of the parent compound. Such salts include: (1) acid addition salts formed with inorganic acids or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and organic acids such as 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, ethane-1,2-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or (2) a salt 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 metal ion, or an aluminum ion); or a coordination compound formed with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc.).

[0053] "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.

[0054] As used herein, "sweetener", "sweet flavoring", "sweet flavor entity" or "sweet compound" refers to a compound or an ingestible acceptable salt thereof that elicits a detectable sweet flavor in a subject, such as a compound that activates T1R2 / T1R3 receptors in vitro.

[0055] The term "C-glycosyl" refers to a glycosyl group that is connected to the rest of the molecule by a carbon atom. Similarly, the term "O-glycosyl" refers to a glycosyl group that is connected to the rest of the molecule by an oxygen atom. As used herein, a C-glycosyl unit refers to a monosaccharide, a disaccharide, an oligosaccharide, or a polysaccharide. Sugar includes 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, sedoheptulose, octulose, fucose, rhamnose, arabinose, turanose, and sialose.

[0056] Sweeteners

[0057] Sweeteners have a wide range of chemically distinct structures and therefore have different properties, such as, but not limited to, aroma, flavor, mouthfeel, and aftertaste. The compositions described herein include any one or more sweeteners, including any combination of one or more sweeteners disclosed herein.

[0058] Natural or artificial sweeteners for use in ingestible compositions comprising a combination of sweeteners and flavor enhancers include, but are not limited to, natural or synthetic carbohydrates or carbohydrate analogs, including monosaccharides, disaccharides, oligosaccharides, and polysaccharides, and include rare sugars or sugars in D- or L- configuration, and include, for example, sucrose, fructose, glucose, L-arabinose, L-fucose, L-glucose, L-ribose, D-arabino-hexulose, psicose, altrose, arabinose, turanose, abequose, allose, abrinose triterpene glycoside A, aldotriose, threose, xylose, xylulose, xylooligosaccharides (e.g., xylotriose and xylobiose), lyxose, polydextrose, oligofructose, fucose, galacto-oligosaccharides, galactosamine, galactose, gentio-oligosaccharides (e.g., gentiobiose, gentiotriose, and gentiotetraose), dextrose, Cellobiose, D-leucrose, D-psicose, D-ribose, D-tagatose, trehalose (mycose), neotrehalose, isotrehalose, raffinose, idose, tagatose, melibiose, manno-oligosaccharides, rhamnose, ribose, ribulose, maltooligosaccharides (e.g., maltotriose, maltotetraose, maltopentaose, maltohexaose and maltoheptaose), maltose, sucrose acetate isobutyrate, dextrose, erythrose, erythrulose, deoxyribose, gulose, ketotriose, lactose, lactulose, kestose, nystose, mannose, sucralose, palatinose, polydextrose, sorbitol, sugaridextrose (mixed sugars) or talose, or a combination of any two or more of the foregoing sweeteners.

[0059] The one or more sweeteners can also include, for example, sweetener compositions comprising 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 hydrolysate (HSH), or other syrups or sweetener concentrates from natural fruit and vegetable sources, or semi-synthetic "sugar alcohol" sweeteners, such as polyols. In some embodiments, non-limiting examples of polyols include erythritol, maltitol, mannitol, sorbitol, lactitol, xylitol, isomalt, propylene glycol, glycerol (glycerine), threitol, galactitol, palatinose, reduced isomaltooligosaccharides, reduced xylo-oligosaccharides, reduced gentio-oligosaccharides, reduced maltose syrup, reduced glucose syrup, isomaltulose, maltodextrin, etc., as well as sugar alcohols or any other carbohydrates or combinations thereof that can be reduced without adversely affecting the taste.

[0060] The one or more sweeteners may be natural or synthetic sweeteners, including but not limited to agave inulin, agave nectar, agave syrup, amazake, brazzein, brown rice syrup, coconut crystals, coconut sugar, coconut syrup, date sugar, fructans (also known as inulin fiber, fructooligosaccharides or oligofructose), green stevia powder, Stevia rebaudiana, stevia syrup, agave nectar, agave ... 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 steviol-based glycosides, steviosides, stevioside extracts, honey, Jerusalem artichoke syrup, licorice root, monk fruit (fruit, powder or extract), lucuma (fruit, powder or extract), maple sap (including, for example, from sugar maple (Acer saccharum), black maple (Acer nigrum), red maple (Acer rubrum), silver maple (Acer saccharinum), Norway maple (Acer platanoides), ash maple (Acer negundo), bigleaf maple (Acer macrophyllum), roughtooth maple (Acer grandidentatum), Rocky Mountain maple (Acer glabrum), mono maple (Acer mono), maple syrup, maple sugar, walnut sap (including, for example, sap extracted from white walnut (Juglans inerea), black walnut (Juglans nigra), ghost walnut (Juglans ailatifolia), butternut (Juglans regia), birch sap (including, for example, sap extracted from paper birch (Betula papyrifera), yellow birch (Betula alleghaniensis), mountain birch (Betula lenta), river birch (Betula nigra), gray birch (Betula populifolia), weeping birch (Betula pendula), sycamore sap (including, for example, sap extracted from Platanus regia), occidentalis), ironwood sap (e.g., sap extracted from the American ironwood (Ostrya virginiana), unrefined cane sugar (mascobado), molasses (e.g., blackstrap molasses), molasses sugar, monatin, monellin, cane sugar (e.g.,sugar (also known as natural sugar, unrefined sucrose or table sugar), palm sugar, panocha, piloncillo, rapadura, raw sugar, rice syrup, sorghum, sorghum syrup, tapioca syrup (also known as tapioca syrup), thaumatin, yacon root, malt syrup, barley malt syrup, barley malt powder, beet sugar, cane sugar (cane sugar) sugar), crystallized fruit juice crystals, caramel, carbitol, carob syrup, castor sugar, hydrogenated starch hydrolates, hydrolyzed canned fruit juices, hydrolyzed starch, invert sugar, anethole, arabinogalactan, concentrated grape juice (arrope), syrup, P-4000, acesulfame potassium (also known as acesulfame potassium or ace-K), alitame (also known as aclame), advantame, aspartame, baiyunosdie, neotame, benzamide derivatives, bernadame, canderel, guanidine sweeteners (carrelame) and other guanidine sweeteners, plant fiber, corn sugar, coupling sugar, curculin, cyclamates, cyclocaryoside I (I), demerara, dextran, dextrin, diastatic malt, dulcin, sucrol, valzin, dulcoside A, dulcoside B, emulin, enoxolone, maltodextrin, saccharin, estragole, ethyl maltol, glucin, gluconic acid, gluconic acid lactone, glucosamine, glucuronic acid, glycerol, glycine, glycyphillin, glycyrrhizin, glycyrrhetinic acid monoglucuronide, golden sugar, brown sugar, golden syrup, granulated sugar, gynostemma pentaphyllum, hernandulcin, isomerized liquid sugar, jallab, chicory root dietary fiber, kynurenine derivatives (including N '-formyl-kynurenine, N'-acetyl-kynurenine, 6-chloro-kynurenine), galactitol, litesse, ligicane, lycasin, N-(4-cyanophenyl)-N-(2,3-methylenedioxybenzyl)guanidineacetic acid (lugduname), guanidine, falernum, mabinin I, mabinin II, maltol, crystalline maltitol (maltisorb), maltodextrin, maltotriol, mannosamine, micraculin, mizuame, mogrosides (including, for example, mogroside IV, mogroside V and neomogroside), mukurozioside, nanosaccharide (nano sugar), naringin dihydrochalcone, neohesperidin dihydrochalcone, nib sugar, nib oligosaccharide, norbu, almond syrup, osladin, pekmez, pentadin, periandrin I, perillaldehyde, perillartine, petphyllum, phenylalanine, phloisosideside I, phloretin, phlorodizin, phyllodulcin, polyglycitol syrup, polypodoside A, pterocaryoside A, pterocaryoside B, rebiana, refined syrup, rub syrup, rubusoside, selligueain A), shugr, simenoside I, siraitiagrosvenorii), soy oligosaccharides, Splenda, SRIoxime V, steviol glycosides, steviol biosides, stevioside, strogins 1, 2 and 4, sucrose, sucronic acid, sucrononate, sugar, sodium p-nitrophenylureidopropionate (suosan), phloridzin, super aspartame, tetrasaccharide, threitol, treacle, trilobtain, tryptophan and derivatives (6-trifluoromethyl-tryptophan, 6-chloro-D-tryptophan), vanilla sugar, heptyl heptol, birch syrup, aspartame-acesulfame, assugrin, and combinations or blends of any two or more thereof.

[0061] In other embodiments, the one or more sweeteners can be chemically or enzymatically modified natural high-potency sweeteners. Modified natural high-potency sweeteners include glycosylated natural high-potency sweeteners, such as glucosyl, galactosyl or fructosyl derivatives containing 1 to 50 glycoside residues. Glycosylated natural high-potency sweeteners can be prepared by enzymatic transglycosylation reactions catalyzed by various enzymes with transglycosylation activity. In some embodiments, modified sweeteners can be substituted or unsubstituted.

[0062] Other sweeteners also include any two or more combinations of any of the aforementioned sweeteners. In some embodiments, the sweetener can include a combination of two, three, four or five sweeteners disclosed herein. In some embodiments, the sweetener can be sugar. In some embodiments, the sweetener can be a combination of one or more sugars and other natural and artificial sweeteners.

[0063] Those skilled in the art will recognize that any one or more of the foregoing sweeteners may be combined in various ratios, amounts or concentrations to produce a single sweetener or a combination of two or more sweeteners, which are then combined with one or more flavor modifying compounds.

[0064] Those skilled in the art will recognize that the sweeteners described above for use in formulations comprising one or more sweeteners and one or more flavor-modifying compounds are provided by way of example and are not intended to be limiting.

[0065] Flavor Modifying Compounds

[0066] In some embodiments, additional flavor-modifying compounds can 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. Application Publication No. 2005 / 0084506, filed on August 6, 2004, entitled "Novel Flavors, Flavor Modifiers, Tastants, Taste Improvers, Umami or Sweet Tastants, and / or Enhancers and Use Thereof," the entire contents of which are incorporated herein by reference. In some embodiments, one or more flavor-modifying compounds are one or more flavor-modifying compounds disclosed in U.S. Application Publication No. 2007 / 0003680, filed on June 15, 2006, entitled "Bis-Aromatic Amides and Their Uses as Sweet Flavor Modifiers, Tastants, and Taste Enhancers," the entire contents of which are incorporated herein by reference. In some embodiments, the one or more flavor-modifying compounds are one or more flavor-modifying compounds disclosed in U.S. Application Publication No. 2008 / 0306093, filed on June 8, 2007, entitled "Modulation of Chemosensory Receptors and Ligands Associated Therewith," 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. Application Publication No. 2011 / 0224155, filed on April 14, 2011, entitled "Modulation of Chemosensory Receptors and Ligands Associated Therewith," 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. Application Publication No. 2011 / 0245353, filed on March 31, 2011, entitled "Sweet Flavor Modifier," 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. Application Publication No. 2013 / 0041046, filed on August 10, 2012, entitled “Sweet Flavor Modifier,” the entire contents of which are incorporated herein by reference.In some embodiments, the one or more flavor-modifying compounds are one or more flavor-modifying compounds disclosed in U.S. Application Publication No. 2014 / 0094453, filed on December 4, 2014, entitled "Sweet Flavor Modifier," the entire contents of which are incorporated herein by reference. In some embodiments, the one or more flavor-modifying compounds are one or more flavor-modifying compounds disclosed in U.S. Application Publication No. 2014 / 0235624, filed on February 19, 2014, entitled "Sweet Flavor Modifier," the entire contents of which are incorporated herein by reference. In some embodiments, the one or more flavor-modifying compounds are one or more flavor-modifying compounds disclosed in U.S. Application Publication No. 2015 / 0376176, filed on August 14, 2015, entitled "Sweet Flavor Modifier," the entire contents of which are incorporated herein by reference. In some embodiments, the one or more flavor-modifying compounds are one or more flavor-modifying compounds disclosed in U.S. Application Publication No. 2016 / 0185727, filed on October 28, 2015, entitled “Substituted 4-amino-5-(cyclohexyloxy)quinolone-3-carboxylic acids as Sweet Flavor Modifiers,” the entire contents of which are incorporated herein by reference.

