WO2022125796A1 - Flavor modulating compounds and compositions - Google Patents

Flavor modulating compounds and compositions Download PDF

Info

Publication number
WO2022125796A1
WO2022125796A1 PCT/US2021/062649 US2021062649W WO2022125796A1 WO 2022125796 A1 WO2022125796 A1 WO 2022125796A1 US 2021062649 W US2021062649 W US 2021062649W WO 2022125796 A1 WO2022125796 A1 WO 2022125796A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
heterocyclic ring
formula
together form
independently selected
Prior art date
Application number
PCT/US2021/062649
Other languages
French (fr)
Inventor
Devin PETERSON
Adeline BONNEAU
Edisson Tello CAMACHO
Original Assignee
Ohio State Innovation Foundation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ohio State Innovation Foundation filed Critical Ohio State Innovation Foundation
Publication of WO2022125796A1 publication Critical patent/WO2022125796A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
    • A23L27/86—Addition of bitterness inhibitors
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A23L2/56—Flavouring or bittering agents
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
    • A23L27/20—Synthetic spices, flavouring agents or condiments
    • A23L27/204—Aromatic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
    • A23L27/84—Flavour masking or reducing agents

Definitions

  • the invention is directed to compounds and compositions useful to modulate the flavors, for instance in consumables, pharmaceuticals, adhesives, and the like.
  • the compounds and compositions are useful to reduce bitterness in food products.
  • the compounds and compositions include one or more flavan-3- ol derivatives.
  • bitter There are five primary tastes perceived by the human tongue: salt, sour, sweet, bitter, and umami (i.e., savory). Many people consider the bitter sensation to be unpleasant, and it is speculated that the ability to sense bitterness evolved as an avoidance mechanism against toxic plants and animals. Nevertheless, many foods with high nutritional value, for instance cruciferous vegetables, whole grain foods, and cranberries, also have bitter flavors. These foods are often prepared with high levels of fats, sugars, and/or salts in order to mask the bitterness. Although these additives increase the palatability of the nutritious foods, excess consumption of fat, sugar, and salt is considered unhealthy. As an alternative, bitter blocking compounds having been developed as an additive for foods and vegetables. However, different foods have different distributions of bitter compounds, and many additives only block a subset of bitter flavors.
  • flavor-modulating and/or bitter blocking compounds having the formula: wherein the R groups are as defined herein. Also disclosed are methods of preparing flavor modulating and/or bitter blocking compounds by reaction of a flavanol with one or more carbohydrates.
  • Figure 1 depicts the effectiveness of disclosed compounds to suppress the bitterness in caffeine solutions.
  • the word “comprise” and variations of the word, such as “comprising” and “comprises,” means “including but not limited to,” and is not intended to exclude, for example, other additives, components, integers or steps.
  • “Exemplary” means “an example of’ and is not intended to convey an indication of a preferred or ideal embodiment. “Such as” is not used in a restrictive sense, but for explanatory purposes.
  • alkyl as used herein is a branched or unbranched hydrocarbon group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, and the like.
  • the alkyl group can also be substituted or unsubstituted. Unless stated otherwise, the term “alkyl” contemplates both substituted and unsubstituted alkyl groups.
  • the alkyl group can be substituted with one or more groups including, but not limited to, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, or thiol.
  • An alkyl group which contains no double or triple carbon-carbon bonds is designated a saturated alkyl group, whereas an alkyl group having one or more such bonds is designated an unsaturated alkyl group.
  • Unsaturated alkyl groups having a double bond can be designated alkenyl groups, and unsaturated alkyl groups having a triple bond can be designated alkynyl groups. Unless specified to the contrary, the term alkyl embraces both saturated and unsaturated groups.
  • cycloalkyl as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms.
  • examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • heterocycloalkyl is a cycloalkyl group as defined above where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, selenium or phosphorus.
  • the cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted.
  • cycloalkyl and heterocycloalkyl contemplate both substituted and unsubstituted cyloalkyl and heterocycloalkyl groups.
  • the cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, or thiol.
  • a cycloalkyl group which contains no double or triple carboncarbon bonds is designated a saturated cycloalkyl group, whereas an cycloalkyl group having one or more such bonds (yet is still not aromatic) is designated an unsaturated cycloalkyl group.
  • the term cycloalkyl embraces both saturated and unsaturated, non-aromatic, ring systems.
  • aryl as used herein is an aromatic ring composed of carbon atoms. Examples of aryl groups include, but are not limited to, phenyl and naphthyl, etc.
  • heteroaryl is an aryl group as defined above where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, selenium or phosphorus.
  • the aryl group and heteroaryl group can be substituted or unsubstituted. Unless stated otherwise, the terms “aryl” and “heteroaryl” contemplate both substituted and unsubstituted aryl and heteroaryl groups.
  • the aryl group and heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, or thiol.
  • heteroaryl and heterocyclyl rings include: benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH carbazolyl, carbolinyl, chromanyl, chromenyl, cirmolinyl, decahydroquinolinyl, 2H,6H ⁇ 1,5,2-dithiazinyl, dihydrofuro[2,3 b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, IH-indazolyl, indolenyl, indolinyl, indolizinyl, in
  • alkoxy has the aforementioned meanings for alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, further providing said group is connected via an oxygen atom.
  • the term “null,” when referring to a possible identity of a chemical moiety, indicates that the group is absent, and the two adjacent groups are directly bonded to one another.
  • the resulting compound has the formula CH3-CH3.
  • certain compounds according to the invention may contain one or more centers of asymmetry and may therefore be prepared and isolated as a mixture of isomers such as a racemic or diastereomeric mixture, or in an enantiomerically or diastereomerically pure form.
  • the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention.
  • stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined.
  • the depiction of a compound without specifying the absolute configuration of an asymmetric center should not be taken as requiring all possible isomers are necessarily present in every embodiment.
  • Certain compounds of the invention will include ionizable functional groups, including carboxylic acids, sulfonic acids, phosphonic acids, amines, and the like.
  • ionizable functional groups including carboxylic acids, sulfonic acids, phosphonic acids, amines, and the like.
  • the skilled person will understand that such groups will contain, or will not contain, an ionizable hydrogen atom depending on pH. Depiction of a particular compound in one state of ionization (e.g., protonated) does not exclude other states (e.g., deprotonated) that would exist at different pH.
  • Acceptable salts are salts that retain the desired flavor modulatingl activity of the parent compound and do not impart undesirable toxicological effects.
  • examples of such salts are acid addition salts formed with inorganic acids, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids and the like; salts formed with organic acids such as acetic, oxalic, tartaric, succinic, maleic, fumaric, gluconic, citric, malic, methanesulfonic, p- toluenesulfonic, napthalenesulfonic, and polygalacturonic acids, and the like; salts formed from elemental anions such as chloride, bromide, and iodide; salts formed from metal hydroxides, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, and magnesium hydroxide; salts formed from metal carbonates, for example, sodium carbonate, potassium carbonate, calcium carbonate, and magnesium carbonate; salt
  • Acceptable salts may be prepared using procedures well known in the art, for example, by reacting a sufficiently basic compound such as an amine with a suitable acid comprising a physiologically acceptable anion.
  • a sufficiently basic compound such as an amine
  • a suitable acid comprising a physiologically acceptable anion.
  • Alkali metal for example, sodium, potassium, or lithium
  • alkaline earth metal for example, calcium
  • a reducing sugar e.g., a cyclic compound having a hemiacetal
  • a linear tautomer of the compound is understood to also include the linear tautomer of the compound as well, and vice versa:
  • flavor-modulating compounds having the formula: and acceptable salts thereof, wherein
  • R a1 is selected from R aa1 , OR aa1 , COOR aa1 , a heterocyclic ring having at least one oxygen, or together forms a heterocyclic ring with R a2 , said ring further spiro- substituted by a heterocyclic ring having at least one oxygen;
  • R a5 is selected from R aa5 , OR aa5 , COOR aa5 , a heterocyclic ring having at least one oxygen, or together forms a heterocyclic ring with R a4 , said ring further spiro- substituted by a heterocyclic ring having at least one oxygen;
  • R a3 is selected from R aa3 , OR aa3 , COOR aa3 ;
  • R a2 when not forming a heterocycle with R 31 , is selected from R aa2 , OR aa2 , COOR aa2 ;
  • R a4 when not forming a heterocycle with R a5 , is selected from R aa4 , OR aa4 , COOR aa4 ; where any two or more of R aa1 , R aa2 , R aa3 , R aa4 , and R aa5 may together form a bond;
  • R b1 is selected from R bb1 , OR bb1 , COOR bb1 , a heterocyclic ring having at least one oxygen, or together forms a heterocyclic ring with R b2 , said ring further spiro- substituted by a heterocyclic ring having at least one oxygen;
  • R b5 is selected from R bb5 , OR bb5 , COOR bb5 , a heterocyclic ring having at least one oxygen, or together forms a heterocyclic ring with R b4 , said ring further spiro- substituted by a heterocyclic ring having at least one oxygen;
  • R b3 is selected from R bb3 , OR bb3 , COOR bb3 ;
  • R b2 when not forming a heterocycle with R b1 , is selected from R bb2 , OR bb2 , COOR bb2 ;
  • R b4 when not forming a heterocycle with R b5 , is selected from R bb4 , OR bb4 , COOR bb4 ; where any two or more of R bb1 , R bb2 , R bb3 , R bb4 , and R bb5 may together form a bond; at least one of R 1 and R 3 is a heterocyclic ring having at least one oxygen, or forms a heterocyclic ring with one of R 2 and R 4 , said ring further spiro-substituted by a heterocyclic ring having at least one oxygen, and when R 1 and R 2 is not part of a heterocyclic ring system, then R 1 and R 2 is hydrogen, provided that not both of R 1 and
  • R 2 is hydrogen; when R 2 is not part of a heterocyclic ring system, is selected from R 2 , OR 2 , COOR 2 ; when R 4 is not part of a heterocyclic ring system, is selected from R 4 , OR 4 , COOR 4 ; and
  • Raai, R aa2 , R aa3 R aa4 , R aa5 , R bb1 , R bb2 , R bb3 , R bb4 , R bb5 , R 2 , and R 3 are independently selected from H, Ci-salkyl, aryl, heterocyclyl, heteroaryl, (-CH2CH2O) z R peg , wherein R peg is H, or Ci-salkyl, and z is from 1-100.
  • neither R 1 nor R 3 are hydrogen.
  • the flavor modulating compounds can have one of the specific stereochemical configurations: stereoisomer, while in other embodiments, a mixture of stereoisomers may be used to modulate flavors.
  • stereoisomer when any compound disclosed herein is designated a single stereoisomer, the stereochemical purity may be such that at least 80%, at least 85%, at least of 90%, at least 95%, at least 97.5%, or at least 99% of the compound is of the depicted stereochemistry, the remainder being other stereoisomeric forms.
  • R 2 can be OH
  • R 1 is a heterocyclic ring having the formula: wherein R cl , R c2 , R c3 , and R c4 are each independently selected from OH and H.
  • the wavy line indicates the bond to the other portion of the compound.
  • R 1 is a heterocyclic ring having the formula:
  • R cl , R c2 , R c3 , and R c4 are each independently selected from OH and H.
  • R 1 and R 2 can together form a heterocyclic ring having the formula: wherein R c5 is selected from H, CH 2 OH, CH 3 ;
  • R c6 and R c7 are each independently selected from OH and H;
  • X is selected from a chemical bond or the group CHR c8 , wherein R c8 is selected from OH and H.
  • the relative direction of the substituents in partial depictions as above is retained from the antecedent structure.
  • the flavor modulating compound has the structure depicted below:
  • R 1 and R 2 together form a heterocyclic ring having the formula: wherein R c5 is selected from H, CH 2 OH, CH 3 ;
  • R c6 and R c7 are each independently selected from OH and H;
  • X is selected from a chemical bond or the group CHR c8 , wherein R c8 is selected from OH and H.
  • R 1 and R 2 together form a heterocyclic ring having the formula:
  • R c5 is selected from H, CH 2 OH, CH 3 ;
  • R C6 R C7 and R c8 are each independently selected from OH and H, and the absolute configuration of the spirocyclic atom can be either of the forms depicted above.
  • R 4 is OH
  • R 3 is a heterocyclic ring having the formula: wherein R d1 , R d2 , R d3 , and R d4 are each independently selected from OH and H.
  • R 3 can be a heterocyclic ring having the formula: wherein R d1 , R d2 , R d3 , and R d4 are each independently selected from OH and H.
  • R 3 and R 4 together form a heterocyclic ring having the formula: wherein R d5 is selected from H, CH 2 OH, CH 3 ; R d6 and R d7 are each independently selected from OH and H; X’ is selected from a chemical bond or the group CHR d8 , R d8 is selected from OH and H.
  • R 3 and R 4 together form a heterocyclic ring having the formula: wherein R d5 is selected from H, CH 2 OH, CH 3 ; R d6 and R d7 are each independently selected from OH and H; X’ is selected from a chemical bond or the group CHR d8 , wherein R d8 is selected from OH and H.
  • R 3 and R 4 together form a heterocyclic ring having the formula: wherein R d5 is selected from H, CH 2 OH, CH 3 ; and R d6 , R d7 and R d8 (when present) are each independently selected from OH and H.
  • R 2 and R 3 together form a heterocyclic ring having the formula: wherein R 35 is selected from H, CH 2 OH, CH 3 ; R 36 and R 37 are each independently selected from OH and H; X” is selected from a chemical bond or the group CHR 38 , wherein R d8 is selected from OH and H.
  • R 3 and R 4 together form a heterocyclic ring having the formula: wherein R e5 is selected from H, CH 2 OH, CH 3 ; R e6 and R e7 are each independently selected from OH and H; X” is selected from a chemical bond or the group CHR e8 , wherein R e8 is selected from OH and H.
  • R 3 and R 4 together form a heterocyclic ring having the formula: wherein R e5 is selected from H, CH 2 OH, CH 3 ; R e6 and R e7 are each independently selected from OH and H; X” is selected from a chemical bond or the group CHR e8 , wherein R e8 is selected from OH and H.
  • R 3 and R 4 together form a heterocyclic ring having the
  • R e5 is selected from H, CH 2 OH, CH 3 ;
  • R e6 , R e7 and R e8 are each independently selected from OH and H.
  • R al can be a heterocyclic ring having the formula: wherein R fl , R r2 , R G , and R f4 are each independently selected from OH and H.
  • R al can be: wherein R fl , R r2 , R G , and R f4 are each independently selected from OH and H.
  • R al and R a2 can together form a heterocyclic ring having the formula: wherein R f5 is selected from H, CH 2 OH, CH 3 ; R f6 and R n are each independently selected from OH and H; X’” is selected from a chemical bond or the group CHRTM, wherein R re is selected from OH and H.
  • the absolute configuration of the spirocycle can be one of: wherein R f5 is selected from H, CH 2 OH, CH 3 ; R f6 and R n are each independently selected from OH and H; X’” is selected from a chemical bond or the group CHRTM, wherein R re is selected from OH and H.
  • the second O-heterocycle can have the following stereochemical
  • R f5 is selected from H, CH 2 OH, CH 3 ; R f6 , R n and R re (when present) are each independently selected from OH and H.
  • R a5 is a heterocyclic ring having the formula: wherein R f1 , R r2 , R G , and R f4 are each independently selected from OH and H.
  • R a5 can be:
  • R fl , R 42 , R 43 , and R f4 are each independently selected from OH and H.
