Flavanone compounds and their use as flavor modifiers

Abstract

The present disclosure relates generally to 3-acyloxyflavanone compounds and the use of such compounds for imparting and / or enhancing sweetness, masking bitter taste, enhancing mouthfeel, or masking astringency. In certain embodiments, such compounds are used in combination with other flavonoid compounds or dihydrochalcone. In certain forms, the present disclosure provides ingestible compositions comprising such flavanone compounds. In some related forms, the ingestible composition is a variety of flavored products or is included in a variety of flavored products, such as a food product, a beverage product, a pharmaceutical product, or an oral care product.

Description

Technical Field

[0001] The present disclosure generally relates to 3-acyloxyflavanone compounds and the use of such compounds for imparting and / or enhancing sweetness, masking bitterness, enhancing mouthfeel, or masking astringency. In certain embodiments, such compounds are used in combination with other flavonoids or dihydrochalcone. In certain aspects, the present disclosure provides ingestible compositions comprising such flavanone compounds. In some related aspects, the ingestible compositions are various flavored products or are included in various flavored products, such as food products, beverage products, pharmaceutical products, or oral care products. Background Art

[0002] The taste system provides sensory information about the chemical composition of the external world. Taste transduction is one of the more complex forms of chemically triggered sensation in animals. Taste signals are found throughout the animal kingdom, from simple metazoans to the most complex vertebrates. Mammals are believed to possess five basic forms of taste: sweet, bitter, sour, salty, and umami.

[0003] Sweetness is the taste most often experienced when consuming foods high in sugar. Mammals generally perceive sweetness as a pleasant sensation, unless consumed in excess. Caloric sweeteners, such as sucrose and fructose, are typical examples of sweet substances. Despite the availability of a variety of non-caloric and low-calorie alternatives, these caloric sweeteners remain the primary means of eliciting sweetness in edible products.

[0004] Metabolic disorders and related conditions, such as obesity, diabetes, and cardiovascular disease, are major public health concerns worldwide. Their prevalence is increasing at an alarming rate in nearly every developed country. Caloric sweeteners are a key factor driving this trend, as they are included in a variety of packaged food and beverage products, making them more palatable to consumers. In many cases, no- or low-calorie alternatives can be used to replace sucrose or fructose in food and beverages. Even so, the sweetness imparted by these compounds differs from that of caloric sweeteners, and many consumers fail to perceive them as suitable substitutes. Moreover, such compounds can be difficult to incorporate into certain products. In some cases, they can be used as partial replacements for caloric sweeteners, but their presence alone can lead to unpleasant off-flavors perceived by many consumers, including astringency, bitterness, metallicity, and licorice. Consequently, low-calorie sweeteners face certain challenges in their adoption.

[0005] Sweetness enhancement provides an alternative approach to overcome some of the adoption challenges faced by low-calorie sweeteners. Such compounds can be used in combination with sucrose or fructose to enhance their sweetness, thereby allowing the use of lower amounts of such caloric sweeteners in various food or beverage products. However, in addition to enhancing the perceived sweetness of the primary sweetener, such compounds still change the perceived taste of the sweetener. Therefore, many consumers find that consuming such sweet-enhanced products is more unpleasant than having higher calorie, unenhanced alternatives. Therefore, there is a continuing need to discover a class of compounds that can improve the sweetness of caloric sweeteners without changing their perceived taste in a way that impairs the pleasure experienced by consumers when eating or drinking products containing such sweeteners. Summary of the Invention

[0006] The present disclosure relates to the discovery that certain flavanones and related compounds impart and / or enhance sweetness in a more natural tasting manner and, in some cases, can also be used to mask bitterness, enhance mouthfeel, or mask astringency.

[0007] In a first aspect, the present disclosure provides a flavor-modifying compound, which is a compound of formula (I):

[0008]

[0009] or a salt thereof, wherein:

[0010] R 1 and R 2 are independently a hydrogen atom, -OH or -OCH3;

[0011] R 3 、R 4 and R 5 are independently a hydrogen atom, -OH or -OCH3; and

[0012] R is methyl, ethyl, isopropyl or benzyl.

[0013] In a second aspect, the present disclosure provides the use of the flavor-modifying compound of the first aspect for enhancing the sweetness of an ingestible composition. In certain related aspects, the present disclosure provides a method for enhancing the sweetness of an ingestible composition, the method comprising introducing the flavor-modifying compound of the first aspect into the ingestible composition. In some embodiments, the ingestible composition comprises one or more sweeteners, such as caloric or non-caloric sweeteners. In some embodiments, the ingestible composition comprises one or more flavonoids or dihydrochalcones.

[0014] In a third aspect, the present disclosure provides a use of the flavor-modifying compound of the first aspect for reducing the bitterness of an ingestible composition. In certain related aspects, the present disclosure provides a method for reducing the bitterness of an ingestible composition, the method comprising introducing the flavor-modifying compound of the first aspect into the ingestible composition. In some embodiments, the ingestible composition comprises one or more bitter tastants, such as certain high-intensity sweeteners, caffeine, tannins, pharmaceutical APIs, etc. In some embodiments, the ingestible composition comprises one or more flavonoids or dihydrochalcones.

[0015] In a fourth aspect, the present disclosure provides the use of the flavor-modifying compound of the first aspect for reducing the astringency of an ingestible composition. In certain related aspects, the present disclosure provides a method for reducing the astringency of an ingestible composition, the method comprising introducing the flavor-modifying compound of the first aspect into the ingestible composition. In some embodiments, the ingestible composition comprises one or more astringent compounds. Non-limiting examples of such uses and methods include reducing the lingering licorice aftertaste of certain high-intensity sweeteners (e.g., stevia-based high-intensity sweeteners). In some embodiments, the ingestible composition comprises one or more flavonoids or dihydrochalcones.

[0016] In a fifth aspect, the present disclosure provides use of the flavor-modifying compound of the first aspect for enhancing the mouthfeel of an ingestible composition. In certain related aspects, the present disclosure provides methods for enhancing the mouthfeel of an ingestible composition, the methods comprising introducing the flavor-modifying compound of the first aspect into the ingestible composition. In some embodiments, the ingestible composition comprises one or more flavonoids or dihydrochalcones.

[0017] In a sixth aspect, the present disclosure provides an ingestible composition comprising one or more flavor-modifying compounds of the first aspect. In some embodiments, the ingestible composition comprises one or more sweeteners. In some embodiments, the ingestible composition comprises one or more bitter tastants, such as high-intensity sweeteners or certain bitter compounds.

[0018] In a seventh aspect, the present disclosure provides a flavored product comprising the ingestible composition of the sixth aspect. In some embodiments, the flavored product is a food or beverage product. In some embodiments, the flavored product is an oral care product or a pharmaceutical product.

[0019] Further aspects and embodiments thereof are set forth in the following detailed description, drawings, abstract, and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The following figures are provided to illustrate various embodiments of the compositions and methods disclosed herein. The figures are provided for illustration purposes only and are not intended to describe any preferred compositions or preferred methods, nor as a source of any limitation on the scope of the claimed invention.

[0021] Figure 1 The chemical formula representing the flavor-modifying compounds disclosed herein is shown, wherein R 1 and R 2 are independently a hydrogen atom, -OH or -OCH3; R 3 、R 4 and R 5 are independently a hydrogen atom, -OH or -OCH3; and R is a methyl group, an ethyl group, an isopropyl group or a benzyl group. DETAILED DESCRIPTION

[0022] The following detailed description sets forth various aspects and embodiments provided herein. This description is intended to be read from the perspective of one of ordinary skill in the relevant art. Therefore, information known to such persons of ordinary skill is not necessarily included.

[0023] definition

[0024] Unless otherwise specified herein, the following terms and phrases have the meanings indicated below. The present disclosure may employ other terms and phrases not expressly defined herein. Such other terms and phrases have the meanings that those of ordinary skill in the art would have in the context of the present disclosure. In some cases, a term or phrase may be defined in the singular or in the plural. In such cases, it will be understood that any term in the singular may include its plural form, and vice versa, unless expressly indicated to the contrary.

[0025] "Sweetener" refers to a compound or an ingestibly acceptable salt thereof that elicits a detectable sweet taste in a subject, such as a compound that activates T1R2 and T1R3 taste receptors in vivo or in vitro.

[0026] A "bitter tastant" is a compound or an ingestibly acceptable salt thereof that elicits a detectable bitter taste in a subject, such as a compound that activates one or more T2R taste receptors in vivo or in vitro.

[0027] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, reference to "a substituent" encompasses a single substituent as well as two or more substituents, and so forth.

[0028] As used herein, "for example," "such as," "such as," or "including" are intended to introduce examples that further illustrate a more general subject matter. Unless expressly stated otherwise, such examples are provided merely to aid in understanding the embodiments shown in the present disclosure and are not meant to be limiting in any way. These phrases also do not indicate any preference for the disclosed embodiments.

[0029] As used herein, "include," "comprising," "containing," and "comprised of" refer to open groups, meaning that the group may include other members in addition to those explicitly stated. For example, the phrase "comprising A" means that A must be present, but other members may also be present. The terms "including," "having," and "composed of" and their grammatical variations have the same meaning. In contrast, "consist of," "composed of," or "composed of" refer to closed groups. For example, the phrase "consisting of A" means that only A is present.

[0030] As used herein, "optionally" means that the subsequently described event may or may not occur. In some embodiments, the optional event does not occur. In some other embodiments, the optional event does occur one or more times.

[0031] As used herein, "or" is to be given its broadest reasonable interpretation and is not limited to an "either / or" construction. Thus, the phrase "comprising A or B" means that A may be present and B may not be present, or B may be present and A may not be present, or both A and B may be present. Furthermore, for example, if A defines a class that may have multiple members (e.g., A1 and A2), then one or more members of the class may be present at the same time.

[0032] Chemical structures are often displayed using a "skeleton" format, so that no carbon atoms are shown explicitly and hydrogen atoms attached to them are omitted entirely. For example, the structure represents butane (i.e., n-butane). In addition, aromatic groups such as benzene are represented by showing a contributing resonance structure. For example, the structure Represents toluene.

[0033] As used herein, the term "flavor-modifying compound" refers to any compound of Formula (I), or a salt thereof, and any embodiment thereof described herein.

[0034] Other terms are defined in other parts of this specification even if not included in this section.

[0035] Flavor-modifying compounds

[0036] In certain aspects, the present disclosure provides a flavor-modifying compound, which is a compound of formula (I):

[0037]

[0038] or a salt thereof, wherein:

[0039] R 1 and R 2 are independently a hydrogen atom, -OH or -OCH3;

[0040] R 3 、R 4 and R 5 are independently a hydrogen atom, -OH or -OCH3; and

[0041] R is methyl, ethyl, isopropyl or benzyl.

[0042] variable R 1 and R 2 Can have any suitable value within the above definition range. In some embodiments, R 1 and R 2 In some embodiments, at least one of R 1 and R 2 are independently hydrogen or -OH. 1 -OH, R 2 In some embodiments, R 1 is a hydrogen atom, R 2 In some embodiments, R 1 -OH, R 2 It is -OH.

[0043] variable R 3 、R 4 and R 5 Can have any suitable value within the above definition range. In some embodiments, R 3 and R 5 In some embodiments, R 3 and R 5 In some embodiments, R 4 is -OH, and R 3 and R 5 In some embodiments, R 3 -OH, R 4 is -OCH3, and R 5 A hydrogen atom.

[0044] The variable R can have any suitable value within the above-defined range. In some embodiments, R is methyl or ethyl. In some embodiments, R is methyl. In some embodiments, R is ethyl. In some embodiments, R is isopropyl. In some embodiments, R is benzyl.

[0045] Table 1 provides examples of flavor-modifying compounds of the present disclosure. In some embodiments, the flavor-modifying compound is Compound 101 or an edible acceptable salt thereof. In some embodiments, the flavor-modifying compound is Compound 102 or an edible acceptable salt thereof. In some embodiments, the flavor-modifying compound is Compound 103 or an edible acceptable salt thereof. In some embodiments, the flavor-modifying compound is Compound 104 or an edible acceptable salt thereof. In some embodiments, the flavor-modifying compound is Compound 105 or an edible acceptable salt thereof. In some embodiments, the flavor-modifying compound is Compound 106 or an edible acceptable salt thereof.

[0046] Table 1

[0047]

[0048]

[0049] When the flavor-modifying compounds disclosed herein have at least one chiral center, they may exist as individual enantiomers and diastereomers or as mixtures of such isomers.In some embodiments related to the second aspect, the sweet taste enhancing compound has substantial enantiomeric purity.

[0050] The separation of each isomer or the selective synthesis of each isomer is completed by applying various methods well known to those skilled in the art. Unless otherwise stated (for example, in the case of clearly showing the stereochemistry of the chiral center), all such isomers and mixtures thereof are included in the scope of compounds disclosed herein. In addition, compounds disclosed herein can exist in one or more crystalline or amorphous forms. Unless otherwise stated, all these forms are included in the scope of compounds disclosed herein, including any polymorphic form. In addition, some compounds disclosed herein can form solvates with water (i.e., hydrates) or common organic solvents. Unless otherwise stated, these solvates are included in the scope of compounds disclosed herein.

[0051] Those skilled in the art will recognize that some of the structures described herein may be resonance forms or tautomers of compounds that can be reasonably represented, even kinetically, by other chemical structures; the skilled artisan recognizes that such structures may represent only a small fraction of such compound samples. Such compounds are considered to be within the scope of the structures shown, even though such resonance forms or tautomers are not shown herein.

[0052] Isotopes may be present in the described compounds. Each chemical element represented in a compound structure may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood to be present in the compound. Any position in the compound where a hydrogen atom may be present may include any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Therefore, the compounds mentioned herein encompass all possible isotopic forms unless the context clearly indicates otherwise.

[0053] In some embodiments, the flavor-modifying compounds disclosed herein are capable of forming acidic and / or basic salts due to the presence of phenolic, amino, and / or carboxyl groups, or groups similar thereto. Edibly 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, and salicylic acid. Edibly 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, and aluminum; ammonium, potassium, sodium, calcium, and magnesium salts are particularly preferred. In some embodiments, treatment of a compound disclosed herein with an inorganic base results in the compound losing a labile hydrogen, thereby yielding a compound comprising an inorganic cation such as Li + 、Na + , K + Mg 2+ and Ca 2+ The 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, particularly isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the salt is an edible salt, which is a salt suitable for inclusion in an ingestible composition, such as a food or beverage product. In some embodiments, the edible salt is a sodium salt or a potassium salt.

[0054] Uses and methods

[0055] In certain aspects, the present disclosure provides a use of a flavor-modifying compound in a first form for enhancing the sweetness of an ingestible composition. In certain related aspects, the present disclosure provides a method for enhancing the sweetness of an ingestible composition, the method comprising introducing the flavor-modifying compound in a first form into the ingestible composition.

[0056] In certain aspects, the present disclosure provides a use of a flavor-modifying compound of a first aspect for reducing the bitterness of an ingestible composition. In certain related aspects, the present disclosure provides a method for reducing the bitterness of an ingestible composition, the method comprising introducing the flavor-modifying compound of a first aspect into the ingestible composition.

[0057] In certain aspects, the present disclosure provides a use of a first form of a flavor-modifying compound for reducing astringency (e.g., a lingering aftertaste of a high-intensity sweetener or a licorice aftertaste) in an ingestible composition. In certain related aspects, the present disclosure provides a method for reducing astringency in an ingestible composition, the method comprising introducing the first form of a flavor-modifying compound into the ingestible composition.