[0067] In some embodiments, the one or more additional flavor-modifying compounds are compounds having a cyclic thiadiazine core.

[0068] Some embodiments include In combination with any one or more of the flavor-modifying compounds described or referenced herein.

[0069] Some embodiments include In combination with any one or more of the flavor-modifying compounds described or referenced herein.

[0070] Some embodiments include and and any one or more additional flavor-modifying compounds described or referenced herein.

[0071] Some embodiments include and and any one or more additional flavor-modifying compounds described or referenced herein.

[0072] Some embodiments include and any one or more additional flavor-modifying compounds described or referenced herein.

[0073] Some embodiments include any combination of a flavor-modifying compound described herein and one or more sweeteners described herein.

[0074] 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 above values.

[0075] Composition and use

[0076] Some compositions herein relate to formulations comprising one or more sweeteners disclosed herein in combination with one or more flavor-modifying compounds described herein. Therefore, it should be recognized that the combination of one or more sweeteners with one or more flavor-modifying compounds disclosed herein is non-limiting. In some embodiments, the formulation comprising one or more sweeteners and one or more flavor-modifying compounds is used as a composition of an ingestible or non-ingestible product.

[0077] The formulations comprising one or more sweeteners and 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, and modulating, treating, or taking preventive measures for conditions associated with chemosensory receptors, such as physiological or pathological conditions. 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 some embodiments, the formulation increases or enhances sweet flavor. In another embodiment, the formulation modulates sweet taste receptors and / or their ligands expressed in body parts other than taste buds (e.g., visceral organs). In general, the formulations of the present disclosure can be provided in the form of a composition, such as an ingestible composition. In some embodiments, the formulations of the present invention can impart a more sugar-like temporal profile and / or flavor profile to the sweetener composition by combining one or more flavor-modifying compounds with one or more sweeteners in a combined formulation. In another embodiment, the formulations of the present invention can increase or enhance the sweetness of a composition by contacting the composition with one or more formulations of the present invention to form a modified composition. In another embodiment, the formulations of the present invention can be a composition that modulates sweet taste receptors and / or their ligands expressed in vivo rather than in taste buds.

[0078] In some embodiments, the formulations of the invention have sucrose modifying behavior and / or sweet agonist behavior in vitro and / or in vivo (e.g., as shown in sensory studies). In some embodiments, the formulations of the invention exhibit a favorable side-taste profile in vivo.

[0079] Whether a formulation exhibits a sweet taste modifying / agonist effect can be determined by any suitable testing method. For example, formulations comprising one or more sweeteners in combination with a flavor modifying compound can be evaluated in a sensory test using a human taste panel.

[0080] In some embodiments, the formulation can be diluted prior to testing. In some embodiments, the formulation is diluted about 2 times, about 5 times, about 10 times, about 50 times, about 100 times, about 200 times, about 300 times, about 400 times, about 500 times, about 1000 times or more prior to testing.

[0081] The test can be carried out with and / or without additives. In some embodiments, the formulation is tested to assess the sweet taste enhancement effect of one or more additives. In the test, participants can provide their impressions of the similarity of the characteristics of the sweetener composition containing and / or not containing additives and the sweetener composition comprising sugar. The appropriate procedure for determining whether the composition has a more sugar-like taste is carried out by using an assessor panel measuring the sweetness of the formulation.

[0082] One embodiment provides a formulation for use in a method of preparing a ready-to-use composition (e.g., a final food or beverage product, or an animal feed product). The method includes contacting a first composition (e.g., a first food or beverage product that may contain one or more sweeteners described herein) with a flavoring concentrate composition or formulation (e.g., solid or liquid) containing one or more flavor-modifying compounds to form a ready-to-use composition.

[0083] In some embodiments, the ingestible composition can be a beverage. In some embodiments, the beverage can be selected from 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 fruit juice, fruit juice beverage, honeydew beverage, vegetable juice, vegetable flavored juice, sports drink, energy drink, fortified water beverage, vitamin-fortified water, near water beverage, coconut water, tea beverage, coffee, cocoa beverage, beverage containing milk ingredients, chocolate milk, pure dairy flavored milk beverage, fruit juice flavored milk beverage, milk substitute beverage (including rice milk, almond milk, cashew milk, coconut milk, hazelnut milk, pistachio milk, oat milk, wheat milk, barley milk, millet milk, spelt milk, black wheat milk and soy milk), yogurt beverage, fermented milk beverage, kefir, beverage containing cereal extract and smoothie. In some embodiments, the beverage can be a soft drink.

[0084] In some embodiments, one or more flavor-modifying compounds described herein and one or more sweeteners described herein can be included in a food or beverage product, wherein the food or beverage product can additionally include:

[0085] Acids, including, for example, citric acid, phosphoric acid, ascorbic acid, sodium bisulfate, lactic acid, or tartaric acid;

[0086] bitter ingredients, including, for example, caffeine, quinine, green tea, catechins, polyphenols, robusta green coffee bean extract, green coffee bean extract, whey protein isolate, or potassium chloride;

[0087] Coloring agents, including, for example, caramel, red #40, yellow #5, yellow #6, blue #1, red #3, purple carrot, black carrot juice, purple sweet potato, vegetable juice, fruit juice, beta-carotene, turmeric curcumin, or titanium dioxide;

[0088] preservatives, including, for example, sodium benzoate, potassium benzoate, potassium sorbate, sodium metabisulfite, sorbic acid, or benzoic acid;

[0089] Antioxidants, including, for example, ascorbic acid, calcium disodium EDTA, alpha-tocopherol, mixed tocopherols, rosemary extract, grape seed extract, resveratrol, or sodium hexametaphosphate;

[0090] Vitamins or functional ingredients, including, for example, resveratrol, Co-Q10, omega 3 fatty acids, theanine, choline chloride (citicoline), safflower, inulin (chicory root), taurine, ginseng extract, guarana extract, ginger extract, L-phenylalanine, L-carnitine, L-tartrate, D-glucuronolactone, inositol, bioflavonoids, echinacea, ginkgo, mate, flaxseed oil, garcinia peel extract, white tea extract, ribose, milk thistle extract, grape seed extract, pyridoxine hydrochloride (vitamin B6), cyanocobalamin (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 mononitrate, vitamin D3, vitamin A palmitate, zinc gluconate, zinc lactate, or zinc sulfate;

[0091] Clouding agents, including, for example, ester gum, brominated vegetable oil (BVO), or sucrose acetate isobutyrate (SAIB);

[0092] buffers, including, for example, sodium citrate, potassium citrate, or salt;

[0093] Flavors, including, for example, propylene glycol, ethanol, glycerin, gum arabic (acacia gum), maltodextrin, modified corn starch, dextrose, natural flavorings, natural flavorings with other natural flavorings (natural flavoring WONF), natural and artificial flavorings, artificial flavorings, silicon dioxide, magnesium carbonate, or tricalcium phosphate; and

[0094] Stabilizers include, for example, pectin, xanthan gum, carboxymethyl cellulose (CMC), polysorbate 60, polysorbate 80, medium chain triglycerides, cellulose gel, cellulose gum, sodium caseinate, modified food starch, gum arabic (acacia gum), or carrageenan.

[0095] Some embodiments provide supplements, nutraceuticals, functional food products (e.g., any fresh or processed food 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, cosmetics such as sweetened lip balm, and other personal care products comprising one or more flavor modifying compounds described herein and the sweeteners described herein.

[0096] In general, over-the-counter (OTC) products and oral care products generally refer to products for home and / or personal use that are sold without a prescription and / or without visiting a medical professional. Examples of OTC products include, but are not limited to, vitamins and dietary supplements; local analgesics and / or anesthetics; remedies for coughs, colds and allergies; antihistamines and / or allergy remedies; and combinations thereof. Vitamins and dietary supplements include, but are not limited to, vitamins, dietary supplements, supplements / bottled nutritional drinks, vitamins for children, dietary supplements, any other products related to nutrition or providing nutrition, and combinations thereof. Local analgesics and / or anesthetics include any topical creams / ointments / gels used to relieve superficial or deep pain, such as muscle pain; teething gels; patches containing analgesic ingredients; and combinations thereof. Cough, cold and allergy remedies include, but are not limited to, decongestants, cough remedies, pharyngeal preparations, medicated candies, antihistamines and cough, cold and allergy remedies for children; and combination products. Antihistamines and / or allergy treatments 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, oral cleaning strips, toothpaste, toothbrushes, mouthwash / teethwash, denture care, mouth fresheners, home teeth whiteners, dentifrices, and dental floss.

[0097] In some embodiments, one or more flavor-modifying compounds described herein and one or more sweeteners described herein may be included in food or beverage products or formulations. Examples of food and beverage products or formulations include, but are not limited to, sweet coatings, frostings, or icings of ingestible products, or any entity included in the following: soups, dry processed foods, beverages, ready-to-eat foods, canned or preserved foods, frozen processed foods, refrigerated processed foods, snack foods, baked foods, candies, dairy products, ice cream, meal replacements, pasta and noodles, and sauces, seasonings, condiments, baby foods, and / or spreads.

[0098] In general, soups refer to canned / preserved, dehydrated, instant, refrigerated, UHT and frozen soups. For the purpose of this definition, soup refers to a food made from meat, poultry, fish, vegetables, grains, fruits and other ingredients, cooked in a liquid, which may contain visible fragments of some or all of these ingredients. It may be clear (as a stock) or thick (as a chowder), smooth, pureed or chunky, ready-to-eat, semi-concentrated or concentrated, and may be served hot or cold, as a first course or main course or as a snack (sipping beverage) between meals. Soup can be used as a raw material for the preparation of other meal ingredients, ranging from broth (consommé) to sauces (cream- or cheese-based soups).

[0099] The Dehydrated and Cooking Foods category generally refers to: (i) cooking aid products, such as powdered, granulated, paste-like, concentrated liquid products, including concentrated bouillon, bouillon, and bouillon-like products in pressed blocks, tablets, or powdered or granulated form, sold individually as finished products or as ingredients in products, sauces, and dressing mixes (regardless of technology); (ii) dietary solution products, such as dehydrated and freeze-dried soups, including dehydrated soup mixes, dehydrated instant soups, dehydrated instant soups, dehydrated ready-to-eat soups, dehydrated or self-heating preparations of ready-made dishes, meals, and single-serving entrees, including pasta, potatoes, and rice; and (iii) dietary garnish products, such as condiments, marinades, salad dressings, salad toppings, dips, mixes, batter mixes, shelf-stable sauces, barbecue sauces, liquid dressing mixes, concentrates, sauces or sauce mixes, including salad dressing mixes, sold as finished products or as ingredients in products, whether dehydrated, liquid, or frozen.

[0100] Beverages generally refer 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 preparing beverages (e.g., soda), and dry powder beverage precursor mixtures. Beverages also include alcoholic beverages, soft drinks, sports drinks, isotonic beverages and hot beverages. Alcoholic beverages include but are not limited to beer, cider / perry, flavored alcoholic beverages, wine and spirits. Soft drinks include but are not limited to carbonated beverages, such as cola and non-cola carbonated beverages; fruit juices, such as fruit juices, honey drinks, fruit drinks and fruit-flavored drinks; bottled water, including soda water, spring water and purified / table water; functional beverages, which can be carbonated or still beverages, including sports drinks, energy drinks or elixir drinks; concentrates, such as ready-to-drink liquids and powder concentrates. The beverages, whether hot or cold, include, but are not limited to, coffee or iced coffee, such as freshly ground coffee, instant coffee, and blended coffee; tea or iced tea, such as black tea, green tea, white tea, oolong tea, and flavored tea; and other beverages, including flavored, malt-based or plant-based powders, granules, blocks, or tablets mixed with milk or water.