  • R a4 and R a5 together form a heterocyclic ring having the formula: wherein R f5 is selected from H, CH 2 OH, CH 3 ; R f6 and R 47 are each independently selected from OH and H; X’” is selected from a chemical bond or the group CHR 48 , wherein R 48 is selected from OH and H.
  • the absolute configuration of the spirocycle can be: wherein R f5 is selected from H, CH 2 OH, CH 3 ; R f6 and R n are each independently selected from OH and H; X’” is selected from a chemical bond or the group CHR 48 , wherein R 48 is selected from OH and H.
  • the second O-heterocycle can have the following stereochemistry:
  • R f5 is selected from H, CH 2 OH, CH 3 ;
  • R f6 , R 76 and R f8 are each independently selected from OH and H.
  • R b1 is a heterocyclic ring having the formula: wherein R f1 , R f2 , R f3 , and R f4 are each independently selecte1d from OH and H.
  • R b1 can be: wherein R f1 , R f2 , R f3 , and R f4 are each independently selected from OH and H.
  • R b1 and R b2 together form a heterocyclic ring having the formula: wherein R f5 is selected from H, CH 2 OH, CH 3 ; R f6 and R G are each independently selected from OH and H; X’” is selected from a chemical bond or the group CHR f8 , wherein R f8 is selected from OH and H.
  • the absolute configuration of the spirocyclic center may have one of the following configurations: wherein R f5 is selected from H, CH 2 OH, CH 3 ; R f6 and R f7 are each independently selected from OH and H; X’ is selected from a chemical bond or the group CHRTM, wherein R f8 is selected from OH and H.
  • the stereochemistry of the second O-heterocycle can be:
  • R f5 is selected from H, CH 2 OH, CH 3 ;
  • R f6 , R f7 and R f8 (when present) are each independently selected from OH and H.
  • R b5 is a heterocyclic ring having the formula: for example, a heterocycle having the formula:
  • R f1 , 1 f2 , R f3 , and R f4 are each independently selected from OH and H.
  • R f3 and R f4 together form a heterocyclic ring having the formula: wherein R f5 is selected from H, CH 2 OH, CH 3 ; R f6 and R 78 are each independently selected from OH and H; X’” is selected from a chemical bond or the group CHR f8 , wherein R f8 is selected from OH and H.
  • the absolute configuration of the spirocyclic atom may be one of the following: wherein R f5 is selected from H, CH 2 OH, CH 3 ; R f6 and R f7 are each independently selected from OH and H; X’ is selected from a chemical bond or the group CHR f8 wherein R f8 is selected from OH and H.
  • the R b4 and R b5 together form a heterocyclic ring having the formula:
  • R f5 is selected from H, CH 2 OH, CH 3 ;
  • R f6 , R f7 and R f8 are each independently selected from OH and H.
  • R a2 is H, OH, OCH3, COOH, OCH2CH3, preferably OH;
  • R a3 is H, OH, OCH3, COOH, OCH2CH3, preferably OH; and
  • R a4 is H, OH, OCH3, COOH, OCH2CH3, preferably OH.
  • one or more of R a2 , R a3 or R a4 is OCH3.
  • R a2 is OCH3;
  • all of R a2 , R a3 and R a4 are OCH3.
  • R b2 is H, OH, OCH 3, COOH, OCH 2 CH 3, preferably OH;
  • Rb3 is H, OH, OCH3, COOH, OCH2CH3, preferably OH;
  • R b4 is H, OH, OCH3, COOH, OCH2CH3, preferably OH.
  • one or more of R b2 , R b3 or R b4 is OCH 3 .
  • R b2 is OCH3;
  • all of R b2 , R b3 and R b4 are OCH3.
  • R al , R a5 , R b1 ,and R b5 are each hydrogen.
  • R c5 is hydrogen
  • R c6 and R c7 are each OH
  • X is CHR c8 and R c8 is OH
  • or X is a bond
  • R c5 is CH2OH
  • R c6 and R c7 are each OH.
  • R d5 is hydrogen
  • R d6 and R d7 are each OH
  • X’ is CHR d8 and R d8 is OH
  • or X’ is a bond
  • R d5 is CH2OH
  • R d6 and R d7 are each OH.
  • R el , R e2 , R e3 , and R e4 are each OH.
  • R fl , R 42 , R 43 , and R f4 are each OH.
  • R e5 is hydrogen
  • R e6 and R e7 are each OH
  • X” is CHR e8 and R e8 is OH.
  • R f5 is hydrogen
  • R f6 and R 47 are each OH
  • X’ is CHR 48 and R 48 is OH
  • X is a bond
  • R e5 is CH 2 OH
  • R e6 and R e7 are each OH
  • X” ’ is a bond
  • R f5 is CH 2 OH
  • R f6 and R 47 are each OH.
  • compositions including the flavor modulating compounds disclosed herein can include at least 1 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 100 mg/kg, at least 250 mg/kg, at least 500 mg/kg, or at least 1,000 mg/kg of the compounds.
  • a composition can include between 1-1,000 mg, between 1-100 mg, between 1-50 mg, between 1-25 mg, between 100- 500 mg, between 500-1,000 mg, between 500-2,500 mg, between 1,000-10,000 mg, of the compounds.
  • a composition can include one or more flavor modulating compounds in an amount of at least 1%, at least 2.5%, at least 5%, at least 7.5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%visor at least 70%, %, at least 80%, or at least 90% the total mass of the composition.
  • the flavor modulating compounds disclosed herein may be prepared by heating a mixture of at least one flavanol and at least one carbohydrate, optionally in the presence of at least one amine, e.g., a primary amine.
  • Suitable primary amines include amino acid, especially natural occurring amino acids, for instance glycine, alanine, leucine, valine, isoleucine, proline, serine, asparagine, cysteine, phenylalanine, tyrosine, aspartic acid, threonine, glutamine, histidine, lysine, arginine, tryptophan, phenylalanine, glutamic acid, or a combination thereof may be favorably employed.
  • the mixture may include a diluent, for instance a solid support like sand, diatomaceous earth, silicates, polymeric resins and the like.
  • the diluent may be a solvent, for example C 1-4 alkyl alcohol (methanol, ethanol, propanols, butanols), propylene glycol, glycerol, and the like.
  • the mixture may also include water.
  • the mixture may include water in an amount of at least 1%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%, by weight relative to the total weight of the mixture.
  • the mixture includes water in an amount of 1-100%, 1-75%, 1-50%, 1-40%, 1-30%, 1-20%, 1-10%, 5-15%, 5-30%, 5-50%, 10-25%, 20-40%, 25-50%, 25-75%, 30-60%, 40-80%, or 50- 100% by weight relative to the total weight of the mixture.
  • the flavanol and carbohydrate may be combined in a molar ratio suitable to produce the flavor modulating compounds.
  • the molar ratio of the flavanol to carbohydrate can be from 25:1 to 1:25, from 25:1 to 1:1, from 25:1 to 10:1, from 10:1 to 1:10, from 10:1 to 1:1, from 10:1 to 5:1, from 5:1 to 1:1, from 5:1 to 1:5, from 2.5:1 to 1:2.5, from 1:1 to 1:25, from 1:10 to 1:25, from 1:1 to 1:10, from 1:1 to 1:5, or from 1:5 to 1:10.
  • the molar ratios refer to the total molar content of the component.
  • the molar ratio of the flavanol to amine component is from 25: 1 to 1:25, from 25:1 to 1:1, from 25:1 to 10:1, from 10:1 to 1:10, from 10:1 to 1:1, from 10:1 to 1:1, from 10:1 to 5:1, from 5:1 to 1:1, from 5:1 to 1:5, from 2.5:1 to 1:25, from 1:1 to 1:25, from 1:10 to 1:25, from 1:1 to 1:10, from 1:1 to 1:5, or from 1:5 to 1:10.
  • the mixture may be heated to a temperature of at least 80° C., at least 100° C., at least 125° C., at least 150° C., at least 175° C., at least 180° C., at least 200° C., or at least 225° C.
  • the mixture is heated for a period of about 5-120 minutes, about 5-100 minutes, about 5-80 minutes, about 5-50 minutes, about 5-25 minutes, about 5-10 minutes, about 10-30 minutes, about 20-80 minutes, or about 50-120 minutes.
  • the heating may be conducted in an inert atmosphere, or under ambient conditions. In some embodiments, the heating maybe conducted under pressure, i.e., sealed tube.
  • the flavanol includes a compound having the formula:
  • R 9 is selected from R a9 , OR a9 , COOR a9 ,
  • R 10 is selected from R a10 , OR a10 , COOR a10 ,
  • R 11 is selected from R a11 , OR a11 , COOR a11 ,
  • R 12 is selected from R a12 , OR a12 , COOR a12 ,
  • R 13 is selected from R a13 , OR a13 , COOR a13 , where any two or more of R 9 , R 10 , R a11 , R a12 , and R 13 may together form a bond;
  • R 14 is selected from R b14 , OR b14 , COOR b14 ,
  • R 15 is selected from R b15 , OR b15 , COOR b15 ,
  • R 16 is selected from R b16 , OR b16 , COOR b16 ,
  • R 17 is selected from R b17 , OR b17 , COOR b17 ,
  • R 18 is selected from R b18 , OR b18 , COOR b18 , here any two or more of R 14 , R 15 , R 16 , R 17 , and R 18 may together form a bond;
  • R a9 , R al °, R al13 , R al2 , R al3 , R b14 , R b15 , R b16 , R b17 , R b18 are independently selected from H, C 1- 8 alkyl, aryl, heterocyclyl, heteroaryl, (-CH 2 CH 2 O) z R peg ), wherein R peg is H, or C 1- 8 alkyl, and z is from 1-100.
  • the flavanol can be a compound having the formula:
  • the flavanol can be stereochemically pure, as defined above, or can be a mixture of two or more stereoisomers.
  • R 5 and R 7 are hydrogen and R 6 and R 8 are OH.
  • the carbohydrate component can include a compound having the formula: wherein R x6 , R x4 , and R x3 are each independently selected from hydrogen and OH, z is 1 or 0, and either R x2 is selected from H and OH and R x2 is H, or R x2 and R x2 ’ together form a carbonyl, are each independently selected from hydrogen and OH.
  • R x6 , R x4 , and R x3 are each independently selected from hydrogen and OH, z is 1 or 0, and either R x2 is selected from H and OH and R x2 is H, or R x2 and R x2 ’ together form a carbonyl, are each independently selected from hydrogen and OH.
  • the carbohydrate can also exist in a tautomeric cyclic form.
  • the carbohydrate can have the formula:
  • Exemplary carbohydrates include those wherein R x6 , R x4 , R x3 , and R x2 are OH, R x2 is H, and z is 1, or R x6 is hydrogen, R x4 , R x3 , and R x2 are OH, R x2 is H, and z is 1, or R x2 and R x2 are each hydrogen, Rx 6 , R x4 , and R x3 are OH, and z is 1, or R x2 and R x2 together form a carbonyl, Rx 6 , R x4 , and R x3 are OH, and z is 1, or R x2 and R x2 together form a carbonyl, and R x6 is H, R x4 and R x3 are OH, and z is 1, or R x2 and R x2 together form a carbonyl, and R x6 is H, R x4 and R x3 are OH, and
  • exemplary articles include consumables, e.g., a food product or beverage, pharmaceuticals, and adhesives.
  • the method includes the step of combining the article with a flavor modulating compound, for example at a treatment rate of at least 1 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 100 mg/kg, at least 250 mg/kg, at least 500 mg/kg, or at least 1,000 mg/kg of the compounds, relative to the total weight of the article.
  • a flavor modulating compound for example at a treatment rate of at least 1 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 100 mg/kg, at least 250 mg/kg, at least 500 mg/kg, or at least 1,000 mg/kg of the compounds, relative to the total weight of the article.
  • the compositions disclosed herein are suitable for combining with target articles.
  • Exemplary food products and beverages include coffees, vegetables, yogurts, grains, e.g., a whole grain, beers, wines, distilled spirits, cocoas, fruits, and vegetables, especially cruciferous vegetables.
  • the sugars D-glucose (GLU), D-galactose (GAL); the amino acids glycine (GLY), alanine (ALA), proline (PRO), cysteine (CYS), tyrosine (TYR), serine (SER), phenylalanine (PHE), asparagine (ASN); and methyl-parabens (methyl 4-hydroxybenzoate) were obtained in food grade quality and high-purity (>98.5%) from Sigma Aldrich Co. (St Louis, MO, USA).
  • the bitter phenolic compounds (-)-epigallocatechin gallate (EGCg) and (-)-epicatechin gallate (ECg) were obtained in food-grade quality and high-purity (98% and 95% respectively) from Erbium Oxide, Easchem (China).
  • the organic solvents methanol and acetone; formic acid (FA) and hydrochloric acid (HC1, 32 wt. % in water) used in UPLC and Prep-LC were obtained in food-grade quality and LC grade (Optima®) from Fisher Chemical (Fisher Scientific, Fair Lawn, NJ, USA).
  • the quartz sand used for Maillard reactions was obtained from Fisher Chemical (Fisher Scientific, Fair Lawn, NJ, USA).
  • Deuterium oxide (D2O, 99.9 atom % D) and deuterated formic acid (DCO2H, 95 wt. % in water, 98 atom % D) for NMR analysis were obtained from Sigma Aldrich Co. (St Louis, MO, USA).
  • the nanopure water at resistivity 18.2 M ⁇ -cm was obtained with distilled deionized water and a purification system (Nanopure Diamond, Barnstead, Thermo Scientific, Dubuque, IA, USA).
  • Maillard reactions were conducted with the phenolic compound (-)-epigallocatechin gallate (EGCg); one of the amino acids catalyst glycine (GLY), alanine (ALA), proline (PRO), cysteine (CYS), tyrosine (TYR), serine (SER), phenylalanine (PHE) or asparagine (ASN); and one of the sugars D-glucose (GLU) or D-galactose (GAL).
  • GLY glycine
  • ALA alanine
  • PRO proline
  • PRO cysteine
  • TMR tyrosine
  • SE serine
  • PHE phenylalanine
  • ASN asparagine
  • GLU sugars D-glucose
  • GAL D-galactose
  • Set up 1 consisted of a circular hotplate stirrer topped with a reaction block with 17 vial holes spaced to perform multiple simultaneous reactions. Reaction vials of 40 mL with a pressure relief cap were used for the Maillard reaction. The temperature was tracked with one probe for the reaction block and one thermocouple thermometer (VWR® Traceable® Expanded Range Thermometer, VWR International) with two probes placed in the Maillard mixture at the bottom of the vial.
  • VWR® Traceable® Expanded Range Thermometer VWR International
  • Maillard reactions were performed with several experimental variables described in Table 1. These optimization reaction tests were run in duplicate and will be compared against a previously described reaction control (Jiang et al., 2009; Zhang et al., 2014). For a continuous reaction, all reactants (i.e.
  • phenolic, amino acid, and sugar were mixed with 2.5 g of quartz sand using a ball grinder (2010 Geno/Grinder, 1000 rpm, 10 min) prior to placing into a reaction vial. Then, the nanopure water was added before the reaction run. For a stepwise reaction, the amino acid and sugar were mixed with the quartz sand as previously described, before placing it into the reaction vial. Then, nanopure water was added before the reaction step 1 proceeded under a targeted temperature between 80-150°C and for a short time (5 or 10 min). Then, the phenolic EGCg was added to the reaction vial to proceed to reaction step 2 at 150°C for 15 min. Reactions were quenched using an ice bath after completion.
  • phenolic, amino compound, and sugar were mixed using a ball grinder (2010 Geno/Grinder) at 1000 rpm during 10 min.
  • the resultant mixture was placed in the reaction flask with nanopure water to attain appropriate moisture and then stirred for 3-5 min to homogenize the mixture. Reactions were quenched using an ice bath after completion.
  • reaction products were isolated from the whole Maillard reaction mixture by three cycles of solvent extraction with 10 mL of methanol/nanopure water mixture (2: 1 v/v, with 0.1% FA, pH 3) enriched with methyl-paraben as an internal standard (240 ⁇ g/mL).
  • the fractions obtained from the three repetitions of extraction were pooled and further centrifuged for 10 min at 6832 x g and 12°C (AllegraTMX-22R Centrifuge, Beckman Coulter, Rotor F0685).
  • the reaction products were isolated by four cycles of solvent extraction using 20 mL of the solvent mixture as previously described and enriched with methyl-paraben (360 pg/mL). The four fractions obtained were then pooled and centrifuged (10 min, 10000 rpm, 12°C). To control the production yield of each blocker, for both small and large-scale reactions, a sample of centrifuged supernatant was diluted at 1 :5 and 1 :9 respectively in nanopure acidified water (0.1% FA, pH 3) and then filtered through a 0.2 ⁇ g Nylon tip filter (Fisher Scientific) before UPLC-UV-MS analysis. The reaction was monitored using blockers ion peak area corrected by the internal standard methyl-paraben.
  • the centrifuged supernatant was subjected to ultrafiltration using a 5 kDa NMW cellulose regenerated membrane (Amicon®, EMD Millipore Sigma, USA) to clean sample from non-desirable big particles.
  • the permeate was dried under vacuum with a rotary evaporator and freeze-dried twice.
  • the solid powder was then recovered in solvent extraction using the appropriate mixture of solvents (nanopure water, methanol or acetone, 0.1% FA) and filtered through a 0.2 ⁇ g Nylon tip filter before Prep-LC fractionation.
  • a sensory analysis was carried out to evaluate the bitterness modulation properties of the BLK-10 and BLK-4 (as well as unmodified against caffeine.
  • the control sample was prepared using a caffeine solution at 265 pg/mL (0.3%o HC1, pH 4) whereas the treatment sample was prepared using a caffeine solution (265 pg/mL, 0.3%o HC1, pH 4) with the addition of one potential blocker in a molar ratio of 1 :5 or 1 : 10 against caffeine (blocker: caffeine).
  • compositions and methods of the appended claims are not limited in scope by the specific compositions and methods described herein, which are intended as illustrations of a few aspects of the claims and any compositions and methods that are functionally equivalent are intended to fall within the scope of the claims.
  • Various modifications of the compositions and methods in addition to those shown and described herein are intended to fall within the scope of the appended claims.

