WO2011159781A2 - Modulateurs de goût amer - Google Patents

Modulateurs de goût amer Download PDF

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WO2011159781A2
WO2011159781A2 PCT/US2011/040491 US2011040491W WO2011159781A2 WO 2011159781 A2 WO2011159781 A2 WO 2011159781A2 US 2011040491 W US2011040491 W US 2011040491W WO 2011159781 A2 WO2011159781 A2 WO 2011159781A2
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Prior art keywords
substituted
compound
aryl
heteroaryl
composition
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PCT/US2011/040491
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English (en)
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WO2011159781A3 (fr
Inventor
Catherine Tachdjian
Xiaodong Li
Donald S. Karanewsky
Joseph Fotsing
Andrew Patron
Vincent Darmohusodo
Victor Selchau
Brett Ching
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Senomyx, Inc.
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Publication of WO2011159781A2 publication Critical patent/WO2011159781A2/fr
Publication of WO2011159781A3 publication Critical patent/WO2011159781A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/116—Heterocyclic compounds
    • A23K20/121—Heterocyclic compounds containing oxygen or sulfur as hetero atom
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups

Definitions

  • This invention relates to the discovery of antagonist of human type 2 taste receptors (hT2Rs), the use of these antagonists for modulating taste perception, particularly bitter taste, and the preparation of these antagonists.
  • hT2Rs human type 2 taste receptors
  • the taste system provides sensory information about the chemical composition of the external world.
  • Taste transduction is one of the most sophisticated forms of
  • T2Rs A novel family of GPCRs, termed T2Rs, has been identified in humans and rodents (Adler et al., Cell 100(6):693-702 (2000); Chandrashekar et al, Cell 100(6): 703-711 (2000); Matsunami H, Montmayeur J P, Buck L B. Nature
  • T2Rs mediate responses to bitter compounds.
  • T2R genes are specifically expressed in subset of taste receptor cells of the tongue and palate epithelia.
  • the gene for one of the human T2Rs (hT2Rl) is located in a chromosomal locus that is linked to sensitivity to bitter compound 6-n-propyl-2-thiouracil in humans (Adler et al., (Id.) (2000)).
  • mT2R5 is located in a chromosomal locus that is linked to sensitivity to bitter compound cycloheximide in mice.
  • mT2R5 can activate gustducin, G protein specifically expressed in taste cells and linked to bitter stimuli transduction (Wong et al, Nature 381 :796-800 (1996)). Gustducin activation by mT2R5 occurs only in response to cycloheximide (Chandrashekar et al, (Id.) (2000). Thus, it has been proposed that mT2R family mediates bitter taste response in mice, whereas hT2R family mediates bitter taste response in humans. Only one human T2R was suggested as having identified bitter ligand ⁇ hT2R4 was shown as being activated by denatonium (Chandrashekar et al, (Id.) 2000).
  • T2R function One of the difficulties of studying T2R function is that these receptors are not readily expressed in cultured mammalian cell lines.
  • T2Rs and TlRs taste receptors are expressed in the gastrointestinal system.
  • enterendocrine cells STCl cells
  • gustducin and transducin subunits enterendocrine cells
  • CCL cholecystokinin
  • T2Rs and TlRs activate phospho lipase C beta 2, PLC beta2, and that there is likely a molecular intestinal sensing system in the gut similar to that present in lingual cells and that gastrointestinal cells such as brush cells or solitary chemosensory cells expressing taste receptors may result in GLUT2 increase and may play a role in nutrient sensing, and nutrition in the treatment of obesity and diabetes.
  • gastrointestinal cells such as brush cells or solitary chemosensory cells expressing taste receptors
  • GLUT2 a molecular intestinal sensing system in the gut
  • Cui et al, Curr Pharm Des. 12(35):4591-600 (2006) suggest that TlRs expressed in the gut may be used in assays for compounds in treating obesity and diabetes as well as artificial sweeteners.
  • T2R members regulate bitter taste and their possible role in gastrointestinal functions there exists a need for the identification of specific ligands which activate human bitter T2R taste receptors.
  • a greater understanding of the binding properties of different T2Rs, particularly human T2Rs, would be highly beneficial as it will greater facilitate the use thereof in selecting compounds having desired taste modulatory properties, i.e., which block or inhibit the taste of specific bitter compounds.
  • it will provide for the identification of compounds for treating and modulating gastrointestinal functions and related diseases such as obesity, diabetes, food absorption, food sensing, eating disorders, and in the regulation of related hormones and peptides such as GLUT2, cholecystokin et al.
  • the present invention relates to the discovery that hT2R67 and/or hT2R61 regulate bitter taste and the identification of compounds that modulate the activation of hT2R67 and/or hT2R61in a screening assay.
  • the present invention provides a compound having structural Formula (I):
  • R 1 is hydrogen, alkyl, or substituted alkyl
  • R 2 is -OR 3 or -NR 3 R 4 ;
  • Ar 1 is aryl, substituted aryl, heteroaryl, or substituted heteroaryl
  • a 1 is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl;
  • a 2 is a covalent bond, Ci to C 3 alkylene, substituted Ci to C 3 alkylene, -C(0)OCR 3 R 4 - , or -C(0)NHCR 3 R 4 -;
  • X is a covalent bond, S, O, CH 2 , NR 3 , -S(O)-, -S(0) 2 -, -C(O)-, or -C(S)-;
  • Y 1 and Y 2 are independently C ⁇ to C 3 alkylene or substituted C ⁇ to C 3 alkylene;
  • a and b are independently 0 or 1, but are not both 0;
  • Z is -S(O)-, -S(0) 2 -, -C(O)-, or -C(S)-; and R 3 and R 4 are independently hydrogen, alkyl or substituted alkyl; or R 3 and R 4 together with the atoms to which they are bonded, form a cycloheteroalkyl or substituted cycloheteroalkyl ring.