[0101] Snacks generally refer to any food that is a simple, informal meal, including but not limited to sweet and savory snacks and snack bars. Examples of snacks include but are not limited to fruit snacks, potato chips / crisps, extruded snacks, tortillas / corn chips, popcorn, pretzels, nuts and other sweet and savory snacks. Examples of snack bars include but are not limited to granola / cereal bars, breakfast bars, energy bars, fruit bars and other snack bars.

[0102] The baked goods category generally refers to any edible product whose preparation process involves exposure to heat or excessive sunlight. Examples of baked goods include, but are not limited to, bread, buns, cookies, muffins, cereals, toaster pastries, cakes, waffles, tortillas, soft cookies, pies, bagels, tarts, quiches, cakes, any baked goods, and any combination thereof.

[0103] Ice cream generally refers to frozen desserts containing cream, sugar and flavorings. Examples of ice cream include, but are not limited to: impulse ice cream; family-packed ice cream; frozen yogurt and handmade ice cream; gelato; sorbet; sherbet; soy, oat, legume (such as red bean and mung bean), coconut, nut and rice-based ice cream.

[0104] Candy generally refers to edible products that taste sweet. Examples of candy include, but are not limited to, hard candy, gelatin, chocolate candy, granulated candy, chewing gum, etc. and any combination of products.

[0105] The meal replacement category generally refers to any food that is intended to replace a normal meal, especially for those who are concerned with health or fitness. Examples of meal replacements include, but are not limited to, weight loss products and recovery products.

[0106] The ready-to-eat food category generally refers to any food that can be consumed as a meal without extensive preparation or processing. Ready-to-eat foods include products to which the manufacturer has added recipe "skills" so that they have a high degree of readiness, completeness, and convenience. Examples of ready-to-eat foods include, but are not limited to, canned / preserved, frozen, dried, refrigerated ready meals; dinner mixes; frozen pizza; refrigerated pizza; and prepared salads.

[0107] The Pasta and Noodle category includes any pasta and / or noodles, including but not limited to canned, dried and refrigerated / fresh pasta; and plain, instant, refrigerated, frozen and snack noodles.

[0108] The canned / preserved foods category includes, but is not limited to, canned / preserved meats and meat products, fish / seafood, vegetables, tomatoes, beans, fruits, ready meals, soups, pasta, and other canned / preserved foods.

[0109] The frozen processed food 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.

[0110] The dry processed food category includes, but is not limited to, rice, dessert mixes, dry ready meals, dehydrated soups, instant soups, dry pasta, plain noodles, and instant noodles. The refrigerated processed food category includes, but is not limited to, refrigerated processed meats, processed fish / seafood products, lunch boxes, fresh-cut fruit, ready meals, pizza, prepared salads, soups, fresh pasta, and noodles.

[0111] The Sauces, Dressings and Condiments category includes, but is not limited to, tomato sauces 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, pickles, and other sauces, dressings and condiments.

[0112] The baby food category includes, but is not limited to, milk- or soy-based formulas; and prepared, dry, and other baby foods.

[0113] Spreads include, but are not limited to, jams and preserves, honey, chocolate spreads, nut spreads, caramel biscuit (speculoos) spreads, butter, flavored butter, margarine, cooking oil spreads, liquid butter (oleos), cheese or cream cheese spreads, savory spreads and yeast spreads.

[0114] Dairy products generally refer to edible products produced from the milk of mammals. Examples of dairy products include, but are not limited to, drinking milk products, cheese, yogurt and sour milk drinks, and other dairy products.

[0115] Additional examples of ingestible compositions, particularly food and beverage products or formulations, are provided below. Exemplary ingestible compositions include one or more candies, chocolate candies, chocolate chips, chocolate slabs (countlines), bagged chocolate bars (selflines) / softlines, boxed assortments, standard boxed assortments, twist-wrapped miniature chocolates, flavored chocolates, chocolates with toys, sandwich cookies, other chocolate candies, mints, standard mints, strong mints, hard candies, pastilles, chewing gum, jellies and chews, toffees, caramels and nougats, medicated candies, lollipops, liquorice, other candies, breads, packaged / industrial breads, bulk / artisanal breads, pastries, cakes, packaged / industrial cakes, bulk / artisanal cakes, cookies, chocolates Coated biscuits, sandwich biscuits, stuffed crackers, saltine crackers and biscuits, bread substitutes, breakfast cereals, ready-to-eat cereals, family breakfast cereals, corn flakes (flakes), muesli, other cereals, children's breakfast cereals, hot cereals, ice cream, ready-to-eat ice cream, single-serve dairy ice cream, single-serve water ice cream, multi-pack dairy ice cream, multi-pack water ice cream, family-pack ice cream, family-pack dairy ice cream, ice cream desserts, loose ice cream, family-pack water ice cream, frozen yogurt, artisanal ice cream, dairy products, milk, fresh / pasteurized milk, whole fat fresh / pasteurized milk, semi-skimmed fresh / pasteurized milk, extended shelf life / UHT milk, whole fat extended shelf life / UHT Warm milk, semi-skimmed extended shelf life / UHT milk, fat-free extended shelf life / UHT milk, goat's milk, condensed milk / evaporated milk, plain condensed milk / evaporated milk, flavored, functional and other condensed milk, flavored milk drinks, chocolate milk, pure dairy flavored milk drinks, juice flavored milk drinks, milk alternative drinks (including rice milk, almond milk, cashew milk, coconut milk, hazelnut milk, pistachio milk, oat milk, wheat milk, barley milk, millet milk, spelt milk, triticale milk and soy milk), yogurt drinks, fermented milk drinks, kefir, coffee creamer, milk powder, flavored milk powder drinks, cream, cheese, processed cheese, spreadable cheese, non-spreadable processed cheese, unprocessed cheese, spreadable unprocessed cheese, hard cheese, packaged hard cheese, unpackaged Hard cheese, Yogurt, Plain / Natural yogurt, Flavored yogurt, Fruit yogurt, Probiotic yogurt, Drinking yogurt, Regular drinking yogurt, Probiotic drinking yogurt, Frozen and shelf-stable snacks, Dairy-based snacks, Soy-based desserts, Frozen snacks, Fresh cheese and quark, Plain fresh cheese and quark, Flavored fresh cheese and quark, Salted fresh cheese and quark, Sweet and savory snacks, Fruit snacks, Chips / potato chips, Extruded snacks, Tortillas / corn chips, Popcorn, Pretzels, Nuts, Other sweet and savory snacks, Snack bars, Granola, Breakfast bars, Energy bars, Fruit bars, Other snack bars, Meal replacements, Weight loss products, Recovery drinks, Ready-to-eat foods, Canned ready-to-eat foods, Frozen ready-to-eat foods,Dried ready meals, frozen ready meals, dinner mixes, frozen pizza, refrigerated pizza, soups, canned soups, dehydrated soups, instant soups, cold soups, hot soups, frozen soups, pasta, canned pasta, dried pasta, frozen / fresh pasta, noodles, plain noodles, instant noodles, instant noodles in cups / bowls, instant noodles in bags, frozen noodles, snack noodles, canned foods, 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, cold 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 baked goods, Frozen desserts, Frozen ready meals, Frozen pizza, Frozen soups, Frozen noodles, Other frozen foods, Dried foods, Dessert mixes, Dried ready meals, Dehydrated soups, Instant soups, Dried pasta, Plain noodles, Instant noodles, Instant noodles in cups / bowls, Instant noodles in bags, Refrigerated foods, Refrigerated processed meats, Refrigerated fish / seafood products, Refrigerated processed fish, Refrigerated coated fish, Refrigerated smoked fish, Refrigerated lunch packs, Refrigerated ready meals, Refrigerated pizza, Refrigerated soups, Refrigerated / fresh pasta, Refrigerated noodles, Oils and fats, Olive oil, Vegetable and seed oils, Cooking fats, Butter, Margarine, Spreads, Functional spreads, Sauces, Dressings and condiments, Tomato pastes and purees, Bouillon / stock cubes, Stock cubes, Gravy granules, Liquid stocks and stock, Herbs and spices, Fermented sauces, Soy sauces, Pasta sauces, Wet sauces, Dry sauces / powder mixes, Ketchup, Mayonnaise, Regular mayonnaise, Mustard, Salad dressings, Conventional salad dressings, low-fat salad dressings, vinaigrettes, dips, marinades, other sauces, seasonings and condiments, baby food, formula milk powder, standard formula milk powder, growing-up formula milk powder, toddler formula milk powder, allergy-proof milk powder formula, pre-made baby food, dry baby food, other baby food, spreads, jams and preserves, honey, chocolate spreads, nut spreads, caramel cream (speculoos) spreads, butter, flavored butter, margarine, edible oil spreads, liquid butter, cheese or cream cheese spreads, savory spreads and yeast spreads. Exemplary ingestible compositions also include candies, baked goods, ice cream, dairy products, sweet and savory snacks, snack bars, meal replacement products, ready-to-eat foods, soups, pasta, noodles, canned foods, frozen foods, dry foods, refrigerated foods, oils and fats, baby foods or spreads or mixtures thereof. Exemplary ingestible compositions also include breakfast cereals, sweetened beverages, or solid or liquid concentrate compositions for preparing beverages, ideally allowing for reduced concentrations of previously known sugar sweeteners or artificial sweeteners.

[0116] Some embodiments provide chewable compositions that may or may not be swallowed. In some embodiments, the chewable composition may be gum, chewing gum, saccharified gum, sugarless gum, functional gum, bubble gum, including one or more flavor-modifying compounds described herein and one or more sweeteners described herein.

[0117] In some embodiments, one or more flavor modification compounds described herein and one or more sweeteners described herein can be provided in the form of a flavoring concentrate preparation, such as suitable for subsequent processing to produce a ready-to-use (e.g., ready-to-eat) product. "Flavoring concentrate preparation" refers to a formulation that should be reconstituted with one or more dilution media to become a ready-to-use composition. The term "ready-to-use composition" is used interchangeably with "ingestible composition" herein, which means that it is intended to be used for or not for consumption, whether alone or with another substance, any substance that can be taken orally. In one embodiment, the ready-to-use composition includes a composition that can be directly eaten by a human or animal. The flavoring concentrate preparation is usually used by mixing or diluting with one or more dilution media, such as any edible or ingestible ingredients or products, to impart or change the dilution medium with one or more flavorings. Such a use process is generally referred to as recovery. Recovery can be carried out in a home environment or an industrial environment. For example, a consumer can recover a frozen fruit juice concentrate in a kitchen with water or other aqueous media to obtain a ready-to-use fruit juice beverage. In another example, soft drink syrup concentrate can be reconstituted with water or other aqueous media on a large-scale industrial scale by manufacturers to produce instant soft drinks. Since the concentration of the flavoring or seasoning that the flavoring concentrate preparation has is higher than the instant composition, the flavoring concentrate preparation is usually not suitable for direct consumption without reconstitution. There are many benefits to using and producing the flavoring concentrate preparation. For example, one benefit is to reduce the weight and volume of transportation, because the flavoring concentrate preparation can be reconstituted by adding a suitable solvent, solid or liquid when using.

[0118] In one embodiment, the flavoring concentrate formulation comprises i) one or more flavor-modifying compounds described herein; ii) a carrier; and iii) optionally at least one adjuvant. The term "carrier" refers to a generally inactive auxiliary substance, such as a solvent, binder, or other inert medium, which 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 flavoring concentrate formulation. In some embodiments, the carrier is the same as the dilution medium used to reconstitute the flavoring concentrate formulation; in other embodiments, the carrier is different from the dilution medium. As used herein, the term "carrier" includes, but is not limited to, an ingestible acceptable carrier.