[0058] In certain aspects, the present disclosure provides a use of a flavor-modifying compound in a first form for enhancing the mouthfeel of an ingestible composition. In certain related aspects, the present disclosure provides a method for enhancing the mouthfeel of an ingestible composition, the method comprising introducing the flavor-modifying compound in a first form into the ingestible composition.

[0059] The aforementioned uses and methods relate to ingestible compositions.In addition to the features of the ingestible compositions set forth above, the ingestible compositions may further comprise any feature or combination of features set forth below.

[0060] Ingestible composition

[0061] In certain aspects, the present disclosure provides an ingestible composition comprising a flavor-modifying compound according to the above embodiments. When introduced into or used in an ingestible composition, the flavor-modifying compound is used or introduced into the ingestible composition in a range of 0.01 ppm to 1000 ppm, or 0.01 ppm to 900 ppm, or 0.01 ppm to 800 ppm, or 0.01 ppm to 700 ppm, or 0.01 ppm to 600 ppm, or 0.1 ppm to 500 ppm, or 0.1 ppm to 400 ppm, or 0.1 ppm to 300 ppm, or 0.1 ppm to 200 ppm, or 1 ppm to 100 ppm, or 1 ppm to 80 ppm, or 1 ppm to 60 ppm, or 1 ppm to 50 ppm, or 1 ppm to 40 ppm.

[0062] In some embodiments, the ingestible composition comprises one or more bitter tastants. In some embodiments, the bitter tastants are high intensity sweeteners such as acesulfame potassium, aspartame, neotame, cyclamate, saccharin, sucralose, steviol glycosides (e.g., rebaudioside A, rebaudioside B, rebaudioside M, rebaudioside D, or rebaudioside E), and mogrosides (e.g., mogroside III, mogroside IV, mogroside V, simonoside I, isomogroside V, mogroside IV E , isomogroside IV, mogroside III E , 11-oxomogroside V, or the 1,6-α isomer of simenoside I). Therefore, the flavor-modifying compound may be suitable for use in low-sugar or zero-sugar products to reduce the bitter taste imparted by low-calorie or zero-calorie sweeteners.

[0063] In some embodiments, the bitter tastant is a potassium salt, such as potassium chloride, which is commonly used as a partial or complete replacement for sodium chloride in certain low-sodium or zero-sodium foods. Therefore, flavor-modifying compounds may be suitable for use in such products to reduce the bitterness imparted by potassium salts.

[0064] In some embodiments, the bitter tastant is a non-animal protein, such as a plant protein, algae protein, or fungal protein. In some embodiments, the ingestible composition comprises plant protein. Non-limiting examples of plant protein include pea protein, soy protein, almond protein, cashew protein, canola (canola) (rapeseed) protein, chickpea protein, broad bean protein, sunflower protein, wheat protein, oat protein, barley protein, and potato protein. Such non-animal proteins are commonly used as partial or complete substitutes for animal proteins in dairy analogs and meat analogs. Therefore, flavor-modifying compounds may be suitable for use in such products to reduce the bitterness imparted by non-animal proteins. By blocking the bitterness of such proteins, flavor-modifying compounds can reduce the perceived cereal tonality and green tonality experienced by consumers.

[0065] In some embodiments, bitter tastants are caffeine, quinine, green tea, catechins, polyphenols (e.g., polyphenol antioxidants), tannins, robusta green coffee bean extract, green coffee bean extract, menthol, etc. Such compounds are commonly found in various natural food products such as tea and coffee, as well as packaged food products such as instant tea, instant coffee, packaged beverages, etc. When one or more such bitter tastants are present, flavor-modifying compounds are suitable for blocking the bitterness of such compounds and improving the perceived taste of the product by the consumer.

[0066] In some embodiments, the bitter tastant is a pharmaceutical compound. Non-limiting examples of bitter pharmaceutical compounds include atropine, brinzolamide, chloramphenicol, chloroquine, clindamycin, dexamethasone, digoxin, diltiazem, diphenhydramine, docusate, dorzolamide, doxepin, doxylamine, enalapril, erythromycin, esomeprazole, famotidine, gabapentin, ginkgolide A, guaifenesin, L-histidine, lomefloxacin, methylprednisolone, ofloxacin, oleuropein, oxphenium bromide, pirenzepine, prednisone, ranitidine, trapidil, trimethoprim and cetirizine. When one or more such pharmaceutical compounds are used in oral pharmaceutical preparations, the flavor modifying compound is suitable for blocking the bitterness of such compounds and improving the perceived taste of the pharmaceutical product by consumers.

[0067] In some embodiments, bitter tastants are oral care ingredients. Many oral care ingredients impart bitterness, and this bitterness must be masked or blocked to improve consumer acceptance of the product. Non-limiting examples of such oral care ingredients include menthol, menthol analogs, mint extract, sodium bicarbonate, alkali metal peroxymonosulfate (potassium peroxymonosulfate), cetylpyridinium chloride, lauramidopropyl betaine, cocamidopropyl betaine, arginine, hydrogen peroxide, chlorhexidine gluconate, potassium nitrate, pentasodium triphosphate, tetrasodium pyrophosphate, stannous fluoride, thymol, methyl salicylate, eucalyptol, thymol, cubebol, and any combination thereof. When one or more such oral care compounds are used in oral care products, flavor modifying compounds are suitable for blocking the bitterness of such compounds and improving the perceived taste of consumers to oral care products.

[0068] In some embodiments, the bitter tastant is a bittering agent found in citrus fruits, such as limonin, nomelin, or naringin. Many citrus-containing formulations impart a bitter off-flavor that must be masked or blocked to improve consumer acceptance of the product. In some cases, this bitter off-flavor may be caused by citrus greening disease, which causes citrus fruits to turn green before they are fully ripe. When one or more such citrus bittering agents are present in a product, flavor-modifying compounds are suitable for blocking the bitterness of such compounds and improving the perceived taste of the citrus product by consumers.

[0069] In some embodiments, the ingestible composition comprises one or more flavanones or dihydrochalcone. In certain embodiments, such flavanones act synergistically with the flavor-modifying compounds disclosed herein to reduce bitterness, enhance the perception of sweetness, or reduce sourness. In some embodiments, the flavanone is eriodictyol, hesperidin, hesperidin, homoeriodictyol, naringenin, hesperidin dihydrochalcone, phloretin, or any combination thereof. In some further embodiments, the flavanone is eriodictyol. In some other embodiments, the flavanone is homoeriodictyol. Such flavanones may be present in the ingestible composition at any suitable concentration, for example, in a concentration ranging from 0.01 ppm to 1000 ppm, or from 0.01 ppm to 900 ppm, or from 0.01 ppm to 800 ppm, or from 0.01 ppm to 700 ppm, or from 0.01 ppm to 600 ppm, or from 0.1 ppm to 500 ppm, or from 0.1 ppm to 400 ppm, or from 0.1 ppm to 300 ppm, or from 0.1 ppm to 200 ppm, or from 1 ppm to 100 ppm, or from 1 ppm to 80 ppm, or from 1 ppm to 60 ppm, or from 1 ppm to 50 ppm, or from 1 ppm to 40 ppm.

[0070] In some embodiments, the composition can be taken in and comprises a combination of a sweetener or a plurality of sweeteners. In some embodiments, the sweetener is a common carbohydrate sweetener, such as sucrose, fructose, glucose, and a sweetener composition comprising natural sugars such as corn syrup (including high fructose corn syrup) or other syrups or sweetener concentrates derived from natural fruit and vegetable sources. In some embodiments, the sweetener is sucrose, fructose or a combination thereof. In some embodiments, the sweetener is sucrose. In some other embodiments, the sweetener is selected from rare natural sugars, including D-allose, D-psicose, L-ribose, D-tagatose, L-glucose, L-fucose, L-arabinose, D-turanose and D-leucrose. In some embodiments, the sweetener is selected from semi-synthetic "sugar alcohol" sweeteners, such as erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, maltodextrin etc. In some embodiments, the sweetener is selected from artificial sweeteners such as aspartame, saccharin, acesulfame potassium, cyclamates, sucralose and alitame. In some embodiments, the sweetener is selected from the group consisting of cyclamic acid, mogroside, tagatose, maltose, galactose, mannose, sucrose, fructose, lactose, allulose, neotame and other aspartame derivatives, glucose, D-tryptophan, glycine, maltitol, lactitol, isomalt, hydrogenated glucose syrup (HGS), hydrogenated starch hydrolysate (HSH), stevioside, rebaudioside A, other sweet steviosides, chemically modified steviol glycosides (such as glucosylated steviol glycosides), other mogrosides, chemically modified mogrosides (such as glucosylated mogrosides), guanidine sweeteners (carrelame) and other guanidine sweeteners. In some embodiments, the sweetener is a combination of two or more sweeteners set forth in this paragraph. In some embodiments, the sweetener can be a combination of two, three, four or five sweeteners disclosed herein. In some embodiments, the sweetener can be sugar. In some embodiments, the sweetener can be a combination of one or more sugars and other natural and artificial sweeteners. In some embodiments, the sweetener is sugar. In some embodiments, sugar is cane sugar. In some embodiments, sugar is beet sugar. In some embodiments, sugar can be sucrose, fructose, glucose or a combination thereof. In some embodiments, sugar can be sucrose. In some embodiments, sugar can be a combination of fructose and glucose.

[0071] Sweeteners can also include, for example, sweetener compositions containing one or more natural or synthetic carbohydrates, such as corn syrup, high fructose corn syrup, high maltose corn syrup, glucose syrup, sucralose syrup, hydrogenated glucose syrup (HGS), hydrogenated starch hydrolysate (HSH), or other syrups or sweetener concentrates from natural fruit and vegetable sources, or semi-synthetic "sugar alcohol" sweeteners, such as polyols. In some embodiments, non-limiting examples of polyols include erythritol, maltitol, mannitol, sorbitol, lactitol, xylitol, isomalt, propylene glycol, glycerol (glycerin), threitol, galactitol, palatinose, reduced isomaltooligosaccharides, reduced xylo-oligosaccharides, reduced gentio-oligosaccharides, reduced maltose syrup, reduced glucose syrup, isomaltulose, maltodextrin, and the like, as well as sugar alcohols or any other carbohydrates or combinations thereof that can be reduced without adversely affecting taste.

[0072] The sweetener may be a natural or synthetic sweetener including, but not limited to, agave inulin, agave nectar, agave syrup, amazake, brazzein, brown rice syrup, coconut crystals, coconut sugar, coconut syrup, date sugar, fructans (also known as inulin fiber, fructooligosaccharides, or oligofructose), green stevia powder, stevia rebaudiana, rebaudioside A, rebaudioside B, rebaudioside C, rebaudioside D, rebaudioside E, rebaudioside F, rebaudioside I, rebaudioside H, rebaudioside L, rebaudioside K, rebaudioside J, rebaudioside N, rebaudioside O, rebaudioside M and other steviol-based glycosides, stevioside, stevioside extract, honey, Jerusalem artichoke, artichoke syrup, licorice root, monk fruit (fruit, powder or extract), lucuma (fruit, powder or extract), maple sap (including, for example, sap extracted from sugar maple (Acer saccharum), black maple (Acer nigrum), red maple (Acer rubrum), silver maple (Acersaccharinum), Norway maple (Acer platanoides), ash maple (Acer negundo), bigleaf maple (Acer macrophyllum), roughtooth maple (Acer grandidentatum), Rocky Mountain maple (Acer glabrum), monochromatic maple (Acer mono), maple syrup, maple sugar, walnut sap (including, for example, sap extracted from white walnut (Juglans cinerea), black walnut (Juglans nigra), ghost walnut (Juglans ailatifolia), walnut (Juglans regia), birch sap (including, for example, sap extracted from paper birch (Betula papyrifera), Canada yellow birch (Betula alleghaniensis), mountain birch (Betula lenta), river birch (Betula nigra), gray birch (Betula populifolia), weeping birch (Betula pendula), sycamore sap (e.g., sap extracted from Platanus occidentalis), ironwood sap (e.g., sap extracted from Ostrya virginiana), unrefined cane sugar (mascobado), molasses (e.g., blackstrap molasses), molasses sugar, monatin, monellin, cane sugar (e.g.,sugar (also known as natural sugar, unrefined sucrose or table sugar), palm sugar, panocha, piloncillo, rapadura, raw sugar, rice syrup, sorghum, sorghum syrup, tapioca syrup (also known as tapioca syrup), thaumatin, yacon root), malt syrup, barley malt syrup, barley malt powder, beet sugar, cane sugar, crystallized fruit juice crystals, caramel, carbitol, carob syrup, castor sugar, hydrogenated starch hydrolates, hydrolyzed canned fruit juice, hydrolyzed starch, invert sugar, anethole, arabinogalactan, concentrated grape juice (arrope), syrup, P-4000, acesulfame potassium (also known as acesulfame potassium or ace-K), alitame (also known as aclame), advantame, aspartame, baiyunosdie, neotame, benzamide derivatives, bernadame,

[0073] Aspartame alias (canderel), guanidine sweetener (carrelame) and other guanidine sweeteners,

[0074] Plant fiber, corn sugar, coupling sugar, curculin, cyclamates,

[0075] Cyclocaryoside I, demerara, glucan, dextrin, diastatic malt, dulcin, sucrol, valzin, dulcoside A, dulcoside B, emulin, enoxolone, maltodextrin, saccharin, estragole, ethyl maltol, glucin, gluconic acid, gluconolactone, glucosamine, glucuronic acid, glycerol, glycine, glycyphillin, glycyrrhizin, glycyrrhetinic acid Monoglucuronide, golden sugar, brown sugar, golden syrup, granulated sugar, gynostemma pentaphyllum, hernandulcin, isomerized liquid sugar, jallab, chicory root dietary fiber, kynurenine derivatives (including N'-formyl-kynurenine, N'-acetyl-kynurenine, 6-chloro-kynurenine), galactitol, litesse, ligicane, lycasin, N-(4-cyanophenyl)-N-(2,3-Methylenedioxybenzyl)guanidineacetic acid (lugduname), guanidine, falernum, mabinin I, mabinin II, maltol, crystalline maltisorb, maltodextrin, maltotriol, mannosamine, miraculin, mizuame, mogrosides (including, for example, mogroside IV, mogroside V, and neomogroside), mukurozioside, nano sugar, naringin dihydrochalcone, neohesperidin dihydrochalcone, nib sugar, black oligosaccharide, norbu, almond syrup, osladin, pekmez, pentadin, periandrin I I), perillaldehyde, perillartine, petphyllum, phenylalanine, phloisosideside I, phloretin, phlorodizin, phyllodulcin, polyglycitol syrup, polypodoside A, pterocaryoside A, pterocaryoside B, rebiana, refined sugar syrup, rub syrup, rubusoside, selligueain A, shugr, simenoside I, siraitia grosvenorii, soybean oligosaccharides, Splenda, SRIoxime V, steviol glycosides, steviol biosides, stevioside, strogins 1, 2, and 4, sucronic acid acid), sucrononate, sugar, sodium p-nitrophenylureidopropionate (suosan), phloridzin, super aspartame, tetrasaccharide, threitol, treacle, trilobtain, tryptophan and derivatives (6-trifluoromethyl-tryptophan, 6-chloro-D-tryptophan), vanilla sugar, heptyl alcohol, birch syrup, aspartame-acesulfame, assugrin, and combinations or blends of any two or more thereof.