  • the present invention provides a composition comprising a compound of the present invention.
  • the present invention provides a method of reducing or alleviating the bitter taste of a composition comprising contacting the composition with a compound of the present invention to form a modified composition.
  • the present invention provides a method of preparing the compound of Formula (I), or a salt or solvate thereof, in a purified form without
  • the present invention provides a method of preparing a salt of the compound of Formula (I), or a solvate thereof, in a purified form without
  • the compounds of the present invention can be used to modulate, e.g., alleviate or reduce, the bitter taste of compositions, e.g., an ingestible composition.
  • Alkyl by itself or as part of another substituent, refers to a saturated or unsaturated, branched, straight-chain or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne.
  • alkyl includes “cycloalkyl” as defined hereinbelow.
  • Typical alkyl groups include, but are not limited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-l-yl, propan-2-yl, cyclopropan-l-yl, prop-l-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), cycloprop-l-en-l-yl; cycloprop-2-en-l-yl, prop-l-yn-l-yl, prop-2-yn-l-yl, etc.; butyls such as butan-l-yl, butan-2-yl, 2-methyl-propan-l-yl, 2-methyl-propan-2-yl, cyclobutan-l-yl, but-l-en-l-yl, but-l-en-2-yl, 2-methyl-prop-l-en-yl, but-2-
  • alkyl is specifically intended to include groups having any degree or level of saturation, i.e., groups having exclusively single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds and groups having mixtures of single, double and triple carbon-carbon bonds. Where a specific level of saturation is intended, the expressions "alkanyl,” “alkenyl,” and “alkynyl” are used.
  • an alkyl group comprises from 1 to 20 carbon atoms (C 1 -C 20 alkyl). In other embodiments, an alkyl group comprises from 1 to 10 carbon atoms (C 1 -C 10 alkyl). In still other embodiments, an alkyl group comprises from 1 to 6 carbon atoms (Ci-C 6 alkyl). It is noted that when an alkyl group is further connected to another atom, it becomes an "alkylene" group. In other words, the term “alkylene” refers to a divalent alkyl. For example, -CH 2 CH 3 is an ethyl, while -CH 2 CH 2 - is an ethylene.
  • Alkylene by itself or as part of another substituent, refers to a saturated or unsaturated, branched, straight-chain or cyclic divalent hydrocarbon radical derived by the removal of two hydrogen atoms from a single carbon atom or two different carbon atoms of a parent alkane, alkene or alkyne.
  • alkylene includes “cycloalkylene” as defined hereinbelow.
  • alkylene is specifically intended to include groups having any degree or level of saturation, i.e., groups having exclusively single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds and groups having mixtures of single, double and triple carbon-carbon bonds.
  • an alkylene group comprises from 1 to 20 carbon atoms (C 1 -C 20 alkylene). In other embodiments, an alkylene group comprises from 1 to 10 carbon atoms (C 1 -C 10 alkylene). In still other embodiments, an alkylene group comprises from 1 to 6 carbon atoms (Ci-C 6 alkylene).
  • alkanyl by itself or as part of another substituent, refers to a saturated branched, straight-chain or cyclic alkyl radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane.
  • alkanyl includes "cycloakanyl” as defined hereinbelow.
  • Typical alkanyl groups include, but are not limited to, methanyl; ethanyl;
  • propanyls such as propan-l-yl, propan-2-yl (isopropyl), cyclopropan-l-yl, etc.; butanyls such as butan-l-yl, butan-2-yl (sec-butyl), 2-methyl-propan-l-yl (isobutyl), 2-methyl-propan-2-yl (t-butyl), cyclobutan-l-yl, etc.; and the like.
  • alkenyl by itself or as part of another substituent, refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene.
  • alkenyl includes “cycloalkenyl” as defined hereinbelow. The group may be in either the cis or trans conformation about the double bond(s).
  • Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-l-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), prop-2-en-2-yl, cycloprop-l-en-l-yl; cycloprop-2-en-l-yl; butenyls such as but-l-en-l-yl, but-l-en-2-yl, 2-methyl-prop-l-en-l-yl, but-2-en-l-yl , but-2-en-l-yl, but-2-en-2-yl, buta-l,3-dien-l-yl, buta-l,3-dien-2-yl, cyclobut-l-en-l-yl, cyclobut-l-en-3-yl, cyclobuta-l,3-dien-l-yl, etc.; and the like.
  • Alkynyl by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne.
  • Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-l-yn-l-yl, prop-2-yn- 1 -yl, etc. ; butynyls such as but- 1 -yn- 1 -yl, but- 1 -yn-3 -yl, but-3 -yn- 1 -yl, etc. ; and the like.
  • Alkoxy by itself or as part of another substituent, refers to a radical of the formula -O-R 199 , where R 199 is alkyl or substituted alkyl as defined herein.
  • Acyl by itself or as part of another substituent refers to a radical -C(0)R 200 , where R 200 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroarylalkyl or substituted heteroarylalkyl as defined herein.
  • Representative examples include, but are not limited to formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl and the like.
  • Aryl by itself or as part of another substituent, refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring.
  • An "aromatic ring” refers to an organic compound having a conjugated planar ring system composed of carbon atoms and with delocalized pi electron clouds.