[0119] The term "adjuvant" refers to an additive that supplements, stabilizes, maintains or enhances the expected function or effectiveness of an active ingredient (e.g., a compound of the present disclosure). In one embodiment, at least one adjuvant includes one or more flavorings. Flavorings can have any flavor known to those skilled in the art or consumers, such as chocolate, coffee, tea, mocha, French vanilla, peanut butter, chai, or the flavor of a combination thereof. In another embodiment, at least one adjuvant includes one or more sweeteners. One or more sweeteners can be any of the above-mentioned sweeteners. In another embodiment, the at least one adjuvant includes one or more ingredients 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. Patent No. 6,468,576, the entire contents of which are incorporated herein by reference for all purposes.

[0120] In one embodiment, the flavoring concentrate formulation of the present invention can be in the form of a liquid, solid, foam, paste, gel, emulsion and a combination thereof selected from solutions and suspensions, such as a liquid containing a certain amount of solid content. In one embodiment, the flavoring concentrate formulation is in the form of a liquid including water-based and non-aqueous. In some embodiments, the flavoring concentrate formulation of the present invention can be carbonated or non-carbonated.

[0121] The flavoring concentrate formulation may further include a freezing point depression agent, a nucleating agent or both as the at least one adjuvant. A freezing point depression agent is an acceptable compound or agent for ingestion, which can reduce the freezing point of a liquid or solvent to which the compound or agent has been added. That is, the freezing point of a liquid or solution containing a freezing point depression agent is lower than the freezing point of a liquid or solvent without a freezing point depression agent. In addition to reducing the initial freezing point, a freezing point depression agent can also reduce the water activity of the flavoring concentrate formulation. Examples of freezing point depression agents include, but are not limited to, carbohydrates, oils, ethanol, polyols such as glycerol and combinations thereof. A nucleating agent represents an acceptable compound or agent for ingestion that can promote nucleation. The presence of a nucleating agent in the flavoring concentrate formulation can improve the mouthfeel of slush, and helps maintain the physical properties and performance of slush at freezing temperatures by increasing the number of required ice crystal centers. Examples of nucleating agents include, but are not limited to, calcium silicate, calcium carbonate, titanium dioxide and combinations thereof.

[0122] In one embodiment, the flavoring 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 water activity of the flavoring concentrate formulation is less than about 0.85. In another embodiment, the water activity of the flavoring concentrate formulation is less than about 0.80. In another embodiment, the water activity of the flavoring concentrate formulation is less than about 0.75.

[0123] In one embodiment, the concentration of one or more flavor-modifying compounds in the flavoring concentrate formulation is at least 2 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of one or more flavor-modifying compounds in the flavoring concentrate formulation is at least 5 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of one or more flavor-modifying compounds in the flavoring concentrate formulation is at least 10 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of one or more flavor-modifying compounds in the flavoring concentrate formulation is at least 15 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of one or more flavor-modifying compounds in the flavoring concentrate formulation is at least 20 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of one or more flavor-modifying compounds in the flavoring concentrate formulation is at least 30 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of one or more flavor-modifying compounds in the flavoring concentrate formulation is at least 40 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of one or more flavor-modifying compounds in the flavoring concentrate formulation is at least 50 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of one or more flavor-modifying compounds in the flavoring concentrate formulation is at least 60 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of one or more flavor-modifying compounds in the flavoring concentrate formulation is up to 100 times the concentration of the compound in the ready-to-use composition.

[0124] Ingestible composition

[0125] In some embodiments, the compounds disclosed and described herein can be used alone or in combination for one or more methods, such as modifying a receptor function associated with chemosensory perception or a receptor function associated with a chemosensory-related sensation or reaction. Some embodiments provide a method of modulating a chemosensory receptor, including modulating the activity, structure, function and / or modification of a chemosensory receptor, and modulating, treating, or taking preventive measures for conditions associated with chemosensory receptors, such as physiological or pathological conditions. 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 some embodiments, the method increases or enhances a sweet flavor. In another embodiment, the method modulates sweet taste receptors and / or their ligands expressed in body parts other than taste buds (e.g., visceral organs).

[0126] In general, the compounds disclosed and described herein can be provided in the form of compositions, such as ingestible compositions, alone or in combination. In one embodiment, the compounds disclosed and described herein can be combined with one or more of the compounds disclosed and described herein and one or more sweeteners in the sweetener composition to give the sweetener composition a more sugar-like time curve and / or flavor curve. In another embodiment, the compounds disclosed and described herein can increase or enhance the sweetness of the composition by contacting its composition with the compounds disclosed and described herein to form a modified composition. In another embodiment, the compounds disclosed and described herein can be present alone or in combination in a composition of sweet receptors and / or their ligands expressed in vivo rather than in taste buds.

[0127] Some embodiments provide a kind of ingestible composition, it comprises formula (I), (II) or (III) any one of the compound, and sweetener.In some embodiments, the composition also comprises vehicle.In some embodiments, vehicle is water.In some embodiments, the compound can be present at a concentration equal to or lower than its sweet taste recognition threshold.In some embodiments, sweetener is present at a concentration of 0.1% to 12% by weight.In some embodiments, sweetener is present at a concentration of 0.2% to 10% by weight.In some embodiments, sweetener is present at a concentration of 0.3% to 8% by weight.In some embodiments, sweetener is present at a concentration of 0.4% to 6% by weight.In some embodiments, sweetener is present at a concentration of 0.5% to 5% by weight.In some embodiments, sweetener is present at a concentration of 1% to 2% by weight.In some embodiments, sweetener is present at a concentration of 0.1% to 5% by weight.In some embodiments, sweetener is present at a concentration of 0.1% to 4% by weight. In some embodiments, the sweetener is present in a concentration of 0.1% to 3% by weight. In some embodiments, the sweetener is present in a concentration of 0.1% to 2% by weight. In some embodiments, the sweetener is present in a concentration of 0.1% to 1% by weight. In some embodiments, the sweetener is present in a concentration of 0.1% to 0.5% by weight. In some embodiments, the sweetener is present in a concentration of 0.5% to 10% by weight. In some embodiments, the sweetener is present in a concentration of 2% to 8% by weight. In some embodiments, the sweetener can be common sugar sweeteners, such as sucrose, fructose, glucose, and sweetener compositions containing natural sugars such as corn syrup (including high fructose corn syrup) or other syrups or sweetener concentrates derived from natural fruit and vegetable sources; rare natural sugars, including D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-arabinose, D-turanose, and D-leucrose; semi-synthetic "sugar alcohol" sweeteners, such as erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, maltodextrin, etc.; and artificial sweeteners, such as aspartame, saccharin, acesulfame potassium, cyclamates, sucralose and alitame. In some embodiments, the sweetener is selected from the group consisting of cyclamic acid, mogroside, 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 hydrolysate (HSH), stevioside, rebaudioside A and other sweet steviosides, carrelame and other guanidine-based sweeteners.In some embodiments, the sweetener can be a combination of two or more sweeteners disclosed herein. In some embodiments, the sweetener can be a combination of two, three, four or five sweeteners disclosed herein. In some embodiments, the sweetener can be sugar. In some embodiments, the sweetener can be a combination of one or more sugars with other natural and artificial sweeteners. In some embodiments, the sweetener is sugar. In some embodiments, the sugar is cane sugar. In some embodiments, the sugar is beet sugar. In some embodiments, the sugar can be sucrose, fructose, glucose or a combination thereof. In some embodiments, the sugar can be sucrose. In some embodiments, the sugar can be a combination of fructose and glucose. In some embodiments, the sugar can be a combination of about 55% fructose and about 42% glucose. In some embodiments, the sugar can be a combination of about 42% fructose and about 53% glucose. In some embodiments, the sugar can be a combination of about 90% fructose and about 10% glucose. In some embodiments, the sweetener can 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-arabinose, 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 can be sucralose.

[0128] In some embodiments, the ingestible composition can be a beverage. In some embodiments, the beverage can be selected from 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 fruit juice, fruit juice drinks, honey juice drinks, vegetable juices, vegetable flavored juices, sports drinks, energy drinks, fortified water drinks, vitamin-fortified water, near water drinks, coconut water, tea drinks, coffee, cocoa drinks, beverages containing milk ingredients, beverages containing cereal extracts and smoothies. In some embodiments, the beverage can be a soft drink.

[0129] In one embodiment, the compounds disclosed and described herein can be used alone or in combination at their ligand-enhancing concentrations (e.g., very low concentrations on the order of a few parts per million) in combination with one or more known natural or artificial sweeteners in order to reduce the concentration of the known sweetener required to prepare an ingestible composition having a desired sweetness.

[0130] In one embodiment, the compounds disclosed and described herein can enhance the sweetness of sweeteners at a wide range of pH values, for example, from a relatively low pH value to a neutral pH value, either individually or in combination. Lower and neutral pH include, but are not limited to, from about 2.5 to about 8.5; from about 3.0 to about 8.0; from about 3.5 to about 7.5; and from about 4.0 to about 7 pH values. In certain embodiments, the compounds disclosed and described herein can enhance the perceived sweetness of a fixed concentration of sweeteners at low to neutral pH values ​​with a compound concentration of 50 μM, 40 μM, 30 μM, 20 μM or 10 μM in a taste test, either individually or in combination. In certain embodiments, the enhancement factor of the compounds disclosed and described herein, either individually or in combination, at a relatively low pH is substantially similar to the enhancement factor of the compounds at a neutral pH. This consistent sweet taste enhancement property over a wide pH range allows the compounds disclosed and described herein to be widely used in a variety of foods and beverages, either individually or in combination. In some embodiments, the sweetener can be common sugar sweeteners, such as sucrose, fructose, glucose, and sweetener compositions containing natural sugars such as corn syrup (including high fructose corn syrup) or other syrups or sweetener concentrates derived from natural fruit and vegetable sources; rare natural sugars, including D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-arabinose, D-turanose, and D-leucrose; semi-synthetic "sugar alcohol" sweeteners, such as erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, maltodextrin, etc.; and artificial sweeteners, such as aspartame, saccharin, acesulfame potassium, cyclamates, sucralose and alitame. In some embodiments, the sweetener is selected from the group consisting of: cyclamic acid, mogroside, 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 hydrolysate (HSH), stevioside, rebaudioside A and other sweet steviosides, guanidine sweeteners (carrelame) and other guanidine sweeteners. In some embodiments, the sweetener can be a combination of two or more sweeteners disclosed herein. In some embodiments, the sweetener can be a combination of two, three, four or five sweeteners disclosed herein. In some embodiments, the sweetener can be sugar. In some embodiments, the sweetener can be a combination of one or more sugars and other natural and artificial sweeteners. In some embodiments, the sweetener is sugar. In some embodiments, the sugar is cane sugar. In some embodiments, the sugar is beet sugar. In some embodiments, sweetener can be one or more sugars and other natural and artificial sweeteners.In some embodiments, sugar can be sucrose, fructose, glucose or their combination (such as high fructose corn syrup).In some embodiments, sugar can be sucrose. In some embodiments, sugar can be a combination of fructose and glucose. In some embodiments, sugar can be a combination of about 55% fructose and about 42% glucose. In some embodiments, sugar can be a combination of about 42% fructose and about 53% glucose. In some embodiments, sugar can be a combination of about 90% fructose and about 10% glucose. In some embodiments, sweeteners can be rare sugars. In some embodiments, rare sugars are selected from the group consisting of: D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-arabinose, D-turanose, D-leucrose and combinations thereof. In some embodiments, rare sugars are D-psicose. In some embodiments, rare sugars are D-tagatose. In some embodiments, sweeteners are artificial sweeteners. In some embodiments, artificial sweeteners are sucralose.