[0076] Additional sweeteners also include any two or more combinations of any of the aforementioned sweeteners. In some embodiments, the sweetener may comprise a combination of two, three, four, or five sweeteners disclosed herein. In some embodiments, the sweetener may be 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 caloric sweetener, such as sucrose, fructose, xylitol, erythritol, or a combination thereof. In some embodiments, the ingestible composition does not contain (or in some embodiments, is substantially free of) stevia-derived sweeteners, such as steviol glycosides, glucosyl steviol glycosides, or rebaudioside.

[0077] In some embodiments, the sweetener is sucrose. In some other embodiments, the sweetener is steviol glycoside.

[0078] In some embodiments, the ingestible composition comprises a sour taste enhancer, such as an organic acid. Non-limiting examples of such organic acids include acetic acid, malonic acid, citric acid, lactic acid, and the like.

[0079] In certain embodiments, the ingestible compositions may include any additional ingredient or combination of ingredients commonly used in food and beverage products, including but not limited to:

[0080] Acids, including, for example, citric acid, phosphoric acid, ascorbic acid, sodium bisulfate, lactic acid, or tartaric acid;

[0081] bitter ingredients, including, for example, caffeine, quinine, green tea, catechins, polyphenols, robusta green coffee bean extract, green coffee bean extract, potassium chloride, menthol, or proteins (e.g., proteins and protein isolates from plants, algae, or fungi);

[0082] Coloring agents, including, for example, caramel, red #40, yellow #5, yellow #6, blue #1, red #3, purple carrot, black carrot juice, purple sweet potato, vegetable juice, fruit juice, beta-carotene, turmeric curcumin, or titanium dioxide;

[0083] preservatives, including, for example, sodium benzoate, potassium benzoate, potassium sorbate, sodium metabisulfite, sorbic acid, or benzoic acid;

[0084] antioxidants, including, for example, ascorbic acid, calcium disodium EDTA, alpha-tocopherol, mixed tocopherols, rosemary extract, grape seed extract, resveratrol, or sodium hexametaphosphate;

[0085] Vitamins or functional ingredients, including, for example, resveratrol, Co-Q10, omega 3 fatty acids, theanine, choline chloride (Citocoline), inositol, inulin (chicory root), taurine, ginseng extract, guarana extract, ginger extract, L-phenylalanine, L-carnitine, L-tartrate, D-glucuronolactone, inositol, bioflavonoids, echinacea, ginkgo biloba, yerba mate, flaxseed oil, Garcinia cambogia peel extract, white tea extract, ribose, milk thistle, thistle extract, grape seed extract, pyridoxine hydrochloride (vitamin B6), cyanocobalamin (vitamin B12), niacinamide (vitamin B3), biotin, calcium lactate, calcium pantothenate (pantothenic acid), calcium phosphate, calcium carbonate, chromium chloride, chromium polynicotinate, copper sulfate, folic acid, ferric pyrophosphate, iron, magnesium lactate, magnesium carbonate, magnesium sulfate, monopotassium phosphate, monosodium phosphate, phosphorus, potassium iodide, potassium phosphate, riboflavin, sodium sulfate, sodium gluconate, sodium polyphosphate, sodium bicarbonate, thiamine mononitrate, vitamin D3, vitamin A palmitate, zinc gluconate, zinc lactate, or zinc sulfate;

[0086] Clouding agents, including, for example, ester gum, brominated vegetable oil (BVO), or sucrose acetate isobutyrate (SAIB);

[0087] buffers, including, for example, sodium citrate, potassium citrate, or salt;

[0088] Flavors, including, for example, propylene glycol, ethanol, glycerin, gum arabic (acacia), maltodextrin, modified corn starch, dextrose, natural flavorings, natural flavorings with other natural flavorings (WONF), natural and artificial flavorings, artificial flavorings, silicon dioxide, magnesium carbonate, or tricalcium phosphate; or

[0089] Starches and stabilizers including, for example, pectin, xanthan gum, carboxymethyl cellulose (CMC), polysorbate 60, polysorbate 80, medium chain triglycerides, cellulose gel, cellulose gum, sodium caseinate, modified food starch, gum arabic (acacia gum), inulin, or carrageenan.

[0090] The ingestible composition may have any suitable pH value. In some embodiments, the amide compound enhances the sweetness of the sweetener over a wide range of pH values, such as from a relatively low pH value to a neutral pH value. Lower and neutral pH values ​​include, but are not limited to, 1.5 to 9.0, or 2.5 to 8.5; 3.0 to 8.0; 3.5 to 7.5, and a pH value of 4.0 to 7; in certain embodiments, the compounds disclosed and described herein, alone or in combination, may enhance the perceived sweetness of a fixed concentration of sweetener at a low to neutral pH value in a taste test at a compound concentration of 50 μM, 40 μM, 30 μM, 20 μM, or 10 μM. In certain embodiments, the enhancement factor of the compounds disclosed and described herein, alone or in combination, at a relatively low pH is substantially similar to the enhancement factor of the compound at a neutral pH. This consistent sweetness enhancement property over a wide pH range allows the compounds disclosed and described herein to be widely used in a variety of foods and beverages, alone or in combination.

[0091] In some embodiments, the ingestible composition includes flavorings. Any suitable flavoring can be used. In some embodiments, the flavoring includes synthetic flavoring oils and flavoring aromatic substances or oils, oleoresins and extracts from plants, leaves, flowers, fruits, etc., and combinations thereof. Non-limiting examples of flavor oils include spearmint oil, cinnamon oil, wintergreen oil (methyl salicylate), peppermint oil, Japanese mint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, nutmeg oil, allspice, sage oil, mace, bitter almond oil, and cassia seed oil. Non-limiting examples of other flavors include natural and synthetic fruit flavors, such as vanilla, and citrus oils, including lemon, orange, lime, grapefruit, yazu, sudachi, and fruit essences, including apple, pear, peach, grape, blueberry, strawberry, raspberry, cherry, plum, pineapple, watermelon, apricot, banana, melon, apricot, plum, cherry, raspberry, blackberry, tropical fruits, mango, mangosteen, pomegranate, papaya, and the like. Other potential flavors include milk flavors, butter flavors, cheese flavors, cream flavors, and yogurt flavors; vanilla flavors; tea or coffee flavors, such as green tea flavors, oolong tea flavors, tea flavors, cocoa flavors, chocolate flavors, and coffee flavors; mint flavors, such as peppermint flavors, spearmint flavors, and Japanese mint flavors; spice flavors, such as asafoetida flavors, ajwain flavors, anise flavors, angelica flavors, fennel flavors, allspice flavors, cinnamon flavors, chamomile flavors, mustard flavors, cardamom flavors, coriander flavors, cumin flavors, clove flavors, pepper flavors, cilantro flavors, sassafras flavors, and cilantro flavors. Flavoring agent, salty flavoring agent, Sichuan pepper flavoring agent, perilla flavoring agent, juniper berry flavoring agent, ginger flavoring agent, star anise flavoring agent, horseradish flavoring agent, thyme flavoring agent, tarragon flavoring agent, dill flavoring agent, green pepper flavoring agent, nutmeg flavoring agent, basil flavoring agent, marjoram flavoring agent, rosemary flavoring agent, bay leaf flavoring agent and wasabi (Japanese horseradish) flavoring agent; Wine flavoring agent, such as red wine flavoring agent, whiskey flavoring agent, brandy flavoring agent, rum flavoring agent, gin flavoring agent and liqueur flavoring agent; Flower flavoring agent; And vegetable flavoring agent, such as onion flavoring agent, garlic flavoring agent, cabbage flavoring agent, carrot flavoring agent, celery flavoring agent, mushroom flavoring agent, and tomato flavoring agent. These flavoring agents can be used in liquid or solid form, and can be used alone or in combination.In dairy or dairy-like products, the most commonly used flavoring agents are those that impart flavors such as vanilla, French vanilla, chocolate, banana, lemon, hazelnut, coconut, almond, strawberry, mocha, coffee, tea, chai, cinnamon, caramel, cream, brown sugar, toffee, pecan, butter pecan, toffee, Irish cream, white chocolate, raspberry, pumpkin pie spice, spearmint, or any combination thereof.

[0092] In some embodiments, the ingestible composition comprises vanillin or a vanillin analog that imparts a vanilla flavor to the flavoring. In some additional embodiments, the ingestible composition comprises one or more lactones that impart a creamy flavor to the flavoring.

[0093] In some embodiments, the ingestible composition comprises a yeast extract, such as a yeast lysate. Such an extract can be obtained from any suitable yeast strain, wherein such an extract is suitable for human consumption. Non-limiting examples of such yeasts include: yeasts of the genus Saccharomyces, such as Saccharomyces cerevisiae or Saccharomyces pastorianus; yeasts of the genus Candida, such as Candida utilis; yeasts of the genus Kluyveromyces, such as Kluyveromyces lactis or Kluyveromyces marxianus; yeasts of the genus Pichia, such as Pichia pastoris; yeasts of the genus Debaryomyces, such as Debaryomyces hansenii; and yeasts of the genus Zygosaccharomyces, such as Zygosaccharomyces mellis. In some embodiments, the yeast is yeast collected after brewing beer, sake, etc. In some embodiments, the yeast is yeast that has been dried after collection (dried yeast).

[0094] Such extracts can be produced by any suitable means. In general, yeast extracts or lysates are prepared by extracting the contents of yeast cells from cell wall material. In many cases, digestive enzymes in the cells (or other enzymes added to the composition) break down the proteins and polynucleotides in the yeast into amino acids, oligopeptides (e.g., 2 to 10 peptides), nucleotides, oligonucleotides (2 to 10 nucleotides), and mixtures thereof. Yeast lysates can be prepared by cracking yeast. For example, in some embodiments, the cultured yeast is crushed or cracked by enzymatic hydrolysis, autodigestion, alkaline extraction, hot water extraction, acid decomposition, ultrasonication, homogenizer crushing, freeze-thaw method, etc. (two or more of which can be used in combination) to obtain yeast lysates. Yeast can be cultured according to conventional methods. In some embodiments, the cultured yeast is heat-treated and then treated with a lytic enzyme to obtain an enzymatic lysate. The heat treatment conditions are, for example, 80°C to 90°C for 5 to 30 minutes. As the lytic enzyme used in the enzymatic hydrolysis method, various enzymes can be used as long as they can crack the cell wall of the yeast. The reaction conditions can be set to be optimal or suitable for the lyase used, and specific examples thereof include a temperature of 50 to 60° C. and a pH of 7.0 to 8.0. The reaction time is also not particularly limited and can be, for example, 3 to 5 hours.

[0095] Compositions comprising yeast lysate can be obtained from a variety of commercial sources. For example, in some embodiments, yeast lysate is provided by a flavoring additive sold under the name MODUMAX (DSM Food Specialties BV, Delft, The Netherlands).

[0096] In some embodiments, the ingestible composition comprises a sweetness enhancer.Any suitable sweetness enhancer can be used in the ingestible compositions disclosed herein, including synthetic sweetness enhancers, natural sweetness enhancers, or any combination thereof.

[0097] Examples of suitable synthetic sweetness enhancers include, but are not limited to, N-(1-((4-amino-2,2-dioxo-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)-2-methylpropan-2-yl)isonicotinamide, or any edible acceptable salt thereof, 3-hydroxybenzoic acid, or any compound listed in U.S. Patent Nos. 8,541,421, 8,815,956, 9,834,544, 8,592,592, 8,877,922, 9,000,054, and 9,000,051, and U.S. Patent Application Publication No. 2017 / 0119032.

[0098] Suitable examples of natural sweetness enhancers include, but are not limited to, hesperetin dihydrochalcone, hesperetin dihydrochalcone-4'-O'glucoside, neohesperetin dihydrochalcone, brazzein, hesperidin, phyllodextrin, naringenin, naringin, phloretin, glucosylated steviol glycosides, (2R,3R)-3-acetoxy-5,7,4'-trihydroxyflavanone, (2R,3R)-3-acetoxy-5,7,3'-trihydroxy-4'-methoxyflavanone Steviol glycosides include glycosides of the type 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 111, 112

[0099] In some embodiments of any of the preceding embodiments, the ingestible composition comprises 3-((4-amino-2,2-dioxo-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)-2,2-dimethyl-N-propyl-propionamide, N-(1-((4-amino-2,2-dioxo-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)-2-methyl-propan-2-yl)isonicotinamide, or an edible acceptable salt thereof. In some embodiments, the ingestible composition comprises N-(1-((4-amino-2,2-dioxo-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)-2-methyl-propan-2-yl)isonicotinamide, or an edible acceptable salt thereof. In some embodiments, the ingestible composition comprises N-(1-((4-amino-2,2-dioxo-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)-2-methyl-propan-2-yl)isonicotinamide.

[0100] In some embodiments, the ingestible composition comprises one or more umami enhancing compounds. Such umami enhancing compounds include, but are not limited to, compounds of natural origin or synthetic compounds, such as any of the compounds described in U.S. Patent Nos. 8,735,081, 8,124,121, and 8,968,708. In some embodiments, the umami enhancing compound is (2R, 4R)-1,2,4-trihydroxy-heptadeca-16-ene, (2R, 4R)-1,2,4-trihydroxy-heptadeca-16-yne, or a mixture thereof. In some embodiments, the umami enhancing compound is (3R, 5S)-1-(4-hydroxy-3-methoxyphenyl)decane-3,5-diol diacetate. In some embodiments, the umami enhancing compound is N-(heptane-4-yl)benzo-[d][1,3]dioxole-5-carboxamide.

[0101] In some other embodiments, the ingestible composition includes one or more cooling enhancing compounds. Such cooling enhancing compounds include, but are not limited to, compounds of natural origin, such as menthol or its analogs, or synthetic compounds, such as any compound described in U.S. Patent Nos. 9,394,287 and 10,421,727. Non-limiting examples include N-ethyl-N-(thiophen-2-ylmethyl)-2-(p-tolyloxy)acetamide, N-(1H-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-2-(p-tolyloxy)acetamide, 2-(4-fluorophenoxy)-N-(1H-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)acetamide, 2-(2-hydroxy-4-methylphenoxy)-N-(1H-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-acetamide, 2-((2,3-dihydro-1H-inden-5-yl)oxy)-N -(1H-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-acetamide, 2-((2,3-dihydro-1H-inden-5-yl)oxy)-N-(1H-pyrazol-3-yl)-N-(thiophen-5-ylmethyl)-acetamide, 2-((5-methoxybenzofuran-2-yl)oxy)-N-(1H-pyrazol-3-yl)-N-(thiophen-2-ylmethyl)-acetamide, (E / Z)-2-methyl-2-butenal, (E / Z)-2-isopropyl-5-methyl-2-hexenal, phloretin, naringenin, and any combination thereof.

[0102] In some further embodiments, the ingestible composition comprises one or more bitter-blocking or bitter-masking compounds. Such bitter-blocking or bitter-masking compounds include, but are not limited to, naturally derived compounds or synthetic compounds, such as any of the compounds described in U.S. Patent Nos. 8,076,491, 8,445,692, and 9,247,759. Non-limiting examples include 3-(1-((3,5-dimethylisoxazol-4-yl)-methyl)-1H-pyrazol-4-yl)-1-(3-hydroxybenzyl)-imidazoline-2,4-dione, 4-(2,2,3-trimethylcyclopentyl)butanoic acid, 3β-hydroxydihydrocostus lactone, 3β-hydroxypelenolide, probenecid, sakuranetin, 6-methoxysakuranetin, jaceosidin, 4'-fluoro-6-methoxyflavone, 6,3'-dimethoxyflavone, 6-methoxyflavone, γ-aminobutyric acid, Nα,Nα-bis(carboxymethyl)-L-lysine Acid, (+ / -) abscisic acid, sodium gluconate, monosodium glutamate, sodium acetate, homoeriodictyol, 7-O-methyleriodictyol (sterubin), eriodictyol, 2,4, dihydrobenzoic acid, neodiosmin, 1-carboxymethyl-5-hydroxy-2-hydroxymethylpyridinium, flavan-3-spiro-C-glycoside, poly-γ-glutamic acid, α,α-trehalose, taurine, (2)-gingerdione, 2,4,-dihydroxybenzoic acid, L-theanine, enterodiol, lariciresinol, enterolactone, matairesinol, and any combination thereof.