  • aryl includes monocyclic and fused-polycyclic groups. Fused- polycyclic group refers to a chemical moiety which contains two or more rings wherein at least one of the rings is an aromatic ring and these two or more rings share one or more connecting bond.
  • the fused-polycyclic aryl may be derived from naphthalene, anthracene, or tetrahydronaphthalene.
  • the fused-polycyclic group can be fused-bicyclic, fused-tricyclic, or fused-tetracyclic.
  • the fused multiple rings may all be aromatic, or one or more of the multiple rings is aromatic while others are not.
  • the monocyclic aryl or fused-polycyclic aryl may be optionally substituted.
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene and the like.
  • an aryl group comprises from 6 to 20 carbon atoms (C 6 -C 20 aryl). In other embodiments, an aryl group comprises from 6 to 15 carbon atoms (C 6 -C 15 aryl). In still other embodiments, an aryl group comprises from 6 to 15 carbon atoms (C 6 -Cio aryl).
  • Arylalkyl by itself or as part of another substituent, refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with an aryl group as, as defined herein.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-l-yl, 2-phenylethen-l-yl,
  • naphthylmethyl 2-naphthylethan-l-yl, 2-naphthylethen-l-yl, naphthobenzyl,
  • an arylalkyl group is (C 6 -C30) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C 1 -C 10 ) alkyl and the aryl moiety is (C 6 -C 20 ) aryl.
  • an arylalkyl group is (C 6 -C 20 ) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (Ci-Cs) alkyl and the aryl moiety is (C 6 -C 12 ) aryl.
  • the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (Ci-Cs) alkyl and the aryl moiety is (C 6 -C 12 ) aryl.
  • an arylalkyl group is (C 6 -C 15 ) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C 1 -C5) alkyl and the aryl moiety is (C 6 -Cio) aryl.
  • Cycloalkyl by itself or as part of another substituent, refers to a saturated or unsaturated cyclic alkyl radical, as defined herein.
  • Cycloalkylene by itself or as part of another substituent, refers to a saturated or unsaturated cyclic alkylene radical, as defined herein. Where a specific level of saturation is intended, the nomenclature
  • cycloalkanyl “cycloalkenyl”, or “cycloalkynyl” is used.
  • Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like.
  • the cycloalkyl group comprises from 3 to 10 ring atoms (C 3 -C 10 cycloalkyl).
  • the cycloalkyl group comprises from 3 to 7 ring atoms (C3-C7 cycloalkyl).
  • the cycloalkyl may be further substituted by one or more heteroatoms including, but not limited to, N, P, O, S, and Si, which attach to the carbon atoms of the cycloalkyl via monovalent or multivalent bond.
  • Heteroalkyl “Heteroalkanyl,” “Heteroalkenyl” and “Heteroalkynyl,” by themselves or as part of other substituents, refer to alkyl, alkanyl, alkenyl and alkynyl groups, respectively, in which one or more of the carbon atoms (and optionally any associated hydrogen atoms), are each, independently of one another, replaced with the same or different heteroatoms or heteroatomic groups.
  • Heteroalkylene “Heteroalkanylene,”
  • Heteroalkenylene and Heteroalkynylene by themselves or as part of other substituents, refer to alkylene, alkanylene, alkenylene and alkynyenel groups, respectively, in which one or more of the carbon atoms (and optionally any associated hydrogen atoms), are each, independently of one another, replaced with the same or different heteroatoms or
  • heteroatomic groups Typical heteroatoms or heteroatomic groups which can replace the carbon atoms include, but are not limited to, -0-, -S-, -N-, -Si-, -NH-, -S(O)-, -S(0) 2 -, -S(0)NH-, -S(0) 2 NH- and the like and combinations thereof.
  • heteroatomic groups may be placed at any interior position of the alkyl, alkenyl or alkynyl groups.
  • Cycloheteroalkyl or “Heterocyclyl,”by itself or as part of another substituent, refers to a saturated or unsaturated cyclic alkyl radical in which one or more carbon atoms (and optionally any associated hydrogen atoms) are independently replaced with the same or different heteroatom.
  • Cycloheteroalkylene by itself or as part of another substituent, refers to a saturated or unsaturated cyclic alkylene radical in which one or more carbon atoms (and optionally any associated hydrogen atoms) are independently replaced with the same or different heteroatom.
  • the cycloheteroalkyl may be further substituted by one or more heteroatoms including, but not limited to, N, P, O, S, and Si, which attach to the carbon atoms of the cycloheteroalkyl via monovalent or multivalent bond.
  • Typical heteroatoms to replace the carbon atom(s) include, but are not limited to, N, P, O, S, Si, etc.
  • Typical cycloheteroalkyl groups include, but are not limited to, groups derived from epoxides, azirines, thiiranes, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidone, quinuclidine, and the like.
  • the cycloheteroalkyl group comprises from 3 to 10 ring atoms (3-10 membered cycloheteroalkyl) In other embodiments, the cycloalkyl group comprise from 5 to 7 ring atoms (5-7 membered cycloheteroalkyl).
  • a cycloheteroalkyl group may be substituted at a heteroatom, for example, a nitrogen atom, with a (Ci-C 6 ) alkyl group.
  • a heteroatom for example, a nitrogen atom, with a (Ci-C 6 ) alkyl group.
  • N-methyl-piperidinyl, N-methyl-pyrazolidinyl and N-methyl-pyrrolidinyl are included within the definition of "cycloheteroalkyl.”
  • a cycloheteroalkyl group may be attached to the remainder of the molecule via a ring carbon atom or a ring heteroatom.