[0131] Typically, a sweet receptor modulating amount, a sweet receptor ligand modulating amount, a sweet flavor modulating amount, a sweet flavor enhancing amount, or a therapeutically effective amount of one or more compounds of the present invention are added to an ingestible composition, optionally in the presence of a sweetener, such that the sweet flavor-modified ingestible composition has an increased sweetness as judged generally by humans or animals, or, in the case of formulation testing, by a majority of a panel of at least eight human taste testers, by procedures well known in the art, compared to an ingestible composition prepared without the compounds of the present invention.

[0132] In some embodiments, the compounds disclosed and described herein, alone or in combination, regulate the sweetness or other taste properties of other natural or synthetic sweet tastants and ingestible compositions prepared therefrom. In one embodiment, the compounds disclosed and described herein can be used or provided alone or in combination with their ligand-enhanced concentrations. For example, the amount of the compounds disclosed and described herein, alone or in combination, can be about 0.001ppm to 100ppm, or a narrower alternative range of about 0.1ppm to about 10ppm, about 0.01ppm to about 30ppm, about 0.05ppm to about 10ppm, about 0.01ppm to about 5ppm, or about 0.02ppm to about 2ppm, or about 0.01ppm to about 1ppm.

[0133] Some embodiments provide sweetness enhancing compositions comprising a sweet flavor enhancing amount of a compound of the present invention in combination with a first amount of a sweetener, wherein the sweetening is greater than the sweetening provided by the first amount of the sweetener without the compound. In some embodiments, the sweetener can be common sugar sweeteners, such as sucrose, fructose, glucose, and sweetener compositions containing natural sugars such as corn syrup (including high fructose corn syrup) or other syrups or sweetener concentrates derived from natural fruit and vegetable sources; rare natural sugars, including D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-arabinose, D-turanose, and D-leucrose; semi-synthetic "sugar alcohol" sweeteners, such as erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, maltodextrin, etc.; and artificial sweeteners, such as aspartame, saccharin, acesulfame potassium, cyclamates, sucralose and alitame. In some embodiments, the sweetener is selected from the group consisting of: cyclamic acid, mogroside, 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 hydrolysate (HSH), stevioside, rebaudioside A and other sweet steviosides, guanidine sweeteners (carrelame) and other guanidine sweeteners. In some embodiments, the sweetener can be a combination of two or more sweeteners disclosed herein. In some embodiments, the sweetener can be a combination of two, three, four or five sweeteners disclosed herein. In some embodiments, the sweetener can be sugar. In some embodiments, the sweetener can be a combination of one or more sugars and other natural and artificial sweeteners. In some embodiments, the sweetener is sugar. In some embodiments, the sugar is cane sugar. In some embodiments, the sugar is beet sugar. In some embodiments, sweetener can be a combination of one or more sugars and other natural and artificial sweeteners. In some embodiments, sugar can be sucrose, fructose, glucose or a combination thereof (e.g., high fructose corn syrup). In some embodiments, sugar can be sucrose. In some embodiments, sugar can be a combination of fructose and glucose. In some embodiments, sugar can be a combination of about 55% fructose and about 42% glucose. In some embodiments, sugar can be a combination of about 42% fructose and about 53% glucose. In some embodiments, sugar can be a combination of about 90% fructose and about 10% glucose. In some embodiments, sweetener can be a rare sugar. In some embodiments, rare sugar is selected from the group consisting of: D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-arabinose, D-turanose, D-leucrose and a combination 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 can be sucralose.

[0134] In some embodiments, the compounds disclosed and described herein, alone or in combination, provide an enhancement of the potency of a sweetener at the T1R2 / T1R3 taste receptors as measured by an enhancement ratio, which is defined as the EC of the sweetener with and without the compounds described herein. 50In some embodiments, the compounds disclosed and described herein, alone or in combination, provide an enhancement ratio greater than 1 and less than 10. In some embodiments, the compounds disclosed and described herein, alone or in combination, provide an enhancement ratio of 10 to 20. In some embodiments, the compounds disclosed and described herein, alone or in combination, provide an enhancement ratio greater than 20. In some embodiments, the sweetener can be common sugar sweeteners, such as sucrose, fructose, glucose, and sweetener compositions containing natural sugars such as corn syrup (including high fructose corn syrup) or other syrups or sweetener concentrates derived from natural fruit and vegetable sources; rare natural sugars, including D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-arabinose, D-turanose, and D-leucrose; semi-synthetic "sugar alcohol" sweeteners, such as erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, maltodextrin, etc.; and artificial sweeteners, such as aspartame, saccharin, acesulfame potassium, cyclamates, sucralose and alitame. In some embodiments, the sweetener is selected from the group consisting of: cyclamic acid, mogroside, 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 hydrolysate (HSH), stevioside, rebaudioside A and other sweet steviosides, guanidine sweeteners (carrelame) and other guanidine sweeteners. In some embodiments, the sweetener can be a combination of two or more sweeteners disclosed herein. In some embodiments, the sweetener can be a combination of two, three, four or five sweeteners disclosed herein. In some embodiments, the sweetener can be sugar. In some embodiments, the sweetener can be a combination of one or more sugars and other natural and artificial sweeteners. In some embodiments, the sweetener is sugar. In some embodiments, the sugar is cane sugar. In some embodiments, the sugar is beet sugar. In some embodiments, sweetener can be a combination of one or more sugars and other natural and artificial sweeteners. In some embodiments, sugar can be sucrose, fructose, glucose or a combination thereof (e.g., high fructose corn syrup). In some embodiments, sugar can be sucrose. In some embodiments, sugar can be a combination of fructose and glucose. In some embodiments, sugar can be a combination of about 55% fructose and about 42% glucose. In some embodiments, sugar can be a combination of about 42% fructose and about 53% glucose. In some embodiments, sugar can be a combination of about 90% fructose and about 10% glucose. In some embodiments, sweetener can 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-arabinose, 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 can be sucralose.

[0135] In one embodiment, the flavoring concentrate formulation of the present invention can be in the form of a liquid, solid, foam, paste, gel, emulsion and a combination thereof selected from solutions and suspensions, such as a liquid containing a certain amount of solid content. In one embodiment, the flavoring concentrate formulation is in the form of a liquid including water-based and non-aqueous. In some embodiments, the flavoring concentrate formulation of the present invention can be carbonated or non-carbonated.

[0136] In one embodiment, the concentration of the compound in the flavoring concentrate formulation is at least 2 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of the compound in the flavoring concentrate formulation is at least 5 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of the compound in the flavoring concentrate formulation is at least 10 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of the compound in the flavoring concentrate formulation is at least 15 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of the compound in the flavoring concentrate formulation is at least 20 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of the compound in the flavoring concentrate formulation is at least 30 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of the compound in the flavoring concentrate formulation is at least 40 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of the compound in the flavoring concentrate formulation is at least 50 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of the compound in the flavoring concentrate formulation is at least 60 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of the present compound in the flavoring concentrate formulation is up to 100 times the concentration of the compound in the ready-to-use composition.

[0137] Therapeutic efficacy

[0138] In some embodiments, the compounds disclosed and described herein can be used alone or in combination for therapeutic purposes, such as modulating chemosensory receptors and / or their ligands to achieve a therapeutic effect. For example, the therapeutic purpose can include modulating chemosensory receptors and / or their ligands expressed in vivo other than taste buds.

[0139] In some embodiments, methods of modulating chemosensory receptors and / or their ligands include modulating the expression, secretion and / or functional level of T1R expressing cells associated with hormone, peptide, enzyme production by administering the compounds disclosed and described herein, alone or in combination, to an individual in need thereof. In one example, the methods of the present invention include modulating glucose levels, for example, inhibitors or modulators of chemosensory receptors such as T1R2 / T1R3 can be used to reduce glucose levels (e.g., glucose absorption) in a subject by administering the compounds disclosed and described herein, alone or in combination, to an individual in need thereof. In some embodiments, the methods include modulating incretin levels, for example, agonists or enhancers of chemosensory receptors such as T1R2 / T1R3 can be used to increase glucagon-like peptide 1 (GLP-1), thereby increasing insulin production, by administering the compounds disclosed and described herein, alone or in combination, to an individual in need thereof. In some embodiments, the method comprises modulating the expression, secretion and / or activity level of hormones or peptides produced by T1R-expressing cells or gastrointestinal hormone-producing cells, such as ligands of 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 compounds disclosed and described herein, alone or in combination, to an individual in need thereof. In some embodiments, the method comprises modulating pathways associated with hormones, peptides and / or enzymes secreted by T1R-expressing cells, by administering compounds disclosed and described herein, alone or in combination, to an individual in need thereof.

[0140] In some embodiments, the method comprises modulating the activity of 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 and smooth muscle cells, etc.), pancreatic cells (e.g., α cells, β cells, δ cells, neurosecretory PP cells, D1 cells, etc.), cells in 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., enteroendocrine cells, brush cells, etc.), salivary gland cells (e.g., plasma mucous cells, mucous cells, myoepithelial cells, intercalated ductal cells, striated ductal cells, etc.), endothelial cells (e.g., endothelial cells ... In some embodiments, the method comprises increasing the expression level of T1R in T1R expressing cells by administering a compound disclosed and described herein, alone or in combination, to an individual in need thereof. In some embodiments, the method comprises increasing the secretion level of T1R expressing cells by administering a compound disclosed and described herein, alone or in combination, to an individual in need thereof.

[0141] In some embodiments, the method comprises regulating, treating and / or preventing disorders associated with the gastrointestinal system, including, but not limited to, disorders associated with esophageal motility (e.g., cricopharyngeal achalasia, globus hystericus, achalasia, diffuse esophageal spasm and related motility disorders, scleroderma involving the esophagus, etc.), inflammatory diseases (e.g., gastroesophageal reflux and esophagitis, infectious esophagitis, etc.), peptic ulcers, duodenal ulcers, gastric ulcers, gastrinomas, stress ulcers and erosions, drug-related ulcers and erosions, gastritis, esophageal cancer, gastric tumors, malabsorption (e.g., absorption of specific nutrients, such as carbohydrates, proteins, amino acids, fats, cholesterol and fat-soluble vitamins, water and sodium, calcium, iron, water-soluble vitamins, etc.), malabsorption diseases, mucosal dysfunction ( such as inflammatory or infiltrative diseases, biochemical or genetic abnormalities, endocrine and metabolic disorders, protein-losing enteropathy, etc.), autoimmune diseases of the digestive tract (such as 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 diseases, intestinal vascular diseases, anorectal diseases (such as hemorrhoids, anal inflammation, etc.), colorectal cancer, small intestinal tumors, anal cancer, abnormal liver metabolism, hyperbilirubinemia, hepatitis, alcoholic liver disease and cirrhosis, biliary cirrhosis, liver tumors, infiltrative and metabolic diseases affecting the liver (such as fatty liver, Reye's syndrome, diabetic glycogenosis, glycogen storage disease, Wilson's disease, hemochromatosis), gallbladder and bile duct diseases, pancreatic diseases (such as pancreatitis, pancreatic exocrine insufficiency, pancreatic cancer, etc.), endocrine tumors of the gastrointestinal tract and pancreas, etc.

[0142] In some embodiments, the method comprises regulating, treating and / or preventing conditions associated with metabolic diseases, such as appetite, body weight, food or liquid intake or a subject's response to food or liquid intake, 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, hypothalamus), eating disorders (e.g., anorexia nervosa, bulimia, etc.), vitamin deficiency and excess, insulin metabolism, diabetes (type 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, alone or in combination, to an individual in need thereof.

[0143] In some embodiments, the method includes regulating, treating and / or preventing conditions associated with functional gastrointestinal disorders, such as in the absence of any specific pathological conditions such as peptic ulcers and cancer, where the subject suffers from abdominal indigestion, such as a sensation of bloating, nausea, vomiting, abdominal pain, anorexia, acid reflux or abnormal bowel movements (constipation, diarrhea, etc.), optionally based on retention of contents in the gastrointestinal tract, especially in the stomach. In one example, functional gastrointestinal disorders include conditions without any organic disease of the gastrointestinal tract, but with one or more reproducible gastrointestinal symptoms, which affect the quality of life of a subject, such as a human, by administering the compounds disclosed and described herein, alone or in combination, to an individual in need thereof.

