Sweetener Composition

Abstract

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

Description

[Technical field]

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

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

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

[0004] High-intensity sweeteners have a wide range of chemically distinct structures and therefore various properties, including but not limited to odor, flavor, mouthfeel, and aftertaste. It is well known that these properties, especially flavor and aftertaste, change over the time of tasting, such that each time 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 generally characterized as having a bitter and / or metallic aftertaste. Products prepared with 2,4-dihydroxybenzoic acid are claimed to exhibit a reduction in the undesirable aftertaste associated with sweeteners and are effective at concentrations below those at which the taste is perceptible per se. In addition, high-intensity sweeteners such as sucralose and aspartame have been reported to have sweetness delivery problems, with slow sweetness onset and lingering sweetness aftertaste.

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

[0007] overview Some embodiments include a flavor-modifying compound having one of the following structures, or a salt or stereoisomer thereof: [ka] [In the formula, R1, R3, R5, R6, R7, R8, and R9 are each independently hydrogen, -OH, or -OMe; R2 and R4 are each independently hydrogen or methyl.

[0008] Some embodiments relate to ingestible compositions comprising a compound described herein and one or more sweeteners. In some embodiments, the sweetener is a sugar. In some embodiments, the sweetener is sucrose. In some embodiments, the sweetener comprises a combination of fructose and glucose. In some embodiments, the sweetener is sucralose. In some embodiments, the sweetener is high fructose corn syrup.

[0009] Some embodiments relate to a method of enhancing the sweetness of a sweetener, comprising combining a compound described herein with a sweetener. In some embodiments, the sweetener is a sugar. In some embodiments, the sweetener is sucrose. In some embodiments, the sweetener comprises a combination of fructose and glucose. In some embodiments, the sweetener is sucralose. In some embodiments, the sweetener is high fructose corn syrup. In some embodiments, the compound is present at a concentration of 0.1-100 ppm. In some embodiments, the compound is present at a concentration of 5-20 ppm.

[0010] Some embodiments relate to a compound described herein for use in enhancing the sweetness of a sweetener.

[0011] Some embodiments relate to the use of the compounds described herein to enhance the sweetness of a sweetener.

[0012] In addition to the above features, additional features and variations will be readily apparent from the following description. It should be understood that the following description describes typical alternatives and is not intended to limit the scope. Although the present disclosure is described in various exemplary alternatives and implementations provided herein, it should be understood that the various features, aspects, and functions described in one or more of the individual alternatives are not limited in applicability to the particular alternatives for which they are described. Rather, they can be applied alone or in various combinations to one or more of the other alternatives, regardless of whether the alternative is described or whether the feature is presented as part of the alternative being described. Thus, the breadth and scope of the present disclosure should not be limited by any exemplary alternatives described herein. [Brief description of the drawings]

[0013] [Figure 1] 1 is a graph showing data from a sensory test with Compound 101. [Diagram 2] 1 is a graph showing data from a sensory test with Compound 101. [Diagram 3] 1 is a graph showing data from a sensory test with Compound 108.

[0014] Detailed Description The embodiments disclosed herein generally relate to flavor modifying compounds. In some embodiments, the flavor modifying compounds are sweetener enhancers. Some embodiments include compositions comprising a flavor modifying compound and one or more sweeteners. In some embodiments, these compositions comprise non-caloric or low-caloric high-sensitivity natural sweeteners. In some embodiments, the compositions comprise a combination of one or more sweeteners and one or more flavor modifying compounds that can activate sweet taste receptors in vitro and provide sweetness enhancement. The combination compositions can be used in a variety of ingestible or non-ingestible compositions. In some embodiments, the ingestible composition comprises one or more flavor modifying compounds and one or more sweeteners that can be natural sweeteners, e.g., sucrose; or synthetic sweeteners, e.g., sucralose. In some embodiments, the natural or synthetic sweeteners are high-potency sweeteners. The present disclosure also relates to compositions that can improve the taste of non-caloric or low-caloric natural and / or synthetic high-potency sweeteners by providing a more sugar-like taste or characteristics by utilizing natural sweeteners in combination with other natural or synthetic sweeteners. In some embodiments, the ingestible composition provides a more sugar-like temporal profile, including a sweet onset and a sweet aftertaste, and / or a more sugar-like flavor profile.

[0015] In some embodiments, the ingestible composition may be a food or beverage product.

[0016] In some embodiments, the beverage may be selected from fortified sparkling beverages, fruit juices, fruit-flavored juices, juice drinks, nectars, vegetable juices, vegetable-flavored juices, sports drinks, energy drinks, fortified water drinks, fortified water with vitamins, near-water drinks, coconut water, tea-based drinks, coffee, cocoa drinks, dairy-containing beverages, dairy substitute beverages, grain extract-containing beverages, and smoothies.

[0017] In some embodiments, the composition may be an animal feed product or an animal feed ingredient.

[0018] In some embodiments, the ingestible composition may be a medicine, a nutritional product, a dietary supplement, or an over-the-counter drug. In some embodiments, the non-ingestible composition may be an oral care product, a hygiene product, or a cosmetic product.

[0019] These and other embodiments, advantages, and features of the present disclosure will be set forth in part in the following description, and in part will be apparent from the description, or may be learned by practice of the embodiments disclosed herein. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the embodiments described.

[0020] compound Some embodiments include a flavor-modifying compound having one of the following structures, or a salt or stereoisomer thereof: [ka] [In the formula, R1, R3, R5, R6, R7, R8, and R9 are each independently hydrogen, -OH, or -OMe; R2 and R4 are each independently hydrogen or methyl.

[0021] In some embodiments of the compound of formula (I), at least one of R2, R4, or R7 is not hydrogen. In some embodiments of the compound of formula (I), at least one of R1, R3, or R5 is not -OH. In some embodiments of the compound of formula (I), at least one of R2 or R4 is methyl.

[0022] In some embodiments, the compound has the structure of Formula (Ia) or a salt or stereoisomer thereof: [ka]

[0023] In some embodiments of the compound of formula (II), at least one of R2 or R4 is methyl. In some embodiments of the compound of formula (II), at least one of R1 and R3 is not -OH.

[0024] In some embodiments, R2 is hydrogen. In some embodiments, R2 is methyl. In some embodiments, R4 is hydrogen. In some embodiments, R4 is methyl.

[0025] In some embodiments, the compound has the structure of Formula (Va) or a salt or stereoisomer thereof: [ka]

[0026] In some embodiments, R8 is hydrogen. In some embodiments, R8 is -OH.

[0027] In some embodiments, R9 is hydrogen. In some embodiments, R9 is -OH. In some embodiments, R9 is -OMe.

[0028] In some embodiments, R1 is -OH. In some embodiments, R1 is -OMe.

[0029] In some embodiments, R3 is hydrogen. In some embodiments, R3 is -OH. In some embodiments, R3 is -OMe.

[0030] In some embodiments, R5 is -OH. In some embodiments, R5 is -OMe.

[0031] In some embodiments, R6 is hydrogen. In some embodiments, R6 is -OH. In some embodiments, R6 is -OMe.

[0032] In some embodiments, R7 is hydrogen. In some embodiments, R7 is -OH. In some embodiments, R7 is -OMe.

[0033] In some embodiments, the compound is [ka] [ka] [ka] or a salt or stereoisomer thereof.

[0034] In some embodiments, the compound is [ka] Not selected from.

[0035] In some embodiments, the compounds disclosed herein are isolated.

[0036] When the compounds disclosed herein have at least one chiral center, they may exist as individual enantiomers and diastereomers, or as mixtures of such isomers, including racemates. Separation of individual isomers or selective synthesis of individual isomers is achieved by applying various methods well known to those skilled in the art. Unless otherwise indicated (e.g., when the stereochemistry of the chiral center is explicitly indicated), all such isomers and mixtures thereof are included within the scope of the compounds disclosed herein. Furthermore, the compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included within the scope of the compounds disclosed herein, including any polymorphs. Furthermore, some of the compounds disclosed herein may form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise indicated, such solvates are included within the scope of the compounds disclosed herein.

[0037] Those skilled in the art will recognize that some structures depicted herein may be resonance forms or tautomers of compounds that may be reasonably represented, even kinetically, by other chemical structures. Those skilled in the art will recognize that such structures may represent only a small sample of such compounds. Although such compounds are considered to be within the scope of the depicted structures, such resonance forms or tautomers are not represented herein.

[0038] Isotopes may be present in the compounds described. Each chemical element represented in the compound structure may include any isotope of the aforementioned element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference to a compound herein encompasses all possible isotopic forms, unless the context clearly indicates otherwise.

[0039] In some embodiments, the compounds disclosed herein can form acid and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto. Physiologically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Physiologically acceptable salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, bases containing sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like, with ammonium, potassium, sodium, calcium, and magnesium salts being particularly preferred. In some embodiments, treatment of the compounds disclosed herein with an inorganic base results in the loss of a labile hydrogen from the compound, forming Li + , Na + , K + , Mg 2+ and Ca 2+ Salt forms can be obtained with inorganic cations such as: Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.

[0040] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs.All patents, applications, published applications, and other publications are incorporated by reference in their entirety.If there are multiple definitions for terms in this specification, the definition in this section shall prevail unless otherwise stated.

[0041] The terms "a" and "an" do not denote a limitation of quantity, but rather the presence of at least one of the referenced items. The terms "or" or "and / or" are used as modifiers indicating that two words or expressions are to be interpreted together or separately. The terms "comprising," "having," "including," and "containing" are to be interpreted as open-ended terms (e.g., meaning "including, but not limited to"). The endpoints of all ranges directed to the same component or characteristic are inclusive and independently combinable.

[0042] Many types of plants are known for producing sweetening compounds and / or flavor modifying compounds, which are isolated and used as sweeteners and / or flavor modifying compounds. In some embodiments herein, the formulation of one or more sweeteners in combination with one or more flavor modifying compounds is obtained in whole or in part from a plant extract. By "extract" is meant a substance or mixture taken from a plant by at least one purification or other processing step. As used herein, "plant" includes, but is not limited to, a whole plant, a plant part, a plant tissue, a plant cell, or a combination thereof. In some embodiments, the extract is obtained from a plant, a plant part, a plant tissue, or a plant cell. As used herein, "plant part" or "plant tissue" refers to any part of a plant. Examples of plant parts include, but are not limited to, leaves, stems, roots, tubers, seeds, branches, pubescence, nodules, axils, flowers, pollen, stamens, pistils, petals, pedicels, stems, stigmas, styles, bracts, fruits, stems, carpels, sepals, anthers, ovules, pedicels, needles, cones, rhizomes, spores, stolons, shoots, pericarp, endosperm, placenta, berries, stamens, sap, and leaf sheaths.

[0043] As used herein, the term "isolated" when referring to a compound means that it is separated or isolated from other components, ingredients, or chemicals that coexist with the compound of interest, whether those other components, ingredients, or chemicals are used or produced in chemically or enzymatically synthesizing the compound of interest, or that other components, materials, or chemicals naturally occur with the compound of interest in its natural state. In some embodiments, the term "isolated" means that the compound of interest is substantially or essentially free from components, materials, or chemicals that are normally associated with it in its natural 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" refers to a compound of interest that has been separated from components, materials, or chemicals that naturally accompany it. In some embodiments, an isolated compound is substantially pure if at least about 50%, at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% of the total material (by volume, wet or dry weight, or by mole percent or fraction) is the compound of interest. Purity can be measured by any appropriate method, for example, by chromatography, gel electrophoresis, or HPLC analysis.

[0044] "Salt" refers to a salt of a compound that has the desired activity of the parent compound. Such salts include, but are not limited to, (1) acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or salts formed with acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methyl ... or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or salts formed with organic bases, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc.

[0045] "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.

[0046] As used herein, "sweetener," "sweet flavoring agent," "sweet flavor entity," or "sweet compound" refers to a compound or an ingestibly acceptable salt thereof that induces a detectable sweet flavor in a subject, e.g., a compound that activates the T1R2 / T1R3 receptor in vitro.

[0047] sweetener Sweeteners have a wide range of chemically distinct structures and therefore have a variety of properties, including, but not limited to, odor, flavor, mouthfeel, and aftertaste. The compositions described herein contain any one or more sweeteners, including combinations of any one or more sweeteners disclosed herein.