  • Compound refers to a compound encompassed by structural formulae disclosed herein and includes any specific compounds within these formulae whose structure is disclosed herein. Compounds may be identified either by their chemical structure and/or chemical name. When the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound.
  • the compounds described herein may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers ⁇ i.e. , geometric isomers), enantiomers or diastereomers. Accordingly, the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form ⁇ e.g.
  • enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan.
  • the compounds may also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds.
  • tautomer refers to isomers that change into one another with great ease so that they can exist together in equilibrium. In general, compounds may be hydrated, solvated or N-oxides.
  • Heteroaryl by itself or as part of another substituent refers to a radical -F, -CI, -Br or -I.
  • Heteroaryl by itself or as part of another substituent, refers to a monovalent heteroaromatic radical derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring.
  • a “heteroaromatic ring” refers to an aromatic ring wherein one or more of the carbon atoms, which constitute the conjugated ring system, is replaced with one or more heteroatom, such as, nitrogen, oxygen, sulfur, phosphorus, boron silicon, etc.
  • heteroaryl includes monocyclic and fused-polycyclic groups.
  • Fused- polycyclic group refers to a chemical moiety which contains two or more rings wherein at least one of the rings is an aromatic ring and these two or more rings share one or more connecting bond.
  • the fused-polycyclic heteroaryl may be derived from benzofuran, isobenzofuran, indole, isoindole, benzothiophene, isobenzothiophene, benzimidazole, purine, indazole, benzoxazole, benzothiazole, benzisoxazole, or
  • the fused-polycyclic group can be fused-bicyclic, fused-tricyclic, or fused-tetracyclic.
  • the fused multiple rings may all be aromatic, or one or more of the multiple rings is aromatic while others are not.
  • the monocyclic aryl or fused-polycyclic aryl may be optionally substituted.
  • Typical heteroaryl groups include, but are not limited to, groups derived from acridine, ⁇ -carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole,
  • the heteroaryl group comprises from 5 to 20 ring atoms (5-20 membered heteroaryl). In other embodiments, the heteroaryl group comprises from 5 to 10 ring atoms (5-10 membered heteroaryl).
  • Exemplary heteroaryl groups include those derived from furan, thiophene, pyrrole, benzothiophene, benzofuran, benzimidazole, indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole and pyrazine.
  • Heteroarylalkyl by itself or as part of another substituent refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with a heteroaryl group. Where specific alkyl moieties are intended, the nomenclature heteroarylalkanyl, heteroarylakenyl and/or heteroarylalkynyl is used.
  • the heteroarylalkyl group is a 6-21 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is (Ci-C 6 ) alkyl and the heteroaryl moiety is a 5-15-membered heteroaryl.
  • the heteroarylalkyl is a 6-13 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety is (C 1 -C3) alkyl and the heteroaryl moiety is a 5-10 membered heteroaryl.
  • Protecting group refers to a grouping of atoms that when attached to a reactive functional group in a molecule masks, reduces or prevents reactivity of the functional group.
  • protecting groups can be found in Green et ah, "Protective Groups in Organic Chemistry", (Wiley, 2 nd ed. 1991) and Harrison et al., “Compendium of Synthetic Organic Methods", Vols. 1-8 (John Wiley and Sons, 1971-1996).
  • Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl,
  • CBZ benzyloxycarbonyl
  • Boc tert-butoxycarbonyl
  • TMS trimethylsilyl
  • hydroxy protecting groups include, but are not limited to, those where the hydroxy group is either acylated or alkylated such as benzyl, and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.
  • Salt refers to a salt of a compound, which possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,
  • 2-naphthalenesulfonic acid 4-toluenesulfonic acid, camphorsulfonic acid,
  • solute means a compound formed by solvation (the combination of solvent molecules with molecules or ions of the solute), or an aggregate that consists of a solute ion or molecule, i.e., a compound of the present invention, with one or more solvent molecules.
  • solvation the combination of solvent molecules with molecules or ions of the solute
  • aggregate that consists of a solute ion or molecule, i.e., a compound of the present invention, with one or more solvent molecules.
  • water the solvent
  • the corresponding solvate is "hydrate”.
  • N-oxide also known as amine oxide or amine-N-oxide, means a compound that derives from a compound of the present invention via oxidation of an amine group of the compound of the present invention.
  • Substituted when used to modify a specified group or radical, means that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent(s).
  • R a is selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; each R b is independently hydrogen or R a ; and each R c is independently R b or alternatively, the two R c s may be taken together with the nitrogen atom to which they are bonded form a 4-, 5-, 6- or 7-membered cycloheteroalkyl which may optionally include from 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O, N and S.
  • -NR C R C is meant to include -NH 2 , -NH-alkyl, N-pyrrolidinyl and
  • a substituted alkyl is meant to include - alkylene-O-alkyl, -alkylene-heteroaryl, -alkylene-cycloheteroalkyl, -alkylene-C(0)OR b , - alkylene-C(0)NR b R b , and -CH 2 -CH 2 -C(0)-CH 3 .
  • the one or more substituent groups, taken together with the atoms to which they are bonded, may form a cyclic ring including cycloalkyl and cycloheteroalkyl.