[0144] Exemplary functional gastrointestinal diseases include, but are not limited to, functional dyspepsia, gastroesophageal reflux disease, diabetic gastroparesis, reflux esophagitis, postoperative gastrointestinal dysfunction, etc., nausea, vomiting, discomfort, heartburn, bloating, heaviness in the stomach, belching, chest twisting, chest pain, stomach discomfort, loss of appetite, difficulty swallowing, acid reflux, abdominal pain, constipation, diarrhea, difficulty breathing, choking, low stimulation or energy level, pharyngeal obstruction, foreign body sensation, fatigue, neck stiffness, muscle rigidity, dry mouth (dry mouth, thirst, etc.), shortness of breath, gastrointestinal burning sensation, cold limbs, inattention, impatience, sleep disorders, headache, general discomfort, palpitations, night sweats, anxiety, dizziness, vertigo, hot flashes, excessive sweating, depression, etc.

[0145] In some embodiments, the method includes increasing or promoting digestion, absorption, blood nutrient levels and / or intestinal motility in the digestive tract of a subject by administering the compounds disclosed and described herein, alone or in combination, to an individual in need thereof, such as promoting gastric emptying (e.g., clearance of gastric contents), reducing bloating in the early postprandial abdomen, improving anorexia, etc. In general, 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, alone or in combination, to an individual in need thereof.

[0146] In some embodiments, the method comprises increasing one or more gastrointestinal functions of a subject by administering the compounds disclosed and described herein, alone or in combination, for example to improve the quality of life or health status of the individual.

[0147] Some embodiments provide a method for treating respiratory tract infections, comprising administering the compounds disclosed and described herein, alone or in combination, to an individual in need thereof. In some embodiments, the compounds disclosed and described herein can be used, alone or in combination, to inhibit respiratory tract infections. Some embodiments provide a method for treating infertility, comprising administering the compounds disclosed and described herein, alone or in combination, to an individual in need thereof.

[0148] Some embodiments provide pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds disclosed and described herein, or a salt, solvate and / or prodrug thereof, optionally with a suitable amount of a pharmaceutically acceptable vehicle. In another embodiment, the pharmaceutical composition comprises a therapeutically effective amount of one or more compounds disclosed and described herein, or a salt, solvate and / or prodrug thereof; and a suitable amount of a pharmaceutically acceptable vehicle to provide a form for appropriate administration to a patient.

[0149] In one embodiment, when applied to a patient, the compound disclosed and described herein and optional pharmaceutically acceptable carrier are sterile. In one embodiment, when the compound disclosed and described herein is administered intravenously, water is a preferred vehicle. Saline solutions and aqueous glucose solutions and glycerol solutions can also be used as liquid carriers, particularly for injection solutions. Suitable pharmaceutical vehicles also include excipients, such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talcum powder, sodium chloride, skim milk powder, glycerol, propylene, ethylene glycol, water, ethanol, etc. If necessary, the pharmaceutical composition of the present invention may also include a small amount of wetting agent or emulsifier or pH buffer. In addition, adjuvants, stabilizers, thickeners, lubricants and coloring agents can be used.

[0150] Pharmaceutical compositions comprising the compounds disclosed and described herein can be prepared by conventional mixing, dissolving, granulating, dragee making, grinding, emulsifying, encapsulating, embedding or lyophilizing methods. Pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients or adjuvants that assist in processing the compounds of the invention into pharmaceutically acceptable preparations. Suitable preparations depend on the selected route of administration.

[0151] In some embodiments, the pharmaceutical composition can be in the form of a solution, suspension, emulsion, tablet, pill, granule, capsule, liquid-containing capsule, powder, sustained-release preparation, suppository, emulsion, aerosol, spray, suspension or any other suitable use. In some embodiments, the pharmaceutically acceptable carrier is a capsule (see, e.g., Grosswald et al., U.S. Patent No. 5,698,155). Examples of other suitable pharmaceutical carriers have been described in the art (see Remington: The Science and Practice of Pharmacy, Philadelphia College of Pharmacy and Science, 20th Edition, 2000).

[0152] For topical (external) administration, the compounds disclosed and described herein can be formulated into solutions, gels, ointments, creams, suspensions, etc., as is known in the art.

[0153] Systemic preparations include those designed for administration by injection, such as subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, and those designed for transdermal, transmucosal, oral or pulmonary administration. Systemic preparations can be prepared in combination with another activating agent that improves mucociliary clearance of airway mucus or reduces mucus viscosity. These activating agents include, but are not limited to, sodium channel blockers, antibiotics, N-acetylcysteine, homocysteine ​​and phospholipids.

[0154] In some embodiments, the compounds disclosed and described herein can be formulated as pharmaceutical compositions suitable for intravenous administration to humans according to conventional procedures. Typically, the compound for intravenous administration is a solution in a sterile isotonic aqueous buffer. For injection, the compound can be formulated in an aqueous solution, preferably in a physiologically compatible buffer, such as Hanks solution, Ringer's solution or a physiological saline buffer. The solution may contain a preparaton, such as a suspending agent, a stabilizer and / or a dispersant. If necessary, the pharmaceutical composition may also include a solubilizing agent.

[0155] The pharmaceutical composition for intravenous administration may optionally include a local anesthetic, such as lidocaine, to relieve pain at the injection site. Typically, the ingredients are provided in unit dose form, either alone or in admixture, such as as a lyophilized powder or anhydrous concentrate in a sealed container such as an ampoule or a sachet indicating the amount of the active agent. When the compound is administered by infusion, it may be dispensed, for example, into an infusion bottle containing sterile pharmaceutical grade water or saline. In some embodiments, an ampoule of sterile water or saline for injection may be provided so that when the compound is administered by injection, the ingredients may be mixed before administration.

[0156] For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are well known in the art.

[0157] Pharmaceutical compositions for oral delivery may be in the form of, for example, tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups or elixirs. Pharmaceutical compositions for oral administration may contain one or more optional agents, such as sweeteners, such as fructose, aspartame or saccharin; flavoring agents, such as peppermint, wintergreen oil or cherry coloring agents and preservatives, to provide a pharmaceutically acceptable preparation.

[0158] In addition, in the case of tablet or pill form, the pharmaceutical composition can be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over an extended period of time. The selective permeability membrane around the osmotic active driving compound is also suitable for oral administration compounds of the present invention. In these later platforms, the fluid from the capsule surrounding environment is absorbed by the driving compound, and the driving compound expands to displace the reagent or reagent composition through the hole. Contrary to the rapid increase curve of the immediate release preparation, these delivery platforms can provide a delivery curve that is substantially zero in degree. Time-delay materials, such as glyceryl monostearate or glyceryl stearate, can also be used. Oral compositions can include standard vehicles, such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. This type of vehicle is preferably pharmaceutical grade.

[0159] For oral liquid preparations, such as suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, saline, alkylene glycols (e.g. propylene glycol), polyalkylene glycols (e.g. polyethylene glycol) oils, alcohols, weakly acidic buffers of pH 4 to pH 6 (e.g. acetate, citrate, ascorbate at a concentration between about 5 mM and about 50 mM), etc. In addition, flavoring agents, preservatives, colorants, bile salts, acylcarnitines, etc. may be added.

[0160] For buccal administration, the pharmaceutical composition may take the form of tablets, lozenges, etc. formulated in conventional manner.

[0161] Liquid drug formulations suitable for nebulizers and liquid spray devices and EHD aerosol devices generally include the compounds of the present invention and a pharmaceutically acceptable carrier. Preferably, the pharmaceutically acceptable carrier is a liquid, such as alcohol, water, polyethylene glycol or perfluorocarbon. Alternatively, another material can be added to change the aerosol properties of the solution or suspension of the compounds of the present invention. Preferably, the material is a liquid, such as alcohol, glycol, polyethylene glycol or fatty acid. Other methods of preparing liquid drug solutions or suspensions suitable for aerosol devices are known to those skilled in the art (see, for example, U.S. Patent No. 5,112,598 of Biesalski; U.S. Patent No. 5,556,611 of Biesalski).

[0162] In some embodiments, the compounds disclosed and described herein may also be formulated in rectal or vaginal pharmaceutical compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter or other glycerides.

[0163] In addition to the preparations described previously, the compounds disclosed and described herein can also be formulated into long-acting preparations. Such long-acting preparations can be applied by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Therefore, for example, the compounds of the present invention can be formulated together with suitable polymerization or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as slightly soluble derivatives, for example, as the form of slightly soluble salts.

[0164] The compounds disclosed and described herein and / or pharmaceutical compositions thereof will generally be used in an amount effective to achieve the intended purpose. For use in treating or preventing a disease or condition, the compounds disclosed and described herein and / or pharmaceutical compositions thereof are administered or applied in a therapeutically effective amount.

[0165] In some embodiments, the dosage can be delivered in a pharmaceutical composition by single administration, multiple administrations, or controlled release. In some embodiments, the compounds disclosed and described herein can be delivered by oral sustained release administration. Administration can be repeated intermittently, can be provided alone or in combination with other drugs, and can be continued for as long as necessary to effectively treat the disease or condition.

[0166] Suitable dosage ranges for oral administration depend on potency, but are generally from about 0.001 mg to about 200 mg per kilogram body weight of a compound disclosed and described herein.

[0167] The suitable dosage range for intravenous (iv) administration is about 0.01 mg to about 100 mg per kilogram of body weight. The suitable dosage range for intranasal administration is generally about 0.01 mg / kg body weight to about 1 mg / kg body weight. Suppositories generally contain about 0.01 milligram to about 50 milligrams of the compound of the present invention per kilogram of body weight, and contain about 0.5 % by weight to about 10 % by weight of active ingredient. The recommended dose for intradermal, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual or intracerebral administration is about 0.001 mg to about 200 mg per kilogram of body weight. The effective dose can be inferred from the dose-response curve drawn from in vitro or animal model test systems.

[0168] In some embodiments, the dosage of the compounds described herein will preferably lie within a range of circulating concentrations that include the effective dose with little or no toxicity.

[0169] In certain embodiments, the compounds disclosed and described herein and / or their pharmaceutical compositions can be used in combination therapy with at least one other agent. In some embodiments, the compounds disclosed and described herein and / or their pharmaceutical compositions are administered simultaneously with another drug, which may be a part of the same pharmaceutical composition as the compounds of the present invention or a different pharmaceutical composition. In other embodiments, the pharmaceutical composition of the present invention is administered before or after administration of another drug.

[0170] Preparation method

[0171] Compounds disclosed herein can be synthesized by the following methods or by improvements of these methods. The way of improving the method includes temperature, solvent, reagent, etc. known to those skilled in the art in particular. Generally, in any method for preparing compounds disclosed herein, it may be necessary or necessary to protect sensitive or reactive groups on any related molecules. This can be accomplished by conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. JFW McOmie, Plenum Press, 1973); and PGM Green, TW Wutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999), the entire contents of which are incorporated herein by reference. Protecting groups can be removed at a convenient subsequent stage using methods known in the art. Synthetic chemical transformations that can be used to synthesize applicable compounds are known in the art, including, 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, the entire contents of which are incorporated herein by reference. The routes shown and described herein are merely illustrative, and are not intended to, nor should they be interpreted as, limiting the scope of the claims in any way. Those skilled in the art will be able to recognize modifications to the disclosed synthesis, and design alternative routes based on the disclosure herein. All of these modifications and alternative routes are within the scope of the claims.