[0048] Natural or artificial sweeteners for use in ingestible compositions comprising a sweetener in combination with a flavor enhancer include natural or synthetic carbohydrates or carbohydrate analogs (including monosaccharides, disaccharides, oligosaccharides, and polysaccharides, including rare sugars, or sugars in either the D- or L-configuration, such as sucrose, fructose, glucose, L-arabinose, L-fucose, L-glucose, L-ribose, D-arabino-hexulose, psicose, altrose, arabinose, turanose, abecose, allose, abrusoside A, aldotriose, threose, xylose, xylulose, xylo-oligosaccharides (e.g., xylotriose and xylobiose), lyxose, polydextrose, oligofructose, fucose, galactose, galactooligosaccharides, galactosamine, galactose, gentiooligosaccharides (e.g., gentiobiose, gentiotriose, and gentiotetraose), and the like. maltose, maltotriose, maltotetraose, maltopentaose, maltohexaose, and maltoheptaose; maltose, maltoisolate, ... Sweeteners include, but are not limited to, sucrose, sucrose acetate isobutyrate, dextrose, erythrose, erythrulose, deoxyribose, gulose, ketotriose, lactose, lactulose, kestose, nystose, mannose, sucralose, palatinose, polydextrose, sorbose, sugar dextrose (mixed sugars), or talose, or a combination of any two or more of the foregoing sweeteners.

[0049] The one or more sweeteners can also include, for example, a sweetener composition 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 hydrolysates (HSH), or other syrups or sweetener concentrates derived from natural fruit and plant sources, or semi-synthetic "sugar alcohol" sweeteners, such as polyols. Non-limiting examples of polyols in some embodiments include erythritol, maltitol, mannitol, sorbitol, lactitol, xylitol, isomalt, propylene glycol, glycerol (glycerin), threitol, galactitol, palatinose, reduced isomaltooligosaccharides, reduced xylooligosaccharides, reduced gentiooligosaccharides, reduced maltose syrup, reduced glucose syrup, isomaltulose, maltodextrin, and the like, as well as sugar alcohols, or any other carbohydrates or combinations thereof that can be reduced and do not adversely affect the taste.

[0050] The one or more sweeteners may be agave inulin, agave nectar, agave syrup, amazake, brazzein, brown rice syrup, coconut crystals, coconut sugar, coconut syrup, date sugar, fructans (also called inulin fiber, fructooligosaccharides or oligofructose), green stevia powder, stevia rebaudiana (stevia rebaudiana), rebaudioside A, rebaudioside B, rebaudioside C, rebaudioside D, rebaudioside E, rebaudioside F, rebaudioside I, rebaudioside H, rebaudioside L, rebaudioside K, rebaudioside J, rebaudioside N, rebaudioside O, rebaudioside M and other sweet stevia glycosides, stevioside, stevioside, stevioside extract, honey, Jerusalem artichoke syrup, licorice root, Monk fruit (fruit, powder or extract), lucuma (fruit, powder or extract), maple sap (e.g., Acer saccharum, Acer nigrum, Acer rubrum, Acer saccharinum), saccharinum, Acer platanoides, Acer negundo, Acer macrophyllum, Acer grandidentatum, Acer glabrum, Acer mono), maple syrup, maple sugar, walnut sap (including sap extracted from, for example, Juglans cinerea, Juglans nigra, Juglans ailatifolia, Juglans regia), birch sap (including sap extracted from, for example, Betula papyrifera, Betula arganiensis, Betula alleghaniensis, Betula lenta, Betula nigra, Betula populifolia,including sap extracted from Betula pendula), sycamore sap (e.g., sap extracted from Platanus occidentalis), asada sap (e.g., sap extracted from Ostrya virginiana), virginiana), mascovado, molasses (e.g., blackstrap molasses), molasses sugar, monatin, monellin, cane sugar (also called natural sugar, unrefined cane sugar or sucrose), palm sugar, panocha, piloncillo, rapadura, raw sugar, rice syrup, sorghum, sorghum syrup, cassava syrup (also called tapioca syrup), thaumatin, yacon root, malt syrup, barley malt syrup, barley malt flour, beet sugar, cane sugar, crystallized fruit juice crystals, caramel , carbitol, carob syrup, castor sugar, hydrogenated starch aqueous extract, hydrolyzed canned juice, hydrolyzed starch, invert sugar, anethole, arabinogalactan, arop syrup, P-4000, acesulfame potassium (also called acesulfame K or ace K), alitame (also called acrème), advantame, aspartame, bayunoside, neotame, benzamide derivatives, bernadame, canderel, carrelame and other guanidine sweeteners, vegetable fiber, corn sugar, coupling sugar, curculin, cyclamate, cyclocaryoside I, demerara, dextran, dextrin, malt syrup, dulcin, sucrose, vulgin, dulcoside A, dulcoside B, erin, enoxolone, maltodextrin, saccharin, estragole, ethyl maltol, glycine, gluconic acid, gluconolactone, glucosamine, glucoronic acid, glycerol, Glycine, glycyphyllin, glycyrrhizin, golden sugar, yellow sugar, golden syrup, granulated sugar, gynostemma, hernandalusine, isomerized liquid sugar, jalab, chicory root dietary fiber, kynurenine derivatives (including N'-formyl-kynurenine, N'-acetyl-kynurenine, 6-chloro-kynurenine), galactitol, litesse, ligicane, lycasin, ragduname, guanidine, falernum, mabinlin I,Mabinlin II, maltol, multisorb, maltodextrin, maltotriol, mannosamine, miraculin, starch syrup, mogrosides (including, for example, mogroside IV, mogroside V, and neomogroside), mukurodiosides, nanosugar, naringin dihydrochalcone, neohesperidin dihydrochalcone, nib sugar, nigero-oligosaccharides, norbu, olgate syrup, osladin, pekmez, pentadin, periandrin I, perillaldehyde, perillartine, petophyllum, phenylalanine, phlomisoside I, phlorogizin, phyllodulcin, polyglycitol syrup, polypodoside A, pterocaryoside A, pterocaryoside B, rebiana, refined syrup, rub syrup The sweetener may be a natural or synthetic sweetener, including, but not limited to, syrup, rubusoside, selligueain A, sugar (shugr), siamenoside I, siraitia grosvenorii, soy oligosaccharides, splenda, SRI oxime V, steviol glycosides, steviolbioside, stevioside, strogin 1, 2 and 4 sucronates, sucrononate, sugar, suosan, phloridzin, super aspartame, tetrasaccharide, threitol, treacle, trilobtain, tryptophan and derivatives (6-trifluoromethyl-tryptophan, 6-chloro-D-tryptophan), vanilla sugar, volemitol, birch xylose, aspartame-acesulfame, asguline, and combinations or blends of any two or more thereof.

[0051] In yet other embodiments, one or more sweeteners may be chemically or enzymatically modified natural high-potency sweeteners. Modified natural high-potency sweeteners include glycosylated natural high-potency sweeteners, such as glycosyl derivatives, galactosyl derivatives or fructosyl derivatives containing 1-50 glycoside residues. Glycosylated natural high-potency sweeteners may be prepared by enzymatic transglycosylation reactions catalyzed by various enzymes with transglycosylation activity. In some embodiments, modified sweeteners may be substituted or unsubstituted.

[0052] The additional sweetener also includes any combination of two or more of any of the aforementioned sweeteners. In some embodiments, the sweetener may include a combination of two, three, four or five sweeteners disclosed herein. In some embodiments, the sweetener may be a sugar. In some embodiments, the sweetener may be a combination of one or more sugars and other natural and artificial sweeteners.

[0053] One of ordinary skill in the art will recognize that any one or more of any of the foregoing sweeteners can be combined in various ratios, amounts, or concentrations to produce a single sweetener or a combination of two or more sweeteners, which can then be combined with one or more flavor modifying compounds.

[0054] Those skilled in the art will recognize that the above-mentioned sweeteners for use in the formulations comprising one or more sweeteners and one or more taste modifying compounds are provided by way of example and are not intended to be limiting.

[0055] Flavor-modifying compounds In some embodiments, additional flavor modifying compounds may be combined with the compounds described herein. In some embodiments, the one or more flavor modifying compounds are one or more flavor modifying compounds as disclosed in U.S. Patent Application Publication No. 2005 / 0084506, entitled "Novel Flavors, Flavor Modifiers, Tastants, Taste Enhancers, Umami or Sweet Tastants, and / or Enhancers and Use Thereof," filed August 6, 2004, which is incorporated herein by reference in its entirety. In some embodiments, the one or more flavor modifying compounds are one or more flavor modifying compounds as disclosed in U.S. Patent Application Publication No. 2007 / 0003680, entitled "Bis-Aromatic Amides and Their Uses as Sweet Flavor Modifiers, Tastants, and Taste Enhancers," filed June 15, 2006, which is incorporated herein by reference in its entirety. In some embodiments, the one or more flavor modifying compounds are one or more flavor modifying compounds as disclosed in U.S. Patent Application Publication No. 2008 / 0306093, entitled "Modulation of Chemosensory Receptors and Ligands Associated Therewith," filed June 8, 2007, which is incorporated herein by reference in its entirety. In some embodiments, the one or more flavor modifying compounds are one or more flavor modifying compounds as disclosed in U.S. Patent Application Publication No. 2011 / 0224155, entitled "Modulation of Chemosensory Receptors and Ligands Associated Therewith," filed April 14, 2011, which is incorporated herein by reference in its entirety.In some embodiments, the one or more flavor modifying compounds are one or more flavor modifying compounds as disclosed in U.S. Patent Application Publication No. 2011 / 0245353, entitled "Sweet Flavor Modifier," filed March 31, 2011, which is incorporated herein by reference in its entirety. In some embodiments, the one or more flavor modifying compounds are one or more flavor modifying compounds as disclosed in U.S. Patent Application Publication No. 2013 / 0041046, entitled "Sweet Flavor Modifier," filed August 10, 2012, which is incorporated herein by reference in its entirety. In some embodiments, the one or more flavor modifying compounds are one or more flavor modifying compounds as disclosed in U.S. Patent Application Publication No. 2014 / 0094453, entitled "Sweet flavor modifier," filed December 4, 2014, which is incorporated herein by reference in its entirety. In some embodiments, the one or more flavor modifying compounds are one or more flavor modifying compounds as disclosed in U.S. Patent Application Publication No. 2014 / 0235624, entitled "Sweet flavor modifier," filed February 19, 2014, which is incorporated herein by reference in its entirety. In some embodiments, the one or more flavor modifying compounds are one or more flavor modifying compounds as disclosed in U.S. Patent Application Publication No. 2015 / 0376176, entitled "Sweet flavor modifier," filed August 14, 2015, which is incorporated herein by reference in its entirety. In some embodiments, the one or more flavor modifying compounds are one or more flavor modifying compounds as disclosed in U.S. Patent Application Publication No. 2016 / 0185727, entitled "Substituted 4-amino-5-(cyclohexyloxy)quinolone-3-carboxylic acids as Sweet Flavor Modifiers," filed October 28, 2015, which is incorporated herein by reference in its entirety.

[0056] In some embodiments, the one or more additional taste modifying compounds are compounds having a cyclic thiadiazine core.

[0057] Some embodiments include [ka] and any one or more of the flavor modifying compounds described or referenced herein.

[0058] Some embodiments include [ka] and any one or more of the flavor modifying compounds described or referenced herein.

[0059] Some embodiments include [ka] and any one or more of the additional flavor modifying compounds described or referenced herein.

[0060] Some embodiments include [ka] and any one or more of the additional flavor modifying compounds described or referenced herein.

[0061] Some embodiments include [ka] and any one or more of the additional flavor modifying compounds described or referenced herein.

[0062] Some embodiments include any combination of a flavor modifying compound described herein with any one or more sweeteners described herein.

[0063] In some embodiments, the one or more flavor modifying compounds are present in an amount of about 0.001 ppm to 500 ppm. Thus, in some alternatives, the amount of the one or more flavor modifying compounds is 0.001, 0.01, 0.1, 1, 5, 10, 20, 50, 100, 200, 300, 400, or 500 ppm, or a value within a range defined by any two of the foregoing values.