Abstract

Disclosed are compounds and compositions for modulating flavors, for example reducing bitterness in food products. Disclosed are flavonol derivatives containing at least one C-glycoside and/or spiroglycoside. The flavanol derivatives may be obtained by subjecting a mixture of flavanols, sugars, and amino acids to conditions suitable to promote a Maillard reaction.

Description

FLAVOR MODULATING COMPOUNDS AND COMPOSITIONS
CROSS-REFERENCE TO RELATED APPLICATION
The application claims the benefit of U.S. Provisional Application 63/123,283, filed on December 9, 2020, the contents of which are hereby incorporated in its entirety.
FIELD OF THE INVENTION
The invention is directed to compounds and compositions useful to modulate the flavors, for instance in consumables, pharmaceuticals, adhesives, and the like. In an embodiment, the compounds and compositions are useful to reduce bitterness in food products. In an embodiment, the compounds and compositions include one or more flavan-3- ol derivatives.
BACKGROUND
There are five primary tastes perceived by the human tongue: salt, sour, sweet, bitter, and umami (i.e., savory). Many people consider the bitter sensation to be unpleasant, and it is speculated that the ability to sense bitterness evolved as an avoidance mechanism against toxic plants and animals. Nevertheless, many foods with high nutritional value, for instance cruciferous vegetables, whole grain foods, and cranberries, also have bitter flavors. These foods are often prepared with high levels of fats, sugars, and/or salts in order to mask the bitterness. Although these additives increase the palatability of the nutritious foods, excess consumption of fat, sugar, and salt is considered unhealthy. As an alternative, bitter blocking compounds having been developed as an additive for foods and vegetables. However, different foods have different distributions of bitter compounds, and many additives only block a subset of bitter flavors.
There remains a need for novel compounds that block the bitter sensations in consumables like foods and beverages. The remains a need for compounds that modulate the flavors of foods and beverages. There remains a need for novel compounds that block the bitter sensations in pharmaceutical products. The remains a need for compounds that modulate the flavors of pharmaceuticals. There remains a need for palatable foodstuffs with reduced sugar and salt additives. SUMMARY
Disclosed herein are flavor-modulating and/or bitter blocking compounds having the formula:
Figure imgf000004_0001
wherein the R groups are as defined herein. Also disclosed are methods of preparing flavor modulating and/or bitter blocking compounds by reaction of a flavanol with one or more carbohydrates.
Additional advantages will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the aspects described below. The advantages described below will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive.
The details of one or more embodiments are set forth in the descriptions below. Other features, objects, and advantages will be apparent from the description and from the claims.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 depicts the effectiveness of disclosed compounds to suppress the bitterness in caffeine solutions.
DETAILED DESCRIPTION
Before the present methods and systems are disclosed and described, it is to be understood that the methods and systems are not limited to specific synthetic methods, specific components, or to particular compositions. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes-1 from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
“Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
Throughout the description and claims of this specification, the word “comprise” and variations of the word, such as “comprising” and “comprises,” means “including but not limited to,” and is not intended to exclude, for example, other additives, components, integers or steps. “Exemplary” means “an example of’ and is not intended to convey an indication of a preferred or ideal embodiment. “Such as” is not used in a restrictive sense, but for explanatory purposes.
Disclosed are components that can be used to perform the disclosed methods and systems. These and other components are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these components are disclosed that while specific reference of each various individual and collective combinations and permutation of these may not be explicitly disclosed, each is specifically contemplated and described herein, for all methods and systems. This applies to all aspects of this application including, but not limited to, steps in disclosed methods. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the disclosed methods. The term “alkyl” as used herein is a branched or unbranched hydrocarbon group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, and the like. The alkyl group can also be substituted or unsubstituted. Unless stated otherwise, the term “alkyl” contemplates both substituted and unsubstituted alkyl groups. The alkyl group can be substituted with one or more groups including, but not limited to, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, or thiol. An alkyl group which contains no double or triple carbon-carbon bonds is designated a saturated alkyl group, whereas an alkyl group having one or more such bonds is designated an unsaturated alkyl group. Unsaturated alkyl groups having a double bond can be designated alkenyl groups, and unsaturated alkyl groups having a triple bond can be designated alkynyl groups. Unless specified to the contrary, the term alkyl embraces both saturated and unsaturated groups.
The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The term “heterocycloalkyl” is a cycloalkyl group as defined above where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, selenium or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. Unless stated otherwise, the terms “cycloalkyl” and “heterocycloalkyl” contemplate both substituted and unsubstituted cyloalkyl and heterocycloalkyl groups. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, or thiol. A cycloalkyl group which contains no double or triple carboncarbon bonds is designated a saturated cycloalkyl group, whereas an cycloalkyl group having one or more such bonds (yet is still not aromatic) is designated an unsaturated cycloalkyl group. Unless specified to the contrary, the term cycloalkyl embraces both saturated and unsaturated, non-aromatic, ring systems.
The term “aryl” as used herein is an aromatic ring composed of carbon atoms. Examples of aryl groups include, but are not limited to, phenyl and naphthyl, etc. The term “heteroaryl” is an aryl group as defined above where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, selenium or phosphorus. The aryl group and heteroaryl group can be substituted or unsubstituted. Unless stated otherwise, the terms “aryl” and “heteroaryl” contemplate both substituted and unsubstituted aryl and heteroaryl groups. The aryl group and heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, or thiol.
Exemplary heteroaryl and heterocyclyl rings include: benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH carbazolyl, carbolinyl, chromanyl, chromenyl, cirmolinyl, decahydroquinolinyl, 2H,6H~ 1,5,2-dithiazinyl, dihydrofuro[2,3 b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, IH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-l,2,5-thiadiazinyl, 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thi enoimidazolyl, thiophenyl, and xanthenyl.
The terms “alkoxy,” “cycloalkoxy,” “heterocycloalkoxy,” “cycloalkoxy,” “aryloxy,” and “heteroaryloxy” have the aforementioned meanings for alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, further providing said group is connected via an oxygen atom.
As used herein, the term “null,” when referring to a possible identity of a chemical moiety, indicates that the group is absent, and the two adjacent groups are directly bonded to one another. By way of example, for a genus of compounds having the formula CH3-X-CH3, if X is null, then the resulting compound has the formula CH3-CH3.
It will be appreciated that certain compounds according to the invention may contain one or more centers of asymmetry and may therefore be prepared and isolated as a mixture of isomers such as a racemic or diastereomeric mixture, or in an enantiomerically or diastereomerically pure form. In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined. However, the depiction of a compound without specifying the absolute configuration of an asymmetric center should not be taken as requiring all possible isomers are necessarily present in every embodiment.
Certain compounds of the invention will include ionizable functional groups, including carboxylic acids, sulfonic acids, phosphonic acids, amines, and the like. The skilled person will understand that such groups will contain, or will not contain, an ionizable hydrogen atom depending on pH. Depiction of a particular compound in one state of ionization (e.g., protonated) does not exclude other states (e.g., deprotonated) that would exist at different pH.
Acceptable salts are salts that retain the desired flavor modulatingl activity of the parent compound and do not impart undesirable toxicological effects. Examples of such salts are acid addition salts formed with inorganic acids, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids and the like; salts formed with organic acids such as acetic, oxalic, tartaric, succinic, maleic, fumaric, gluconic, citric, malic, methanesulfonic, p- toluenesulfonic, napthalenesulfonic, and polygalacturonic acids, and the like; salts formed from elemental anions such as chloride, bromide, and iodide; salts formed from metal hydroxides, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, and magnesium hydroxide; salts formed from metal carbonates, for example, sodium carbonate, potassium carbonate, calcium carbonate, and magnesium carbonate; salts formed from metal bicarbonates, for example, sodium bicarbonate and potassium bicarbonate; salts formed from metal sulfates, for example, sodium sulfate and potassium sulfate; and salts formed from metal nitrates, for example, sodium nitrate and potassium nitrate. Acceptable salts may be prepared using procedures well known in the art, for example, by reacting a sufficiently basic compound such as an amine with a suitable acid comprising a physiologically acceptable anion. Alkali metal (for example, sodium, potassium, or lithium) or alkaline earth metal (for example, calcium) salts of carboxylic acids can also be made.
In some embodiments reference is made to various carbohydrate compounds. As used here, the depiction of a reducing sugar, e.g., a cyclic compound having a hemiacetal, is understood to also include the linear tautomer of the compound as well, and vice versa:
Figure imgf000009_0001
Disclosed herein are flavor-modulating compounds having the formula:
Figure imgf000009_0002
and acceptable salts thereof, wherein
Ra1 is selected from Raa1, ORaa1, COORaa1, a heterocyclic ring having at least one oxygen, or together forms a heterocyclic ring with Ra2, said ring further spiro- substituted by a heterocyclic ring having at least one oxygen;
Ra5 is selected from Raa5, ORaa5, COORaa5, a heterocyclic ring having at least one oxygen, or together forms a heterocyclic ring with Ra4, said ring further spiro- substituted by a heterocyclic ring having at least one oxygen;
Ra3 is selected from Raa3, ORaa3, COORaa3;
Ra2, when not forming a heterocycle with R31, is selected from Raa2, ORaa2, COORaa2;
Ra4, when not forming a heterocycle with Ra5, is selected from Raa4, ORaa4, COORaa4; where any two or more of Raa1, Raa2, Raa3, Raa4, and Raa5 may together form a bond;
Rb1 is selected from Rbb1, ORbb1, COORbb1, a heterocyclic ring having at least one oxygen, or together forms a heterocyclic ring with Rb2, said ring further spiro- substituted by a heterocyclic ring having at least one oxygen;
Rb5 is selected from Rbb5, ORbb5, COORbb5, a heterocyclic ring having at least one oxygen, or together forms a heterocyclic ring with Rb4, said ring further spiro- substituted by a heterocyclic ring having at least one oxygen;
Rb3 is selected from Rbb3, ORbb3, COORbb3;
Rb2, when not forming a heterocycle with Rb1, is selected from Rbb2, ORbb2, COORbb2;
Rb4, when not forming a heterocycle with Rb5, is selected from Rbb4, ORbb4, COORbb4; where any two or more of Rbb1, Rbb2, Rbb3, Rbb4, and Rbb5 may together form a bond; at least one of R1 and R3 is a heterocyclic ring having at least one oxygen, or forms a heterocyclic ring with one of R2 and R4, said ring further spiro-substituted by a heterocyclic ring having at least one oxygen, and when R1 and R2 is not part of a heterocyclic ring system, then R1 and R2 is hydrogen, provided that not both of R1 and
R2 is hydrogen; when R2 is not part of a heterocyclic ring system, is selected from R2 , OR2 , COOR2 ; when R4 is not part of a heterocyclic ring system, is selected from R4 , OR4 , COOR4 ; and
Raai, Raa2, Raa3 Raa4, Raa5, Rbb1, Rbb2, Rbb3, Rbb4, Rbb5, R2 , and R3 , are independently selected from H, Ci-salkyl, aryl, heterocyclyl, heteroaryl, (-CH2CH2O)zRpeg, wherein Rpeg is H, or Ci-salkyl, and z is from 1-100.
In certain preferred embodiment, neither R1 nor R3 are hydrogen.