[0172] The general procedure for the synthesis of flavonoid-C-glycosides described herein is as follows: flavanone / DHC (1 equiv.) and D-glucose (2 equiv.) in a sealed tube were mixed with 2:1 CH 3 CN–H 2 O solution in Sc(OTf) 3(0.2 equivalents) in the presence of 2-(4-(4-hydroxy-1-nitropropene)-2-nitropropene and 1-(4-hydroxy-1-nitropropene)-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene-2-nitropropene

[0173] Example

[0174] To further illustrate the present invention, the following examples are included. Of course, these examples should not be interpreted as specifically limiting the present invention. Variations of these embodiments are within the capabilities of those skilled in the art within the scope of the claims and are considered to fall within the scope of the present invention as described and claimed herein. The reader will recognize that the skilled artisan and those skilled in the art who have mastered this disclosure are able to prepare and use the present invention without exhaustive examples.

[0175] Example 1: Synthesis of Compounds 1, 2 and 3

[0176]

[0177] Naringenin (3 g, 11.0 mmol) and D-glucose (3.9 g, 21.6 mmol) in a 100 mL sealed tube were mixed with 2:1 CH 3 CN–H 2 A solution of O (42 mL) in Sc(OTf) 3 (1.2 g, 2.44 mmol) was refluxed in an oil bath for 24 hours. The reaction mixture was then concentrated and passed through an MCI GEL (80 g) column pretreated 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 fractions were concentrated and assayed by UHPLC-UV-HRMS. Three compounds (1, 2, 3) were confirmed using LC HRMS analysis. The fractions were then purified using a preparative LC equipped with a Luna C18 (2) column (Phenomenex, 250×21.20 mm×5 μm). Two white amorphous powders were obtained after freeze drying, namely compound 1 (620 mg) and compound 2 (25 mg). By 1 H and 13C NMR and HR-ESI-MS spectroscopy confirmed the structures of compounds 1 and 2 as naringenin 6-C-β-D glucoside and naringenin 8-C-β-D glucoside. The structure of compound 3 was confirmed as naringenin 6,8-di-C-β-D glucoside by HR-ESI-MS spectroscopy.

[0178] Example 2: Synthesis of Compounds 4, 5 and 6

[0179]

[0180] Eriochoric acid (1.6 g, 5.5 mmol) and D-glucose (4 g, 22.2 mmol) in a 100 mL sealed tube were mixed with 2:1 CH 3 CN–H 2 A solution of O (36 mL) in Sc(OTf) 3 (0.5 g, 1 mmol) was refluxed in an oil bath for 24 hours. The reaction mixture was then concentrated and passed through a MCI GEL (80 g) column pretreated with water. The column was washed with water and eluted with 40% aqueous ethanol and 100% ethanol. The combined 40% aqueous ethanol fractions were concentrated and detected by U(H)PLC-UV-HRMS. Three compounds (4, 5 and 6) were detected using LCHRMS analysis. The fractions were then purified using a preparative LC equipped with a Luna C18 (2) column (Phenomenex, 250×21.20 mm×5 μm). After freeze drying, two white amorphous powders were obtained, namely compound 4 (620 mg) and compound 5 (3 mg). By 1 H and 13 C NMR and HR-ESI-MS spectroscopy confirmed the structures of compounds 4 and 5 as eriodictyol 6-C-β-D glucoside and eriodictyol 8-C-β-D glucoside. The structure of compound 6 was confirmed as eriodictyol 6,8-di-C-β-D glucoside by HR-ESI-MS spectroscopy.

[0181] Example 3: Synthesis of Compounds 7, 8 and 9

[0182]

[0183]

[0184] Hesperidin (2 g, 6.6 mmol) and D-glucose (5 g, 27.7 mmol) in a 100 mL sealed tube were mixed with 2:1 CH 3 CN–H 2 A solution of O (45 mL) in Sc(OTf) 3(1.6 g, 3.3 mmol) was refluxed in an oil bath for 48 hours. The reaction mixture was then concentrated and passed through a MCI GEL (80 g) column pretreated with a 5% ethanol aqueous solution. The column was washed with 250 mL of 10% ethanol aqueous solution and eluted with 750 mL of 15% ethanol aqueous solution and 1000 mL of 40% ethanol aqueous solution in sequence. The fractions were checked by UHPLC-UV-HRMS. Three compounds (7, 8, 9) were detected using LC HRMS analysis.

[0185] The combined 15% ethanol aqueous fractions containing compound 9 were concentrated and purified by preparative LC equipped with a Luna C18(2) column (Phenomenex, 250×21.20 mm×5 μm). After freeze drying, 170 mg of hesperidin-6,8-di-C-glucoside (Compound 9) was obtained as a white amorphous powder.

[0186] The combined 40% ethanol aqueous solution fractions containing compounds 7 and 8 were concentrated and purified by preparative LC equipped with a Luna C18 (2) column (Phenomenex, 250×21.20 mm×5 μm). After freeze-drying, 420 mg of hesperidin-6-C-β-D-glucoside (compound 7) was obtained as a white amorphous powder. 1 H and 13 The structures of compounds 7 and 9 were determined to be hesperetin 6-C-β-D glucoside and hesperetin 6,8-di-C-β-D glucoside by C NMR and HR-ESI-MS spectroscopy. The structure of compound 8 was determined to be hesperetin 8-C-β-D glucoside by HR-ESI-MS spectroscopy.

[0187] Example 4: Synthesis of Compounds 10, 11 and 12

[0188]

[0189]

[0190] Homoeriocarbol (0.3 g, 1.0 mmol) and D-glucose (0.35 g, 1.9 mmol) in a 15 mL sealed tube were mixed with 2:1 CH 3 CN–H 2 A solution of O (4 mL) in Sc(OTf) 3(0.11 g, 0.2 mmol) was refluxed in an oil bath for 24 hours. The reaction mixture was then concentrated and passed through an MCI GEL (80 g) column pretreated with water. The column was washed with water and eluted with 40% aqueous ethanol and 100% ethanol. The combined 40% aqueous ethanol fractions were concentrated and detected by UHPLC-UV-HRMS. Three compounds (10, 11 and 12) were detected using LC HRMS analysis. The fractions were then purified by preparative LC equipped with a Luna C18 (2) column (Phenomenex, 250×21.20 mm×5 μm). Two white amorphous powders, compound 10 (105 mg) and compound 12 (5 mg), were obtained after freeze drying. By 1 H and 13 C NMR and HR-ESI-MS spectroscopy confirmed the structures of compounds 10 and 12 as homochrysinol 6-C-β-D glucoside and homochrysinol 6,8-di-C-β-D glucoside. The structure of compound 11 was determined to be homochrysinol 8-C-β-D glucoside by HR-ESI-MS spectroscopy.

[0191] Example 5: Synthesis of Compound 13

[0192]

[0193] Trilobatin (0.9 g, 1.9 mmol) and D-glucose (1.36 g, 7.5 mmol) in a 15 mL sealed tube were mixed with 2:1 CH 3 CN–H 2 A solution of O (7.3 mL) in Sc(OTf) 3 (0.41 g, 0.83 mmol) was refluxed in an oil bath for 24 hours. The reaction mixture was then concentrated and passed through an MCI GEL (80 g) column pretreated with water. The column was washed with water and eluted with 40% aqueous ethanol and 100% ethanol. The combined 40% aqueous ethanol fractions were concentrated and detected by UHPLC-UV-HRMS. New compound 13 was detected by HRMS spectroscopy. The fraction was then purified by preparative LC equipped with a Luna C18 (2) column (Phenomenex, 250×21.20 mm×5 μm). A white amorphous powder, compound 13 (200 mg), was obtained after freeze drying. 1 H and 13 C NMR and HR-ESI-MS spectroscopy confirmed the structure of compound 13 to be trilobatin 3′-C-β-D-glucoside.

[0194] Example 6: Synthesis of Compound 14

[0195]

[0196] Hesperidin dihydrochalcone 4'-O-β-D-glucoside (0.5 g, 1.1 mmol) and D-glucose (0.4 g, 2.2 mmol) in a 15 mL sealed tube were mixed with 2:1 CH 3 CN–H 2 A solution of O (7.5 mL) in Sc(OTf) 3 (0.3 g, 0.61 mmol) was refluxed in an oil bath for 24 hours. The reaction mixture was then concentrated and passed through an MCI GEL (80 g) column pretreated with water. The column was washed with water and eluted with 40% aqueous ethanol and 100% ethanol. The combined 40% aqueous ethanol fractions were concentrated and detected by UHPLC-UV-HRMS. New compound 14 was detected by two HRMS spectra. The fraction was then purified by preparative LC equipped with a Luna C18 (2) column (Phenomenex, 250×21.20 mm×5 μm). A white amorphous powder, compound 14 (120 mg), was obtained after freeze drying. By 1 H and 13 C NMR and HR-ESI-MS spectroscopy confirmed the structure of compound 14 as hesperetin dihydrochalcone 4′-O-β-D-glucopyranosyl-3′-C-β-D-glucoside.

[0197] Example 7: Synthesis of Compounds 15-16

[0198]

[0199] Naringenin (2 g, 7.4 mmol) and L-rhamnose (5 g, 30.5 mmol) in a 100 mL sealed tube were mixed with 2:1 CH 3 CN–H 2 A solution of O (28 mL) in Sc(OTf) 3 (1.6 g, 3.3 mmol) was refluxed in an oil bath for 24 hours. The reaction mixture was then concentrated and passed through an MCI GEL (80 g) column pretreated with water. The column was washed with water and eluted with 60% aqueous ethanol and 100% ethanol. The combined 60% aqueous ethanol fractions were concentrated and detected by UHPLC-UV-HRMS. Compounds 15 and 16 were detected by UV and HRMS spectroscopy. The fractions were then purified by preparative LC equipped with a Luna C18 (2) column (Phenomenex, 250×21.20 mm×5 μm). A white amorphous powder, composition 1 (200 mg), was obtained after freeze-drying. Composition 1 consists of compound 15 and compound 16 in a ratio of 2.7:1. By 1 H and 13C NMR and HR-ESI-MS spectroscopy confirmed the structures of compounds 15 and 16 to be naringenin 6-C-rhamnoside and naringenin 6-C-rhamnoside.

[0200] Example 8: Isolation of Compounds 4, 17, 18 and 19

[0201]

[0202]

[0203] 300 g of fermented rooibos tea was extracted five times with 50% ethanol in water. The solution was concentrated under reduced pressure using a rotary evaporator. The aqueous solution was extracted with cyclohexane, ethyl acetate and butanol in sequence. The combined butanol extracts were concentrated. The dried extracts were first separated by silica gel chromatography on a flash chromatography system (DCM:MeOH 10:1 to 2:1). The fractions containing the flavonoid C-glucoside were combined and dried. Chemical separation was performed in a Prep-LC system using a C18 column (Phenomenex Luna C18 (2) column (5 μm, 250×21.20 mm, 100A). The column was eluted with water and acetonitrile (ACN) gradient (10% ACN to 30% ACN) at 30°C. 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. 1 H and 13 The structures of compounds 4, 17 to 19 were confirmed by C NMR and HR-ESI-MS spectroscopy.

[0204] Example 9: Separation of compounds 20 and 21

[0205]

[0206] 70 g of unfermented (raw) rooibos tea powder was extracted three times with 50% ethanol in water. The solution was concentrated under reduced pressure on a rotary evaporator to remove the solvent. The aqueous solution was first extracted three times with cyclohexane to remove volatiles and then extracted four times with ethyl acetate. The combined organic extracts were concentrated. The dry extract was pre-diluted with ethanol and loaded onto an MCI gel column. The column was run on a flash chromatography system using solvent A (MeOH:H 2 O:FA 5:95:0.1) and solvent B (MeOH:H 2The column was eluted with a gradient of 1:10:10:0.1 (O:FA 75:25:0.1). Subfractions were further purified by preparative LC chromatography to give aspalathin (Compound 20, 1000 mg) and nothofagin (Compound 21, 100 mg). 1 H and 13 The structures of compounds 20 and 21 were confirmed by C NMR and HR-ESI-MS spectroscopy.