  • substituent groups useful for substituting unsaturated carbon atoms in the specified group or radical include, but are not limited to, -R a , halo, -O " , -OR b , -SR b , -S " , -NR C R C , trihalomethyl, -CF 3 , -CN, -OCN, -SCN, -NO, -N0 2 , -N 3 , -S(0) 2 R b , -S(0) 2 0 " , -S(0) 2 OR b , -OS(0) 2 R b , -OS(0) 2 0 " , -OS(0) 2 OR b , -P(0)(0 ) 2 , -P(0)(OR b )(0 ), -P(0)(OR b )(OR b ), -C(0)R b , -C(S)R b , -C(NR b )R b , -C(0)
  • Substituent groups useful for substituting nitrogen atoms in heteroalkyl and cycloheteroalkyl groups include, but are not limited to, -R a , -O " , -OR b , -SR b , -S " , -NR C R C , trihalomethyl, -CF 3 , -CN, -NO, -N0 2 , -S(0) 2 R b , -S(0) 2 0 ⁇ , -S(0) 2 OR b , -OS(0) 2 R b ,
  • the substituents used to substitute a specified group can be further substituted, typically with one or more of the same or different groups selected from the various groups specified above.
  • Carrier refers to a diluent, adjuvant, excipient or vehicle with which a compound is ingested or administered.
  • composition denotes one or more substance in a physical form, such as solid, liquid, gas, or a mixture thereof.
  • an "ingestible composition” includes any substance that, either alone or together with another substance, can be taken by mouth whether intended for consumption or not.
  • the ingestible composition includes both "food or beverage products” and “non-edible products”.
  • Food or beverage products it is meant any edible product intended for consumption by humans or animals, including solids, semisolids, or liquids (e.g., beverages).
  • non-edible products or “noncomestible composition” includes supplements, nutraceuticals, functional food products (e.g., any fresh or processed food claimed to have a health-promoting and/or disease-preventing properties beyond the basic nutritional function of supplying nutrients), pharmaceutical and over the counter medications, oral care products such as dentifrices and mouthwashes, cosmetic products, and other personal care products that have a bitter taste.
  • functional food products e.g., any fresh or processed food claimed to have a health-promoting and/or disease-preventing properties beyond the basic nutritional function of supplying nutrients
  • pharmaceutical and over the counter medications e.g., any fresh or processed food claimed to have a health-promoting and/or disease-preventing properties beyond the basic nutritional function of supplying nutrients
  • oral care products such as dentifrices and mouthwashes, cosmetic products, and other personal care products that have a bitter taste.
  • a "ingestibly acceptable carrier or excipient” is a solid or liquid medium and/or composition that is used to prepare a desired dispersed dosage form of the inventive compound, in order to administer the inventive compound in a dispersed/diluted form, so that the biological effectiveness of the inventive compound is maximized.
  • Ingestibly acceptable carriers includes many common food ingredients, such as water at neutral, acidic, or basic pH, fruit or vegetable juices, vinegar, marinades, beer, wine, natural water/fat emulsions such as milk or condensed milk, edible oils and shortenings, fatty acids and their alkyl esters, low molecular weight oligomers of propylene glycol, glyceryl esters of fatty acids, and dispersions or emulsions of such hydrophobic substances in aqueous media, salts such as sodium chloride, wheat flours, solvents such as ethanol, solid edible diluents such as vegetable powders or flours, or other liquid vehicles; dispersion or suspension aids; surface active agents; isotonic agents; thickening or emulsifying agents, preservatives; solid binders; lubricants and the like.
  • common food ingredients such as water at neutral, acidic, or basic pH, fruit or vegetable juices, vinegar, marinades, beer, wine, natural water/fat
  • a “modulator” herein refers to a compound that modulates the activation of a particular receptor, preferably the chemosensory, e.g., T2R61 and/or T2R67 receptor.
  • a “flavor” herein refers to the perception of taste in a subject, which include sweet, sour, salty, bitter and umami.
  • the subject may be a human or an animal.
  • flavoring agent herein refers to a compound or a biologically acceptable salt or solvate thereof that induces a flavor or taste in an animal or a human.
  • flavor modifier refers to a compound or biologically acceptable salt or solvate thereof that modulates, including reducing or alleviating, and inducing, the tastes of a natural or synthetic flavoring agent in an animal or a human.
  • a “bitter flavor modulating amount” herein refers to an amount of a compound of
  • Formula (I) that is sufficient to alter, e.g., decrease, the bitter taste in a composition, or a precursor thereof, sufficiently to be perceived by a human subject.
  • at least about 0.001 ppm of the present compound would need to be present in order for most human subjects to perceive a modulation of the bitter flavor of an ingestible composition comprising the present compound.
  • a broad range of concentration that would typically be employed in order to economically provide a desirable degree of bitter flavor modulation can be from about 0.001 ppm to 100 ppm, or a narrow range from about 0.1 ppm to about 10 ppm.
  • Alternative ranges of bitter flavor modulating amounts can be from about 0.01 ppm to about 30 ppm, from about 0.05 ppm to about 15 ppm, from about 0.1 ppm to about 5 ppm, or from about 0.1 ppm to about 3 ppm.
  • bitter flavor reducing amount herein refers to an amount of a compound that is sufficient to reduce the taste of a natural or synthetic bitter flavor/taste in a composition, as perceived by an animal or a human.
  • a broad range of a bitter flavor reducing amount can be from about 0.001 ppm to 100 ppm, or a narrow range from about 0.1 ppm to about 10 ppm.
  • Alternative ranges of bitter flavor reducing amounts can be from about 0.01 ppm to about 30 ppm, from about 0.05 ppm to about 15 ppm, from about 0.1 ppm to about 5 ppm, or from about 0.1 ppm to about 3 ppm.