[0064] Compositions and Uses Some compositions herein relate to a formulation comprising one or more sweeteners disclosed herein in combination with one or more flavor modifying compounds described herein.Therefore, it is recognized that the combination of one or more sweeteners and one or more flavor modifying compounds disclosed herein is not limiting.In some embodiments, the aforementioned formulation comprising one or more sweeteners and one or more flavor modifying compounds is used as a composition for ingestible or non-ingestible products.

[0065] A formulation comprising one or more sweeteners in combination with one or more flavor modifying compounds can be used to modulate chemosensory receptors and / or their ligands, including modulating the activity, structure, function, expression, and / or modification of chemosensory receptors, and modulating, treating, or taking preventative measures against conditions, e.g., physiological or pathological conditions, associated with chemosensory receptors. Generally, physiological or pathological conditions associated with chemosensory receptors include conditions, diseases, or disorders associated with chemosensory receptors and / or their ligands, e.g., gastrointestinal disorders, metabolic disorders, functional gastrointestinal disorders, and the like. In some embodiments, the formulation increases or enhances sweetness. In another embodiment, the formulation modulates sweet receptors and / or their ligands expressed in body locations other than taste buds, such as internal organs. Generally, the formulations of the present disclosure can be provided in a composition, e.g., an ingestible composition. In some embodiments, the formulations can impart a more sugar-like temporal and / or flavor profile to a sweetener composition by combining one or more flavor modifying compounds with one or more sweeteners in a combination formulation. In another embodiment, the present formulations can increase or enhance the sweetness of a composition by contacting the composition with one or more of the present formulations to form an altered composition. In another embodiment, the present formulations can be present in a composition that modulates sweet receptors and / or their ligands expressed in the body other than taste buds.

[0066] In some embodiments, the formulations have sucrose-modifying and / or sweet agonist behavior in vitro and / or in vivo (e.g., as shown in sensory studies). In some embodiments, the formulations exhibit a favorable side-taste profile in vivo.

[0067] Whether a formulation exhibits a sweetness-modifying / agonist effect can be determined by any suitable test method. For example, a formulation containing one or more sweeteners in combination with one or more flavor-modifying compounds can be evaluated in a sensory test using a human taste panel.

[0068] In some embodiments, the formulation may be diluted before being tested, hi some embodiments, the formulation is diluted about 2-fold, about 5-fold, about 10-fold, about 50-fold, about 100-fold, about 200-fold, about 300-fold, about 400-fold, about 500-fold, about 1000-fold or more before being tested.

[0069] Testing can be done with or without additives. In some embodiments, the formulation is tested to evaluate the sweetness enhancement to one or more additives. In the test, participants can provide their impression of the similarity between the characteristics of the sweetener composition with or without additives and the characteristics of the sweetener composition containing sugar. A suitable procedure for determining whether a composition has a more sugar-like taste is by using a panel of evaluators to measure the sweetness of the formulation.

[0070] One embodiment provides a formulation for use in a method for preparing a ready-to-use composition, such as a final food or beverage product, or an animal feed product, comprising contacting a first composition, such as a first food or beverage product, which may contain one or more sweeteners as described herein, with a flavor concentrate composition or formulation (e.g., solid or liquid) comprising one or more flavor modifying compounds to form a ready-to-use composition.

[0071] In some embodiments, the ingestible composition may be a beverage. In some embodiments, the beverage may be selected from the group consisting of enhanced sparkling beverages, cola, lemon-lime flavored sparkling beverages, orange flavored sparkling beverages, grape flavored sparkling beverages, strawberry flavored sparkling beverages, pineapple flavored sparkling beverages, ginger ale, root beer, fruit juice, fruit flavored juice, juice drink, nectar, vegetable juice, vegetable flavored juice, sports drink, energy drink, enhanced water drink, enhanced water with vitamins, near water drink, coconut water, tea drink, coffee, cocoa drink, dairy beverage, chocolate milk, dairy only flavored milk drink, fruit juice flavored milk drink, rice milk, almond milk, cashew milk, coconut milk, hazelnut milk, hemp milk, pistachio milk, oat milk, wheat milk, barley milk, millet milk, spelt milk, triticale milk and soy milk, sour milk drink, fermented milk drink, kefir, grain extract and smoothie. In some embodiments, the beverage may be a soft drink.

[0072] In some embodiments, one or more flavor modifying compounds described herein and one or more sweeteners described herein may be included in a food or beverage product, wherein the food or beverage product comprises: Acids, including for example citric acid, phosphoric acid, ascorbic acid, sodium sulfate, lactic acid, or tartaric acid; bitter ingredients, such as caffeine, quinine, green tea, catechins, polyphenols, green robusta coffee extract, green coffee extract, whey protein isolate, or potassium chloride; Colorants containing, for example, caramel color, Red No. 40, Yellow No. 5, Yellow No. 6, Blue No. 1, Red No. 3, purple carrot, black carrot juice, purple sweet potato, vegetable juice, fruit juice, beta carotene, turmeric curcumin, or titanium dioxide; Preservatives, such as sodium benzoate, potassium benzoate, potassium sorbate, sodium metabisulfate, sorbic acid, or benzoic acid; antioxidants, such as ascorbic acid, disodium calcium EDTA, alpha tocopherol, mixed tocopherols, rosemary extract, grape seed extract, resveratrol, or sodium hexametaphosphate; For example, resveratrol, Co-Q10, omega-3 fatty acids, theanine, choline chloride (cytocholine), fibrosol, inulin (chicory root), taurine, ginseng extract, guarana extract, ginger extract, L-phenylalanine, L-carnitine, L-tartrate, D-glucoronolactone, inositol, bioflavonoids, echinacea, ginkgo biloba, yerba mate, flaxseed oil, garcinia cambogia peel extract, white tea extract, ribose, milk thistle extract, grape seed extract, pyrodixine HCl (vitamin B6), cyanocobalamin (vitamin B12), niacinamide (vitamin B 3), vitamins or functional ingredients including biotin, calcium lactate, calcium pantothenate (pantothenic acid), calcium phosphate, calcium carbonate, chromium chloride, chromium polynicotinate, copper(II) sulfate, folic acid, ferric pyrophosphate, iron, magnesium lactate, magnesium carbonate, magnesium sulfate, monopotassium phosphate, monosodium phosphate, phosphorus, potassium iodide, potassium phosphate, riboflavin, sodium sulfate, sodium gluconate, sodium polyphosphate, sodium bicarbonate, thiamine nitrate, vitamin D3, vitamin A palmitate, zinc gluconate, zinc lactate, or zinc sulfate; Opacifying agents including, for example, ester gun, brominated vegetable oil (BVO), or sucrose acetate isobutyrate (SAIB); buffers containing, for example, sodium citrate, potassium citrate, or salts; For example, propylene glycol, ethyl alcohol, glycerin, gum arabic (gum acacia), maltodextrin, modified corn starch, dextrose, natural flavors, natural flavors including other natural flavors (natural flavors WONF), natural and artificial flavors, flavors containing artificial flavors, silicon dioxide, magnesium carbonate, or tricalcium phosphate; and Additional stabilizers may be included, including, for example, pectin, xanthan gum, carboxymethylcellulose (CMC), polysorbate 60, polysorbate 80, medium chain triglycerides, cellulose gel, cellulose gum, sodium caseinate, modified food starch, gum arabic (acacia gum), or carrageenan.

[0073] Some embodiments provide supplements, nutraceuticals, functional foods (e.g., any fresh or processed food that is claimed to have health-promoting and / or disease-preventing properties beyond the basic nutritional function of providing nutrients), animal feed products, pharmaceuticals, over-the-counter (OTC) products, oral care products, cosmetic products such as sweetened lip balms, and other personal care products that comprise one or more flavor-modifying compounds described herein and a sweetener described herein.

[0074] In general, over-the-counter (OTC) products and oral care products generally refer to products for home and / or personal use that may be sold without a prescription and / or without a medical professional visit. Examples of OTC products include, but are not limited to, vitamins and dietary supplements; topical pain relievers and / or anesthetics; cough, cold and allergy remedies; antihistamines and / or allergy remedies; and combinations thereof. Vitamins and dietary supplements include, but are not limited to, vitamins, dietary supplements, tonics / bottled nutritional drinks, children's vitamins, dietary supplements, nutrition-related or nutrition-providing products, and combinations thereof. Topical pain relievers and / or anesthetics include any topical cream / ointment / gel used to relieve superficial or deep aches and pains, such as muscle pain; pain relief gels; patches containing pain relieving ingredients; and combinations thereof. Cough, cold and allergy remedies include, but are not limited to, decongestants, cough suppressants, throat preparations, medicated confectionery, antihistamines and children's specific cough, cold and allergy remedies; and combination products. Antihistamines and / or allergy medications include, but are not limited to, any systemic treatment for hay fever, nasal allergies, insect bites and stings.Examples of oral care products include, but are not limited to, mouthwash strips, toothpaste, toothbrushes, mouthwash / dental rinses, denture care products, breath fresheners, home whitening toothpastes, tooth powders, and dental floss.

[0075] In some embodiments, one or more flavor modifying compounds as described herein and one or more sweeteners as described herein can be included in a food or beverage product or formulation.Further non-limiting examples of food and beverage products or formulations include, but are not limited to, sweetened coatings, frostings, or glazes for ingestible products or any products included in the soup category, the dry processed food category, the beverage category, the ready meal category, the canned or preserved food category, the frozen processed food category, the chilled processed food category, the snack food category, the baked goods category, the confectionery category, the dairy category, the ice cream category, the meal replacement category, the pasta and noodle category, and the sauce, dressing, condiment category, the baby food category, and / or the spread category.

[0076] In general, the soup category refers to canned / preserved, dehydrated, instant, chilled, UHT and frozen soups. For the purposes of this definition, soup means food prepared from meat, poultry, fish, vegetables, grains, fruits and other ingredients, cooked in a liquid that may contain some or all visible portions of these ingredients. Soups may be clear (as broths) or thick (as chowders), smooth, pureed or chunky, ready to serve, semi-condensed or condensed, and may be served hot or cold, as a first course or as the main course of a meal, or as a snack between meals (sipped in sips like a beverage). Soups may be used as an ingredient for cooking other meal components and may range from broths (consomme) to sauces (cream or cheese-based soups).

[0077] The dehydrated and prepared food category generally refers to: (i) cooking aid products, such as powders, granules, pastes, concentrated liquid products, such as concentrated bouillons, bouillons and bouillon-like products in compressed cubes, tablets, powders or granules form, sold separately (regardless of technology) as finished products or as ingredients in products, sauces and recipe mixes; (ii) dietary solution products, such as dehydrated and freeze-dried soups, such as dehydrated soup mixes, dehydrated instant soups, dehydrated semi-cooked soups, dehydrated or packaged ready-made staples and single-serving main dishes including pasta, potato and rice dishes; (iii) meal accompaniment products, such as condiments, marinades, salad dressings, salad toppings, dips, bread crumbs, batter mixes, shelf stable spreads, barbecue sauces, liquid recipe mixes, concentrates, sauces or sauce mixes, such as salad recipe mixes, sold in dehydrated, liquid or frozen state, either as finished products or as ingredients in products.

[0078] The beverage category generally refers to beverages, beverage mixes and concentrates, including but not limited to carbonated and non-carbonated beverages, alcoholic and non-alcoholic beverages, ready-to-drink, liquid concentrate formulations for producing beverages such as sodas, and dry powdered beverage pre-mixes. The beverage category also includes alcoholic drinks, soft drinks, sports drinks, isotonic drinks, and hot drinks. Alcoholic beverages include but are not limited to beer, cider / perry, FAB, wine and spirits. Soft drinks include carbonated, e.g. cola and non-cola carbonated; fruit juices, e.g. juices, nectars, juice drinks and fruit flavored drinks; bottled waters, e.g. sparkling water, spring water and purified / table water; functional drinks, e.g. which may be carbonated or non-carbonated and include sports drinks, energy drinks or elixir drinks; concentrates, e.g. ready-to-drink measured liquid and powder concentrates. Hot or cold drinks include, but are not limited to, coffee or iced coffee, such as brewed, instant and combination coffees; tea or iced tea, such as black tea, green tea, white tea, oolong tea and flavored teas; and other drinks, including flavored, malt or plant-based powders, granules, blocks or tablets mixed with milk or water.