[0207] Example 10: Isolation of Compound 22

[0208]

[0209] 1774 grams of kumquat fruit were extracted three times with 2L of 50% ethanol in water. The solution was concentrated under reduced pressure using a rotary evaporator. The concentrated solution was loaded onto an MCI column connected to a flash chromatography system. The column was first washed with water, then eluted with 50% ethanol and 80% ethanol in sequence. The 50% ethanol solution was collected and further subjected to reverse phase ODS column chromatography. The system was eluted on a flash chromatography system with solvent A (water) and solvent B (ethanol) in a gradient of 9:1 to 1:1. The fractions containing flavonoid C-glucoside were combined, concentrated, and graded using silica gel chromatography (DCM:MeOH 5:1 to 3:1). Finally, a C18 column (Phenomenex Luna C18 (2) column (5 μm, 250×21.20 mm, 100A) was used for purification in a Prep-LC system. The column was eluted with a gradient of water and acetonitrile (ACN) (10% ACN to 30% ACN) at 30°C to obtain compound 22 (1.9434 g). The structure was determined to be phloretin-3',5'-di-C-β-D-glucoside (compound 22) by NMR analysis.

[0210] Compound 23 was purchased.

[0211]

[0212] Example 11: Synthesis of Compounds 24, 25 and 26

[0213]

[0214] Pinocembrin (0.5 g, 1.9 mmol) and D-glucose (0.7 g, 3.8 mmol) in a 15 mL sealed tube were mixed with 2:1 CH 3 CN–H 2 A solution of O (7.5 mL) in Sc(OTf) 3(0.22 g, 0.4 mmol) was refluxed in an oil bath for 24 hours. The reaction mixture was then concentrated and passed through an MCI GEL (80 g) column pretreated with water. The column was washed with water and eluted with 50% aqueous ethanol and 100% ethanol. The combined 50% aqueous ethanol fractions were concentrated and detected by UHPLC-UV-HRMS. Three compounds (24, 25, 26) were detected by UV and HRMS spectroscopy. The fractions were then purified by preparative LC equipped with a Luna C18 (2) column (Phenomenex, 250×21.20 mm×5 μm). Two white amorphous powders, compound 24 (80 mg) and compound 26 (10 mg), were obtained after freeze drying. The structure of compound 25 was determined to be pine 8-C-β-D-glucoside by HR-ESI-MS spectroscopy. By 1 H and 13 C NMR and HR-ESI-MS spectroscopy confirmed the structures of compounds 24 and 26 to be pyralidin 6-C-β-D-glucoside and pyralidin 6,8-di-C-β-D-glucoside.

[0215] Example 12: Synthesis of Compounds 27 and 28

[0216]

[0217] Hesperidin dihydrochalcone (50 mg, 0.16 mmol) and D-glucose (50 mg, 0.28 mmol) in a 2 mL sealed vial were mixed with 2:1 CH 3 CN–H 2 A solution of O (0.5 mL) in Sc(OTf) 3 (20 mg, 0.04 mmol) was refluxed at 80 degrees in a parallel reactor. The reaction was monitored by UHPLC-UV-HRMS. After the reaction was completed, it was cooled to room temperature, the reaction mixture was diluted with ethanol, filtered with a 0.2 μm PTFE filter, and detected by UHPLC-UV-HRMS. New compounds 27 and 28 were detected by both UV and HRMS spectroscopy. By HR-ESI-MS mass spectrometry analysis, the structure of compound 27 was determined to be hesperidin dihydrochalcone 3'-C-β-D-glucoside, and the structure of compound 28 was determined to be hesperidin dihydrochalcone 3',5'-di-C-β-D-glucoside.

[0218] Example 13: Synthesis of Compounds 21, 29 and 30

[0219]

[0220] Phlorizin (50 mg, 0.11 mmol) and D-glucose (40 mg, 0.22 mmol) in a 2 mL sealed vial were mixed with 2:1 CH3 CN–H 2 A solution of O (0.5 mL) in Sc(OTf) 3 (20mg, 0.04mmol) was refluxed at 80 degrees in a parallel reactor. The reaction was monitored by UHPLC-UV-HRMS. After the reaction was completed, it was cooled to room temperature, the reaction mixture was diluted with ethanol, filtered with a 0.2μm PTFE filter, and detected by UHPLC-UV-HRMS. Compounds 21, 29 and 30 were detected by UV and HRMS spectroscopy. The structure of compound 21 was determined to be phloridzin 3'-C-β-D-glucoside corresponding to the standard using HR-ESI-MS spectroscopy. By HR-ESI-MS mass spectrometry, the structure of compound 29 was determined to be phloridzin 3'-C-β-D-glucoside, and the structure of compound 30 was determined to be phloridzin 5'-C-β-D-glucoside.

[0221] Sensory experiment

[0222] Methods: A panel of 8 to 25 trained panelists evaluated the taste attributes (sweetness and / or sweet off-notes such as lingering) of the samples on a scale of -5 to 5 (-5 indicating strong masking effect, 5 indicating strong enhancing effect, and 0 indicating the intensity of a reference aqueous solution containing either 4% sucrose or 0.02% SG95 stevia product).

[0223] The results of these experiments are listed in Tables 1 to 12. Compounds 1, 4, 7, 21, 13, 20, 23 and 18 showed significant sweetness enhancement effects on sucrose solutions. Compounds 9, 22, 15, 16 and 17 showed sweetness enhancement effects on sucrose solutions. Compound 21 showed a sweetness enhancement effect on SG95 stevia product solutions. Compound 22 showed a sweetness enhancement effect and residual masking of off-flavor masking effects on SG95 stevia product solutions.

[0224] Table 1. Sensory data of sweetness enhancer Compound 1.

[0225] Matrix smell Compound Dosage (ppm) strength Sucrose solution sweet 1 10 0.49

[0226] Table 2. Sensory data of sweetness enhancer Compound 4.

[0227] Matrix smell Compound Dosage (ppm) strength Sucrose solution sweet 4 10 0.64

[0228] Table 3. Sensory data of sweetness enhancer Compound 7.

[0229] Matrix smell Compound Dosage (ppm) strength Sucrose solution sweet 7 10 0.57

[0230] Table 4. Sensory data of sweetness enhancer Compound 9.

[0231] Matrix smell Compound Dosage (ppm) strength Sucrose solution sweet 9 10 0.31

[0232] Table 5. Sensory data of sweetness enhancer Compound 21.

[0233] Matrix smell Compound Dosage (ppm) strength Sucrose solution sweet 21 10 0.46 SG95 Stevia Product Solution sweet 21 20 0.25

[0234] Table 6. Sensory data of Compound 22 (sweetness enhancer and SG sweet off-taste masker).

[0235] Matrix smell Compound Dosage (ppm) strength Sucrose solution sweet 22 40 0.23 SG95 Stevia Product Solution sweet 22 40 0.25 SG95 Stevia Product Solution Residue 22 40 -0.33

[0236] Table 7. Sensory data of sweetness enhancer Compound 13.

[0237] Matrix smell Compound Dosage (ppm) strength Sucrose solution sweet 13 10 0.67

[0238] Table 8. Sensory data for sweetness enhancer Compound 20.

[0239] Matrix smell Compound Dosage (ppm) strength Sucrose solution sweet 20 10 0.42

[0240] Table 9. Sensory data for sweetness enhancer Compound 23.

[0241] Matrix smell Compound Dosage (ppm) strength Sucrose solution sweet 23 10 0.50

[0242] Table 10. Sensory data of sweetness enhancer Compound 18.

[0243] Matrix smell Compound Dosage (ppm) strength Sucrose solution sweet 18 40 0.50

[0244] Table 11. Sensory data for sweetness enhancer Compound 17.

[0245] Matrix smell Compound Dosage (ppm) strength Sucrose solution sweet 17 40 0.25

[0246] Table 12. Sensory data of sweetness enhancer composition 1 consisting of compounds 15 and 16.

[0247] Matrix smell Compound Dosage (ppm) strength Sucrose solution sweet 1 10 0.28

[0248] The foregoing detailed description is given only for clarity of understanding, 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 presently claimed embodiments, nor is any admission made that any publication explicitly or implicitly cited is prior art.

Claims

1. Use of a compound for enhancing the sweetness of a sweetener, wherein the compound is a compound having a structure of formula (I) to (III): or a salt or stereoisomer thereof, wherein: R2 and R4 are each independently hydrogen or C-glycosyl, and one or both of R2 and R4 are C-glycosyl; and R1, R3, R5, R6, R7, R8, R9 and R 10 Each is independently hydrogen, -OH, methyl, -OMe or O-glycosyl.

2. The compound according to claim 1, having the structure of formula (II): or a salt or a stereoisomer thereof.

3. The compound according to claim 1 or 2, wherein R 10 It is -OH.

4. The compound according to claim 1 or 2, wherein R3 or R 10 is an O-sugar group, or R2 and R4 are both C-sugar groups, and R7 is -OMe.

5. The compound according to claim 1, having the structure of formula (I): or a salt or a stereoisomer thereof.

6. The compound of claim 5, wherein R4 is a C-glycosyl and R7 is -OMe, R2 is a C-glycosyl and R6 is -OMe, the C-glycosyl is a C-rhamnosyl, or each of R6, R7 and R8 is hydrogen.

7. The compound according to claim 1, having the structure of formula (III): or a salt or a stereoisomer thereof.

8. The compound according to any one of claims 1 to 7, wherein R1 is -OH.

9. The compound according to any one of claims 1 to 7, wherein R1 is an O-glycosyl group.

10. The compound according to any one of claims 1 to 8, wherein R2 is hydrogen.

11. The compound according to any one of claims 1 to 8, wherein R2 is a C-glycosyl group.

12. The compound according to any one of claims 1 to 11, wherein R3 is -OH.

13. The compound according to any one of claims 1 to 11, wherein R3 is an O-glycosyl group.

14. The compound according to any one of claims 1 to 13, wherein R4 is hydrogen.

15. The compound according to any one of claims 1 to 13, wherein R4 is a C-glycosyl group.

16. The compound according to any one of claims 1 to 15, wherein R5 is hydrogen.

17. The compound according to any one of claims 1 to 16, wherein R6 is hydrogen.

18. The compound according to any one of claims 1 to 16, wherein R6 is -OH.

19. The compound according to any one of claims 1 to 16, wherein R6 is -OMe.

20. The compound according to any one of claims 1 to 19, wherein R7 is -OH.

21. The compound according to any one of claims 1 to 19, wherein R7 is -OMe.

22. The compound according to any one of claims 1 to 21, wherein R8 is hydrogen.

23. The compound according to any one of claims 1 to 21, wherein R8 is -OH.

24. The compound according to any one of claims 1 to 21, wherein R8 is -OMe.

25. The compound according to any one of claims 1 to 24, wherein R9 is hydrogen.

26. The compound according to claim 1, wherein the compound is selected from the group consisting of: or a salt or a stereoisomer thereof.

27. A compound having a structure selected from the group consisting of: or a salt or a stereoisomer thereof.

28. The compound according to any one of claims 1 to 26, wherein the compound is not or a salt or a stereoisomer thereof.

29. The compound according to any one of claims 1 to 28, wherein the compound is in pure and isolated form.

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

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

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

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

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

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

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

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

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

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

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

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

42. The method according to any one of claims 36 to 41, wherein the compound is present in a concentration of 0.001 to 1000 ppm.

43. The method according to any one of claims 36 to 41, wherein the compound is present in a concentration of 0.1 to 500 ppm.

44. The method according to any one of claims 36 to 41, wherein the compound is present in a concentration of 0.1 to 100 ppm.

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

46. ​​Use of the compound of claim 27 for enhancing the sweetness of a sweetener.

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