The flavor modulating compounds can have one of the specific stereochemical configurations:
Figure imgf000010_0001
stereoisomer, while in other embodiments, a mixture of stereoisomers may be used to modulate flavors. As used herein, when any compound disclosed herein is designated a single stereoisomer, the stereochemical purity may be such that at least 80%, at least 85%, at least of 90%, at least 95%, at least 97.5%, or at least 99% of the compound is of the depicted stereochemistry, the remainder being other stereoisomeric forms. In some embodiments, wherein R2 can be OH, and R1 is a heterocyclic ring having the formula:
Figure imgf000011_0001
wherein Rcl, Rc2, Rc3, and Rc4 are each independently selected from OH and H. As used throughout this application, the wavy line indicates the bond to the other portion of the compound.
In some embodiments, R1 is a heterocyclic ring having the formula:
Figure imgf000011_0002
Figure imgf000012_0001
wherein Rcl, Rc2, Rc3, and Rc4 are each independently selected from OH and H.
In other embodiments, R1 and R2 can together form a heterocyclic ring having the formula:
Figure imgf000012_0002
wherein Rc5 is selected from H, CH2OH, CH3;
Rc6 and Rc7 are each independently selected from OH and H;
X is selected from a chemical bond or the group CHRc8, wherein Rc8 is selected from OH and H.
As used throughout this disclosure, the relative direction of the substituents in partial depictions as above is retained from the antecedent structure. By way of example, when R1 and R2 form the spirocyclic system shown above, the flavor modulating compound has the structure depicted below:
Figure imgf000013_0001
In some embodiments, R1 and R2 together form a heterocyclic ring having the formula:
Figure imgf000013_0002
wherein Rc5 is selected from H, CH2OH, CH3;
Rc6 and Rc7 are each independently selected from OH and H;
X is selected from a chemical bond or the group CHRc8, wherein Rc8 is selected from OH and H.
In some embodiments, R1 and R2 together form a heterocyclic ring having the formula:
Figure imgf000014_0001
wherein Rc5 is selected from H, CH2OH, CH3;
RC6 RC7 and Rc8 (when present) are each independently selected from OH and H, and the absolute configuration of the spirocyclic atom can be either of the forms depicted above.
In certain embodiments, R4 is OH, and R3 is a heterocyclic ring having the formula:
Figure imgf000014_0002
wherein Rd1, Rd2, Rd3, and Rd4 are each independently selected from OH and H. For example,
R3 can be a heterocyclic ring having the formula:
Figure imgf000015_0001
wherein Rd1, Rd2, Rd3, and Rd4 are each independently selected from OH and H.
In other embodiments, R3 and R4 together form a heterocyclic ring having the formula:
Figure imgf000015_0002
wherein Rd5 is selected from H, CH2OH, CH3; Rd6 and Rd7 are each independently selected from OH and H; X’ is selected from a chemical bond or the group CHRd8, Rd8 is selected from OH and H. In some embodiments, R3 and R4 together form a heterocyclic ring having the formula:
Figure imgf000016_0001
wherein Rd5 is selected from H, CH2OH, CH3; Rd6 and Rd7 are each independently selected from OH and H; X’ is selected from a chemical bond or the group CHRd8, wherein Rd8 is selected from OH and H. For example, R3 and R4 together form a heterocyclic ring having the formula:
Figure imgf000016_0002
wherein Rd5 is selected from H, CH2OH, CH3; and Rd6, Rd7 and Rd8 (when present) are each independently selected from OH and H.
In other embodiments, R2 and R3 together form a heterocyclic ring having the formula:
Figure imgf000017_0001
wherein R35 is selected from H, CH2OH, CH3; R36 and R37 are each independently selected from OH and H; X” is selected from a chemical bond or the group CHR38, wherein Rd8 is selected from OH and H.
In some embodiments, R3 and R4 together form a heterocyclic ring having the formula:
Figure imgf000017_0002
wherein Re5 is selected from H, CH2OH, CH3; Re6 and Re7 are each independently selected from OH and H; X” is selected from a chemical bond or the group CHRe8, wherein Re8 is selected from OH and H. For example, R3 and R4 together form a heterocyclic ring having the
Figure imgf000017_0003
Figure imgf000018_0001
wherein Re5 is selected from H, CH2OH, CH3; Re6, Re7 and Re8 (when present) are each independently selected from OH and H.
In certain embodiments, Ral can be a heterocyclic ring having the formula:
Figure imgf000018_0002
wherein Rfl, Rr2, RG, and Rf4 are each independently selected from OH and H. For example, Ral can be:
Figure imgf000019_0001
wherein Rfl, Rr2, RG, and Rf4 are each independently selected from OH and H.
In some instances Ral and Ra2 can together form a heterocyclic ring having the formula:
Figure imgf000019_0002
wherein Rf5 is selected from H, CH2OH, CH3; Rf6 and Rn are each independently selected from OH and H; X’” is selected from a chemical bond or the group CHR™, wherein Rre is selected from OH and H. The absolute configuration of the spirocycle can be one of:
Figure imgf000020_0001
wherein Rf5 is selected from H, CH2OH, CH3; Rf6 and Rn are each independently selected from OH and H; X’” is selected from a chemical bond or the group CHR™, wherein Rre is selected from OH and H. The second O-heterocycle can have the following stereochemical
Figure imgf000020_0002
Figure imgf000021_0001
wherein Rf5 is selected from H, CH2OH, CH3; Rf6, Rn and Rre (when present) are each independently selected from OH and H. In some embodiments, Ra5 is a heterocyclic ring having the formula:
Figure imgf000021_0002
wherein Rf1, Rr2, RG, and Rf4 are each independently selected from OH and H. For example,
Ra5 can be:
Figure imgf000021_0003
Figure imgf000022_0001
wherein Rfl, R42, R43, and Rf4 are each independently selected from OH and H.
In other embodiments, Ra4 and Ra5 together form a heterocyclic ring having the formula:
Figure imgf000022_0002
wherein Rf5 is selected from H, CH2OH, CH3; Rf6 and R47 are each independently selected from OH and H; X’” is selected from a chemical bond or the group CHR48, wherein R48 is selected from OH and H. The absolute configuration of the spirocycle can be:
Figure imgf000022_0003
wherein Rf5 is selected from H, CH2OH, CH3; Rf6 and Rn are each independently selected from OH and H; X’” is selected from a chemical bond or the group CHR48, wherein R48 is selected from OH and H. For example, the second O-heterocycle can have the following stereochemistry:
Figure imgf000023_0002
wherein Rf5 is selected from H, CH2OH, CH3; Rf6, R76 and Rf8 (when present) are each independently selected from OH and H.
In some embodiments, Rb1 is a heterocyclic ring having the formula:
Figure imgf000023_0001
wherein Rf1, Rf2, Rf3, and Rf4 are each independently selecte1d from OH and H. For example, Rb1 can be:
Figure imgf000024_0001
wherein Rf1, Rf2, Rf3, and Rf4 are each independently selected from OH and H.
In some embodiments, Rb1 and Rb2 together form a heterocyclic ring having the formula:
Figure imgf000024_0002
wherein Rf5 is selected from H, CH2OH, CH3; Rf6 and RG are each independently selected from OH and H; X’” is selected from a chemical bond or the group CHRf8, wherein Rf8 is selected from OH and H. The absolute configuration of the spirocyclic center may have one of the following configurations:
Figure imgf000025_0001
wherein Rf5 is selected from H, CH2OH, CH3; Rf6 and Rf7 are each independently selected from OH and H; X’ is selected from a chemical bond or the group CHR™, wherein Rf8 is selected from OH and H. For example, the stereochemistry of the second O-heterocycle can be:
Figure imgf000025_0002
Figure imgf000026_0001
wherein Rf5 is selected from H, CH2OH, CH3; Rf6, Rf7 and Rf8 (when present) are each independently selected from OH and H. In some embodiments, Rb5 is a heterocyclic ring having the formula:
Figure imgf000026_0002
for example, a heterocycle having the formula:
Figure imgf000026_0003
Figure imgf000027_0001
wherein Rf1, 1f2, Rf3, and Rf4 are each independently selected from OH and H.
In some embodiments, Rf3 and Rf4 together form a heterocyclic ring having the formula:
Figure imgf000027_0002
wherein Rf5 is selected from H, CH2OH, CH3; Rf6 and R78 are each independently selected from OH and H; X’” is selected from a chemical bond or the group CHRf8, wherein Rf8 is selected from OH and H. The absolute configuration of the spirocyclic atom may be one of the following:
Figure imgf000027_0003
wherein Rf5 is selected from H, CH2OH, CH3; Rf6 and Rf7 are each independently selected from OH and H; X’ is selected from a chemical bond or the group CHRf8 wherein Rf8 is selected from OH and H. For example, the Rb4 and Rb5 together form a heterocyclic ring having the formula:
Figure imgf000028_0001
wherein Rf5 is selected from H, CH2OH, CH3; Rf6, Rf7 and Rf8 (when present) are each independently selected from OH and H.
In some embodiments, Ra2 is H, OH, OCH3, COOH, OCH2CH3, preferably OH; Ra3 is H, OH, OCH3, COOH, OCH2CH3, preferably OH; and Ra4 is H, OH, OCH3, COOH, OCH2CH3, preferably OH. In other embodiments, one or more of Ra2, Ra3 or Ra4 is OCH3. For example, Ra2 is OCH3; Ra3 is OCH3; or Ra4 is OCH3. In an embodiment, all of Ra2, Ra3 and Ra4 are OCH3. In some embodiments, Rb2 is H, OH, OCH3, COOH, OCH2CH3, preferably OH; Rb3 is H, OH, OCH3, COOH, OCH2CH3, preferably OH; and Rb4 is H, OH, OCH3, COOH, OCH2CH3, preferably OH. In other embodiments, one or more of Rb2, Rb3 or Rb4 is OCH3. For example, Rb2 is OCH3; Rb3 is OCH3; or Rb4 is OCH3. In an embodiment, all of Rb2, Rb3 and Rb4 are OCH3.
In certain embodiments, Ral, Ra5 , Rb1 ,and Rb5 are each hydrogen.
In some preferred embodiments, Rc5 is hydrogen, Rc6 and Rc7 are each OH, X is CHRc8 and Rc8 is OH, or X is a bond, Rc5 is CH2OH, and Rc6 and Rc7 are each OH.
In some preferred embodiments, Rd5 is hydrogen, Rd6 and Rd7 are each OH, X’ is CHRd8 and Rd8 is OH, or X’ is a bond, Rd5 is CH2OH, and Rd6 and Rd7 are each OH.
In some preferred embodiments, Rel, Re2, Re3, and Re4 are each OH.
In some preferred embodiments, Rfl, R42, R43, and Rf4 are each OH.
In some preferred embodiments, Re5 is hydrogen, Re6 and Re7 are each OH, X” is CHRe8 and Re8 is OH.
In some preferred embodiments, Rf5 is hydrogen, Rf6 and R47 are each OH, X’” is CHR48 and R48 is OH, or X” is a bond, Re5 is CH2OH, and Re6 and Re7 are each OH, or X” ’ is a bond, Rf5 is CH2OH, and Rf6 and R47 are each OH.
Also disclosed are compositions including the flavor modulating compounds disclosed herein. A composition can include at least 1 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 100 mg/kg, at least 250 mg/kg, at least 500 mg/kg, or at least 1,000 mg/kg of the compounds. In some embodiments, a composition can include between 1-1,000 mg, between 1-100 mg, between 1-50 mg, between 1-25 mg, between 100- 500 mg, between 500-1,000 mg, between 500-2,500 mg, between 1,000-10,000 mg, of the compounds. In yet further embodiments, a composition can include one or more flavor modulating compounds in an amount of at least 1%, at least 2.5%, at least 5%, at least 7.5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%„ at least 70%, %, at least 80%, or at least 90% the total mass of the composition.
The flavor modulating compounds disclosed herein may be prepared by heating a mixture of at least one flavanol and at least one carbohydrate, optionally in the presence of at least one amine, e.g., a primary amine. Suitable primary amines include amino acid, especially natural occurring amino acids, for instance glycine, alanine, leucine, valine, isoleucine, proline, serine, asparagine, cysteine, phenylalanine, tyrosine, aspartic acid, threonine, glutamine, histidine, lysine, arginine, tryptophan, phenylalanine, glutamic acid, or a combination thereof may be favorably employed. Other suitable primary amines include short chain peptides. The mixture may include a diluent, for instance a solid support like sand, diatomaceous earth, silicates, polymeric resins and the like. In other examples, the diluent may be a solvent, for example C1-4alkyl alcohol (methanol, ethanol, propanols, butanols), propylene glycol, glycerol, and the like.
The mixture may also include water. For instance, the mixture may include water in an amount of at least 1%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%, by weight relative to the total weight of the mixture. In some embodiments, the mixture includes water in an amount of 1-100%, 1-75%, 1-50%, 1-40%, 1-30%, 1-20%, 1-10%, 5-15%, 5-30%, 5-50%, 10-25%, 20-40%, 25-50%, 25-75%, 30-60%, 40-80%, or 50- 100% by weight relative to the total weight of the mixture.
The flavanol and carbohydrate may be combined in a molar ratio suitable to produce the flavor modulating compounds. For example, the molar ratio of the flavanol to carbohydrate can be from 25:1 to 1:25, from 25:1 to 1:1, from 25:1 to 10:1, from 10:1 to 1:10, from 10:1 to 1:1, from 10:1 to 5:1, from 5:1 to 1:1, from 5:1 to 1:5, from 2.5:1 to 1:2.5, from 1:1 to 1:25, from 1:10 to 1:25, from 1:1 to 1:10, from 1:1 to 1:5, or from 1:5 to 1:10. In embodiments in which carbohydrate component contains more than one carbohydrate, or flavanol component contains more than one flavanol, the molar ratios refer to the total molar content of the component.
When present, the molar ratio of the flavanol to amine component is from 25: 1 to 1:25, from 25:1 to 1:1, from 25:1 to 10:1, from 10:1 to 1:10, from 10:1 to 1:1, from 10:1 to 5:1, from 5:1 to 1:1, from 5:1 to 1:5, from 2.5:1 to 1:25, from 1:1 to 1:25, from 1:10 to 1:25, from 1:1 to 1:10, from 1:1 to 1:5, or from 1:5 to 1:10.