[0079] The snack food category generally refers to any food that can be a light informal meal, including but not limited to sweet and savory snacks and snack bars. Examples of snack foods include, but are not limited to, fruit snacks, chips / crisps, extruded snacks, tortilla / corn chips, popcorn, pretzels, nuts, and other sweet and savory snacks. Examples of snack bars include, but are not limited to, granola / muesli bars, breakfast bars, energy bars, fruit bars, and other snack bars.

[0080] The baked goods category generally refers to any edible product whose preparation method involves exposure to heat or excessive sunlight. Examples of baked goods include, but are not limited to, bread, buns, cookies, muffins, cereals, toaster pastries, pastries, waffles, tortillas, biscuits, pies, bagels, tarts, quiches, cakes, any baked food product, and any combination thereof.

[0081] The ice cream category generally refers to frozen desserts containing cream and sugar and flavorings. Examples of ice cream include, but are not limited to, impulse ice cream; takeaway ice cream; frozen yogurt and artisanal ice cream; gelato; sorbet; soy, oat, bean (e.g., red and mung bean), coconut, nut and rice based ice cream.

[0082] The confectionery category generally refers to edible products that have a sweet taste. Examples of confectionery include, but are not limited to, candy, gelatin, chocolate confectionery, sugar confectionery, gum, and the like, and any combination products.

[0083] The meal replacement category generally refers to any food product intended to replace a regular meal, especially for people who are health or fitness conscious. Examples of meal replacements include, but are not limited to, slimming products and recovery products.

[0084] The ready meal category generally refers to any food that can be served as a meal without extensive cooking or processing. Ready meals include products to which recipe "skill" has been added by the manufacturer, resulting in a high degree of preparation, completion, and convenience. Examples of ready meals include, but are not limited to, canned / preserved, frozen, dried, chilled ready meals; dinner mixes; frozen pizza; chilled pizza; and pre-prepared salads.

[0085] The pasta and noodles category includes any pasta and / or noodles, including but not limited to canned, dried and chilled / fresh pasta; regular, instant, chilled, frozen and snack noodles.

[0086] The canned / preserved food category includes, but is not limited to, canned / preserved meat and meat products, fish / seafood, vegetables, tomatoes, beans, fruit, ready meals, soups, pasta and other canned / preserved foods.

[0087] The frozen processed foods category includes, but is not limited to, frozen processed red meat, processed poultry, processed fish / seafood, processed vegetables, meat substitutes, processed potatoes, bakery products, desserts, ready meals, pizza, soups, noodles and other frozen foods.

[0088] The dry processed food category includes, but is not limited to, rice, dessert mixes, dry ready meals, dehydrated soups, instant soups, dry pasta, regular noodles and instant noodles. The chilled processed food category includes, but is not limited to, chilled processed meats, processed fish / seafood products, lunch kits, fresh cut fruit, ready meals, pizza, prepared salads, soups, fresh pasta and noodles.

[0089] The sauces, dressings and condiments category includes, but is not limited to, tomato paste and purees, bouillon / stock cubes, herbs and spices, monosodium glutamate (MSG), table sauces, soy-based sauces, pasta sauces, wet / cooking sauces, dry sauces / powder mixes, ketchup, mayonnaise, mustard, salad dressings, vinaigrettes, dips, pickle products and other sauces, dressings and condiments.

[0090] Baby food categories include, but are not limited to, milk or soy-based formulas; cooked, dried and other baby foods.

[0091] Spread categories include, but are not limited to, jams and preserves, honey, chocolate spreads, nut-based spreads, speckle spreads, butter, flavored butter, margarine, edible oil spreads, Oreo, cheese or cream cheese spreads, savory spreads, and yeast-based spreads.

[0092] The dairy category generally refers to edible products produced from mammalian milk. Examples of dairy products include, but are not limited to, drinking dairy products, cheese, yogurt and sour milk drinks, and other dairy products.

[0093] Additional examples of ingestible compositions, particularly food and beverage products or formulations, are provided below. Exemplary ingestible compositions include one or more of confectionery, chocolate confectionery, tablets, countlines, bagged selflines / softlines, boxed assortments, standard boxed assortments, twist wrapped miniatures, and the like. miniatures, seasonal chocolates, chocolates with toys, alfajores, other chocolate confectionery, mints, standard mints, power mints, boiled sweets, pastilles, gums, jellies and chews, toffees, caramel and nougat, medicated confectionery, lollipops, liquorice, other sugar confectionery, bread, packaged / industrial bread, unpackaged / artisan bread, pastries, cakes, packaged / industrial cakes, unpackaged / artisan cakes, cookies, chocolate coated biscuits, sandwich biscuits, filled biscuits, savoury biscuits and crackers, bread substitutes, breakfast cereals, rte cereals, family breakfast cereals, flakes, muesli, other cereals, children's breakfast cereals, hot cereals, ice cream, impulse ice cream, single portion dairy ice cream, single portion water ice cream, multi-pack dairy ice cream, marmalade Chipac water ice cream, take away ice cream, take away dairy ice cream, ice cream desserts, bulk ice cream, take away water ice cream, frozen yogurt, artisanal ice cream, dairy products, milk, raw milk / pasteurized milk, whole fat raw milk / pasteurized milk, semi skimmed milk / pasteurized milk, long life / uht milk, full fat long life / uht milk, semi skimmed long life / uht milk, non fat long life / uht milk, goat milk, condensed milk / evaporated milk, plain condensed milk / evaporated milk, flavoured, functional and other condensed milk, flavoured milk drinks, chocolate milk, dairy only flavoured milk drinks, flavoured milk drinks with fruit juice, rice milk, almond milk, cashew milk, coconut milk, hazelnut milk, hemp milk, pistachio milk, oat milk, wheat milk, barley milk, millet milk, spelt milk,Rye milk, and soy milk, Sour milk drinks, Fermented milk drinks, Coffee whiteners, Powdered milk, Flavoured powdered milk drinks, Cream, Cheese, Processed cheese, Spreadable processed cheese, Non-spreadable processed cheese, Raw cheese, Spreadable raw cheese, Hard cheese, Packaged hard cheese, Unpackaged hard cheese, Yogurt, Plain yogurt / natural yogurt, Flavoured yogurt, Fruit yogurt, Probiotic yogurt, Drinking yogurt, Regular drinking yogurt, Probiotic drinking yogurt, Refrigerated shelf stable desserts, Dairy based desserts, Soy based desserts, Chilled snacks, Fromage frais and quark, Plain fromage frais and quark, Flavoured fromage frais and quark, Savory fromage frais and quark, Sweet and savoury snacks, Fruit snacks, Chips / crisps, Extruded snacks, Tortilla / corn chips, Popcorn, Pretzels, Nuts, Other sweet and savoury snacks, Snack bars, Granola bars, Breakfast bars, Energy bars, Fruit Bars, Other Snack Bars, Meal Replacement Products, Slimming Products, Recovery Drinks, Ready Meals, Canned Ready Meals, Frozen Ready Meals, Dried Ready Meals, Chilled Ready Meals, Dinner Mixes, Frozen Pizza, Chilled Pizza, Soup, Canned Soup, Dehydrated Soup, Instant Soup, Chilled Soup, Hot Soup, Frozen Soup, Pasta, Canned Pasta, Dried Pasta, Chilled / Fresh Pasta, Noodles, Regular Noodles, Instant Noodles, Cup / Bowl Instant Noodles, Pouch Instant Noodles, Chilled Noodles, Snack Noodles, Canned Food, Canned Meat and Meat Products, Canned Fish / Seafood , canned vegetables, canned tomatoes, canned beans, canned fruit, canned ready meals, canned soups, canned pasta, other canned foods, frozen foods, frozen processed red meat, frozen processed poultry, frozen processed fish / seafood, frozen processed vegetables, frozen meat substitutes, frozen potatoes, oven baked potato chips, other oven baked potato products, non-oven frozen potatoes, frozen bakery products, frozen desserts, frozen ready meals, frozen pizza, frozen soups, frozen noodles, other frozen foods, dehydrated foods, dessert mixes, dehydrated ready meals, dehydrated soups, instant soups, dehydrated pasta, regular noodles, instant noodles,Cup / Bowl Instant Noodles, Pouch Instant Noodles, Chilled Food, Chilled Processed Meat, Chilled Fish / Seafood Products, Chilled Processed Fish, Chilled Coated Fish, Chilled Smoked Fish, Chilled Lunch Kits, Chilled Ready Meals, Chilled Pizza, Chilled Soup, Chilled / Fresh Pasta, Chilled Noodles, Oils & Fats, Olive Oil, Vegetable Seed Oils, Cooking Oils & Fats, Butter, Margarine, Spreadable Oils & Fats, Functional Spreadable Oils & Fats, Sauces, Dressings & Condiments, Tomato Paste & Puree, Bouillon / Stock Cubes, Stock Cubes, Gravy Granules, Liquid Stocks & Fonds, Herbs & Spices, Fermented Sauces, Soy Based Sauces, Included are pasta sauces, wet sauces, dry sauces / powder mixes, ketchup, mayonnaise, regular mayonnaise, mustard, salad dressings, regular salad dressings, low-fat salad dressings, vinaigrettes, dips, pickle products, other sauces, dressings and condiments, baby foods, formulas, standard formulas, follow-on formulas, toddler formulas, hypoallergenic formulas, prepared baby foods, dry baby foods, other baby foods, spreads, jams and preserves, honey, chocolate spreads, nut-based spreads, and yeast-based spreads. Exemplary ingestible compositions include confectionery, bakery products, ice cream, dairy products, sweet and savory snacks, snack bars, meal replacement products, ready meals, soups, pastas, noodles, canned foods, frozen foods, dry foods, chilled foods, oils and fats, baby foods or spreads, or mixtures thereof. Exemplary ingestible compositions also include solid or liquid concentrate compositions for producing breakfast cereals, sweetened drinks, or beverages, ideally allowing for reduced concentrations of previously known sugar or artificial sweeteners.

[0094] Some embodiments provide chewable compositions that may or may not be intended to be swallowed. In some embodiments, the chewable composition may be a gum, chewing gum, sugar-coated gum, sugar-free gum, functional gum, bubble gum, which comprises one or more taste-modifying compounds as described herein and a sweetener as described herein.

[0095] In some embodiments, one or more flavor modifying compounds described herein and one or more sweeteners described herein may be provided in a flavor concentrate formulation, suitable for subsequent processing to produce, for example, a ready-to-use (e.g., ready-to-serve) product. A "flavor concentrate formulation" refers to a formulation that is to be reconstituted with one or more dilution media to become a ready-to-use composition. The term "ready-to-use composition" is used interchangeably herein with "ingestible composition," which refers to any substance that can be taken orally, whether or not intended for consumption, alone or together with another substance. In one embodiment, a ready-to-use composition includes a composition that can be directly consumed by a human or animal. A flavor concentrate formulation is typically used by mixing with or diluting with one or more dilution media, e.g., any consumable or ingestible ingredient or product, to impart or modify one or more flavors to the dilution medium. Such a method of use is often referred to as reconstitution. Reconstitution can be performed in a domestic or industrial environment. For example, a frozen fruit juice concentrate can be reconstituted with water or other aqueous medium by a consumer in the kitchen to obtain a ready-to-use fruit juice beverage. In another example, soft drink syrup concentrates can be reconstituted with water or other aqueous media by manufacturers on a large industrial scale to produce ready-to-use soft drinks. Because flavor concentrate formulations have higher concentrations of flavoring agents or flavor modifiers than ready-to-use compositions, flavor concentrate formulations are typically not suitable for direct consumption without reconstitution. There are many benefits to the use and manufacture of flavor concentrate formulations. For example, one benefit is that flavor concentrate formulations can be reconstituted at the time of use by adding a suitable solvent, solid or liquid, thus reducing the weight and volume of shipping.

[0096] In one embodiment, the flavor concentrate formulation comprises i) one or more flavor modifying compounds as described herein, ii) a carrier, and iii) optionally at least one adjuvant. The term "carrier" refers to a normally inert accessory substance, such as a solvent, binder, or other inert medium, 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 flavor concentrate formulation. In some embodiments, the carrier is the same as the dilution medium for reconstituting the flavor concentrate formulation, and in other embodiments, the carrier is different from the dilution medium. The term "carrier" as used herein includes, but is not limited to, ingestibly acceptable carriers.