[0103] In some additional embodiments, the ingestible composition comprises one or more sour taste-modifying compounds.

[0104] In some further embodiments, the ingestible composition comprises one or more mouthfeel-modifying compounds. Such mouthfeel-modifying compounds include, but are not limited to, tannins, cellulosic materials, bamboo powder, and the like.

[0105] In some further embodiments, the ingestible composition comprises one or more flavor masking compounds. Such flavor masking compounds include, but are not limited to, cellulosic materials, materials extracted from fungi, materials extracted from plants, citric acid, carbonic acid (or carbonates), and the like.

[0106] Flavored products

[0107] In certain aspects, the present disclosure provides a flavored product comprising any of the ingestible compositions of the aforementioned aspects. In some embodiments, the flavored product is a beverage product, such as soda, flavored water, tea, etc. In some other embodiments, the flavored product is a food product, such as yogurt. In some embodiments, the flavored product is an oral care product, such as toothpaste, mouthwash, dentifrice, whitener, etc.

[0108] In embodiments where the flavored product is a beverage, 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, juices, fruit-flavored juices, fruit drinks, nectar drinks, vegetable juices, vegetable-flavored juices, sports drinks, energy drinks, fortified waters, vitamin-fortified waters, near-water beverages, coconut water, teas, coffee, cocoa drinks, beverages containing milk ingredients, beverages containing cereal extracts, and smoothies. In some embodiments, the beverage may be a soft drink.

[0109] In certain embodiments of any of the forms and embodiments described herein involving a flavored product, the flavored product is a non-naturally occurring product, such as a packaged food or beverage product.

[0110] Other non-limiting examples of food and beverage products or formulations include sweetened coatings, frostings or icings of such products, or any entity included in the following: soups, dry processed foods, beverages, ready-to-eat foods, canned or preserved foods, frozen processed foods, refrigerated processed foods, snack foods, baked goods, confectionery, dairy products, ice cream, meal replacements, pasta and noodles, as well as sauces, dressings, condiments, baby foods and / or spreads.

[0111] In general, soup refers to canned / preserved, dehydrated, instant, refrigerated, UHT, and frozen soups. For the purposes of this definition, soup is a food made from meat, poultry, fish, vegetables, grains, fruit, and other ingredients, cooked in a liquid that may contain visible fragments of some or all of these ingredients. It may be clear (as a broth) or thick (as a chowder), smooth, pureed, or chunky, ready-to-eat, semi-concentrated, or concentrated, and served hot or cold, as a first or main course, or as a snack (sipping beverage) between meals. Soup can be used as a raw material for preparing other meal ingredients, ranging from stocks (consommé) to sauces (cream- or cheese-based soups).

[0112] The Dehydrated and Cooking Foods category generally refers to: (i) cooking aid products, such as powdered, granulated, paste-like, concentrated liquid products, including concentrated bouillon, bouillon, and bouillon-like products in pressed blocks, tablets, or powdered or granulated form, sold individually as finished products or as ingredients in products, sauces, and recipe mixes (regardless of technology); (ii) meal solution products, such as dehydrated soups and freeze-dried soups, including dehydrated soup mixes, dehydrated instant soups, dehydrated instant soups, and dehydrated or self-heating preparations of ready-made dishes, meals, and single-serving entrees, including pasta, potatoes, and rice; and (iii) meal garnish products, such as condiments, marinades, salad dressings, salad toppings, dips, mixes, batter mixes, shelf-stable sauces, barbecue sauces, liquid recipe mixes, concentrates, sauces, or sauce mixes, including salad recipe mixes, sold as finished products or as ingredients in products, whether dehydrated, liquid, or frozen.

[0113] Beverages generally refer to beverages, beverage mixes, and concentrates, including but not limited to carbonated and non-carbonated beverages, alcoholic and non-alcoholic beverages, ready-to-drink beverages, liquid concentrate formulations for preparing beverages (e.g., soda), and dry powder beverage precursor mixes. Beverages also include alcoholic beverages, soft drinks, sports drinks, isotonic beverages, and hot drinks. Alcoholic beverages include but are not limited to beer, cider / perry, FABs, wine, and spirits. Soft drinks include but are not limited to carbonated beverages, such as cola and non-cola carbonated beverages; fruit juices, such as fruit juices, nectars, juice drinks, and fruit-flavored drinks; bottled water, including soda water, spring water, and purified / table water; functional beverages, which can be carbonated or still, including sports drinks, energy drinks, or elixir drinks; concentrates, such as ready-to-drink liquids and powdered concentrates. Beverages, whether hot or cold, include, but are not limited to, coffee or iced coffee, such as fresh, instant, and blended coffee; tea or iced tea, such as black, green, white, oolong, and flavored teas; and other beverages, including flavored, malt-based, or plant-based powders, granules, blocks, or tablets mixed with milk or water.

[0114] Snacks generally refer to any food that is a simple, informal meal, including but not limited to sweet and savory snacks (salty, spicy, and other non-sweet snacks) and snack bars. Examples of snacks include but are not limited to fruit snacks, potato chips / crisps, extruded snacks, tortillas / corn chips, popcorn, pretzels, nuts, and other sweet and savory snacks. Examples of snack bars include but are not limited to granola / cereal bars, breakfast bars, energy bars, fruit bars, and other snack bars.

[0115] Baked goods generally refer to any edible product whose preparation involves exposure to heat or excessive sunlight. Examples of baked goods include, but are not limited to, bread, buns, cookies, muffins, cereal, toaster pastries, cakes, waffles, tortillas, soft cookies, pies, bagels, tarts, quiches, cakes, any baked good, and any combination thereof.

[0116] Ice cream generally refers to a frozen dessert containing cream, sugar, and flavorings. Examples of ice cream include, but are not limited to, impulse ice cream, family-packed ice cream, frozen yogurt, and handmade ice cream, as well as soy, oat, legume (e.g., red bean and mung bean), and rice-based ice cream.

[0117] Candy generally refers to edible products that are sweet in taste. Examples of candy include, but are not limited to, hard candy, gelatin, chocolate candy, granulated candy, chewing gum, etc., as well as any combination of products.

[0118] The meal replacement category generally refers to any food product intended to replace a regular meal, particularly for those focused on health or fitness. Examples of meal replacements include, but are not limited to, weight loss products and recovery products.

[0119] Ready-to-eat foods generally refer to any food that can be consumed as a meal without extensive preparation or processing. Ready-to-eat foods include products to which manufacturers have added recipe "skills," resulting in a high degree of readiness, completeness, and convenience. Examples of ready-to-eat foods include, but are not limited to, canned / preserved, frozen, dried, and refrigerated ready meals; dinner mixes; frozen pizza; refrigerated pizza; and prepared salads.

[0120] The Pasta & Noodles category includes any pasta and / or noodles, including but not limited to canned, dried, and refrigerated / fresh pasta; as well as plain, instant, refrigerated, frozen, and snack noodles.

[0121] 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.

[0122] The frozen processed food category includes, but is not limited to, frozen processed red meat, processed poultry, processed fish / seafood, processed vegetables, meat substitutes, processed potatoes, baked products, desserts, ready meals, pizza, soups, noodles, and other frozen foods.

[0123] The dry processed food category includes, but is not limited to, rice, dessert mixes, dry ready-to-eat meals, dehydrated soups, instant soups, dry pasta, plain noodles, and instant noodles. The refrigerated processed food category includes, but is not limited to, refrigerated processed meats, processed fish / seafood products, lunch boxes, fresh-cut fruit, ready-to-eat meals, pizza, prepared salads, soups, and fresh pasta and noodles.

[0124] The sauces, dressings and condiments category includes, but is not limited to, tomato sauces and purees, bouillons / stock cubes, herbs and spices, monosodium glutamate (MSG), table sauces, soy-based sauces, pasta sauces, wet / cooking sauces, dry sauces / powder mixes, ketchup, mayonnaise, mustard, salad dressings, vinaigrettes, dips, pickles, and other sauces, dressings and condiments.

[0125] The baby food category includes, but is not limited to, milk- or soy-based formulas; and prepared, dry, and other baby foods.

[0126] Spreads include, but are not limited to, jams and preserves, honey, chocolate spread, nut-based spreads, and yeast-based spreads.

[0127] Dairy products generally refer to edible products produced from the milk of mammals. Examples of dairy products include, but are not limited to, drinking milk products, cheese, yogurt and sour milk drinks, and other dairy products.

[0128] Additional examples of flavored products, particularly food and beverage products or formulations, are provided below. Exemplary ingestible compositions include one or more candies, chocolates, chocolate chips, chocolate countlines, selflines / softlines, boxed varieties, standard boxed varieties, twist-wrapped miniature chocolates, flavored chocolates, chocolates with toys, sandwich cookies, other chocolate candies, mints, standard mints, strong mints, hard candies, pastilles, gums, jellies and chews, toffees, caramels and nougats, medicated candies, lollipops, licorice, other candies, breads, packaged / industrial breads, bulk / artisanal breads, pastries, cakes, packaged / industrial cakes, bulk / artisanal cakes, cookies, chocolate coatings Biscuits, sandwich biscuits, sandwich cookies, saltine crackers and crackers, bread substitutes, breakfast cereals, ready-to-eat cereals, family breakfast cereals, corn flakes (flakes), muesli, other cereals, children's breakfast cereals, hot cereals, ice cream, ready-to-eat ice cream, single-serve dairy ice cream, single-serve water ice cream, multi-pack dairy ice cream, multi-pack water ice cream, family-pack ice cream, family-pack dairy ice cream, ice cream desserts, bulk ice cream, family-pack water ice cream, frozen yogurt, artisanal ice cream, dairy products, milk, fresh / pasteurized milk, whole fat fresh / pasteurized milk, semi-skimmed fresh / pasteurized milk, extended shelf life / ULT milk, whole fat extended shelf life / ULT milk , semi-skimmed extended shelf life / UTH milk, fat-free extended shelf life / UTH milk, goat's milk, condensed milk / evaporated milk, plain condensed milk / evaporated milk, flavored, functional and other condensed milk, flavored milk drinks, dairy-only flavored milk drinks, flavored milk drinks with fruit juice, soy milk, yogurt drinks, fermented milk drinks, coffee creamer, milk powder, flavored milk powder drinks, cream, cheese, processed cheese, spreadable cheese, non-spreadable processed cheese, unprocessed cheese, spreadable unprocessed cheese, hard cheese, packaged hard cheese, unpackaged hard cheese, yogurt, plain / natural yogurt, flavored yogurt, fruit yogurt, probiotic yogurt, drinkable yogurt, regular drinkable yogurt, probiotic drinkable yogurt, frozen and shelf-stable snacks, dairy-based snacks, dairy-based snacks Bean desserts, frozen snacks, fresh cheese and quark cheese, original fresh cheese and quark cheese, flavored fresh cheese and quark cheese, salty fresh cheese and quark cheese, sweet and salty snacks, fruit snacks, chips / potato chips, puffed snacks, tortillas / corn chips, popcorn, pretzels, nuts, other sweet and savory snacks, snack bars, granola bars, breakfast bars, energy bars, fruit bars, other snack bars, meal replacements, weight loss products, recovery drinks, ready meals, canned ready meals, frozen ready meals, dried ready meals, frozen ready meals, dinner mixes, frozen pizza, refrigerated pizza, soup, canned soup, dehydrated soup, instant soup, cold soup, hot soup, frozen soup, pasta, canned pasta, dried pasta,Frozen / fresh pasta, noodles, plain noodles, instant noodles, instant noodles in cups / bowls, instant noodles in bags, frozen noodles, snack noodles, canned foods, canned meat and meat products, canned fish / seafood, canned vegetables, canned tomatoes, canned beans, canned fruit, canned ready-to-eat foods, 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 baked foods, frozen desserts, frozen ready-to-eat foods, frozen pizza, frozen soups, frozen noodles, other frozen foods, dried foods, dessert mixes, dried ready-to-eat foods, dehydrated soups, instant soups, dried pasta, plain noodles, instant noodles, instant noodles in cups / bowls, instant noodles in bags, refrigerated foods, refrigerated processed meats, refrigerated fish / seafood products, refrigerated processed fish, refrigerated coated fish , refrigerated smoked fish, refrigerated lunch packs, refrigerated ready meals, refrigerated pizza, refrigerated soups, refrigerated / fresh pasta, refrigerated noodles, oils and fats, olive oil, vegetable and seed oils, cooking fats, butter, margarine, spreads and fats, functional spreads and fats, sauces, dressings and condiments, tomato pastes and purées, bouillon / stock cubes, stock cubes, gravy granules, liquid stocks and stocks, herbs and spices, fermented sauces, soy-based sauces, pasta sauces, wet sauces, dry sauces / powder mixes, ketchup, mayonnaise, regular mayonnaise, mustard, salad dressings, regular salad dressings, reduced-fat salad dressings, balsamic vinaigrette, dips, pickles, other sauces, dressings and condiments, baby food, formula, standard formula, growing-up formula, toddler formula, hypoallergenic formula, prepared baby food, dried baby food, other baby food, spreads, jams and preserves, honey, chocolate spreads, nut-based spreads and yeast-based spreads. Exemplary ingestible compositions also include candies, baked goods, ice cream, dairy products, sweet and savory snacks, snack bars, meal replacement products, ready-to-eat foods, soups, pasta, noodles, canned foods, frozen foods, dry foods, refrigerated foods, oils and fats, baby foods or spreads, or mixtures thereof. Exemplary ingestible compositions also include breakfast cereals, sweetened beverages, or solid or liquid concentrate compositions for preparing beverages, ideally allowing for reduced concentrations of previously known sugar sweeteners or artificial sweeteners.

[0129] Some embodiments provide chewable compositions that may or may not be swallowed. In some embodiments, the chewable composition may be gum, chewing gum, saccharified gum, sugarless gum, functional gum, bubble gum, which contain the compounds disclosed and described herein, alone or in combination.

[0130] Typically, a sweet receptor modulating amount, a sweet receptor ligand modulating amount, a sweet flavor modulating amount, a sweet flavor enhancing amount, or a therapeutically effective amount of one or more compounds of the present invention are added to an ingestible composition, optionally in the presence of a sweetener, such that the sweet flavor-modified ingestible composition has an increased sweetness as judged generally by humans or animals, or, in the case of formulation testing, by a majority of a panel of at least eight human taste testers, using procedures well known in the art, compared to an ingestible composition prepared without the compound of the present invention.