The mixture may be heated to a temperature of at least 80° C., at least 100° C., at least 125° C., at least 150° C., at least 175° C., at least 180° C., at least 200° C., or at least 225° C. The mixture is heated for a period of about 5-120 minutes, about 5-100 minutes, about 5-80 minutes, about 5-50 minutes, about 5-25 minutes, about 5-10 minutes, about 10-30 minutes, about 20-80 minutes, or about 50-120 minutes. The heating may be conducted in an inert atmosphere, or under ambient conditions. In some embodiments, the heating maybe conducted under pressure, i.e., sealed tube.
In some embodiments, the flavanol includes a compound having the formula:
Figure imgf000031_0001
R9 is selected from Ra9, ORa9, COORa9,
R10 is selected from Ra10, ORa10, COORa10,
R11 is selected from Ra11, ORa11, COORa11,
R12 is selected from Ra12, ORa12, COORa12,
R13 is selected from Ra13, ORa13, COORa13, where any two or more of R9, R10, Ra11, Ra12, and R13 may together form a bond;
R14 is selected from Rb14, ORb14, COORb14,
R15 is selected from Rb15, ORb15, COORb15,
R16 is selected from Rb16, ORb16, COORb16,
R17 is selected from Rb17, ORb17, COORb17,
R18 is selected from Rb18, ORb18, COORb18, here any two or more of R14, R15, R16, R17, and R18 may together form a bond;
Ra9, Ral°, Ral13, Ral2, Ral3, Rb14, Rb15, Rb16, Rb17, Rb18, are independently selected from H, C1- 8alkyl, aryl, heterocyclyl, heteroaryl, (-CH2CH2O)zRpeg), wherein Rpeg is H, or C1- 8alkyl, and z is from 1-100.
In some embodiments, the flavanol can be a compound having the formula:
Figure imgf000032_0001
The flavanol can be stereochemically pure, as defined above, or can be a mixture of two or more stereoisomers. In a preferred embodiment, R5 and R7 are hydrogen and R6 and R8 are OH.
The carbohydrate component can include a compound having the formula:
Figure imgf000032_0002
wherein Rx6, Rx4, and Rx3 are each independently selected from hydrogen and OH, z is 1 or 0, and either Rx2 is selected from H and OH and Rx2 is H, or Rx2 and Rx2’ together form a carbonyl, are each independently selected from hydrogen and OH. Although not depicted, the carbohydrate can also exist in a tautomeric cyclic form.
In some embodiments, the carbohydrate can have the formula:
Figure imgf000033_0001
Exemplary carbohydrates include those wherein Rx6, Rx4, Rx3, and Rx2 are OH, Rx2 is H, and z is 1, or Rx6 is hydrogen, Rx4, Rx3, and Rx2 are OH, Rx2 is H, and z is 1, or Rx2 and Rx2 are each hydrogen, Rx6, Rx4, and Rx3 are OH, and z is 1, or Rx2 and Rx2 together form a carbonyl, Rx6, Rx4, and Rx3 are OH, and z is 1, or Rx2 and Rx2 together form a carbonyl, and Rx6 is H, Rx4 and Rx3 are OH, and z is 1, or Rx2 and Rx2 together form a carbonyl, and Rx4 is H, Rx6 and Rx3 are OH, and z is 1, or Rx2 and Rx2 together form a carbonyl, and Rx3 is H, Rx4 and Rx6 are OH, and z is 1. Disclosed herein are compounds having the formula:
Figure imgf000033_0002
Figure imgf000033_0003
Figure imgf000034_0001
Also disclosed herein are method for modulating flavor in an article in need thereof. Exemplary articles include consumables, e.g., a food product or beverage, pharmaceuticals, and adhesives. The method includes the step of combining the article with a flavor modulating compound, for example at a treatment rate of at least 1 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 100 mg/kg, at least 250 mg/kg, at least 500 mg/kg, or at least 1,000 mg/kg of the compounds, relative to the total weight of the article. The compositions disclosed herein are suitable for combining with target articles.
Exemplary food products and beverages include coffees, vegetables, yogurts, grains, e.g., a whole grain, beers, wines, distilled spirits, cocoas, fruits, and vegetables, especially cruciferous vegetables.
EXAMPLES
The following examples are for the purpose of illustration of the invention only and are not intended to limit the scope of the present invention in any manner whatsoever.
The sugars D-glucose (GLU), D-galactose (GAL); the amino acids glycine (GLY), alanine (ALA), proline (PRO), cysteine (CYS), tyrosine (TYR), serine (SER), phenylalanine (PHE), asparagine (ASN); and methyl-parabens (methyl 4-hydroxybenzoate) were obtained in food grade quality and high-purity (>98.5%) from Sigma Aldrich Co. (St Louis, MO, USA). The bitter phenolic compounds (-)-epigallocatechin gallate (EGCg) and (-)-epicatechin gallate (ECg) were obtained in food-grade quality and high-purity (98% and 95% respectively) from Erbium Oxide, Easchem (China). The organic solvents methanol and acetone; formic acid (FA) and hydrochloric acid (HC1, 32 wt. % in water) used in UPLC and Prep-LC were obtained in food-grade quality and LC grade (Optima®) from Fisher Chemical (Fisher Scientific, Fair Lawn, NJ, USA). The quartz sand used for Maillard reactions was obtained from Fisher Chemical (Fisher Scientific, Fair Lawn, NJ, USA). Deuterium oxide (D2O, 99.9 atom % D) and deuterated formic acid (DCO2H, 95 wt. % in water, 98 atom % D) for NMR analysis were obtained from Sigma Aldrich Co. (St Louis, MO, USA). The nanopure water at resistivity 18.2 MΩ-cm was obtained with distilled deionized water and a purification system (Nanopure Diamond, Barnstead, Thermo Scientific, Dubuque, IA, USA).
Maillard reactions were conducted with the phenolic compound (-)-epigallocatechin gallate (EGCg); one of the amino acids catalyst glycine (GLY), alanine (ALA), proline (PRO), cysteine (CYS), tyrosine (TYR), serine (SER), phenylalanine (PHE) or asparagine (ASN); and one of the sugars D-glucose (GLU) or D-galactose (GAL).
Set up 1 consisted of a circular hotplate stirrer topped with a reaction block with 17 vial holes spaced to perform multiple simultaneous reactions. Reaction vials of 40 mL with a pressure relief cap were used for the Maillard reaction. The temperature was tracked with one probe for the reaction block and one thermocouple thermometer (VWR® Traceable® Expanded Range Thermometer, VWR International) with two probes placed in the Maillard mixture at the bottom of the vial. For the optimization tests, Maillard reactions were performed with several experimental variables described in Table 1. These optimization reaction tests were run in duplicate and will be compared against a previously described reaction control (Jiang et al., 2009; Zhang et al., 2014). For a continuous reaction, all reactants (i.e. phenolic, amino acid, and sugar) were mixed with 2.5 g of quartz sand using a ball grinder (2010 Geno/Grinder, 1000 rpm, 10 min) prior to placing into a reaction vial. Then, the nanopure water was added before the reaction run. For a stepwise reaction, the amino acid and sugar were mixed with the quartz sand as previously described, before placing it into the reaction vial. Then, nanopure water was added before the reaction step 1 proceeded under a targeted temperature between 80-150°C and for a short time (5 or 10 min). Then, the phenolic EGCg was added to the reaction vial to proceed to reaction step 2 at 150°C for 15 min. Reactions were quenched using an ice bath after completion.
Figure imgf000035_0001
Figure imgf000036_0001
Set up 2 consisted of a 500 mL two neck angled round-bottom flask equipped with a Graham reflux condenser and a glass stirrer coupled with a PTFE moon shape blade, a vacuum stirrer bearing (Kimble Chase, USA) and a mixing head (ACE Glass Inc., 13650-12 High Torque Economy Laboratory Stirrer). Three different Maillard reaction models (A-C) were performed to obtain the five targeted blockers from the EGCg-GLU and EGCg-GAL mixtures (Table 2). For each Maillard reaction, 20 g of quartz sand and approximately 4 g of the appropriate reactant mass and ratio (i.e. phenolic, amino compound, and sugar) were mixed using a ball grinder (2010 Geno/Grinder) at 1000 rpm during 10 min. The resultant mixture was placed in the reaction flask with nanopure water to attain appropriate moisture and then stirred for 3-5 min to homogenize the mixture. Reactions were quenched using an ice bath after completion.
Figure imgf000036_0002
After Maillard reaction, further sample preparation steps were required to proceed to UPLC-MS analysis and Prep-LC Fractionation of blockers. For the small-scale production, the reaction products were isolated from the whole Maillard reaction mixture by three cycles of solvent extraction with 10 mL of methanol/nanopure water mixture (2: 1 v/v, with 0.1% FA, pH 3) enriched with methyl-paraben as an internal standard (240 μg/mL). The fractions obtained from the three repetitions of extraction were pooled and further centrifuged for 10 min at 6832 x g and 12°C (Allegra™X-22R Centrifuge, Beckman Coulter, Rotor F0685). For the large-scale production, the reaction products were isolated by four cycles of solvent extraction using 20 mL of the solvent mixture as previously described and enriched with methyl-paraben (360 pg/mL). The four fractions obtained were then pooled and centrifuged (10 min, 10000 rpm, 12°C). To control the production yield of each blocker, for both small and large-scale reactions, a sample of centrifuged supernatant was diluted at 1 :5 and 1 :9 respectively in nanopure acidified water (0.1% FA, pH 3) and then filtered through a 0.2 μg Nylon tip filter (Fisher Scientific) before UPLC-UV-MS analysis. The reaction was monitored using blockers ion peak area corrected by the internal standard methyl-paraben.
The centrifuged supernatant was subjected to ultrafiltration using a 5 kDa NMW cellulose regenerated membrane (Amicon®, EMD Millipore Sigma, USA) to clean sample from non-desirable big particles. The permeate was dried under vacuum with a rotary evaporator and freeze-dried twice. The solid powder was then recovered in solvent extraction using the appropriate mixture of solvents (nanopure water, methanol or acetone, 0.1% FA) and filtered through a 0.2 μg Nylon tip filter before Prep-LC fractionation.
Compounds obtainable using the conditions described above include BLK-10 and BLK-4:
Figure imgf000037_0001
BLK-10 BLK-4
A sensory analysis was carried out to evaluate the bitterness modulation properties of the BLK-10 and BLK-4 (as well as unmodified against caffeine. Eight trained panelists from the Flavor Research and Education Center, Columbus, OH, were recruited to perform a 2- AFC sensory difference test. The evaluation was completed in 3 sessions. In each session, panelists were presented with 4 pairwise sample sets, using 4 control samples and 4 treatment samples. The control sample was prepared using a caffeine solution at 265 pg/mL (0.3%o HC1, pH 4) whereas the treatment sample was prepared using a caffeine solution (265 pg/mL, 0.3%o HC1, pH 4) with the addition of one potential blocker in a molar ratio of 1 :5 or 1 : 10 against caffeine (blocker: caffeine). Sample sets were presented in randomized order using blind-coded portion cups filled with 2.5 mL of solution. For each pair of samples (control and treatment), panelists were asked to evaluate the bitterness and indicate which of the two samples was the most bitter (forced choice). There was a two-minute break between samples sets to allow panelists to cleanse their pallet with water and crackers and recover neutral flavor sensation in mouth. The sensory responses were collected using Compusense® software (Compusense Inc., Guelph, ON, Canada). Both BLK 10 and BLK 4 substantially reduced the bitter perception of the caffeine samples. Moreover, BLK 10, by itself in water, exhibited no bitter flavor and only threshold astringency. BLK 4, by itself in water, exhibited low bitter flavor and only threshold astringency. These results are depicted in Figure 1.
The compositions and methods of the appended claims are not limited in scope by the specific compositions and methods described herein, which are intended as illustrations of a few aspects of the claims and any compositions and methods that are functionally equivalent are intended to fall within the scope of the claims. Various modifications of the compositions and methods in addition to those shown and described herein are intended to fall within the scope of the appended claims. Further, while only certain representative compositions and method steps disclosed herein are specifically described, other combinations of the compositions and method steps also are intended to fall within the scope of the appended claims, even if not specifically recited. Thus, a combination of steps, elements, components, or constituents may be explicitly mentioned herein or less, however, other combinations of steps, elements, components, and constituents are included, even though not explicitly stated. The term “comprising” and variations thereof as used herein is used synonymously with the term “including” and variations thereof and are open, non-limiting terms. Although the terms “comprising” and “including” have been used herein to describe various embodiments, the terms “consisting essentially of’ and “consisting of’ can be used in place of “comprising” and “including” to provide for more specific embodiments of the invention and are also disclosed. Other than in the examples, or where otherwise noted, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood at the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, to be construed in light of the number of significant digits and ordinary rounding approaches.