[0097] The term "adjuvant" refers to an additive that supplements, stabilizes, maintains or enhances the intended function or effectiveness of an active ingredient, such as a compound of the present disclosure. In one embodiment, the at least one adjuvant includes one or more flavoring agents. The flavoring agents can be of any flavor known to the artisan or consumer, such as the flavors of chocolate, coffee, tea, mocha, French vanilla, peanut butter, chai, or combinations thereof. In another embodiment, the at least one adjuvant includes one or more sweeteners. The one or more sweeteners can be any of the sweeteners described above. 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. Pat. No. 6,468,576, the contents of which are incorporated herein by reference in their entirety for all purposes.

[0098] In one embodiment, the flavor concentrate formulation may be in a form selected from the group consisting of liquids, including solutions and suspensions, solids, foams, pastes, gels, creams, and combinations thereof, such as liquids containing a certain amount of solids. In one embodiment, the flavor concentrate formulation is in the form of a liquid, including aqueous and non-aqueous. In some embodiments, the flavor concentrate formulation may be carbonated or non-carbonated.

[0099] The flavor concentrate formulation may further include a freezing point depressant, a nucleating agent, or both as at least one adjuvant. A freezing point depressant is a ingestibly acceptable compound or agent that can depress the freezing point of a liquid or solvent to which the compound or agent is added. That is, a liquid or solution containing a freezing point depressant has a lower freezing point than a liquid or solvent without the freezing point depressant. In addition to depressing the starting freezing point, the freezing point depressant can also reduce the water activity of the flavor concentrate formulation. Examples of freezing point depressants include, but are not limited to, carbohydrates, oils, ethyl alcohol, polyols such as glycerol, and combinations thereof. A nucleating agent refers to a ingestibly acceptable compound or agent that can promote nucleation. The presence of a nucleating agent in the flavor concentrate formulation can improve the texture of the frozen blushes of the frozen slush and help maintain the physical properties and performance of the slush at freezing temperatures by increasing the number of desirable ice crystallization centers. Examples of nucleating agents include, but are not limited to, calcium silicate, calcium carbonate, titanium dioxide, and combinations thereof.

[0100] In one embodiment, the flavor concentrate formulation is formulated to have a low water activity to extend shelf life. Water activity is the ratio of the vapor pressure of water in the formulation to the vapor pressure of pure water at the same temperature. In one embodiment, the flavor concentrate formulation has a water activity of less than about 0.85. In another embodiment, the flavor concentrate formulation has a water activity of less than about 0.80. In another embodiment, the flavor concentrate formulation has a water activity of less than about 0.75.

[0101] In one embodiment, the flavoring concentrated formulation comprises one or more flavor modifying compounds at a concentration of at least 2 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavoring concentrated formulation comprises one or more flavor modifying compounds at a concentration of at least 5 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavoring concentrated formulation comprises one or more flavor modifying compounds at a concentration of at least 10 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavoring concentrated formulation comprises one or more flavor modifying compounds at a concentration of at least 15 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavoring concentrated formulation comprises one or more flavor modifying compounds at a concentration of at least 20 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavoring concentrated formulation comprises one or more flavor modifying compounds at a concentration of at least 30 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavoring concentrated formulation comprises one or more flavor modifying compounds at a concentration of at least 40 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavoring concentrated formulation comprises one or more flavor modifying compounds at a concentration of at least 50 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation comprises one or more flavor modifying compounds at a concentration of at least 60 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation comprises one or more flavor modifying compounds at a concentration of up to 100 times the concentration of the compound in the ready-to-use composition.

[0102] Ingestible Composition In some embodiments, the compounds disclosed and described herein can be used individually or in combination in one or more methods, such as modifying receptor function associated with chemosensory or chemosensory-related sensations or responses. Some embodiments provide methods for modulating chemosensory receptors and / or their ligands, including modulating the activity, structure, function, and / or modification of chemosensory receptors, and modulating, treating, or taking preventative measures for conditions, such as physiological or pathological conditions, associated with chemosensory receptors. In general, physiological or pathological conditions associated with chemosensory receptors include conditions, diseases, or disorders associated with chemosensory receptors and / or their ligands, such as gastrointestinal disorders, metabolic disorders, functional gastrointestinal disorders, and the like. In one embodiment, the method includes increasing or enhancing sweet taste. In another embodiment, the method includes modulating sweet taste receptors and / or their ligands expressed in body locations other than taste buds, such as internal organs.

[0103] In general, the compounds disclosed and described herein can be provided individually or in combination in a composition, such as an ingestible composition. In one embodiment, the compounds disclosed and described herein can be provided individually or in combination in a sweetener composition by combining one or more of the compounds disclosed and described herein with one or more sweeteners in the sweetener composition to impart a sugar-like temporal profile and / or flavor profile. In another embodiment, the compounds disclosed and described herein can be provided individually or in combination in a composition to increase or enhance the sweetness of a composition by contacting the composition with a compound disclosed and described herein to form an altered composition. In another embodiment, the compounds disclosed and described herein can be provided individually or in combination in a composition that modulates sweet receptors and / or their ligands expressed in the body other than taste buds.

[0104] Some embodiments provide an ingestible composition comprising a compound of any one of formulas (I), (II), (III), (IV), (V), or (VI) and a sweetener. In some embodiments, the composition further comprises a vehicle. In some embodiments, the vehicle is water. In some embodiments, the compound is present at a concentration below its sweetness perception threshold. In some embodiments, the sweetener is present in an amount of about 0.1% to about 12% by weight. In some embodiments, the sweetener is present in an amount of about 0.2% to about 10% by weight. In some embodiments, the sweetener is present in an amount of about 0.3% to about 8% by weight. In some embodiments, the sweetener is present in an amount of about 0.4% to about 6% by weight. In some embodiments, the sweetener is present in an amount of about 0.5% to about 5% by weight. In some embodiments, the sweetener is present in an amount of about 1% to about 2% by weight. In some embodiments, the sweetener is present in an amount of about 0.1% to about 5% by weight. In some embodiments, the sweetener is present in an amount of about 0.1% to about 4% by weight. In some embodiments, the sweetener is present in an amount of about 0.1% to about 3% by weight. In some embodiments, the sweetener is present in an amount of about 0.1% to about 2% by weight. In some embodiments, the sweetener is present in an amount of about 0.1% to about 1% by weight. In some embodiments, the sweetener is present in an amount of about 0.1% to about 0.5% by weight. In some embodiments, the sweetener is present in an amount of about 0.5% to about 10% by weight. In some embodiments, the sweetener is present in an amount of about 2% to about 8% by weight.In some embodiments, the sweetener may be a common sugar sweetener, such as sucrose, fructose, glucose, and natural sugars, such as corn syrup (including high fructose corn syrup) or natural fruit and plant sources; sweetener compositions including other syrups or sweetener concentrates derived from rare natural sugars, including D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-albinose, D-turanose, D-leucrose; semi-synthetic "sugar alcohol" sweeteners, such as erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, maltodextrin; and artificial sweeteners, such as aspartame, saccharin, acesulfame-K, cyclamate, sucralose, and alitame. In some embodiments, the sweetener may be selected from the group consisting of cyclamic acid, mogrosides, tagatose, maltose, galactose, mannose, sucrose, fructose, lactose, neotame and other aspartame derivatives, glucose, D-tryptophan, glycine, maltitol, lactitol, isomalt, hydrogenated glucose syrup (HGS), hydrogenated starch hydrolysates (HSH), stevioside, rebaudioside A, other sweet stevia-based glycosides, carreme and other guanidine-based sweeteners. In some embodiments, the sweetener may be a combination of two or more sweeteners disclosed herein. In some embodiments, the sweetener may be a combination of two, three, four or five sweeteners disclosed herein. In some embodiments, the sweetener may be a sugar. In some embodiments, the sweetener may be a combination of one or more sugars and other natural and artificial sweeteners. In some embodiments, the sweetener is a sugar. In some embodiments, the sugar is cane sugar. In some embodiments, the sugar is sugar 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-albinose, D-turanose, D-leucrose, and combinations thereof. In some embodiments, the rare sugar is D-psicose. In some embodiments, the rare sugar is D-tagatose. In some embodiments, the sweetener is an artificial sweetener. In some embodiments, the artificial sweetener can be sucralose.

[0105] In some embodiments, the ingestible composition may be a beverage.In some embodiments, the beverage may be selected from the group consisting of enhanced sparkling beverage, cola, lemon-lime flavored sparkling beverage, orange flavored sparkling beverage, grape flavored sparkling beverage, strawberry flavored sparkling beverage, pineapple flavored sparkling beverage, ginger ale, root beer, fruit juice, fruit flavored juice, juice drink, nectar, vegetable juice, vegetable flavored juice, sports drink, energy drink, enhanced water drink, enhanced water with vitamins, near water drink, coconut water, tea drink, coffee, cocoa drink, beverage containing dairy ingredients, beverage containing cereal extract, and smoothie.In some embodiments, the beverage may be a soft drink.

[0106] In one embodiment, the compounds disclosed and described herein can be used in combination with one or more known sweeteners, natural or artificial, at their ligand-enhancing concentrations, e.g., very low concentrations on the order of parts per million, either individually or in combination, to reduce the concentration of the known sweetener required to prepare an ingestible composition having a desired degree of sweetness.

[0107] In one embodiment, the compounds disclosed and described herein, individually or in combination, can enhance the sweetness of a sweetener under a wide range of pH, for example, from lower to neutral pH. Lower neutral pH includes, but is not limited to, a pH of about 2.5 to about 8.5; about 3.0 to about 8.0; about 3.5 to about 7.5; about 4.0 to about 7. In certain embodiments, the compounds disclosed and described herein, individually or in combination, can enhance the perceived sweetness of a certain concentration of a sweetener in a taste test at a compound concentration of about 50 μM, 40 μM, 30 μM, 20 μM, or 10 μM, both from low to neutral pH values. In certain embodiments, the enhancement factor of the compounds disclosed and described herein at lower pH is substantially similar to the enhancement factor of the compounds at neutral pH. Such consistent sweetness enhancement properties under a wide range of pH allow the compounds disclosed and described herein to be widely used, individually or in combination, in a wide variety of foods and beverages. In some embodiments, the sweetener may be a common sugar sweetener, such as sucrose, fructose, glucose, and natural sugars, such as corn syrup (including high fructose corn syrup) or natural fruit and plant sources; sweetener compositions including other syrups or sweetener concentrates derived from rare natural sugars, including D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-albinose, D-turanose, D-leucrose; semi-synthetic "sugar alcohol" sweeteners, such as erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, maltodextrin; and artificial sweeteners, such as aspartame, saccharin, acesulfame-K, cyclamate, sucralose, and alitame.In some embodiments, the sweetener may be selected from the group consisting of cyclamic acid, mogrosides, tagatose, maltose, galactose, mannose, sucrose, fructose, lactose, neotame and other aspartame derivatives, glucose, D-tryptophan, glycine, maltitol, lactitol, isomalt, hydrogenated glucose syrup (HGS), hydrogenated starch hydrolysates (HSH), stevioside, rebaudioside A, other sweet stevia-based glycosides, carreme and other guanidine-based sweeteners. In some embodiments, the sweetener may be a combination of two or more sweeteners disclosed herein. In some embodiments, the sweetener may be a combination of two, three, four or five sweeteners disclosed herein. In some embodiments, the sweetener may be a sugar. In some embodiments, the sweetener may be a combination of one or more sugars and other natural and artificial sweeteners. In some embodiments, the sweetener may be a sugar. In some embodiments, the sugar is cane sugar. In some embodiments, the sugar is sugar beet 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 sugar can be sucrose, fructose, glucose or a combination thereof (e.g., high fructose corn syrup). 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-albinose, D-turanose, D-leucrose, and combinations thereof.In some embodiments, the rare sugar is D-psicose.In some embodiments, the rare sugar is D-tagatose.In some embodiments, the sweetener is an artificial sweetener. In some embodiments, the artificial sweetener is sucralose.

[0108] Typically, at least one sweet receptor modulating amount, sweet receptor ligand modulating amount, sweet flavor modulating amount, sweet flavoring agent amount, sweet enhancing amount, or therapeutically effective amount of one or more of the present compounds, optionally in the presence of a sweetener, is added to an ingestible composition such that the sweet flavor modified ingestible composition has increased sweetness compared to an ingestible composition prepared without the compound of the present invention, as judged generally by a human or animal, or, in the case of formulation testing, by a majority of a panel of at least eight human taste testers, via procedures commonly known in the art.