[0131] In some embodiments, the compounds disclosed and described herein, alone or in combination, modulate the sweetness or other taste properties of other natural or synthetic sweet tastants and ingestible compositions prepared therefrom. In one embodiment, the compounds disclosed and described herein can be used or provided alone or in combination at their ligand-enhanced concentrations. For example, the compounds disclosed and described herein, alone or in combination, can be present in an amount of 0.001 ppm to 100 ppm, or a narrower alternative range of 0.1 ppm to 50 ppm, 0.01 ppm to 40 ppm, 0.05 ppm to 30 ppm, 0.01 ppm to 25 ppm, 0.1 ppm to 30 ppm, or 0.1 ppm to 25 ppm, or 1 ppm to 30 ppm, or 1 ppm to 25 ppm.

[0132] In some embodiments, the ingestible compositions disclosed herein can be provided in the form of flavoring concentrate formulations, either alone or in combination, such as being suitable for subsequent processing to produce ready-to-use (i.e., instant) products. "Flavoring concentrate formulations" refer to formulations that should be reconstituted with one or more dilution media to become ready-to-use compositions. The term "ready-to-use composition" is used interchangeably herein with "ingestible composition," and it represents any substance that can be taken in orally, whether alone or together with another substance. In one embodiment, ready-to-use compositions include compositions that can be directly eaten by humans or animals. Flavoring concentrate formulations are typically used by mixing or diluting with one or more dilution media, such as any edible or ingestible ingredient or product, to impart or change the dilution medium with one or more flavorings. Such a use process is generally referred to as reconstitution. Reconstitution can be carried out in a domestic environment or an industrial environment. For example, consumers can reconstitute frozen fruit juice concentrates in the kitchen with water or other aqueous media to obtain ready-to-use fruit juice beverages. In another example, soft drink syrup concentrate can be reconstituted with water or other aqueous media on a large-scale industrial scale by the manufacturer to produce instant soft drinks. Because the concentration of the flavoring or seasoning that the flavoring concentrate preparation has is higher than that of the instant composition, the flavoring concentrate preparation is usually not suitable for directly edible without reconstitution. There are many benefits to using and producing the flavoring concentrate preparation. For example, a benefit is to reduce the weight and volume of transportation because the flavoring concentrate preparation can be reconstituted by adding a suitable solvent, solid or liquid when in use.

[0133] The flavor product according to any of the preceding embodiments further comprises, in certain embodiments, one or more additional flavor-modifying compounds, such as compounds that enhance sweetness (e.g., hesperetin, naringenin, glucosylated steviol glycosides, etc.), compounds that block bitterness, compounds that enhance umami, compounds that reduce sourness, compounds that enhance saltiness, compounds that enhance cooling effects, or any combination of the foregoing.

[0134] In certain embodiments of any of the forms and embodiments described herein involving a sweetening or flavoring concentrate, the sweetening or flavoring concentrate is a non-naturally occurring product, such as a composition specifically manufactured for the production of a flavored product, such as a food or beverage product.

[0135] In one embodiment, the flavoring concentrate formulation comprises i) a compound disclosed and described herein, alone or in combination; ii) a carrier; and iii) optionally at least one adjuvant. The term "carrier" refers to a generally inactive auxiliary substance, such as a solvent, binder, or other inert medium, which is used in combination with the compound of the present invention and one or more optional adjuvants to form a formulation. For example, water or starch can be a carrier for the flavoring concentrate formulation. In some embodiments, the carrier is the same as the dilution medium used to reconstitute the flavoring concentrate formulation; in other embodiments, the carrier is different from the dilution medium. As used herein, the term "carrier" includes, but is not limited to, a carrier that is acceptable for ingestion.

[0136] The term "adjuvant" refers to an additive that supplements, stabilizes, maintains, or enhances the intended function or efficacy of an active ingredient, such as the compounds of the present invention. In one embodiment, at least one adjuvant comprises one or more flavorings. The flavoring can have any flavor known to those skilled in the art or consumers, such as chocolate, coffee, tea, mocha, French vanilla, peanut butter, chai, or a combination thereof. In another embodiment, at least one adjuvant comprises one or more sweeteners. The one or more sweeteners can be any sweetener described in this application. In another embodiment, the at least one adjuvant comprises one or more ingredients selected from the group consisting of: emulsifiers, stabilizers, antimicrobial preservatives, antioxidants, vitamins, minerals, fats, starches, protein concentrates and isolates, salts, and combinations thereof. Examples of emulsifiers, stabilizers, antimicrobial preservatives, antioxidants, vitamins, minerals, fats, starches, protein concentrates and isolates, and salts are described in U.S. Patent No. 6,468,576, the entire contents of which are incorporated herein by reference for all purposes.

[0137] In one embodiment, the flavoring concentrate formulation of the present invention can be in the form of a liquid selected from the group consisting of solutions and suspensions, solids, foams, pastes, gels, emulsions, and combinations thereof, such as a liquid containing a certain amount of solid content. In one embodiment, the flavoring concentrate formulation is in the form of a liquid comprising an aqueous base and a non-aqueous base. In some embodiments, the flavoring concentrate formulation of the present invention can be carbonated or non-carbonated.

[0138] The flavoring concentrate formulation may further include a freezing point depression agent, a nucleating agent, or both as the at least one adjuvant. A freezing point depression agent is an acceptable compound or agent for ingestion that can lower the freezing point of a liquid or solvent to which the compound or agent is added. That is, the freezing point of a liquid or solution containing a freezing point depression agent is lower than the freezing point of a liquid or solvent without the freezing point depression agent. In addition to lowering the initial freezing point, freezing point depression agents can also reduce the water activity of the flavoring concentrate formulation. Examples of freezing point depression agents include, but are not limited to, carbohydrates, oils, ethanol, polyols such as glycerol, and combinations thereof. A nucleating agent refers to an acceptable compound or agent for ingestion that can promote nucleation. The presence of a nucleating agent in the flavoring concentrate formulation can improve the mouthfeel of the slush and help maintain the physical properties and performance of the slush at freezing temperatures by increasing the number of required ice crystal centers. Examples of nucleating agents include, but are not limited to, calcium silicate, calcium carbonate, titanium dioxide, and combinations thereof.

[0139] In one embodiment, the flavoring concentrate formulation is formulated to have a low water activity to extend shelf life. Water activity is the ratio of the vapor pressure of water in the formulation to the vapor pressure of pure water at the same temperature. In one embodiment, the flavoring concentrate formulation has a water activity of less than about 0.85. In another embodiment, the flavoring concentrate formulation has a water activity of less than about 0.80. In another embodiment, the flavoring concentrate formulation has a water activity of less than about 0.75.

[0140] In one embodiment, the concentration of the present compound in the flavoring concentrate formulation is at least 2 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of the present compound in the flavoring concentrate formulation is at least 5 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of the present compound in the flavoring concentrate formulation is at least 10 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of the present compound in the flavoring concentrate formulation is at least 15 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of the present compound in the flavoring concentrate formulation is at least 20 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of the present compound in the flavoring concentrate formulation is at least 30 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of the present compound in the flavoring concentrate formulation is at least 40 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of the present compound in the flavoring concentrate formulation is at least 50 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of the present compound in the flavoring concentrate formulation is at least 60 times the concentration of the compound in the ready-to-use composition. In one embodiment, the concentration of the present compound in the flavoring concentrate formulation is up to 100 times the concentration of the compound in the ready-to-use composition.

[0141] In some embodiments, flavoring agents can be used in many different physical forms well known in the art to provide an initial flavor burst and / or a prolonged flavor sensation. Without being limited thereto, these physical forms include free forms, such as spray-dried, powdered, beaded, encapsulated, and mixtures thereof.

[0142] In some embodiments, the composition can be taken in and comprises the flavor modification compound according to any of the above-mentioned embodiments and a bulking agent. Suitable bulking agents include, but are not limited to, maltodextrin (10DE, 18DE or 5DE), corn syrup solids (20 or 36DE), sucrose, fructose, glucose, invert sugar, sorbitol, xylose, ribose, mannose, xylitol, mannitol, galactitol, erythritol, maltitol, lactitol, isomalt, maltose, tagatose, lactose, inulin, glycerol, propylene glycol, polyols, polydextrose, oligofructose, cellulose and cellulose derivatives, and mixtures thereof. In addition, granulated sugar (sucrose) or other caloric sweeteners (such as crystalline fructose, other carbohydrates or sugar alcohols) can be used as bulking agents because they provide good content uniformity without increasing significant calories.

[0143] In one embodiment, the at least one extender may be an extender as described in US Pat. No. 8,993,027.

[0144] In one embodiment, the at least one bulking agent may be a bulking agent described in US Pat. No. 6,607,771.

[0145] In one embodiment, the at least one extender may be an extender as described in US Pat. No. 6,932,982.

[0146] In some embodiments, the tabletop sweetener composition may further include at least one anti-caking agent. As used herein, the phrases "anti-caking agent" and "flowing agent" refer to any composition that prevents, reduces, inhibits or suppresses at least one sweetener from attaching, binding or contacting with another sweetener molecule. Alternatively, an anti-caking agent may refer to any composition that contributes to content uniformity and uniform dissolution. Non-limiting examples of anti-caking agents include cream of tartar, calcium silicate, silicon dioxide, microcrystalline cellulose (Avicel, FMC BioPolymer, Philadelphia, Pennsylvania) and tricalcium phosphate. In one embodiment, the anti-caking agent is present in the tabletop sweetener composition in an amount of about 0.001% to about 3% by weight of the tabletop sweetener composition.

[0147] In some embodiments, the sweetener composition of any of the foregoing forms and embodiments thereof is encapsulated using typical methods for encapsulating flavor or fragrance compounds. Non-limiting examples of such technologies are described in U.S. Patent Application Publication Nos. 2016 / 0235102, 2019 / 0082727, 2018 / 0369777, 2018 / 0103667, 2016 / 0346752, 2015 / 0164117, 2014 / 0056836, 2012 / 0027866, 2010 / 0172945, and 2007 / 0128234, and U.S. Patent Nos. 7,488,503, 6,416,799, 5,897,897, 5,786,017, 5,603,971, 4,689,235, 4,610,890, 3,704,137, 3,041,180, and 2,809,895. All prior patent publications and patents are incorporated herein by reference as if set forth in their entirety.

[0148] Non-animal protein materials and products made therefrom

[0149] Products intended to replace or substitute meat or dairy products generally rely on various non-animal based materials, such as starch and protein derived from plants, algae, fungi or a combination thereof, to simulate the texture and flavor of meat or dairy products. Non-limiting examples of non-animal based proteins are plant proteins, such as pea protein, soy protein, almond protein, cashew protein, canola (rapeseed) protein, chickpea protein, faba bean protein, sunflower protein, wheat protein, oat protein, barley protein, potato protein and a combination thereof. Due to the compositional differences between such plant-based materials and materials derived from animals, such as lacking glutamic acid-containing protein and glutathione, these products may lack the umami or rich taste that consumers are traditionally associated with meat or dairy products, or may have a bitter taste that animal protein lacks.

[0150] Therefore, in certain forms, the present disclosure provides a flavored product comprising a plant-based material (e.g., plant-based starch, plant-based protein, or a combination thereof) and a zinc salt according to any of the embodiments described. In some further embodiments, the flavored product may include any of the features of the above-mentioned combination of features for an ingestible composition containing a zinc salt. In some embodiments, the flavored product is a beverage, such as soy milk, almond milk, rice milk, oat milk, protein beverage, meal replacement beverage, or other similar product. In some other embodiments, the flavored product is a meat substitute product, such as a plant-based chicken product (e.g., plant-based chicken nuggets), a plant-based beef product (e.g., plant-based burgers), etc. In some other embodiments, the flavored product is a protein powder, a meal replacement powder, a plant-based creamer for coffee or tea, etc. In certain other embodiments, any such product comprises additional ingredients and has additional features, such as those commonly used in the preparation and / or manufacture of such products. For example, according to known techniques in the relevant art, flavor modification compounds can be combined with other flavoring agents and taste modifiers, or even encapsulated in certain materials. The suitable concentration of the flavor modification compound is as described above.

[0151] In some embodiments, the flavored product comprises one or more plant-based proteins that impart a bitter taste that is at least partially reduced by using a flavor-modifying compound in the product. Such plant-based proteins include, but are not limited to, pea protein, soy protein, almond protein, cashew protein, canola (rapeseed) protein, chickpea protein, faba bean protein, sunflower protein, wheat protein, oat protein, barley protein, potato protein, and combinations thereof.

[0152] In some further embodiments similar to the above embodiments, algae or fungal proteins or starch are used instead. In some embodiments, these flavored products also contain fiber to provide texture to the product. Suitable fibers for use include but are not limited to psyllium fiber, pea fiber, potato fiber, curdlan, soluble corn fiber (glucan and / or maltodextrin), citrus fiber, and combinations thereof. In such products, flavor-modifying compounds can be introduced in any suitable manner. In some embodiments, flavor-modifying compounds are incorporated into a flavoring emulsion, such as a water-in-oil emulsion, together with other flavor-imparting ingredients.

[0153] Non-meat protein materials and products made therefrom

[0154] Certain non-meat animal proteins, such as milk protein and protein in bone broth, are commonly used in food and are also sold as the main ingredient of certain protein powders. Such proteins may impart a bitter taste that consumers may not want. This is especially true for protein isolates, such as protein isolates of whey protein, collagen, casein, etc. Therefore, the present disclosure provides an ingestible composition comprising non-meat animal protein and a flavor-modifying compound. According to the embodiments described in the preceding sections of this disclosure, the flavor-modifying composition may exist in any suitable combination. In some embodiments, the non-meat animal protein is bone protein, such as collagen derived from animal bones, such as cattle, pigs, donkeys, horses, chickens, ducks, goats, geese, rabbits, lambs, sheep, buffaloes, ostriches, camels, etc. In some embodiments, the non-meat animal protein is milk protein, such as whey protein, casein, or any combination thereof. Milk can be the milk of any suitable animal, such as cattle, donkeys, horses, sheep, buffaloes, camels, etc.

[0155] The flavor-modifying composition can also be included in certain food or beverage products that include animal milk or materials derived from animal milk. Such products include cheese, cheese spreads, yogurt, kefir, milk, processed dairy products, cottage cheese, sour cream, butter, and the like.

[0156] Blocking bitter taste in pharmaceutical APIs

[0157] Many pharmaceutical compounds have a bitter taste, which limits their formulation and administration. Therefore, in certain forms, the present disclosure provides pharmaceutical compositions comprising bitter pharmaceutical active ingredients and flavor-modifying compounds. Such pharmaceutical compositions can be in any form suitable for oral administration, such as tablets, lozenges, capsules, powders, liquid solutions, liquid suspensions, etc. Such pharmaceutical compositions can include any suitable pharmaceutical excipients, binders, etc., such as those described in Remington's Pharmaceutical Sciences. In some embodiments, the bitter pharmaceutical active ingredient is an ion channel inhibitor, such as a proton channel inhibitor. Other examples of bitter APIs whose bitterness is reduced by flavor-modifying compounds include, but are not limited to, atropine, brinzolamide, chloramphenicol, chloroquine, clindamycin, dexamethasone, digoxin, diltiazem, diphenhydramine, docusate, dorzolamide, doxepin, doxylamine, enalapril, erythromycin, esomeprazole, famotidine, gabapentin, ginkgolide A, guaifenesin, L-histidine, lomefloxacin, methylprednisolone, ofloxacin, oleuropein, oxphenium bromide, pirenzepine, prednisone, ranitidine, trapidil, trimethoprim, and cetirizine.