  • the present invention provides a compound having structural Formula (I):
  • R is hydrogen, alkyl, or substituted alkyl
  • R 2 is -OR 3 or -NR 3 R 4 ;
  • Ar 1 is aryl, substituted aryl, heteroaryl, or substituted heteroaryl
  • a 1 is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl;
  • a 2 is a covalent bond, Ci to C 3 alkylene, substituted Ci to C 3 alkylene, -C(0)OCR 3 R 4 - , or -C(0)NHCR 3 R 4 -;
  • X is a covalent bond, S, O, CH 2 , NR 3 , -S(O)-, -S(0) 2 -, -C(O)-, or -C(S)-;
  • Y 1 and Y 2 are independently Ci to C 3 alkylene or substituted Ci to C 3 alkylene;
  • a and b are independently 0 or 1, but are not both 0;
  • Z is -S(O)-, -S(0) 2 -, -C(O)-, or -C(S)-;
  • R 3 and R 4 are independently hydrogen, alkyl or substituted alkyl; or R 3 and R 4 together with the atoms to which they are bonded, form a cycloheteroalkyl or substituted cycloheteroalkyl ring.
  • Z is -S(0) 2 - or -C(O)-.
  • a 2 is a covalent bond; and R 2 is -OR 3 .
  • a 2 is Ci to C 3 alkylene; and R 2 is -OR 3 .
  • a 2 is -C(0)NHCR 3 R 4 -; and R 2 is -OR 3 .
  • Ar 1 is monocyclic aryl, substituted monocyclic aryl, monocyclic heteroaryl, substituted monocyclic heteroaryl, fused-bicyclic aryl, substituted fused-bicyclic aryl, fused-bicyclic heteroaryl, or substituted fused-bicyclic heteroaryl.
  • Ar 1 examples include, but are not limited to, phenyl, substituted phenyl, naphthyl, substituted naphthyl, furanyl, substituted furanyl, benzofuran, substituted benzofuran, indole, substituted indole, benzothiophene, substituted benzothiophene, benzooxazole, substituted benzooxazole, pyrazolopyridine, substituted pyrazolopyridine, dihydrobenzofuran, substituted dihydrobenzofuran, thienopyridine, substituted
  • thienopyridine thienopyrazole, substituted thienopyrazole, thienopyrazine, substituted thienopyrazine, chromen-2-one, substituted chromen-2-one, quinolin-2-one, and substituted quinolin-2-one.
  • a 1 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, monocyclic aryl, substituted monocyclic aryl, monocyclic heteroaryl, substituted monocyclic heteroaryl, fused-bicyclic aryl, substituted fused-bicyclic aryl, fused- bicyclic heteroaryl, or substituted fused-bicyclic heteroaryl.
  • a 1 is selected from the group consisting of Ci to C 6 alkyl, substituted Ci to C 6 alkyl, C 3 to C 7 cycloalkyl, substituted C 3 to C 7 cycloalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, furanyl, substituted furanyl, benzofuran, substituted benzofuran, indole, substituted indole, benzothiophene, substituted benzothiophene, benzooxazole, substituted benzooxazole, pyrazolopyridine, substituted pyrazolopyridine, dihydrobenzofuran, substituted dihydrobenzofuran,
  • thienopyridine substituted thienopyridine, thienopyrazole, substituted thienopyrazole, thienopyrazine, substituted thienopyrazine, chromen-2-one, substituted chromen-2-one, quinolin-2-one, and substituted quinolin-2-one.
  • Y 1 and Y 2 are independently Ci to C 3 alkylene or substituted Ci to C 3 alkylene; a and b are 1; and X is S, O, CH 2 ,NR 3 , -S(O)-, - S(0) 2 -, -C(O)-, or -C(S)-.
  • Y 1 is Ci to C 3 alkylene or substituted Ci to C 3 alkylene; a is 1; b is 0; and X is a covalent bond.
  • the compound of structural Formula (I) has a structural Formula (II):
  • Ar 1 and Ar 2 are independently aryl, substituted aryl, heteroaryl, or substituted heteroaryl; X is a covalent bond; and a and b are independently 0 or 1, but are not both 0.
  • the compound of structural Formula (I) has a structural Formula (III):
  • Ar 1 and Ar 2 are independently aryl, substituted aryl, heteroaryl, or substituted heteroaryl; and X is S, O, CH 2 , or NR 3 .
  • the compound of structural Formula (I) has a structural Formula (IV):
  • Ar 1 and Ar 2 are independently aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
  • the compound has a structure of the following: , or a mixture thereof.
  • Ar 1 and Ar 2 are independently monocyclic aryl, substituted monocyclic aryl, monocyclic heteroaryl, substituted monocyclic heteroaryl, fused-bicyclic aryl, substituted fused-bicyclic aryl, fused- bicyclic heteroaryl, or substituted fused-bicyclic heteroaryl.
  • the present invention provides compounds having the following structures:
  • the present compounds can be used for one or more methods of the present invention, e.g., modulating, e.g., reducing or alleviating, a bitter taste.
  • the present compounds can reduce or alleviate the bitter taste in a composition, such as coffee, coffee-flavored product, or a composition containing a whey protein, by contacting the present compounds with a composition to form a modified composition.
  • the compounds of the present invention are provided in compositions, such as, e.g., an ingestible composition.
  • the ingestible composition includes both "food or beverage products" and "non-edible products".
  • Food or beverage products any edible product intended for consumption by humans or animals, including solids, semi-solids, or liquids (e.g., beverages).
  • non- edible products or “noncomestible composition” includes supplements, nutraceuticals, functional food products (e.g., any fresh or processed food claimed to have a health- promoting and/or disease-preventing properties beyond the basic nutritional function of supplying nutrients), pharmaceutical and over the counter medications, oral care products such as dentifrices and mouthwashes, cosmetic products, and other personal care products that have bitter taste.