[0109] In some embodiments, the compounds disclosed and described herein, individually or in combination, modulate the sweetness or other taste characteristics of other natural or synthetic sweeteners and ingestible compositions made therefrom. In one embodiment, the compounds disclosed and described herein, individually or in combination, can be used or provided at their ligand-enhanced concentrations. For example, the compounds disclosed and described herein, individually or in combination, can be present in an amount of about 0.001 ppm to 100 ppm, or about 0.1 ppm to about 10 ppm, about 0.01 ppm to about 30 ppm, about 0.05 ppm to about 10 ppm, about 0.01 ppm to about 5 ppm, or about 0.02 ppm to about 2 ppm, or narrower alternative ranges of about 0.01 ppm to about 1 ppm.

[0110] Some embodiments provide a sweetness enhancing composition comprising a sweet flavor enhancing amount of a compound of the present invention in combination with a first amount of a sweetener, wherein the sweetness is greater than the sweetness provided by the first amount of the sweetener without the compound. In some embodiments, the sweetener may be a common sugar sweetener, such as sucrose, fructose, glucose, and natural sugars, such as corn syrup (including high fructose corn syrup) or natural fruit and plant sources; sweetener compositions including other syrups or sweetener concentrates derived from rare natural sugars, including D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-albinose, D-turanose, D-leucrose; semi-synthetic "sugar alcohol" sweeteners, such as erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, maltodextrin; and artificial sweeteners, such as aspartame, saccharin, acesulfame-K, cyclamate, sucralose, and alitame. In some embodiments, the sweetener may be selected from the group consisting of cyclamic acid, mogrosides, tagatose, maltose, galactose, mannose, sucrose, fructose, lactose, neotame and other aspartame derivatives, glucose, D-tryptophan, glycine, maltitol, lactitol, isomalt, hydrogenated glucose syrup (HGS), hydrogenated starch hydrolysates (HSH), stevioside, rebaudioside A, other sweet stevia-based glycosides, carreme and other guanidine-based sweeteners. In some embodiments, the sweetener may be a combination of two or more sweeteners disclosed herein. In some embodiments, the sweetener may be a combination of two, three, four or five sweeteners disclosed herein. In some embodiments, the sweetener may be a sugar. In some embodiments, the sweetener may be a combination of one or more sugars and other natural and artificial sweeteners. In some embodiments, the sweetener may be a sugar. In some embodiments, the sugar is cane sugar. In some embodiments, the sugar is beet sugar. In some embodiments, the sweetener may be a combination of one or more sugars and other natural and artificial sweeteners.In some embodiments, the sugar can be sucrose, fructose, glucose or a combination thereof (e.g., high fructose corn syrup). 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-albinose, D-turanose, D-leucrose and combinations thereof. In some embodiments, the rare sugar is D-psicose. In some embodiments, the rare sugar is D-tagatose. In some embodiments, the sweetener is an artificial sweetener. In some embodiments, the artificial sweetener can be sucralose.

[0111] In some embodiments, the compounds disclosed and described herein, individually or in combination, are effective in reducing the EC of sweeteners with and without the compounds described herein. 50In some embodiments, the compounds disclosed and described herein, individually or in combination, provide an enhancement ratio of greater than 1 and less than 10. In some embodiments, the compounds disclosed and described herein, individually or in combination, provide an enhancement ratio of 10-20. In some embodiments, the compounds disclosed and described herein, individually or in combination, provide an enhancement ratio of greater than 20. In some embodiments, the sweetener may be a common sugar sweetener, such as sucrose, fructose, glucose, and natural sugars, such as corn syrup (including high fructose corn syrup) or natural fruit and plant sources; sweetener compositions including other syrups or sweetener concentrates derived from rare natural sugars, including D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-albinose, D-turanose, D-leucrose; semi-synthetic "sugar alcohol" sweeteners, such as erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, maltodextrin; and artificial sweeteners, such as aspartame, saccharin, acesulfame-K, cyclamate, sucralose, and alitame. In some embodiments, the sweetener may be selected from the group consisting of cyclamic acid, mogrosides, tagatose, maltose, galactose, mannose, sucrose, fructose, lactose, neotame and other aspartame derivatives, glucose, D-tryptophan, glycine, maltitol, lactitol, isomalt, hydrogenated glucose syrup (HGS), hydrogenated starch hydrolysates (HSH), stevioside, rebaudioside A, other sweet stevia-based glycosides, carreme and other guanidine-based sweeteners. In some embodiments, the sweetener may be a combination of two or more sweeteners disclosed herein. In some embodiments, the sweetener may be a combination of two, three, four or five sweeteners disclosed herein. In some embodiments, the sweetener may be a sugar. In some embodiments, the sweetener may be a combination of one or more sugars with other natural and artificial sweeteners.In some embodiments, the sweetener may be a sugar. In some embodiments, the sweetener may be a combination of one or more sugars and other natural and artificial sweeteners. In some embodiments, the sugar may be sucrose, fructose, glucose, or a combination thereof (e.g., high fructose corn syrup). In some embodiments, the sugar may be sucrose. In some embodiments, the sugar may be a combination of fructose and glucose. In some embodiments, the sugar may be a combination of about 55% fructose and about 42% glucose. In some embodiments, the sugar may be a combination of about 42% fructose and about 53% glucose. In some embodiments, the sugar may be a combination of about 90% fructose and about 10% glucose. In some embodiments, the sweetener may be a rare sugar. In some embodiments, the rare sugar is selected from the group consisting of D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-albinose, D-turanose, D-leucrose, and combinations thereof. In some embodiments, the rare sugar is D-psicose. In some embodiments, the rare sugar is D-tagatose. In some embodiments, the sweetener is an artificial sweetener. In some embodiments, the artificial sweetener can be sucralose.

[0112] In one embodiment, the flavor concentrate formulation may be in a form selected from the group consisting of liquids, including solutions and suspensions, solids, foams, pastes, gels, creams, and combinations thereof, such as liquids containing a certain amount of solids. In one embodiment, the flavor concentrate formulation is in the form of a liquid, including aqueous and non-aqueous. In some embodiments, the flavor concentrate formulation may be carbonated or non-carbonated.

[0113] In one embodiment, the flavor concentrate formulation has the compound at a concentration at least twice the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation has the compound at a concentration at least 5 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation has the compound at a concentration at least 10 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation has the compound at a concentration at least 15 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation has the compound at a concentration at least 20 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation has the compound at a concentration at least 30 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation has the compound at a concentration at least 40 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation has the compound at a concentration at least 50 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation has the compound at a concentration at least 60 times the concentration of the compound in the ready-to-use composition. In one embodiment, the flavor concentrate formulation has the compound at a concentration up to 100 times the concentration of the compound in the ready-to-use composition.

[0114] Therapeutic benefits In some embodiments, the compounds disclosed and described herein, individually or in combination, can be used for therapeutic purposes, such as modulating chemosensory receptors and / or their ligands to achieve a therapeutic effect. For example, therapeutic purposes can include modulating chemosensory receptors and / or their ligands expressed in the body other than in taste buds.

[0115] In some embodiments, the method of modulating a chemosensory receptor and / or its ligand comprises modulating the expression, secretion, and / or function levels of T1R expressing cells associated with hormone, peptide, enzyme production by administering the compounds disclosed and described herein, individually or in combination, to an individual in need of modulating the chemosensory receptor and / or its ligand. In one example, the method of the present invention comprises modulating glucose levels, for example, using inhibitors or modulators of chemosensory receptors such as T1R2 / T1R3, the compounds disclosed and described herein, individually or in combination, can be administered to an individual in need of modulating glucose levels to reduce glucose levels (e.g., glucose absorption) in a subject. In some embodiments, the method comprises modulating the levels of incretins, for example, using agonists or enhancers of chemosensory receptors such as T1R2 / T1R3, the compounds disclosed and described herein, individually or in combination, can be administered to an individual in need of modulating the levels of incretins to increase glucagon-like peptide 1 (GLP-1), and thus increase insulin production. In some embodiments, the method includes modulating the expression, secretion and / or activity levels of hormones or peptides produced by T1R expressing cells or gastrointestinal hormone producing cells, such as ligands for 5HT receptors (e.g., serotonin), incretins (e.g., GLP-1 and glucose-dependent insulinotropic polypeptide (GIP)), gastrin, secretin, pepsin, cholecystokinin, amylase, ghrelin, leptin, somatostatin, etc., by administering a compound disclosed and described herein, individually or in combination, to an individual in need of such modulation. In some embodiments, the method includes modulating pathways associated with hormones, peptides and / or enzymes secreted by T1R expressing cells, by administering a compound disclosed and described herein, individually or in combination, to an individual in need of such modulation.

[0116] In some embodiments, the methods involve the use 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, cardiomyocytes and smooth muscle cells, etc.), pancreatic cells (e.g., alpha cells, beta cells, delta cells, neurosecretory PP cells, D1 cells), papillary cells (e.g., ductal epithelial cells), gastric cells (e.g., mucous cells, parietal cells, chief cells, G cells, P / D1 cells), intestinal cells (e.g., enteroendocrine cells, brush cells), salivary gland cells (e.g., serous cells, mucous cells, myoepithelial cells, interstitial cells, striate cells), L cells (e.g., , expression of GLP-1), enterochromaffin cells (e.g., expression of serotonin), enterochromaffin-like cells, G cells (e.g., expressing gastrin), D cells (delta cells, e.g., expressing somatostatin), I cells (e.g., expressing cholecystokinin (CCK)), K cells (e.g., expression of gastric inhibitory polypeptide), P / D1 cells (e.g., expression of ghrelin), chief cells (e.g., expression of pepsin), and S cells (e.g., expression of secretin) by administering a compound disclosed and described herein, individually or in combination, to an individual in need of such modulation. In some embodiments, the method includes increasing the expression level of T1R in T1R-expressing cells by administering a compound disclosed and described herein, individually or in combination, to an individual in need of such increase. In some embodiments, the method includes increasing the secretion level of T1R in T1R-expressing cells by administering a compound disclosed and described herein, individually or in combination, to an individual in need of such increase.

[0117] In some embodiments, the methods are directed to treating conditions associated with esophageal motility (e.g., cricopharyngeal achalasia, globus hystericus, achalasia, diffuse esophageal spasms and related motility disorders, scleroderma involving the esophagus, etc.), inflammatory disorders (e.g., gastroesophageal reflux and esophagitis, infectious esophagitis, etc.), peptic ulcers, duodenal ulcers, gastric ulcers, gastrinomas, stress ulcers and erosions, drug-related ulcers and erosions, gastritis, esophageal cancer, gastric tumors, absorption disorders (e.g., absorption of carbohydrates, proteins, amino acids, fats, cholesterol and fat-soluble vitamins, water and certain nutrients such as sodium, calcium, iron, water-soluble vitamins), malabsorption disorders, defects in mucosal function (e.g., inflammatory or infiltrative disorders, biochemical or genetic abnormalities, endocrine and metabolic disorders, protein-losing enteropathy, etc.), autoimmune diseases of the digestive tract (e.g., celiac disease, Crohn's disease, ulcerative colitis, etc.), irritable bowel syndrome. and / or by administering the compounds disclosed and described herein, individually or in combination, to an individual in need of such regulation, treatment and / or prevention of conditions related to the gastrointestinal system, including, but not limited to, inflammatory bowel disease, complications of inflammatory bowel disease, extraintestinal manifestations of inflammatory bowel disease, intestinal motility disorders, intestinal vascular disorders, anorectal disorders (e.g., hemorrhoids, anal inflammation, etc.), colorectal cancer, small intestinal tumors, anal cancer, liver metabolic disorders, hyperbilirubinemia, hepatitis, alcoholic liver disease and cirrhosis, biliary cirrhosis, liver neoplasms, invasive and metabolic diseases affecting the liver (e.g., fatty liver, Reye's syndrome, diabetic glycogenosis, glycogen storage disease, Wilson's disease, hemochromatosis), diseases of the gallbladder and bile duct, disorders of the pancreas (e.g., pancreatitis, exocrine pancreatic insufficiency, pancreatic cancer, etc.), endocrine tumors of the gastrointestinal tract and pancreas, and the like.