Claims

What is claimed is:
1. A compound having the formula:
Figure imgf000039_0001
or an acceptable salt thereof, wherein
Ral is selected from Raa1, ORaa1, COORaa1, a heterocyclic ring having at least one oxygen, or together forms a heterocyclic ring with Ra2, said ring further spiro-substituted by a heterocyclic ring having at least one oxygen;
Ra5 is selected from Raa5, ORaa5, COORaa5, a heterocyclic ring having at least one oxygen, or together forms a heterocyclic ring with Ra4, said ring further spiro-substituted by a heterocyclic ring having at least one oxygen;
Ra3 is selected from Raa3, ORaa3, COORaa3;
Ra2, when not forming a heterocycle with R31, is selected from Raa2, ORaa2, COORaa2;
Ra4, when not forming a heterocycle with Ra5, is selected from Raa4, ORaa4, COORaa4; where any two or more of Raa1, Raa2, Raa3, Raa4, and Raa5 may together form a bond;
Rb1 is selected from Rbb1, ORbb1, COORbb1, a heterocyclic ring having at least one oxygen, or together forms a heterocyclic ring with Rb2, said ring further spiro-substituted by a heterocyclic ring having at least one oxygen;
Rb5 is selected from Rbb5, ORbb5, COORbb5, a heterocyclic ring having at least one oxygen, or together forms a heterocyclic ring with Rb4, said ring further spiro-substituted by a heterocyclic ring having at least one oxygen;
Rb3 is selected from Rbb3, ORbb3, COORbb3;
Rb2, when not forming a heterocycle with Rb1, is selected from Rbb2, ORbb2, COORbb2;
Rb4, when not forming a heterocycle with Rb5, is selected from Rbb4, ORbb4, COORbb4; where any two or more of Rbb1, Rbb2, Rbb3, Rbb4, and Rbb5 may together form a bond; at least one of R1 and R3 is a heterocyclic ring having at least one oxygen, or forms a heterocyclic ring with one of R2 and R4, said ring further spiro-substituted by a heterocyclic ring having at least one oxygen, and when R1 and R2 is not part of a heterocyclic ring system, then R1 and R2 is hydrogen, provided that not both of R1 and R2 is hydrogen; when R2 is not part of a heterocyclic ring system, is selected from R2 , OR2 , COOR2 ; when R4 is not part of a heterocyclic ring system, is selected from R4 , OR4 , COOR4 ; and Raai, Raa2, Raa3 Raa4, Raa5, Rbb1, Rbb2, Rbb3, Rbb4, Rbb5, R2 , and R3 , are independently selected from H, C1-8alkyl, aryl, heterocyclyl, heteroaryl, (-CH2CH2ORpeg)z, wherein Rpeg is H, or C1-8alkyl, and z is from 1-100.
2. The compound of any preceding claim, wherein neither R1 or R3 are hydrogen.
3. The compound of any preceding claim, having the formula:
Figure imgf000040_0001
4. The compound according to any preceding claim, wherein R2 is OH, and R1 is a heterocyclic ring having the formula:
Figure imgf000041_0001
wherein Rc1, Rc2, Rc3, and Rc4 are each independently selected from OH and H.
5. The compound of any preceding claim, wherein R2 is OH, and R1 is a heterocyclic ring having the formula:
Figure imgf000041_0002
wherein Rc1, Rc2, Rc3, and Rc4 are each independently selected from OH and H.
6. The compound of any preceding claim, wherein R1 and R2 together form a heterocyclic ring having the formula:
Figure imgf000042_0001
wherein Rc5 is selected from H, CH2OH, CH3;
Rc6 and Rc7 are each independently selected from OH and H;
X is selected from a chemical bond or the group CHRc8, wherein Rc8 is selected from OH and H.
7. The compound of any preceding claim, wherein R1 and R2 together form a heterocyclic ring having the formula:
Figure imgf000042_0002
wherein Rc5 is selected from H, CH2OH, CH3;
Rc6 and Rc7 are each independently selected from OH and H;
X is selected from a chemical bond or the group CHRc8, wherein Rc8 is selected from OH and
H.
8. The compound of any preceding claim, wherein R1 and R2 together form a heterocyclic ring having the formula:
Figure imgf000043_0001
wherein Rc5 is selected from H, CH2OH, CH3;
RC6 RC7 and Rc8 (when present) are each independently selected from OH and H.
9. The compound according to any preceding claim, wherein R4 is OH, and R3 is a heterocyclic ring having the formula:
Figure imgf000043_0002
wherein Rd1, Rd2, Rd3, and Rd4 are each independently selected from OH and H.
10. The compound of any preceding claim, wherein R4 is OH, and R3 is a heterocyclic ring having the formula:
Figure imgf000044_0001
wherein Rd1, Rd2, Rd3, and Rd4 are each independently selected from OH and H.
11. The compound of any preceding claim, wherein R3 and R4 together form a heterocyclic ring having the formula: wherein Rd5 is selected from H, CH2OH, CH3;
Rd6 and Rd7 are each independently selected from OH and H; X’ is selected from a chemical bond or the group CHRd8, wherein Rd8 is selected from OH and H.
12. The compound of any preceding claim, wherein R3 and R4 together form a heterocyclic ring having the formula:
Figure imgf000045_0001
Rd6 and Rd7 are each independently selected from OH and H;
X’ is selected from a chemical bond or the group CHRd8, wherein Rd8 is selected from OH and H.
13. The compound of any preceding claim, wherein R3 and R4 together form a heterocyclic ring having the formula:
Figure imgf000045_0002
Figure imgf000046_0001
wherein Rd5 is selected from H, CH2OH, CH3;
Rd6, Rd7 and Rd8 (when present) are each independently selected from OH and H.
14. The compound of any preceding claim, wherein R2 and R3 together form a heterocyclic ring having the formula:
Figure imgf000046_0002
wherein R35 is selected from H, CH2OH, CH3;
R36 and R37 are each independently selected from OH and H;
X” is selected from a chemical bond or the group CHR38, wherein Rd8 is selected from OH and H.
15. The compound of any preceding claim, wherein R3 and R4 together form a heterocyclic ring having the formula:
Figure imgf000046_0003
wherein Re5 is selected from H, CH2OH, CH3;
Re6 and Re7 are each independently selected from OH and H; X’ is selected from a chemical bond or the group CHRe8, wherein Re8 is selected from OH and H.
16. The compound of any preceding claim, wherein R3 and R4 together form a heterocyclic ring having the formula:
Figure imgf000047_0001
wherein Re5 is selected from H, CH2OH, CH3;
Re6, Re7 and Re8 (when present) are each independently selected from OH and H.
17. The compound according to any preceding claim, wherein Ra1 is is a heterocyclic ring having the formula:
Figure imgf000048_0001
wherein Rf1, Rf2, R3f3 and Rf4 are each independently selected from OH and H.
18. The compound of any preceding claim, wherein Ra1 and Ra2 together form a heterocyclic ring having the formula:
Figure imgf000048_0002
wherein Rf5 is selected from H, CH2OH, CH3;
Rf6 and Rf7 are each independently selected from OH and H; X’” is selected from a chemical bond or the group CHR , wherein Rf8 is selected from OH and H.
19. The compound of any preceding claim, wherein Ra1 and Ra2 together form a heterocyclic ring having the formula:
Figure imgf000049_0001
wherein Rf5 is selected from H, CH2OH, CH3;
Rf6 and Rf7 are each independently selected from OH and H;
X’ is selected from a chemical bond or the group CHR , wherein Rf8 is selected from OH and H.
20. The compound of any preceding claim, wherein Ra1 and Ra2 together form a
Figure imgf000049_0002
Figure imgf000050_0001
wherein Rf5 is selected from H, CH2OH, CH3;
Rf6, R72 and Rf8 (when present) are each independently selected from OH and H.
21. The compound according to any preceding claim, wherein Ra5 is a heterocyclic ring having the formula:
Figure imgf000050_0002
Figure imgf000051_0001
wherein Rf1, Rf2, Rf3, and Rf4 are each independently selected from OH and H.
22. The compound of any preceding claim, wherein Ra4 and Ra5 together form a heterocyclic ring having the formula:
Figure imgf000051_0002
wherein Rf5 is selected from H, CH2OH, CH3;
Rf6 and Rf7 are each independently selected from OH and H;
X’” is selected from a chemical bond or the group CHRf8, wherein Rf8 is selected from OH and H.
23. The compound of any preceding claim, wherein Ra4 and Ra5 together form a heterocyclic ring having the formula:
Figure imgf000051_0003
Rf6 and Rf7 are each independently selected from OH and H;
X’ is selected from a chemical bond or the group CHRf8, wherein Rf8 is selected from OH and
H.
24. The compound of any preceding claim, wherein Ra4 and Ra5 together form a heterocyclic ring having the formula:
Figure imgf000052_0001
wherein Rf5 is selected from H, CH2OH, CH3;
Rf6, Rf7 and Rf8 (when present) are each independently selected from OH and H.
25. The compound according to any preceding claim, wherein Rb1 is a heterocyclic ring having the formula:
50
Figure imgf000053_0001
wherein Rf1, Rf2, Rf3, and Rf4 are each independently selected from OH and H.
26. The compound of any preceding claim, wherein Rb1 and Rb2 together form a heterocyclic ring having the formula:
Figure imgf000053_0002
wherein Rf5 is selected from H, CH2OH, CH3;
Rf6 and Rf7 are each independently selected from OH and H;
X’” is selected from a chemical bond or the group CHR™, wherein Rf8 is selected from OH and H.
27. The compound of any preceding claim, wherein Ral and Ra2 together form a heterocyclic ring having the formula:
Figure imgf000054_0001
wherein Rf5 is selected from H, CH2OH, CH3;
Rf6 and Rf7 are each independently selected from OH and H;
X’ is selected from a chemical bond or the group CHR , wherein Rf8 is selected from OH and H.
28. The compound of any preceding claim, wherein Ral and Ra2 together form a heterocyclic ring having the formula:
Figure imgf000054_0002
Figure imgf000055_0001
wherein Rf5 is selected from H, CH2OH, CH3;
Rf6, Rf7 and Rf8 (when present) are each independently selected from OH and H.
29. The compound according to any preceding claim, wherein Rb5 is a heterocyclic ring having the formula:
Figure imgf000055_0002
wherein Rf1, Rf2, Rf3, and Rf4 are each independently selected from OH and H. The compound of any preceding claim, wherein Rb4 and Rb5 together form a heterocyclic ring having the formula:
Figure imgf000056_0001
wherein Rf5 is selected from H, CH2OH, CH3;
Rf6 and Rf7 are each independently selected from OH and H;
X’” is selected from a chemical bond or the group CHRf8, wherein Rf8 is selected from OH and H.
31. The compound of any preceding claim, wherein Rb4 and Rb5 together form a heterocyclic ring having the formula:
Figure imgf000056_0002
wherein Rf5 is selected from H, CH2OH, CH3;
Rf6 and Rf7 are each independently selected from OH and H;
X’ is selected from a chemical bond or the group CHRf8, wherein Rf8 is selected from OH and H.
32. The compound of any preceding claim, wherein Rb4 and Rb5 together form a heterocyclic ring having the formula:
Figure imgf000057_0001
wherein Rf5 is selected from H, CH2OH, CH3;
Rf6, Rf7 and Rf8 (when present) are each independently selected from OH and H.
33. The compound of any preceding claim, wherein Ra3 is H, OH, OCH3, COOH, OCH2CH3.
34. The compound of any preceding claim, wherein Ra4 is H, OH, OCH3, COOH, OCH2CH3.
35. The compound of any preceding claim, wherein R32 is H, OH, OCH3, COOH, OCH2CH3.
36. The compound of any preceding claim, wherein Ra3 is OH. The compound of any preceding claim, wherein Ra2 is OH. The compound of any preceding claim, wherein Ra4 is OH. The compound of any preceding claim, wherein Rb3 is H, OH, OCH3, COOH,
OCH2CH3. The compound of any preceding claim, wherein Rb4 is H, OH, OCH3, COOH,
OCH2CH3. The compound of any preceding claim, wherein Rb2 is H, OH, OCH3, COOH,
OCH2CH3. The compound of any preceding claim, wherein Rb3 is OH. The compound of any preceding claim, wherein Rb2 is OH. The compound of any preceding claim, wherein Rb4 is OH. The compound of any preceding claim, wherein Ra3 is OCH3. The compound of any preceding claim, wherein R32 is OCH3. The compound of any preceding claim, wherein Ra4 is OCH3. The compound of any preceding claim, wherein Rb3 is OCH3. The compound of any preceding claim, wherein Rb2 is OCH3. The compound of any preceding claim, wherein Rb4 is OCH3. The compound of any preceding claim, wherein Ra1 and Ra5 are each hydrogen. The compound of any preceding claim, wherein Ra2, Ra3, and Ra4 are each OH. The compound of any preceding claim, wherein Rb1 and Rb5 are each hydrogen. The compound of any preceding claim, wherein Rb2, Rb3, and Rb4 are each OH. The compound of any preceding claim, wherein Rd1, Rc2, Rc3, and Rc4 are each OH. The compound of any preceding claim, wherein Rd1, Rd2, Rd3, and Rd4 are each OH. The compound of any preceding claim, wherein Rc5 is hydrogen, Rc6 and Rc7 are each OH, X is CHRc8 and Rc8 is OH. The compound of any preceding claim, wherein Rd5 is hydrogen, Rd6 and Rd7 are each OH, X is CHRd8 and Rd8 is OH. The compound any preceding claim, wherein X is a bond, Rc5 is CH2OH, and Rc6 and Rc7 are each OH. The compound any preceding claim, wherein X’ is a bond, Rd5 is CH2OH, and Rd6 and Rd7 are each OH. The compound of any preceding claim, wherein Re1, Re2, Re3, and Re4 are each OH. The compound of any preceding claim, wherein Rf1, Rf2, Rf3, and Rf4 are each OH. The compound of any preceding claim, wherein Re5 is hydrogen, Re6 and Re7 are each OH, X” is CHRe8 and Re8 is OH. The compound of any preceding claim, wherein Rf5 is hydrogen, Rf6 and Rf7 are each OH, X’” is CHR™ and Rre is OH. The compound any preceding claim, wherein X” is a bond, Re5 is CH2OH, and Re6 and Re7 are each OH. The compound any preceding claim, wherein X’” is a bond, Rf5 is CH2OH, and Rf6 and R17 are each OH. A composition comprising one or more compounds according to any of the preceding compound claims. The composition according to any preceding composition claim, wherein the composition comprises at least 1 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 100 mg/kg, at least 250 mg/kg, at least 500 mg/kg, or at least 1,000 mg/kg of the compounds. The composition according to any preceding composition claim, wherein the composition comprises between 1-1,000 mg, between 1-100 mg, between 1-50 mg, between 1-25 mg, between 100-500 mg, between 500-1,000 mg, between 500-2,500 mg, between 1,000-10,000 mg, of the compounds. The composition according to any preceding composition claim, wherein the compounds are present in an amount of at least 1%, at least 2.5%, at least 5%, at least 7.5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%„ at least 70%, %, at least 80%, or at least 90% the total mass of the composition. A method of preparing a flavor modulating compound, comprising heating a mixture comprising at least one flavanol and at least one carbohydrate. The method according to any preceding claim, wherein the mixture further comprises at least one primary amine. The method according to any preceding claim, wherein the mixture further comprises at least one amino acid or peptide. The method according to any preceding claim, wherein the mixture further comprises glycine, alanine, leucine, valine, isoleucine, proline, or a combination thereof. The method according to any preceding claim, wherein the mixture further comprises an inert diluent.
57
76. The method according to any preceding claim, wherein the inert diluent comprises sand.
77. The method according to any preceding claim, wherein the mixture comp10ses water in an of at least 1%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%, by weight relative to the total weight of the composition.
78. The method according to any preceding claim, wherein the mixture comprises water in an amount of 1-100%, 1-75%, 1-50%, 1-40%, 1-30%, 1-20%, 1-10%, 5-15%, 5- 30%, 5-50%, 10-25%, 20-40%, 25-50%, 25-75%, 30-60%, 40-80%, or 50-100% by weight relative to the total weight of the composition.
79. The method according to any preceding claim, wherein the flavanol comprises a compound having the formula:
Figure imgf000060_0001
R9 is selected from Ra9, ORa9, COORa9,
R10 is selected from Ra10, ORa10, COORa10,
R11 is selected from Ra11, ORa11, COORa11,
R12 is selected from Ra12, ORa12, COORa12,
R13 is selected from Ra11, ORa13, COORa13, where any two or more of R9, R10, Ral1, Ra12, and R13 may together form a bond;
R14 is selected from Rb14, ORb14, COORb14,
R15 is selected from Rb15, ORb15, COORb15,
R16 is selected from Rb16, ORb16, COORb16,
R17 is selected from Rb17, ORb17, COORb17,
R18 is selected from Rb18, ORb18, COORb18, here any two or more of R14, R15, R16, R17, and R18 may together form a bond; Ra9, Ral°, Ral13, Ral2, Ral3, Rb14, Rb15, Rb16, Rb17, Rb18, are independently selected from H, C1- salkyl, aryl, heterocyclyl, heteroaryl, (-CH2CH2ORpeg)z, wherein Rpeg is H, or C1- salkyl, and z is from 1-100.
80. The method of any preceding claim, wherein the flavanol comprises a compound having the formula:
Figure imgf000061_0001
81. The method according to any preceding claim, wherein R5 and R7 are hydrogen and R6 and R8 are OH.
82. The method according to any preceding claim, wherein the carbohydrate comprises a compound having the formula: wherein Re1, Re2, Re3, and Re4 are each independently selected from hydrogen and OH.
83. The method according to any preceding claim, wherein the carbohydrate comprises a compound having the formula:
Figure imgf000062_0001
or tautomer thereof, wherein Rx6, Rx4, and Rx3 are each independently selected from hydrogen and OH, z is 1 or 0, and either Rx2 is selected from H and OH and Rx2 is H, or Rx2 and Rx2’ together form a carbonyl, are each independently selected from hydrogen and OH.
84. The method of any preceding claim, wherein the carbohydrate has the formula:
Figure imgf000062_0002
85. The method of any preceding claim, wherein Rx6, Rx4, Rx3, and Rx2 are OH, Rx2 is H, and z is 1.
86. The method of any preceding claim, wherein Rx6 is hydrogen, Rx4, Rx3, and Rx2 are OH, Rx2 is H, and z is 1.
87. The method of any preceding claim, wherein Rx2 and Rx2 are each hydrogen, Rx6, Rx4, and Rx3 are OH, and z is 1.
88. The method of any preceding claim, wherein Rx2 and Rx2 together form a carbonyl, Rx6, Rx4, and Rx3 are OH, and z is 1.
89. The method of any preceding claim, wherein Rx2 and Rx2 together form a carbonyl, and Rx6 is H, Rx4 and Rx3 are OH, and z is 1. The method of any preceding claim, wherein Rx2 and Rx2 together form a carbonyl, and Rx4 is H, Rx6 and Rx3 are OH, and z is 1. The method of any preceding claim, wherein Rx2 and Rx2 together form a carbonyl, and Rx3 is H, Rx4 and Rx6 are OH, and z is 1. The method according to any preceding claim, wherein the molar ratio of the flavanol to primary amine is from 25:1 to 1:25, from 25:1 to 1:1, from 25:1 to 10:1, from 10:1 to 1:10, from 10:1 to 1:1, from 10:1 to 5:1, from 5:1 to 1:1, from 5:1 to 1:5, from 2.5:1 to 1:25, from 1:1 to 1:25, from 1:10 to 1:25, from 1:1 to 1:10, from 1:1 to 1:5, or from 1:5 to 1:10. The method according to any preceding claim, wherein the molar ratio of the flavanol to carbohydrate is from 25:1 to 1:25, from 25:1 to 1:1, from 25:1 to 10:1, from 10:1 to 1:10, from 10:1 to 1:1, from 10:1 to 5:1, from 5:1 to 1:1, from 5:1 to 1:5, from 2.5:1 to 1:2.5, from 1:1 to 1:25, from 1:10 to 1:25, from 1:1 to 1:10, from 1:1 to 1:5, or from 1:5 to 1:10. The method according to any preceding claim, wherein the mixture is heated to a temperature of at least 80° C., at least 100° C., at least 125° C., at least 150° C., at least 175° C., at least 180° C., at least 200° C., or at least 225° C. The method according to any preceding clam, wherein the mixture is heated for a period of about 5-120 minutes, about 5-100 minutes, about 5-80 minutes, about 5-50 minutes, about 5-25 minutes, about 5-10 minutes, about 10-30 minutes, about 20-80 minutes, or about 50-120 minutes. A flavor modulating compound, obtained by a process described in any preceding process claim. A method for modulating the flavor of a food product, comprising combining a food product with a composition comprising one or more compounds according to any of preceding claims. The method according to any preceding claim, wherein the composition comprises at least 1 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 100 mg/kg, at least 250 mg/kg, at least 500 mg/kg, or at least 1,000 mg/kg of the compounds, relative to the total weight of the food product. The method according to any preceding method claim, wherein the composition comprises between 1-1,000 mg, between 1-100 mg, between 1-50 mg, between 1-25
61 mg, between 100-500 mg, between 500-1,000 mg, between 500-2,500 mg, between 1,000-10,000 mg, of the compounds. The method according to any preceding method claim, wherein the compounds are present in an amount of at least 1%, at least 2.5%, at least 5%, at least 7.5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%„ at least 70%, %, at least 80%, or at least 90% the total mass of the composition. The method according to any preceding claim, wherein the food product comprises a coffee, a vegetable, a yogurt, a whole grain, a beer, a wine, a distilled spirit, a cocoa, a yogurt, or a fruit.
62
PCT/US2021/062649 2020-12-09 2021-12-09 Flavor modulating compounds and compositions WO2022125796A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202063123283P 2020-12-09 2020-12-09
US63/123,283 2020-12-09