[0158] Uses in oral care products

[0159] Oral care products typically contain ingredients that impart astringency or bitterness. These ingredients include menthol, menthol analogs, mint extract, sodium bicarbonate, alkali metal peroxymonosulfate (potassium peroxymonosulfate), cetylpyridinium chloride, lauramidopropyl betaine, cocamidopropyl betaine, arginine, hydrogen peroxide, chlorhexidine gluconate, potassium nitrate, pentasodium triphosphate, tetrasodium pyrophosphate, stannous fluoride, thymol, methyl salicylate, eucalyptol, or any combination thereof. Suitable oral care products include toothpaste, mouthwash, whitening agent, dentifrice, etc. Such oral care products may include flavor-modifying compounds to block or mask the bitterness of such compounds.

[0160] Example

[0161] The following examples are included to further illustrate the present invention. These examples should not, of course, be construed as specifically limiting the present invention. Variations of these examples within the scope of the claims are within the capabilities of those skilled in the art and are considered to fall within the scope of the invention as described and claimed herein. The reader will recognize that those skilled in the art and those skilled in the art, having grasped this disclosure, will be able to prepare and use the present invention without exhaustive illustration.

[0162] Example 1: Acetic acid (2,3-trans)-5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-4-oxobenzodihydro Preparation of pyran-3-yl ester (101)

[0163]

[0164] A solution of flavanonol 1 (Example 1a, 1.0 g, 3.3 mmol) in AcOH (70 mL) was placed in a 250 mL pressure flask equipped with a stir bar. The solution was degassed by bubbling vigorously with N2 for 15 minutes. The headspace was purged with N2, and the sealed solution was heated at 120°C for 60 hours. The solvent was removed under reduced pressure, and the residue was partitioned between EtOAc (100 mL) and brine (100 mL). The aqueous layer was extracted (2 x 100 mL EtOAc), and the combined organic layers were dried over MgSO4, filtered, and concentrated. The crude residue was purified by preparative RP HPLC (10→90% MeCN / H2O) to give 290 mg (25% yield) of 101 as a light yellow oil. 1 H NMR (400 MHz, MeOD) δ 7.46 (t, J = 8.3 Hz, 1H), 6.98 (s, 1H), 6.95 (s, 2H), 6.55 (d, J = 8.4 Hz, 1H), 6.52 (d, J = 8.3 Hz, 1H), 5.87 (d, J = 12.0 Hz, 1H), 5.38 (d, J = 12.0 Hz, 1H), 3.88 (s, 3H), 1.99 (s, 3H); MS (ESI) calcd for C 18 H17 O7[M+H] + The measured value is 345.1 and 345.0.

[0165] Example 1a: (2,3-trans)-3,5-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-chroman- Preparation of 4-ketone (1)

[0166]

[0167] Under N2 atmosphere, a 100 mL round-bottom flask equipped with a stir bar, condenser (air cooling), and rubber septum was charged with epoxide 2 (Example 1b, 816 mg, 188 mmol) followed by anhydrous methanolic HCl (1.25 M, 20 mL). The reaction mixture was heated at 55°C for 2 hours, after which time LCMS analysis indicated that the starting material had been consumed. The solvent was removed under reduced pressure, and the residue was redissolved in MeOH (150 mL) and the solvent removed under reduced pressure. The crude residue was purified by preparative RP HPLC (10→90% MeCN / H2O) to provide 400 mg (71% yield) of flavanol 1 as a white solid. 1 H NMR(400MHz,MeOD)δ7.42(td,J=8.3,0.8Hz,1H),7.02(d,J=1.8Hz,1H),7.00–6.90(m,2H),6.51(dd,J=8.3,0.9H z,1H),6.47(dd,J=8.3,0.9Hz,1H),5.04(d,J=11.8Hz,1H),4.62(dd,J=11.8,0.8Hz,1H),3.88(d,J=0.7Hz,3H); 13 C NMR (101 MHz, MeOD) δ 199.8, 161.7, 161.5, 148.2, 146.2, 138.2, 129.6, 119.4, 114.2, 110.9, 108.8, 107.2, 106.4, 83.6, 72.8, 55.0; MS (ESI) calcd for C 16 H 15 O6[M+H] + The measured value is 303.0 and 303.1.

[0168] Example 1b: (E)-1-(2,6-bis(methoxymethoxy)phenyl)-3-(4-methoxy-3-(methoxymethoxy)phenyl)- Preparation of 2-(4-(4-amino)phenyl)prop-2-en-1-one (2)

[0169]

[0170] To an emulsion of chalcone 3 (Example 1c, 1.8 g, 4.4 mmol) in methanol (120 mL) was added NaOH (530 mg, 13 mmol) in one portion at 22°C, followed by dropwise addition of aqueous hydrogen peroxide (30 wt%, 3.6 mL, 35 mmol). The reaction mixture was stirred for 18 hours, after which time LCMS analysis indicated that the starting material had been consumed. The reaction was quenched with saturated aqueous NH4Cl (120 mL) and extracted with EtOAc (3 x 100 mL). The organics were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0→60% EtOAc / hexanes) to afford 1.36 g (72% yield) of chalcone epoxide 2 as a light yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.28 (t, J = 8.4 Hz, 1H), 7.06 (d, J = 2.1 Hz, 1H), 6.95 (dd, J = 8.4, 2.1 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 2H), 5.27–5.19 (m, 2H), 5.18–5.14 (m, 4H), 3.97 (d, J = 1.8 Hz, 1H), 3.89 (d, J = 1.8 Hz, 1H), 3.87 (s, 3H), 3.49 (s, 3H), 3.42 (s, 6H); MS (ESI) calcd for C 22 H 27 O9[M+H] + The actual measured value is 435.2.

[0171] Example 1c: (E)-1-(2,6-bis(methoxymethoxy)phenyl)-3-(4-methoxy-3-(methoxymethoxy)phenyl)- Preparation of 2-(4-(4-amino)phenyl)prop-2-en-1-one (3)

[0172]

[0173] To a solution of 4 (Example 1d, 3.50 g, 14.6 mmol) in methanol (40 mL) was added aqueous NaOH (30 wt%, 20 mL, 150 mmol) at 0°C. After stirring for 30 minutes, a solution of 5 (Example 1e, 3.44 g, 17.5 mmol) in MeOH (35 mL) was added dropwise. The reaction mixture was stirred for 20 hours (allowing the ice bath to melt), after which time LCMS analysis indicated that the starting material had been consumed. The mixture was diluted with EtOAc (75 mL) and washed with saturated aqueous NH4Cl (2×75 mL). The aqueous layers were combined and extracted with (2×75 mL EtOAc). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0→100% EtOAc / hexanes) to afford 5.70 g (93% yield) of chalcone 3 as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 2.1 Hz, 1H), 7.29 (t, J = 8.4 Hz, 1H), 7.23 (d, J = 16.1 Hz, 1H), 7.16 (dd, J = 8.6, 2.0 Hz, 1H), 6.91–6.83 (m, 4H), 5.23 (s, 2H), 5.14 (s, 4H), 3.91 (s, 3H), 3.51 (s, 3H), 3.39 (s, 6H); MS (ESI) calculated for C 22 H 27 O8[M+H] + The measured value is 419.2.

[0174] Example 1d: Preparation of 1-(2,6-bis(methoxymethoxy)phenyl)ethan-1-one (4)

[0175]

[0176] Under N₂ atmosphere, a 500 mL oven-dried round-bottom flask equipped with a stir bar and a rubber septum was charged with NaH (4.0 g, 60% dispersion in mineral oil, 100 mmol) followed by anhydrous THF (80 mL). The suspension was cooled to 0°C in an ice bath, and a solution of 2',6'-dihydroxyacetophenone (S1, 5.0 g, 33 mmol) in THF (100 mL) was added dropwise over 15 minutes (venting was performed with a 22G needle to avoid overpressure). After stirring at 22°C for 20 minutes (gas evolution ceased), the solution was cooled back to 0°C, and MOMCl (7.5 mL, 99 mmol) was added dropwise over 15 minutes to the 0°C suspension. The reaction was stirred for 12 hours (allowing the ice bath to melt), after which time LCMS analysis indicated that the starting material was consumed. An ice-water mixture (150 mL) was slowly added, followed by extraction with EtOAc (3 x 150 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0→40% EtOAc / hexanes) to afford 5.6 g (70% yield) of acetophenone 4 as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.22 (t, J = 8.4 Hz, 1H), 6.80 (d, J = 8.4 Hz, 2H), 5.16 (s, 4H), 3.46 (s, 6H), 2.52 (s, 3H); MS (ESI) calculated for C 11 H 13 O4[M-OMe - ] + The measured value is 209.1 and 209.0.

[0177] Example 1e: Preparation of 4-methoxy-3-(methoxymethoxy)benzaldehyde (5)

[0178]

[0179] Under N2 atmosphere, a 1L oven-dried round-bottom flask equipped with a stirring bar and a rubber septum was charged with isovanillin (S2, 10 g, 66 mmol), followed by anhydrous DCM (400 mL). The mixture was cooled to 0°C in an ice bath, and then DIPEA (16 mL, 92 mmol) was slowly added. After stirring for 20 minutes, MOMCl (6.0 mL, 80 mmol) was added dropwise at 0°C over 15 minutes. The reaction was stirred for 18 hours (allowing the ice bath to melt), after which time LCMS analysis indicated that the starting material had been consumed. Water (300 mL) was added, followed by extraction with DCM (3×150 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0→50% EtOAc / hexane) to give compound 5 (12.7 g, 98% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 9.86 (s, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.55 (dd, J = 8.3, 1.9 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 5.29 (s, 2H), 3.97 (s, 3H), 3.53 (s, 3H); MS (ESI) calculated for C 10 H 13 O4[M+H] + The measured value is 197.1 and 197.0.

[0180] Example 2: Propionic acid (2,3-trans)-5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-4-oxobenzodihydro Preparation of pyran-3-yl ester (102)

[0181]

[0182] According to the method of Example 1, compound 102 (2.3 mg, yield 11%) was prepared from 1 (Example 1a) and propionic acid to obtain a transparent film. 1 H NMR(500MHz,MeOD)δ7.49(t,J=8.3Hz,1H),7.00(q,J=1.6Hz,1H),6.98(d,J=1.4Hz,2H),6.58(dd,J=8.4,1.0Hz,1H),6.55(dd,J=8.3,1.0Hz,1H) ,5.90(d,J=12.1Hz,1H),5.41(d,J=12.1Hz,1H),3.90(s,3H),2.36(dq, J=16.6,7.6Hz,1H),2.27(dq,J=16.5,7.5Hz,1H),1.03(t,J=7.6Hz,3H).

[0183] Example 3: Acetic acid (2,3-trans)-7-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-4-oxobenzodihydrogen Preparation of pyran-3-yl ester (103)

[0184]

[0185] A solution of flavanone alcohol 1B (Example 3a, 1.11 g, 3.67 mmol) in AcOH (85 mL) was placed in a 250 mL pressure flask equipped with a stir bar. The solution was degassed by bubbling vigorously with N2 for 15 minutes. The headspace was purged with N2, and the sealed solution was heated at 120°C for 60 hours. The solvent was removed under reduced pressure, and the residue was partitioned between EtOAc (100 mL) and brine (100 mL). The aqueous layer was extracted (2 x 100 mL EtOAc), and the combined organic layers were dried over MgSO4, filtered, and concentrated. The crude residue was purified by preparative RP HPLC (25 → 45% MeCN / H2O) to give 260 mg (22% yield) of 103 as a light yellow oil. 1 H NMR (400 MHz, MeOD) δ 7.72 (d, J = 8.7 Hz, 1H), 6.97 (t, J = 1.3 Hz, 1H), 6.94 (d, J = 1.3 Hz, 2H), 6.55 (dd, J = 8.7, 2.2 Hz, 1H), 6.36 (d, J = 2.2 Hz, 1H), 5.72 (d, J = 12.0 Hz, 1H), 5.29 (d, J = 12.0 Hz, 1H), 3.87 (s, 3H), 1.96 (s, 3H); MS (ESI) calcd for C 18 H 17 O7[M+H] + The measured value is 345.1 and 345.0.

[0186] Example 3a: (2,3-trans)-3,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-chroman- Preparation of 4-keto-methanol (1B)

[0187]

[0188] Under N2 atmosphere, a 100 mL round-bottom flask equipped with a stir bar and air condenser was charged with 2B (Example 3b, 2.3 g, 510 μmol) followed by anhydrous methanolic HCl (1.25 M, 65 mL). The reaction mixture was heated at 55°C for 6 hours, after which time LCMS analysis indicated that the starting material had been consumed. The solvent was removed under reduced pressure, and the residue was redissolved in MeOH (50 mL) and the solvent removed under reduced pressure. The crude residue was purified by preparative RP HPLC (10→90% MeCN / H2O) to afford 1.21 g (78% yield) of flavanol 1B as a clear oil. 1H NMR (400 MHz, MeOD) δ 7.72 (d, J = 8.7 Hz, 1H), 7.01 (d, J = 1.8 Hz, 1H), 7.00–6.88 (m, 2H), 6.53 (dd, J = 8.7, 2.2 Hz, 1H), 6.33 (d, J = 2.2 Hz, 1H), 4.97 (d, J = 11.8 Hz, 1H), 4.48 (d, J = 11.8 Hz, 1H), 3.88 (s, 3H); MS (ESI) calcd for C 16 H 15 O6[M+H] + The measured value is 303.0 and 303.1.

[0189] Example 3b: (E)-1-(2,6-bis(methoxymethoxy)phenyl)-3-(4-methoxy-3-(methoxymethoxy)phenyl)- Preparation of 2-(4-(4-amino)phenyl)prop-2-en-1-one (2B)

[0190]

[0191] To an emulsion of chalcone 3B (Example 3c, 3.3 g, 7.9 mmol) in methanol (200 mL) was added NaOH (950 mg, 24 mmol) in one portion at 22°C, followed by the dropwise addition of aqueous hydrogen peroxide (30 wt% in water, 6.4 mL, 63 mmol). The reaction mixture was stirred for 15 hours, after which time LCMS analysis indicated the starting material was consumed. The solvent was partially removed in vacuo, and the mixture was diluted with MBTE (200 mL), washed with saturated aqueous NH4Cl (200 mL), and extracted with MBTE (2 x 150 mL). The organics were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0→60% EtOAc / hexanes) to afford 2.3 g (67% yield) of chalcone epoxide 2B as a light yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.6 Hz, 1H), 7.12 (d, J = 2.1 Hz, 1H), 7.02 (dd, J = 8.3, 2.1 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.81–6.74 (m, 2H), 5.26–5.19 (m, 4H), 4.96 (d, J = 6.9 Hz, 1H), 4.87 (d, J = 6.9 Hz, 1H), 4.32 (d, J = 2.0 Hz, 1H), 3.92 (d, J = 2.0 Hz, 1H), 3.90 (s, 3H), 3.48 (d, J = 9.3 Hz, 6H), 3.15 (s, 3H); MS (ESI) calcd for C 22 H 27 O9[M+H] + The actual measured value is 435.2.