[0118] In some embodiments, the methods include modulating, treating, and / or preventing symptoms associated with metabolic disorders, such as appetite, body weight, food or liquid intake, or a subject's response to food or liquid intake, or satiety, or a subject's perception of satiety, nutrient intake and regulation (e.g., protein-energy malnutrition, physiological disorders associated with protein-energy malnutrition, etc.), obesity, secondary obesity (e.g., hypothyroidism, Cushing's disease, insulinoma, hypothalamic disorders, etc.), eating disorders (e.g., anorexia nervosa, bulimia, etc.), vitamin deficiency and excess, insulin metabolism, diabetes (types I and II) and its complications (e.g., circulatory abnormalities, retinopathy, diabetic nephropathy, diabetic neuropathy, diabetic foot ulcers, etc.), glucose metabolism, fat metabolism, hypoglycemia, hyperglycemia, hyperlipoproteinemia, etc., by administering the compounds disclosed and described herein, individually or in combination, to an individual in need of such modulation, treatment, and / or prevention.

[0119] In some embodiments, the methods include measures of regulation, treatment, and / or prevention of symptoms associated with functional gastrointestinal disorders, e.g., symptoms (optionally based on retention of contents in the gastrointestinal tract, particularly in the stomach) in which a subject has abdominal indigestion, e.g., abdominal bloating, nausea, vomiting, abdominal pain, loss of appetite, acid reflux, or abnormal bowel movements (constipation, diarrhea, etc.) in the absence of specific pathological conditions such as peptic ulcers and cancer. In one example, functional gastrointestinal disorders include those that are not accompanied by organic disease of the gastrointestinal tract but have one or more reproducible gastrointestinal symptoms and that affect the quality of life of a subject, e.g., a human, by administering the compounds disclosed and described herein, individually or in combination, to an individual in need of such an effect.

[0120] Exemplary functional gastrointestinal disorders include, but are not limited to, functional dyspepsia, gastroesophageal reflux disease, diabetic gastroparesis, reflux esophagitis, postoperative gastrointestinal dysfunction, nausea, vomiting, feeling unwell, heartburn and abdominal bloating, heavy stomach, burping, chest rising, chest pain, stomach discomfort, loss of appetite, dysphagia, acid reflux, abdominal pain, constipation, diarrhea, shortness of breath, feeling of choking, loss of motivation or energy, feeling of obstruction in the pharynx, foreign body sensation, fatigue, stiff shoulders, muscle tension, dry mouth (dry mouth, dry mouth, etc.), tachypnea, burning sensation in the digestive tract, cold extremities, difficulty concentrating, restlessness, sleep disorders, headache, general malaise, palpitations, night sweats, anxiety, dizziness, lightheadedness, hot flashes, excessive sweating, depression, and the like.

[0121] In some embodiments, the methods include increasing or promoting digestion, absorption, blood nutrient levels, and / or gastrointestinal motility in a subject, such as promoting gastric emptying (e.g., clearance of gastric contents), reducing abdominal distension during the early postprandial period, improving anorexia, etc., by administering the compounds disclosed and described herein, individually or in combination, to an individual in need thereof. Generally, such promotion can be achieved by administering the compounds disclosed and described herein, individually or in combination, to an individual in need thereof, either directly or by increasing the secretion of regulatory entities, such as hormones.

[0122] In some embodiments, the methods include increasing one or more gastrointestinal functions in a subject, e.g., to improve the quality of life or health of an individual, by administering, individually or in combination, the compounds disclosed and described herein.

[0123] Some embodiments provide a method of treating a respiratory tract infection, comprising administering a compound as disclosed and described herein, either individually or in combination, to an individual in need of treatment for a respiratory tract infection. In some embodiments, the compounds as disclosed and described herein, either individually or in combination, can be used to inhibit a respiratory tract infection. Some embodiments provide a method of treating infertility, comprising administering a compound as disclosed and described herein, either individually or in combination, to an individual in need of treatment for infertility.

[0124] Some embodiments provide pharmaceutical compositions containing a therapeutically effective amount of one or more compounds disclosed and described herein, or salts, solvates, and / or prodrugs thereof, optionally together with a suitable amount of a pharma- ceutically acceptable vehicle. In another embodiment, the pharmaceutical composition comprises a therapeutically effective amount of one or more compounds disclosed and described herein, or salts, solvates, and / or prodrugs thereof, and a suitable amount of a pharma- ceutically acceptable vehicle to provide the form for proper administration to a patient.

[0125] In one embodiment, when administered to a patient, the compounds disclosed and described herein and any pharma- ceutically acceptable vehicle are sterile. In one embodiment, when the compounds disclosed and described herein are administered intravenously, water is the preferred vehicle. Saline and aqueous dextrose and glycerol solutions can also be used as liquid vehicles, particularly for injectable solutions. Suitable pharmaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like. The pharmaceutical compositions of the present invention can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents can be used.

[0126] The pharmaceutical composition comprising the compound disclosed and described herein can be manufactured by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, encapsulating or lyophilizing process.The pharmaceutical composition can be prepared in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliary agents, which facilitate the processing of the compound of the present invention into medicament-usable preparations.The appropriate formulation depends on the selected administration route.

[0127] In some embodiments, pharmaceutical composition can be in the form of solution, suspension, emulsion, tablet, pill, pellet, capsule, capsule containing liquid, powder, sustained release formulation, suppository, emulsion, aerosol, spray, suspension, or any other form suitable for use.In some embodiments, the pharmaceutically acceptable vehicle is a capsule (see, for example, Grosswald et al., U.S. Patent Application Publication No. 5,698,155).Other examples of suitable pharmaceutical vehicles are described in the art (see, for example, Remington: The Science and Practice of Pharmacy, Philadelphia College of Pharmacy and Science, 20th Edition, 2000).

[0128] For topical administration, the compounds disclosed and described herein may be formulated as solutions, gels, ointments, creams, suspensions, etc., as is well known in the art.

[0129] Systemic formulations include those designed for administration by injection, such as subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or pulmonary administration.Systemic formulations can be made in combination with additional active agents that improve the mucociliary clearance of airway mucus or reduce mucus viscosity.These active agents include, but are not limited to, sodium channel blockers, antibiotics, N-acetylcysteine, homocysteine ​​and phospholipids.

[0130] In some embodiments, the compounds disclosed and described herein can be prepared according to routine procedures as pharmaceutical compositions adapted for intravenous administration to humans. Typically, compounds for intravenous administration are solutions in sterile isotonic aqueous buffer. For injection, compounds can be prepared in aqueous solutions, preferably in physiologically compatible buffers (such as Hanks' solution, Ringer's solution, or saline buffer). The solutions may contain formulating agents such as suspending agents, stabilizing agents, and / or dispersing agents. If necessary, pharmaceutical compositions may also contain solubilizing agents.

[0131] Pharmaceutical compositions for intravenous administration may optionally include a local anesthetic, such as lignocaine, to ease pain at the site of the injection. Generally, the ingredients are supplied separately or mixed together in unit dosage form, for example as a lyophilized powder or water-free concentrate in a sealed container, such as an ampoule or sachet indicating the quantity of active agent. When the compound is administered by infusion, it can be dispensed, for example, in an infusion bottle containing sterile pharmaceutical grade water or saline. In some embodiments, when the compound is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.

[0132] For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0133] The pharmaceutical composition for oral delivery can be in the form of, for example, tablet, lozenge, aqueous or oily suspension, granule, powder, emulsion, capsule, syrup or elixir.The pharmaceutical composition for oral administration can contain one or more optional agents, for example, sweeteners such as fructose, aspartame or saccharin; flavorings such as peppermint, wintergreen oil or cherry colorings and preservatives, to provide medicamentically palatable preparations.

[0134] Additionally, in tablet or pill form, the pharmaceutical composition can be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over an extended period of time. Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for the orally administered compounds of the present invention. In these later platforms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells and displaces the drug or drug composition through an opening. These delivery platforms can provide an essentially zero order delivery profile, as opposed to the spiked profiles of immediate release formulations. Time-delay materials such as glycerol monostearate or glycerol stearate can also be used. Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Such vehicles are preferably of pharmaceutical grade.

[0135] In the case of oral liquid preparations, such as suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, physiological saline, alkylene glycols (e.g., propylene glycol), polyalkylene glycols (e.g., polyethylene glycol), oils, alcohols, weakly acidic buffers of pH 4 to pH 6 (e.g., about 5 mM to about 50 mM acetate, citrate, ascorbate), etc. Furthermore, flavoring agents, preservatives, coloring agents, bile salts, acylcarnitines, etc. may be added.

[0136] For buccal administration, the pharmaceutical compositions may take the form of tablets, lozenges, etc. formulated in a conventional manner.

[0137] Liquid drug formulations suitable for use with nebulizers and liquid spray devices and EHD aerosol devices typically comprise the compound of the present invention with a pharmaceutically acceptable vehicle.Preferably, the pharmaceutically acceptable vehicle is a liquid such as alcohol, water, polyethylene glycol or perfluorocarbon.Optionally, another substance may be added to change the aerosol properties of the solution or suspension of the compound of the present invention.Preferably, this substance is a liquid such as alcohol, glycol, polyglycol or fatty acid.Other methods of formulating liquid drug solutions or suspensions suitable for use with aerosol devices are known to those skilled in the art (see, for example, Biesalski, U.S. Pat. No. 5,112,598; Biesalski, U.S. Pat. No. 5,556,611).

[0138] In some embodiments, the compounds disclosed and described herein may also be formulated into rectal or vaginal pharmaceutical compositions such as suppositories or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides.

[0139] In addition to the above-mentioned preparation, the compounds disclosed and described herein can be prepared as depot preparations.Such long-acting preparations can be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection.Thus, for example, the compounds of the present invention can be prepared with suitable polymer or hydrophobic material (e.g., as emulsion in acceptable oil) or ion exchange resin, or as sparingly soluble derivatives, for example, as sparingly soluble salts.

[0140] The compounds and / or pharmaceutical compositions disclosed and described herein are generally used in an amount effective to achieve the intended purpose. For use in treating or preventing a disease or disorder, the compounds and / or pharmaceutical compositions disclosed and described herein are administered or applied in a therapeutically effective amount.

[0141] In some embodiments, the dosage can be delivered in the pharmaceutical composition by single administration, multiple application 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 continue as long as necessary for effective treatment of a disease state or disorder.

[0142] Suitable dosage ranges for oral administration depend on potency, but are generally about 0.001 mg to about 200 mg of a compound disclosed and described herein per kilogram of body weight.

[0143] A suitable dosage range for intravenous (iv) administration is about 0.01 mg to about 100 mg per kilogram of body weight. A suitable dosage range for intranasal administration is generally about 0.01 mg per kilogram of body weight to about 1 mg per kilogram of body weight. Suppositories generally contain about 0.01 milligrams to about 50 milligrams of the compound of the present invention per kilogram of body weight, with active ingredient in the range of about 0.5% to about 10% by weight. Recommended dosages for intradermal, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual or intracerebral administration are in the range of about 0.001 mg to about 200 mg per kilogram of body weight. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0144] In some embodiments, the dosage of the compounds described herein lies preferably within a range of circulating concentrations that include the effective dose with little or no toxicity.

[0145] In certain embodiments, the compounds and / or pharmaceutical compositions disclosed and described herein can be used in combination therapy with at least one other agent. In some embodiments, the compounds and / or pharmaceutical compositions disclosed and described herein are administered simultaneously with the administration of another agent, which may be part of the same pharmaceutical composition as the compound of the present invention or a different pharmaceutical composition. In other embodiments, the pharmaceutical composition of the present invention is administered before or after the administration of the other agent.