Publications (1)

Publication Number Publication Date
WO2022125796A1 true WO2022125796A1 (en) 2022-06-16

Family

ID=81973835

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2021/062649 WO2022125796A1 (en) 2020-12-09 2021-12-09 Flavor modulating compounds and compositions

Country Status (1)

Country Link
WO (1) WO2022125796A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115093403A (en) * 2022-07-19 2022-09-23 安徽农业大学 Phenylpropanoid ester type catechin and preparation method and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011103454A1 (en) * 2010-02-18 2011-08-25 The Hershey Company Cocoa-based exercise recovery beverages
US20160015064A1 (en) * 2013-03-14 2016-01-21 Chromocell Corporation Compounds, compositions, and methods for modulating sweet taste
WO2021198199A1 (en) * 2020-03-31 2021-10-07 Firmenich Sa Flavor composition

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011103454A1 (en) * 2010-02-18 2011-08-25 The Hershey Company Cocoa-based exercise recovery beverages
US20160015064A1 (en) * 2013-03-14 2016-01-21 Chromocell Corporation Compounds, compositions, and methods for modulating sweet taste
WO2021198199A1 (en) * 2020-03-31 2021-10-07 Firmenich Sa Flavor composition

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE Pubmed U.S. National Library of Medicine; 25 December 2015 (2015-12-25), "2R)-2alpha-(3,4,5-Trihydroxyphenyl)-3alpha- [(3,4,5-trihydroxybenzoyl)oxy]-6,8-bis(beta-D-glucopyranosyl)-3,4-dihydro-2H-1-benzopyran-5,7- diol", XP055951753, Database accession no. 102341275 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115093403A (en) * 2022-07-19 2022-09-23 安徽农业大学 Phenylpropanoid ester type catechin and preparation method and application thereof
CN115093403B (en) * 2022-07-19 2023-07-14 安徽农业大学 Phenylpropanoid ester catechin and preparation method and application thereof

Similar Documents

Publication Publication Date Title
CA2467285C (en) Crystals of non-natural-type stereoisomer salt of monatin and use thereof
JP5079379B2 (en) Production of purified chlorogenic acids with reduced secondary precipitation
TWI394537B (en) Flavor improving agent and food and beverage containing the flavor improving agent
JP5079373B2 (en) Process for producing purified chlorogenic acids
WO2011037959A1 (en) Novel polymorphs of rebaudioside c and methods for making and using the same
US20220395007A1 (en) Taste modulating compounds and methods of improving the quality of foods and beverages
JP2008214261A (en) Aromatic compound, aromatic composition and aromatic hop extract
WO2012005293A1 (en) Process for production of purified chlorogenic acid-containing pharmaceutical preparation
JP5285194B1 (en) Food and drink
WO2020237060A1 (en) Taste modulating compounds and methods of improving the quality of foods and beverages
JP6277128B2 (en) Coffee substitute
EP2700322A1 (en) Composition containing scirpusin b, and process for producing composition containing scirpusin b
WO2022125796A1 (en) Flavor modulating compounds and compositions
WO2018151156A1 (en) Packaged unfermented beverage and production method therefor
US20130203867A1 (en) Stevia formulation
JPH0994080A (en) Taste improver comprising extract of hydrolyzate of coffee bean
JPS59109133A (en) Production of coffee flavor
JP2017048185A (en) Xanthine oxidase inhibitor
JP5854752B2 (en) Beverages containing chlorogenic acids
JP2017175966A (en) Pyrroloquinoline quinone-containing black tea-like beverage
JP2731882B2 (en) Gelling agent
BR112021001097A2 (en) steviol glycoside aggregates with specific particle size distribution
JP5033080B2 (en) Taste improving agent
WO2023013555A1 (en) Coffee bean extract with improved flavor, food or beverage, packaged beverage and method for producing coffee bean extract
JP2014028771A (en) Method of producing resveratrol derivative or pharmacologically acceptable salt thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21904411

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21904411

Country of ref document: EP

Kind code of ref document: A1