[0192] Example 3c: (E)-1-(2,6-bis(methoxymethoxy)phenyl)-3-(4-methoxy-3-(methoxymethoxy)phenyl)- Preparation of 2-(4-(4-amino)phenyl)prop-2-en-1-one (3B)

[0193]

[0194] At 0 ℃, to a solution of 4B (Example 3d, 2.0 g, 8.3 mmol) in methanol (30 mL) was added a NaOH aqueous solution (30 wt %, 6 mL, 42 mmol). After stirring for 30 minutes, a MeOH (15 mL) solution of MOM-isovanillin 5 (Example 1e, 1.8 g, 9.2 mmol) was added dropwise. The reaction mixture was stirred for 45 hours (melting the ice bath), after which time LCMS analysis showed that the starting material had been exhausted. The mixture was diluted with Et2O (50 mL) and washed with a saturated NH4Cl aqueous solution (2 × 30 mL). The aqueous layers were combined and extracted with (2 × 40 mL Et2O). The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 → 60% EtOAc / hexane) to obtain 2.8 g (80% yield) of chalcone 3B as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.7 Hz, 1H), 7.59 (d, J = 15.8 Hz, 1H), 7.46 (d, J = 2.1 Hz, 1H), 7.35 (d, J = 15.7 Hz, 1H), 7.22 (dd, J = 8.5, 2.1 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 2.2 Hz, 1H), 6.77 (dd, J = 8.6, 2.3 Hz, 1H), 5.25 (d, J = 0.5 Hz, 4H), 5.22 (s, 2H), 3.92 (s, 3H), 3.52 (s, 3H), 3.51 (s, 3H), 3.50 (s, 3H); MS (ESI) calcd for C 22 H 27 O8[M+H] + The measured value is 419.2.

[0195] Example 3d: Preparation of 1-(2,4-bis(methoxymethoxy)phenyl)ethan-1-one (4B)

[0196]

[0197] Under N₂ atmosphere, a 500 mL oven-dried round-bottom flask equipped with a stir bar and a rubber septum was charged with NaH (4.10 g, 60% dispersion in mineral oil, 103 mmol) followed by anhydrous DCM (200 mL). The suspension was cooled to 0°C in an ice bath, and a solution of 2',4'-dihydroxyacetophenone S3 (4.46 g, 29.3 mmol) in DMF (10 mL) was added dropwise over 15 minutes (venting was performed with a 22G needle to avoid overpressure). After stirring for 25 minutes (gas evolution ceased), MOMCl (5.12 mL, 67.4 mmol) was added dropwise over 5 minutes to the 0°C suspension. The reaction was stirred for 19 hours (allowing the ice bath to melt), after which time LCMS analysis indicated that the starting material was consumed. Water (40 mL) was added, followed by extraction with DCM (3 x 100 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0→40% EtOAc / hexanes) to afford 5.9 g (84% yield) of acetophenone 4B as a clear oil. 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 2.3 Hz, 1H), 6.72 (dd, J = 8.7, 2.3 Hz, 1H), 5.27 (s, 2H), 5.20 (s, 2H), 3.52 (s, 3H), 3.48 (s, 3H), 2.60 (s, 3H); MS (ESI) calculated for C 11 H 13 O4[M– - OMe] + The actual measured value is 209.0.

[0198] Example 4: Propionic acid (2,3-trans)-7-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-4-oxobenzodihydro Preparation of pyran-3-yl ester (104)

[0199]

[0200] To a solution of ID (Example 4a, 22 mg, 49 μmol) in MeOH (5 mL) was added concentrated HCl (1 mL). The resulting solution was allowed to stand at 22°C for 60 minutes, after which time LCMS analysis indicated that the starting material had been consumed. The solvent was removed under reduced pressure, and the residue was redissolved in MeOH (5 mL) and the solvent removed under reduced pressure. The crude residue was purified by preparative RP HPLC (10→90% MeCN / H2O) to afford 104 (10 mg, 59% yield) as a clear oil. 1H NMR (500 MHz, MeOD) δ 7.75 (d, J = 8.8 Hz, 1H), 6.99 (d, J = 1.4 Hz, 1H), 6.97 (d, J = 1.2 Hz, 2H), 6.59 (dd, J = 8.7, 2.2 Hz, 1H), 6.40 (d, J = 2.2 Hz, 1H), 5.75 (d, J = 12.0 Hz, 1H), 5.33 (d, J = 12.0 Hz, 1H), 3.90 (s, 3H), 2.41–2.28 (m, 1H), 2.24 (dt, J = 16.5, 7.5 Hz, 1H), 1.01 (t, J = 7.5 Hz, 3H); MS (ESI) calcd for C 19 H 19 O6[M+H] + The measured value is 359.1 and 359.0.

[0201] Example 4a: Propionic acid (2,3-trans)-2-(4-methoxy-3-(methoxymethoxy)phenyl)-7-(methoxymethyl) Preparation of 4-oxochroman-3-yl ester (1D)

[0202]

[0203] To a solution of 2D (Example 4b, 20 mg, 51 μM) in DCM (3 mL) was added DMAP (13 mg, 110 μM), EDCI (21 mg, 110 μM), followed by a solution of propionic acid (7.6 mg, 100 μM) in DCM (1 mL). The resulting solution was allowed to stand at 22°C for 18 hours, after which time LCMS analysis indicated that the starting material had been consumed. The reaction mixture was directly loaded onto a silica gel column and purified by silica gel chromatography (0→50% EtOAc / hexanes) to afford 22 mg (96% yield) of ester 1D as a clear oil. 1 H NMR (500MHz, CDCl3) δ7.71(d,J=8.8Hz,1H),7.17(d,J=2.1Hz,1H),7.08(dd,J=8.4,2.1Hz,1H),6.94(d ,J=8.4Hz,1H),6.70(dd,J=8.8,2.3Hz,1H),6.59(d,J=2.2Hz,1H),5.72(d,J=12.2Hz,1H),5.31(d,J=1 2.2Hz,1H),5.17(s,2H),5.10(d,J=6.5Hz,1H),5.06(d,J=6.6Hz,1H),4.75(s,5H),3.77(s,3H),3.39( s, 3H), 3.36 (s, 3H), 2.23 (dq, J = 16.4, 7.5Hz, 1H), 2.13 (dq, J = 16.5, 7.6Hz, 1H), 0.88 (t, J = 7.6Hz, 3H).

[0204] Example 4b: (2,3-trans)-3-hydroxy-2-(4-methoxy-3-(methoxymethoxy)-phenyl)-7-(methoxy Preparation of (4-(2-methyl-2-methoxy)chroman-4-one (2D)

[0205]

[0206] To a solution of 3D (Example 4c, 800 mg, 2 mmol) in dioxane (25 mL) was added EtNH (1.1 mL, 11 mmol) under a N atmosphere, followed by the slow addition of H2O2 (30 wt%, 6.6 mL, 64 mmol) over 15 minutes. The reaction mixture was stirred vigorously for 18 hours, after which time LCMS analysis indicated the starting material was consumed. The solution was cooled to 0°C in an ice bath, and then a solution of Na2S2O3·5H2O (50 g, 0.28 mol) in H2O (~150 mL) was slowly added over 30 minutes (caution: exothermic!) to quench excess hydrogen peroxide. The mixture was then extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (25→40% EtOAc / hexanes) to afford 513 mg of compound 2D (62% yield) as a white solid. 1 H NMR(400MHz, CDCl3) δ7.86(d,J=8.8Hz,1H),7.39(d,J=2.1Hz,1H),7.19(dd,J=8.4, 2.1Hz,1H),6.97(d,J=8.4Hz,1H),6.76(dd,J=8.8,2.3Hz,1H),6.68(d,J=2.3Hz,1H) ,5.37–5.24 (m, 2H),5.21 (d, J = 1.0 Hz, 2H),5.04 (d, J = 12.3 Hz, 1H),4.58 (d, J = 12.3 Hz, 1H),3.92 (s, 3H),3.68 (d, J = 1.7 Hz, 1H),3.53 (s, 3H),3.48 (s, 3H); MS (ESI) calculated for C 20 H 23 O8[M+H] + The measured value is 391.1.

[0207] Example 4c: (E)-1-(2-hydroxy-4-(methoxymethoxy)phenyl)-3-(4-methoxy-3-(methoxymethoxy)phenyl)- Preparation of 2-(4-(2-oxy)phenyl)prop-2-en-1-one (3D)

[0208]

[0209] To a solution of 4D (Example 4d, 740 mg, 3.8 mmol) in ethanol (20 mL) was added KOH aqueous solution (50 wt %, 5.4 mL, 75 mmol), followed by the dropwise addition of a solution of compound 5 (Example 1e, 780 mg, 4.0 mmol) in EtOH (5 mL). The reaction mixture was stirred for 60 hours, after which time LCMS analysis indicated that the starting material had been consumed. The mixture was diluted with Et2O (100 mL) and quenched with HCl aqueous solution (0.5 N, 100 mL). The aqueous layer was extracted with Et2O (3×100 mL). The ether layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0→40% EtOAc / hexane) to afford 0.8 g (57% yield) of chalcone 3D as a yellow solid. 1 H NMR (400 MHz, MeOD) δ 8.10 (d, J = 9.0 Hz, 1H), 7.82 (d, J = 15.3 Hz, 1H), 7.69 (d, J = 15.3 Hz, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.42 (dd, J = 8.5, 2.2 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 6.64 (dd, J = 8.9, 2.5 Hz, 1H), 6.57 (d, J = 2.5 Hz, 1H), 5.26 (d, J = 2.1 Hz, 4H), 3.90 (s, 3H), 3.53 (s, 3H), 3.47 (s, 4H); MS (ESI) calcd for C 20 H 23 O7[M+H] + The measured value is 375.1 and 375.0.

[0210] Example 4d: Preparation of 1-(2-hydroxy-4,6-bis(methoxymethoxy)phenyl)ethan-1-one (4D)

[0211]

[0212] Under N2 atmosphere, a 500 mL oven-dried round-bottom flask equipped with a stir bar and a rubber septum was charged with 2,4-dihydroxyacetophenone S3 (6.8 g, 45 mmol) followed by anhydrous DCM (150 mL). DIPEA (14 mL, 80 mmol) was slowly added to the stirred suspension to give a clear solution. MOMCl (4.1 mL, 54 mmol) was added dropwise to the stirred clear solution over 15 minutes. The reaction was stirred for 18 hours, after which time LCMS analysis indicated that the starting material had been consumed. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (0→40% EtOAc / hexane) to give 8.5 g (97% yield) of acetophenone 4D as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 12.61 (s, 1H), 7.65 (d, J = 8.8 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 6.55 (dd, J = 8.9, 2.5 Hz, 1H), 5.21 (s, 2H), 3.48 (s, 3H), 2.57 (s, 3H); MS (ESI) calculated for C 10 H 13 O4[M+H] + The measured value is 197.1 and the actual value is 197.2.

[0213] Example 5: Propionic acid (2,3-trans)-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-4-oxobenzo Preparation of dihydropyran-3-yl ester-methanol (105)

[0214]

[0215] To a solution of 1E (Example 5a, 15 mg, 30 μM) in DCM (2 mL) was added TiPS (10 μL) followed by TFA (1 mL). The resulting solution was allowed to stand at 22° C. for 40 minutes, after which time LCMS analysis indicated that the starting material had been consumed. The solvent was removed under reduced pressure, and the residue was redissolved in MeOH (5 mL) and the solvent removed under reduced pressure. The crude residue was purified by preparative RP HPLC (10→90% MeCN / H 2 O) to afford 1.8 mg (16% yield) of flavanol 105 as a clear oil. 1 H NMR (500 MHz, MeOD) δ 7.05–6.85 (m, 3H), 6.03–5.87 (m, 2H), 5.80 (d, J = 11.7 Hz, 1H), 5.29 (d, J = 11.7 Hz, 1H), 3.89 (s, 3H), 2.35 (dq, J = 16.7, 7.6 Hz, 1H), 2.32–2.15 (m, 1H), 1.02 (t, J = 7.6 Hz, 3H); MS (ESI) calcd for C 19 H 19 O6[M+H] + The measured value is 375.1 and 375.0.

[0216] Example 5a: Propionic acid (2,3-trans)-2-(4-methoxy-3-(methoxymethoxy)phenyl)-5,7-bis(methoxy Preparation of 4-oxochroman-3-yl ester (1E)

[0217]

[0218] To a solution of 2E (Example 5b, 14 mg, 31 μM) in DCM (3 mL) was added DMAP (7.6 mg, 62 μM), EDCI (12 mg, 62 μM), followed by a solution of propionic acid (4.6 mg, 62 μM) in DCM (1 mL). The resulting solution was allowed to stand at 22° C. for 18 hours, after which time LCMS analysis indicated that the starting material had been consumed. The reaction mixture was directly loaded onto a silica gel column and purified by silica gel chromatography (0→50% EtOAc / hexanes) to afford 15 mg (97% yield) of ester S20 as a clear oil. 1 H NMR (500 MHz, CDCl3) δ 7.05 (dd, J = 8.4, 2.1 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.41 (d, J = 2.3 Hz, 1H), 6.30 (d, J = 2.3 Hz, 1H), 5.61 (d, J = 12.2 Hz, 1H), 5.28–5.14 (m, 5H), 5.14–4.96 (m, 2H), 3.83 (d, J = 1.7 Hz, 3H), 3.45 (s, 6H), 3.40 (s, 3H), 2.31 (dq, J = 16.6, 7.6 Hz, 1H), 2.26–2.07 (m, 1H), 0.98 (t, J = 7.6 Hz, 3H); MS (ESI) calcd for C 25 H 31 O 11 [M+H] + The measured value is 507.5 and 507.2.

[0219] Example 5b: (trans)-3-hydroxy-2-(4-methoxy-3-(methoxymethoxy)phenyl)-5,7-bis(methoxy Preparation of (4-(2-methyl-2-methoxy)chroman-4-one (2E)

[0220]

[0221] To an ice-cold (ice bath) solution of 3E (Example 5c, 3.77 g, 8.68 mmol) in dioxane (100 mL) under N2 atmosphere was added Et2NH (4.5 mL, 43 mmol), followed by the slow addition of H2O2 (30 wt%); precipitation occurred after the addition of approximately 85 mL of H2O2 solution to afford 2E (557 mg, 14% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ

[0222] 7.36 (d, J = 2.1 Hz, 1H), 7.17 (dd, J = 8.3, 2.1 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.46 (d, J = 2.2 Hz, 1H), 6.37 (d, J = 2.2 Hz, 1H), 5.42–5.22 (m, 4H), 5.19–5.16 (m, 2H), 4.97 (d, J = 12.2 Hz, 1H), 4.46 (d, J = 12.2 Hz, 1H), 4.01 (s, 1H), 3.91 (s, 3H), 3.54 (s, 3H), 3.53 (s, 3H), 3.47 (s, 3H); MS (ESI) calcd for C 22 H 27 O 10 [M+H] + The measured value is 421.2, and the actual value is 451.2.

[0223] Example 5c: (E)-1-(2-hydroxy-4,6-bis(methoxymethoxy)phenyl)-3-(4-methoxy-3-(methoxy Preparation of (4-(2-(4-(2-(2-((2-((4-((2-( ...

[0224]

[0225] Prepared from 4E (Example 5d, 3.32 g, 13.0 mmol), KOH (50 wt%, 20 mL, 180 mmol) and 5 (Example 1e, 2.67 g, 13.6 mmol) in ethanol (60 mL) according to the method described in Example-1c, 3E (5.5 g, 97% yield) was obtained as a yellow oil. MS (ESI) calculated for C 22 H 27 O9[M+H] + The actual measured value is 435.2.