[0146] Preparation method The compounds disclosed herein can be synthesized by the methods described below or by modification of these methods. Modifications of the methods include, among others, temperature, solvent, reagents, etc., known to those skilled in the art. In general, during any of the methods for preparing the compounds disclosed herein, it may be necessary and / or desirable to protect any sensitive or reactive groups of the molecules involved. This can be achieved by conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. J.F.W. MacOmie, Plenum Press, 1973); and P.G.M.Green, T.W. Hutts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999), both of which are incorporated herein by reference in their entirety. Protecting groups can be removed at a convenient later stage using methods known in the art. Synthetic chemical transformations useful for synthesizing applicable compounds are known in the art and are described, for example, in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995, both of which are incorporated herein by reference in their entirety. The routes shown and described herein are exemplary only and are not intended or construed to limit the scope of the claims in any manner. Those skilled in the art will recognize modifications of the disclosed syntheses and be able to devise alternative routes based on the disclosure herein; all such modifications and alternative routes are within the scope of the claims. EXAMPLES

[0147] The following examples are included to further illustrate the present invention. Of course, the examples should not be construed as specifically limiting the present invention. Variations of these examples within the scope of the claims are within the scope of those skilled in the art and are considered to be within the scope of the invention described and claimed herein. The reader will recognize that, armed with this disclosure, those skilled in the art can prepare and use the present invention without the exhaustive examples.

[0148] Example 1: Synthesis of Compounds 101-107 [ka] To 500 mg of phloretin (1.8 mmol), 10 mL of Me2CO was added under N2, followed by 2 eq. (497 mg, 3.6 mmol) K2CO3, followed by 2 eq. (598 mg, 3.6 mmol) CH3I or 6 eq. (1794 mg, 10.8 mmol) CH3I to the mixture. The reaction was stirred at room temperature and monitored by LC-MS / UV. After the reaction was completed, the mixture was acidified to pH 6-7 by 1 M HCl, extracted three times with ethyl acetate, washed five times with brine, and concentrated to give a mixture of compounds 102-104 (2 eq. CH3I) and 101, 105-107 (6 eq. CH3I). The mixture was further isolated and purified by preparative RP-HPLC. The purified compounds were lyophilized to obtain bulk powders before NMR analysis and evaluation.

[0149] Example 2: Synthesis of Compound 108 [ka] Phloretin (1.0 g, 3.6 mmol) was added to a round-bottom flask along with p-coumaric acid (0.72 g, 1.2 equiv.) followed by introducing THF (5 mL) to dissolve the reactants under N2. 90% phosphoric acid (25 mL) was added dropwise to the stirred solution, gradually turning the clear solution into a yellow cloudy solution. The mixture was stirred at room temperature and the reaction was monitored by LC-UV-MS. After the reaction was completed, the mixture was adjusted to pH 6-7 under an ice bath, extracted twice with EtOAc, and the extracts were washed twice with saline. The extracts were dried, dissolved in ethanol, and subsequently purified by preparative RP-HPLC to obtain approximately 500 mg of crude product (purity approximately 70%). The crude product was then recrystallized twice in ethanol under room temperature overnight to obtain approximately 140 mg of beige product. The product was lyophilized to obtain a bulk powder before NMR analysis and evaluation.

[0150] Example 3: Synthesis of Compound 109 [ka] Naringenin (1.0 g, 3.7 mmol) was added to a round-bottom flask together with p-coumaric acid (0.72 g, 1.2 equiv.) followed by the introduction of THF (5 mL) to dissolve the reactants under N2. 90% phosphoric acid (25 mL) was added dropwise to the stirred solution, gradually turning the clear solution into a yellow cloudy solution. The mixture was stirred at room temperature, and the reaction was monitored by LC-UV-MS. After the reaction was completed, the mixture was adjusted to pH 6-7 under an ice bath, extracted twice with EtOAc, and the extracts were washed twice with saline. The extracts were dried, dissolved in ethanol, and subsequently purified by preparative RP-HPLC and lyophilized to obtain bulk powder, followed by NMR analysis and evaluation.

[0151] Example 4: Synthesis of Compound 110 [ka] Naringenin (50 mg, 0.184 mmol) was added separately to a 2 mL vial along with caffeic acid (36 mg), followed by the introduction of THF (0.25 mL) to dissolve the reactants under N2. 90% phosphoric acid (1.25 mL) was added to the solution, and the clear solution gradually became cloudy. The mixture was kept at room temperature, and the reaction was monitored by LC-UV-MS. The formation of compound 110 was confirmed by HRMS.

[0152] Example 5: Synthesis of Compound 111 [ka] Naringenin (50 mg, 0.184 mmol) was added independently to a 2 mL vial along with ferulic acid (36 mg), followed by the introduction of THF (0.25 mL) to dissolve the reactants under N2. 90% phosphoric acid (1.25 mL) was added to the solution, and the clear solution gradually became a cloudy solution. The mixture was kept at room temperature, and the reaction was monitored by LC-UV-MS. The formation of compound 111 was confirmed by HRMS.

[0153] Example 6: Synthesis of Compound 112 [ka] Naringenin (50 mg, 0.184 mmol) was added independently to a 2 mL vial along with isoferulic acid (36 mg), followed by the introduction of THF (0.25 mL) to dissolve the reactants under N2. 90% phosphoric acid (1.25 mL) was added to the solution, and the clear solution gradually became cloudy. The mixture was kept at room temperature, and the reaction was monitored by LC-UV-MS. The formation of compound 112 was confirmed by HRMS.

[0154] Example 7: Synthesis of Compound 113 [ka] Eriodictyol (50 mg) was added independently to a 2 mL vial with p-coumaric acid (36 mg), followed by the introduction of THF (0.25 mL) to dissolve the reactants under N2. 90% phosphoric acid (1.25 mL) was added to the solution, and the clear solution gradually became a cloudy solution. The mixture was kept at room temperature, and the reaction was monitored by LC-UV-MS. The MS / MS spectrum of the product has the same fragmentation rules as compound 110. The formation of compound 113 was confirmed by HRMS.

[0155] Example 8: Synthesis of Compound 114 [ka] Hesperetin (50 mg) was added independently to a 2 mL vial along with p-coumaric acid (36 mg), followed by the introduction of THF (0.25 mL) to dissolve the reactants under N2. 90% phosphoric acid (1.25 mL) was added to the solution, and the clear solution gradually became cloudy. The mixture was kept at room temperature, and the reaction was monitored by LC-UV-MS. The MS / MS spectrum of the product has the same fragmentation rules as compound 110. The formation of compound 114 was confirmed by HRMS.

[0156] Example 9: Synthesis of Compound 115 [ka] Phloretin (50 mg, 0.182 mmol) was added separately to a 2 mL vial along with caffeic acid (36 mg), followed by the introduction of THF (0.25 mL) to dissolve the reactants under N2. 90% phosphoric acid (1.25 mL) was added to the solution, and the clear solution gradually became cloudy. The mixture was kept at room temperature, and the reaction was monitored by LC-UV-MS. The formation of compound 115 was confirmed by HRMS.

[0157] Example 10: Synthesis of Compound 116 [ka] Phloretin (50 mg, 0.182 mmol) was added independently to a 2 mL vial along with ferulic acid (36 mg), followed by the introduction of THF (0.25 mL) to dissolve the reactants under N2. 90% phosphoric acid (1.25 mL) was added to the solution, and the clear solution gradually became cloudy. The mixture was kept at room temperature, and the reaction was monitored by LC-UV-MS. The formation of compound 116 was confirmed by HRMS.

[0158] Example 11: Synthesis of Compound 117 [ka] Phloretin (50 mg, 0.182 mmol) was added independently to a 2 mL vial along with isoferulic acid (36 mg), followed by the introduction of THF (0.25 mL) to dissolve the reactants under N2. 90% phosphoric acid (1.25 mL) was added to the solution, and the clear solution gradually became a cloudy solution. The mixture was kept at room temperature, and the reaction was monitored by LC-UV-MS. The formation of compound 117 was confirmed by HRMS.

[0159] Sensory Test Methods: Compounds 101 and 108 were evaluated as sweetness modifiers in a 10 ppm sweet (aqueous solution containing 4% sucrose) or sweet-sour base (a mixture of 7% and 0.15% invert sugar and citric acid). Twenty trained panelists were asked to compare the difference in sweetness between the reference and compound 101 or compound 108. Taste attributes (sweetness, sourness, etc.) were rated on a scale of -5 to 5 (-5 indicates a strong masking effect, 5 indicates a strong enhancing effect, and 0 is the intensity of the reference).

[0160] The results collected for these experiments for a 10 ppm dose of Compound 101 are shown in Figures 1 and 2. The data in Figure 1 show that Compound 101 can increase sweetness intensity in sucrose base and has a significant effect in nose clip. The data in Figure 2 show that Compound 101 can significantly increase sweetness and sourness intensity in a sweet and sour base of invert sugar and citric acid without changing the pH value.

[0161] The results collected for these experiments for a 10 ppm dose of compound 108 are shown in Figure 3. The data show that compound 108 is able to increase sweetness intensity in sucrose base, with a significant effect without the nose clip.

[0162] The foregoing detailed description is provided for clarity of understanding only. Modifications will be apparent to those skilled in the art, and no unnecessary limitations should be understood therefrom. No admission is made that any of the information provided herein is prior art or relevant to the embodiments claimed herein, or that any publication specifically or implicitly referenced is prior art.

Claims

1. A compound having the structure of formula (I) to (VI), a salt or stereoisomer thereof. 【Chemistry 1】 [In the formula, R １ , R ３ , R ５ , R ６ , R ７ , R ８ , and R ９ are each independently hydrogen, —OH, or —OMe; R ２ and R ４ are each independently hydrogen or methyl.

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

3. R ２ , R ４ , or R ７ The compound of claim 2, wherein at least one of is not hydrogen.

4. R １ , R ３ , or R ５ The compound of claim 2, wherein at least one of is not —OH.

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

6. 2. The compound of claim 1, a salt or stereoisomer thereof, having the structure of formula (II): 【Chemistry 4】

7. R ２ or R ４ 7. The compound of claim 6, wherein at least one of is methyl.

8. R １ and R ３ The compound of claim 6, wherein at least one of is not —OH.

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

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

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

12. R ４ The compound of claim 1 , wherein is methyl.

13. 2. The compound of claim 1, a salt or stereoisomer thereof, having the structure of formula (III): 【Transformation 5】

14. 2. The compound of claim 1, a salt or stereoisomer thereof, having the structure of formula (IV): 【Transformation 6】

15. 2. The compound of claim 1, a salt or stereoisomer thereof, having the structure of formula (V): 【Transformation 7】

16. 16. The compound of claim 15, a salt or stereoisomer thereof, having the structure of formula (Va): 【Transformation 8】

17. 10. The compound of claim 1 having the structure of formula (VI) or a salt or stereoisomer thereof: 【Chemistry 9】

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

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

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

21. R ９ The compound of claim 1 , wherein is —OH.

22. R ９ The compound of claim 1, wherein is -OMe.

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

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

25. R ３ The compound of claim 1 , wherein is hydrogen.

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

27. R ３ The compound of claim 1, wherein is -OMe.

28. R ５ The compound of claim 1 , wherein is —OH.

29. R ５ The compound of claim 1, wherein is -OMe.

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

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

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

33. R ７ The compound of claim 1 , wherein is hydrogen.

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

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

36. The compound is 【Chemistry 10-1】 【Chemistry 10-2】 【Chemistry 10-3】 2. The compound of claim 1, which is a compound selected from the group consisting of:

37. 37. An ingestible composition comprising a compound of any one of claims 1 to 36 and one or more sweeteners.

38. 38. The ingestible composition of claim 37, wherein the sweetener is a sugar.

39. 39. The ingestible composition of claim 38, wherein the sweetener is sucrose.

40. 39. The ingestible composition of claim 38, wherein the sweetener comprises a combination of fructose and glucose.

41. 38. The ingestible composition of claim 37, wherein the sweetener is sucralose.

42. 38. The ingestible composition of claim 37, wherein the sweetener is high fructose corn syrup.

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

44. 44. The method of claim 43, wherein the sweetener is a sugar.

45. 45. The method of claim 44, wherein the sweetener is sucrose.

46. 45. The method of claim 44, wherein the sweetener comprises a combination of fructose and glucose.

47. 44. The method of claim 43, wherein the sweetener is sucralose.

48. 44. The method of claim 43, wherein the sweetener is high fructose corn syrup.

49. 44. The method of claim 43, wherein the compound is present at a concentration of 0.1 to 100 ppm.

50. 44. The method of claim 43, wherein the compound is present at a concentration of 5 to 20 ppm.

51. A compound according to any one of claims 1 to 36 for use in enhancing the sweetness of a sweetener.

52. Use of a compound according to any one of claims 1 to 36 for enhancing the sweetness of a sweetener.

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