  • the ingestible composition also includes pharmaceutical, medicinal or comestible composition, or alternatively in a formulation, e.g., a pharmaceutical or medicinal
  • the compounds of Formula (I) and its various subgenuses, and their salts should preferably be comestibly acceptable, i.e. deemed suitable for consumption in food or drink from the perspective of giving unmodified comestible compositions an improved and/or reduced/alleviated bitter taste, and would not be significantly toxic or causes unpleasant or undesirable pharmacological or toxicological effects on an animal or human at the typically low concentrations they are employed as flavoring agents for the comestible compositions.
  • the typical method of demonstrating that a flavorant compound is comestibly acceptable is to have the compound tested and/or evaluated by an Expert Panel of the Flavor and Extract Manufacturers Association and declared as to be “Generally Recognized As Safe” ("GRAS").
  • GRAS Generally Recognized As Safe
  • the FEMA/GRAS evaluation process for flavorant compounds is complex but well known to those of ordinary skill in the food product preparation arts, as is discussed by Smith, et al. in an article entitled “GRAS Flavoring Substances 21," Food Technology, 57(5), pgs 46-59, May 2003, the entire contents of which are hereby incorporated herein by reference.
  • the present compounds can also be provided, individually or in combination, with any ingestible composition known or later discovered.
  • the ingestible composition can be a comestible composition or noncomestible composition.
  • “comestible composition” it is meant any composition that can be consumed as food by humans or animals, including solids, gel, paste, foamy material, semi-solids, liquids,or mixtures thereof.
  • noncomestible composition it is meant any composition that is intended to be consumed or used by humans or animals not as food, including solids, gel, paste, foamy material, semi-solids, liquids, or mixtures thereof.
  • the noncomestible composition includs, but is not limited to medical composition, which refers to a noncomestible composition intended to be used by humans or animals for therapeutic purposes.
  • “animal” it includes any non-human animal, such as, for example, farm animals and pets.
  • the present compound is added to a noncomestible composition or non-edible product, such as supplements, nutraceuticals, functional food products (e.g., any fresh or processed food claimed to have a health-promoting and/or disease-preventing properties beyond the basic nutritional function of supplying nutrients), pharmaceutical and over the counter medications, oral care products such as dentifrices and mouthwashes, cosmetic products and other personal care products that have a bitter taste.
  • a noncomestible composition or non-edible product such as supplements, nutraceuticals, functional food products (e.g., any fresh or processed food claimed to have a health-promoting and/or disease-preventing properties beyond the basic nutritional function of supplying nutrients), pharmaceutical and over the counter medications, oral care products such as dentifrices and mouthwashes, cosmetic products and other personal care products that have a bitter taste.
  • over the counter (OTC) product and oral hygiene product generally refer to product for household and/or personal use which may be sold without a prescription and/or without a visit to a medical professional.
  • OTC products include, but are not limited to Vitamins and dietary supplements; Topical analgesics and/or anaesthetic; Cough, cold and allergy remedies; Antihistamines and/or allergy remedies; and combinations thereof.
  • Vitamins and dietary supplements include, but are not limited to vitamins, dietary
  • Topical analgesics and/or anaesthetic include any topical creams/ointments/gels used to alleviate superficial or deep-seated aches and pains, e.g. muscle pain; teething gel; patches with analgesic ingredient; and combinations thereof.
  • Cough, cold and allergy remedies include, but are not limited to decongestants, cough remedies, pharyngeal preparations, medicated confectionery, antihistamines and child-specific cough, cold and allergy remedies; and combination products.
  • Antihistamines and/or allergy remedies include, but are not limited to any systemic treatments for hay fever, nasal allergies, insect bites and stings.
  • oral hygiene product include, but are not limited to mouth cleaning strips, toothpaste, toothbrushes, mouthwashes/dental rinses, denture care, mouth fresheners at-home teeth whiteners and dental floss.
  • the present compounds can be added to food or beverage products or formulations.
  • food and beverage products or formulations include, but are not limited to coatings, frostings, or glazes for comestible products or any entity included in the Soup category, the Dried Processed Food category, the Beverage category, the Ready Meal category, the Canned or Preserved Food category, the Frozen Processed Food category, the Chilled Processed Food category, the Snack Food category, the Baked Goods category, the Confectionary category, the Dairy Product category, the Ice Cream category, the Meal Replacement category, the Pasta and Noodle category, and the Sauces, Dressings, Condiments category, the Baby Food category, and/or the Spreads category.
  • the present compounds can be added to compositions comprising vegetable and/or non-vegetable proteins.
  • non- vegetable protein(s) means any protein(s), with the exception of vegetable proteins.
  • non- vegetable proteins include, but are not limited to proteins derived from milk (e.g., whey proteins, isolates and other dairy hydrolysates such as milk casein hydrolysates).
  • vegetable proteins means any plant and vegetable protein(s) including, without limitation, proteins from grains (e.g., wheat, corn, barley, oats, rye, millet, and buckwheat); proteins from nuts (e.g., walnuts, cashews, almonds, pecans); proteins from seeds (e.g., sunflower, pumpkin, hemp, and flax); proteins from legumes (e.g., beans, lentils, and garbanzos (chickpeas)); and proteins from rice and pea isolates.
  • grains e.g., wheat, corn, barley, oats, rye, millet, and buckwheat
  • proteins from nuts e.g., walnuts, cashews, almonds, pecans
  • proteins from seeds e.g., sunflower
  • the Soup category refers to canned/preserved, dehydrated, instant, chilled, UHT and frozen soup.