[0226] Example 5d: Preparation of 1-(2-hydroxy-4,6-bis(methoxymethoxy)phenyl)ethan-1-one (4E)

[0227]

[0228] Under N2 atmosphere, a 500 mL oven-dried round-bottom flask equipped with a stir bar and a rubber septum was charged with 2,4,6-trihydroxyacetophenone S4 (3.8 g, 23 mmol) followed by anhydrous DCM (100 mL). The mixture was cooled to 0°C in an ice bath, and DIPEA (11 mL, 63 mmol) was slowly added. After stirring for 20 minutes, MOMCl (3.8 mL, 50 mmol) was added dropwise to the suspension at 0°C over 15 minutes. The reaction was stirred for 4 hours (allowing the ice bath to melt and the suspension to turn into a light brown solution), after which time LCMS analysis indicated that the starting material had been consumed. Water (100 mL) was added, followed by extraction with DCM (3 x 75 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0→100% EtOAc / hexanes) to afford 3.0 g (51% yield) of acetophenone 4E as a clear oil which solidified upon standing. 1 H NMR (400 MHz, DMSO-d6) δ 13.34 (s, 1H), 6.23 (d, J = 2.3 Hz, 1H), 6.19 (d, J = 2.3 Hz, 1H), 5.30 (s, 2H), 5.23 (s, 2H), 3.44 (s, 3H), 3.38 (s, 3H), 2.60 (s, 3H); MS (ESI) calculated for C 12 H 17 O6[M+H] + The measured value is 257.1 and 257.2.

[0229] Example 6: (2,3-trans)-5-hydroxy-2-(4-hydroxyphenyl)-4-oxochroman-3-yl acetate Preparation of ester (106)

[0230]

[0231] Under N2 atmosphere, a 40 mL vial equipped with a stirring bar and a Teflon cap was charged with 1F (Example 6a, 190 mg, 0.48 mmol), followed by MeOH (6 mL), and a solution of Na2SO3 (180 mg, 1.4 mmol) in H2O (6 mL). The resulting yellow solution was stirred at 28°C for 18 hours, then quenched with HCl (0.3 M, 6 mL) and extracted into EtOAc (3 x 25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. A small amount of product was purified by recrystallization from a MeCN-H2O mixture to afford 4.2 mg (3% yield) of 106 as a white solid. 1H NMR (400 MHz, CDCl3) δ 11.18 (s, 1H), 7.42 (t, J = 8.3 Hz, 1H), 7.39–7.32 (m, 2H), 6.95–6.81 (m, 2H), 6.59 (dd, J = 8.4, 0.9 Hz, 1H), 6.50 (dd, J = 8.2, 1.0 Hz, 1H), 5.84 (d, J = 12.1 Hz, 1H), 5.34 (d, J = 12.1 Hz, 1H), 4.84 (s, 1H), 2.04 (s, 3H); MS (ESI) calcd for C 15 H 11 O4[M– - OAc] + The measured value is 255.1 and 255.2.

[0232] Example 6a: (2,3-trans)-2-(4-acetoxyphenyl)-4-oxochroman-3,5-diacetate Preparation of dialkyl ester (1F)

[0233]

[0234] A 200 mL round-bottomed vial equipped with a stirring bar and a rubber septum was charged with 1F (Example 6b, 234 mg, 745 μmol, a 3:1 mixture of trans-cis isomers) followed by anhydrous DCM (40 mL). Acetic anhydride (380 μL, 4.1 mmol) was added to the mixture, followed by DIPEA (860 μL, 5.2 mmol). After stirring for 5 minutes, a solution of DMAP (14 mg, 110 μmol) in DCM (3 mL) was added. The reaction was stirred for 21 hours, after which time LCMS analysis indicated that the starting material had been exhausted. Water (40 mL) was added, followed by extraction with DCM (2×40 mL). The combined organic layers were dried over MgSO 4 , filtered, and concentrated under reduced pressure. Purification by preparative RP HPLC (10→90% MeCN / H2O) gave 233 mg (79% yield, 10:1 trans:cis mixture) of flavanol triacetate 2F as a white solid. A small amount of the trans-cis mixture was purified to the pure trans isomer by trituration with MeOH. 1 H NMR (400 MHz, CDCl3) δ 7.57–7.44 (m, 3H), 7.22–7.10 (m, 2H), 6.96 (dd, J = 8.5, 1.1 Hz, 1H), 6.76 (dd, J = 8.0, 1.0 Hz, 1H), 5.73 (d, J = 12.4 Hz, 1H), 5.44 (d, J = 12.3 Hz, 1H), 2.39 (s, 3H), 2.32 (s, 3H), 2.02 (s, 3H). MS (ESI) calcd for C 21 H 19 O8[M+H]+ The actual measured value is 399.0.

[0235] Example 6b: (2,3-trans)-3,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one-methanol Preparation of (1 / 1)(2E)

[0236]

[0237] Under N₂ atmosphere, a 40 mL round-bottom vial equipped with a stir bar and Teflon cap was charged with 3F (Example 6c, 410 mg, 1.0 mmol) followed by anhydrous methanolic HCl (1.25 M, 12 mL). The reaction mixture was heated at 55°C for 2 hours, after which time LCMS analysis indicated that the starting material was consumed. The solvent was removed under reduced pressure, and the residue was redissolved in MeOH (20 mL) and the solvent removed under reduced pressure. The crude residue was purified by preparative RP HPLC (10→90% MeCN / H₂O) to afford 234 mg (85% yield) of flavanol 2F as a white solid (approximately a 3:1 mixture of trans and cis isomers; epimerization may have occurred during the purification procedure). A small amount of the trans-cis mixture was purified to the pure trans isomer by trituration with MeOH. 1 H NMR (400 MHz, MeOD) δ 7.42 (t, J = 8.3 Hz, 1H), 7.39–7.32 (m, 2H), 6.91–6.80 (m, 2H), 6.51 (d, J = 8.3 Hz, 1H), 6.46 (d, J = 8.3 Hz, 1H), 5.07 (d, J = 11.9 Hz, 1H), 4.66 (d, J = 11.9 Hz, 1H); MS (ESI) calcd for C 15 H 13 O5[M+H] + The measured value is 273.1 and the actual value is 273.2.

[0238] Example 6c: (E)-1-(2-hydroxy-4,6-bis(methoxymethoxy)phenyl)-3-(4-methoxy-3-(methoxy Preparation of (4-(2-(4-(2-(2-((2-((4-((2-( ...

[0239]

[0240] To a solution of chalcone 4F (Example 6d, 1.34 g, 3.45 mmol) in methanol (100 mL) was added NaOH (0.4 g, 10 mmol) in one portion at 22°C, followed by dropwise addition of aqueous hydrogen peroxide (30 wt%, 2.8 mL, 28 mmol). The reaction mixture was stirred for 24 hours, after which time LCMS analysis indicated that the starting material had been consumed. The reaction was diluted with Et2O (75 mL), washed with saturated aqueous NH4Cl (2 x 75 mL), and extracted with Et2O (2 x 75 mL). The organics were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to afford 1.26 g (90% yield) of chalcone epoxide 3F as a light yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.4 Hz, 1H), 7.25–7.17 (m, 2H), 7.07–6.96 (m, 2H), 6.82 (d, J = 8.4 Hz, 2H), 5.17 (s, 2H), 5.15 (s, 2H), 5.15 (s, 2H), 3.99 (d, J = 1.8 Hz, 1H), 3.89 (d, J = 1.9 Hz, 1H), 3.46 (s, 3H), 3.42 (s, 6H); MS (ESI) calculated for C 21 H 25 O8[M+H] + It is 405.2, and the measured value is 405.0.

[0241] Example 6d: (E)-1-(2,6-bis(methoxymethoxy)phenyl)-3-(4-(methoxymethoxy)phenyl)propane- Preparation of 2-en-1-one (4F)

[0242]

[0243] To a solution of 4 (Example 1d, 0.94 g, 3.9 mmol) in methanol (10 mL) was added aqueous NaOH (30 wt%, 5 mL, 35 mmol) at 22°C, followed by a solution of 5A (Example 6e, 0.72 g, 4.3 mmol) in MeOH (7 mL). The reaction mixture was stirred for 18 hours, after which time LCMS analysis indicated that the starting material had been consumed. The mixture was diluted with Et2O (50 mL) and washed with saturated aqueous NH4Cl (2 x 25 mL). The aqueous layers were combined and extracted with (2 x 50 mL Et2O). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0 → 100% EtOAc / hexanes) to afford 1.34 g (88% yield) of chalcone 4F as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.54–7.42 (m, 2H), 7.34–7.24 (m, 2H, overlapped with CHCl3), 7.09–6.96 (m, 2H), 6.95–6.77 (m, 3H), 5.19 (s, 2H), 5.13 (s, 4H), 3.47 (s, 3H), 3.38 (s, 6H); MS (ESI) calculated for C 21 H 25 O7[M+H] + The measured value is 389.2.

[0244] Example 6e: Preparation of 4-(methoxymethoxy)benzaldehyde (5A)

[0245]

[0246] Under N₂ atmosphere, a 1 L oven-dried round-bottom flask equipped with a stir bar and a rubber septum was charged with 4-hydroxybenzaldehyde S5 (12 g, 98 mmol) followed by anhydrous DCM (250 mL). The mixture was cooled to 0°C in an ice bath, DIPEA (24 mL, 140 mmol) was added, and then MOMCl (8.2 mL, 110 mmol) was added dropwise to the suspension at 0°C over 15 minutes. The reaction was stirred for 18 hours (allowing the ice bath to melt), after which time LCMS analysis indicated that the starting material had been consumed. Water (100 mL) was added, followed by extraction with DCM (3 x 75 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0→50% EtOAc / hexanes) to afford 15.7 g (96% yield) of aldehyde 5A as a clear oil. 1 H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 7.92–7.74 (m, 2H), 7.22–7.05 (m, 2H), 5.25 (s, 2H), 3.49 (s, 3H); MS (ESI) calculated for C9H 11 O3[M+H] + The measured value is 167.1 and 167.0.

[0247] Example 7 - Compound Testing

[0248] Each of compounds 101-106 was synthesized. These compounds were then tested in an in vitro cell-based assay using cells overexpressing the T1R sweet taste receptor. Sweetness dose-response curves were recorded, and EC50 values ​​were determined. Table 2 summarizes the calculated EC50 values ​​for the specific test compounds.

[0249] Table 2

[0250] <![CDATA[ Compound ]]> <![CDATA[ EC50 (μM) ]]> 101 ～1 102 ~2 (partial agonist) 103 ～8 104 ～10 105 ～5 106 ～45

[0251] Example 8 - Sensory test: testing sweetness only

[0252] Test samples were prepared from compound 101 (4 ppm aqueous solution) and compound 103 (7 ppm aqueous solution). The sensory panel evaluated the sweetness of each test sample relative to a 1.5 wt % sucrose solution. Panelists were asked to select the sweeter sample between the compound test sample and the 1.5 wt % sucrose solution. For compound 101, the taste sample was selected as the sweeter sample 14 times, while the sucrose control sample was selected as the sweeter sample 46 times (60 times in total). For compound 103, the taste sample was selected as the sweeter sample 14 times, while the sucrose control sample was selected as the sweeter sample 55 times (69 times in total).

[0253] Example 9 - Sensory Test: Enhancement

[0254] Two control samples were prepared in low sodium buffer, containing 6% sucrose by weight and 7.5% sucrose by weight. Two test samples were prepared: one containing 6% sucrose by weight plus 4 ppm of compound 101, and the other containing 6% sucrose by weight plus 7 ppm of compound 103. Panelists were asked to evaluate these four samples and rate their sweetness on a scale of 0 to 10, with higher scores indicating greater sweetness. Table 3 shows the average panelist ratings.

[0255] Table 3

[0256] <![CDATA[ sample ]]> <![CDATA[ Sweetness rating ]]> 6 wt% sucrose 6.6 7.5 wt% sucrose 8.6 6 wt% sucrose + 4 ppm compound 101 9.8 6 wt% sucrose + 7 ppm compound 103 8.8 .

Claims

1. A flavor-modifying compound, which is a compound of formula (I): or a salt thereof, wherein: R 1 and R 2 are independently a hydrogen atom, -OH or -OCH3; R 3 、R 4 and R 5 are independently a hydrogen atom, -OH or -OCH3; and R is methyl, ethyl, isopropyl or benzyl.

2. The flavor-modifying compound of claim 1, wherein R 1 and R 2 All are -OH.

3. The flavor-modifying compound of claim 1, wherein R 1 and R 2 One of them is a hydrogen atom and the other is a hydrogen atom.

4. The flavor-modifying compound according to any one of claims 1 to 3, wherein R 4 is -OH, and R 3 and R 5 Each is a hydrogen atom.

5. The flavor-modifying compound according to any one of claims 1 to 3, wherein R 3 -OH, R 4 is -OCH3, and R 5 A hydrogen atom. The flavor-modifying compound according to claim 1 , wherein R is a methyl group or an ethyl group.

7. The flavor-modifying compound according to any one of claims 1 to 6, which is Compound 101, Compound 102, Compound 103, Compound 104, Compound 105, Compound 106, or an edible acceptable salt of any one of the foregoing.

8. Use of a flavor-modifying compound according to any one of claims 1 to 7 for reducing the bitter taste of an ingestible composition.

9. The use according to claim 8, wherein the concentration of the flavor-modifying compound used in the ingestible composition ranges from 0.1 ppm to 1000 ppm.

10. The use according to claim 8 or 9, wherein the ingestible composition comprises one or more bitter tastants.

11. The use according to claim 10, wherein the bitter tastant is a high intensity sweetener, such as acesulfame potassium, aspartame, neotame, cyclamate, saccharin, sucralose, steviol glycosides (such as rebaudioside A, rebaudioside B, rebaudioside M, rebaudioside D or rebaudioside E), and mogrosides (such as mogroside III, mogroside IV, mogroside V, simenoside I, isomogroside V, mogroside IV E , isomogroside IV, mogroside III E , 11-oxomogroside V, or 1,6-α isomer of simenoside I), or any combination thereof.

12. The use according to claim 10, wherein the bitter tastant is a potassium salt, such as potassium chloride.

13. The method according to claim 10, wherein the bitter tastant is a plant protein, such as pea protein, soy protein, almond protein, cashew protein, rapeseed protein, chickpea protein, faba bean protein, sunflower protein, wheat protein, oat protein, barley protein, potato protein, or any combination thereof.

14. The method of claim 10, wherein the bitter tastant is a pharmaceutical compound such as atropine, brinzolamide, chloramphenicol, chloroquine, clindamycin, dexamethasone, digoxin, diltiazem, diphenhydramine, docusate, dorzolamide, doxepin, doxylamine, enalapril, erythromycin, esomeprazole, famotidine, gabapentin, ginkgolide A, guaifenesin, L-histidine, lomefloxacin, methylprednisolone, ofloxacin, oleuropein, oxphenium bromide, pirenzepine, prednisone, ranitidine, trapidil, trimethoprim, cetirizine, or any combination thereof.

15. Use of a flavor-modifying compound according to any one of claims 1 to 7 for enhancing the sweet taste of an ingestible composition.

16. The use according to claim 15, wherein the concentration of the flavor-modifying compound used in the ingestible composition ranges from 0.1 ppm to 1000 ppm.

17. Use according to claim 15 or 16, wherein the ingestible composition comprises one or more bitter tastants.

18. An ingestible composition comprising the flavor-modifying compound of any one of claims 1 to 7, and a bulking agent.

19. The ingestible composition of claim 18, wherein the ingestible composition comprises a sweetener.

20. The ingestible composition of claim 18 or 19, wherein the flavor-modifying compound is present in the ingestible composition at a concentration in the range of 0.1 ppm to 1000 ppm.

21. A flavored product comprising the ingestible composition of any one of claims 18 to 20.

22. The flavored product of claim 21, which is a beverage product, a food product, an oral care product, or a pharmaceutical product.

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