  • soup(s) means a food prepared from meat, poultry, fish, vegetables, grains, fruit and other ingredients, cooked in a liquid which may include visible pieces of some or all of these ingredients. It may be clear (as a broth) or thick (as a chowder), smooth, pureed or chunky, ready-to-serve, semi-condensed or condensed and may be served hot or cold, as a first course or as the main course of a meal or as a between meal snack (sipped like a beverage). Soup may be used as an ingredient for preparing other meal components and may range from broths (consomme) to sauces (cream or cheese-based soups).
  • “Dehydrated and Culinary Food Category” usually means: (i) Cooking aid products such as: powders, granules, pastes, concentrated liquid products, including concentrated bouillon, bouillon and bouillon like products in pressed cubes, tablets or powder or granulated form, which are sold separately as a finished product or as an ingredient within a product, sauces and recipe mixes (regardless of technology); (ii) Meal solutions products such as: dehydrated and freeze dried soups, including dehydrated soup mixes, dehydrated instant soups, dehydrated ready-to-cook soups, dehydrated or ambient preparations of ready-made dishes, meals and single serve entrees including pasta, potato and rice dishes; and (iii) Meal embellishment products such as: condiments, marinades, salad dressings, salad toppings, dips, breading, batter mixes, shelf stable spreads, barbecue sauces, liquid recipe mixes, concentrates, sauces or sauce mixes, including recipe mixes for salad, sold as a finished product or as an ingredient within a product, whether dehydrated,
  • the Beverage category usually means beverages, beverage mixes and concentrates, including but not limited to, carbonated and non-carbonated beverages, alcoholic and non-alcoholic beverages, ready to drink beverages, liquid concentrate formulations for preparing beverages such as sodas, and dry powdered beverage precursor mixes.
  • the Beverage category also includes the alcoholic drinks, the soft drinks, sports drinks, isotonic beverages, and hot drinks.
  • the alcoholic drinks include, but are not limited to beer, cider/perry, FABs, wine, and spirits.
  • the soft drinks include, but are not limited to carbonates, sucha as colas and non-cola carbonates; fruit juice, such as juice, nectars, juice drinks and fruit flavoured drinks; bottled water, which includes sparkling water, spring water and purified/table water; functional drinks, which can be carbonated or still and include sport, energy or elixir drinks; concentrates, such as liquid and powder concentrates in ready to drink measure.
  • the hot drinks include, but are not limited to coffee, such as fresh, instant, and combined coffee; tea, such as black, green, white, oolong, and flavored tea; and other hot drinks including flavour-, malt- or plant-based powders, granules, blocks or tablets mixed with milk or water.
  • the Snack Food category generally refers to any food that can be a light informal meal including, but not limited to, snacks and snack bars.
  • snacke food include, but are not limited to fruit snacks, chips/crisps, extruded snacks, tortilla/corn chips, popcorn, pretzels, nuts and other snacks.
  • snack bars include, but are not limited to granola/muesli bars, breakfast bars, energy bars, fruit bars and other snack bars.
  • the Baked Goods category generally refers to any edible product the process of preparing which involves exposure to heat or excessive sunlight.
  • baked goods include, but are not limited to bread, buns, cookies, muffins, cereal, toaster pastries, pastries, waffles, tortillas, biscuits, pies, bagels, tarts, quiches, cake, any baked foods, and any combination thereof.
  • the Ice Cream category generally refers to frozen dessert containing cream and sugar and flavoring. Examples of ice cream include, but are not limited to: impulse ice cream; take-home ice cream; frozen yoghurt and artisanal ice cream; oat, bean (e.g., red bean and mung bean), and rice-based ice creams.
  • the Confectionary category generally refers to edible product that is sweet to the taste.
  • Examples of confectionary include, but are not limited to candies, gelatins, chocolate confectionery, sugar confectionery, gum, and the likes and any combination products.
  • the Meal Replacement category generally refers to any food intended to replace the normal meals, particularly for people having health or fitness concerns. Examples of meal replacement include, but are not limited to slimming products and convalescence products.
  • the Ready Meal category generally refers to any food that can be served as meal without extensive preparation or processing. The ready meal includes products that have had recipe "skills" added to them by the manufacturer, resulting in a high degree of readiness, completion and convenience. Examples of ready meal include, but are not limited to canned/preserved, frozen, dried, chilled ready meals; dinner mixes; frozen pizza; chilled pizza; and prepared salads.
  • the Pasta and Noodle category includes any pastas and/or noodles including, but not limited to canned, dried and chilled/fresh pasta; and plain, instant, chilled, frozen and snack noodles.
  • the Canned/Preserved Food category includes, but is not limited to canned/preserved meat and meat products, fish/seafood, vegetables, tomatoes, beans, fruit, ready meals, soup, pasta, and other canned/preserved foods.
  • the Frozen Processed Food category includes, but is not limited to frozen processed red meat, processed poultry, processed fish/seafood, processed vegetables, meat substitutes, processed potatoes, bakery products, desserts, ready meals, pizza, soup, noodles, and other frozen food.
  • the Dried Processed Food category includes, but is not limited to rice, dessert mixes, dried ready meals, dehydrated soup, instant soup, dried pasta, plain noodles, and instant noodles.
  • the Chill Processed Food categroy includes, but is not limited to chilled processed meats, processed fish/seafood products, lunch kits, fresh cut fruits, ready meals, pizza, prepared salads, soup, fresh pasta and noodles.
  • the Sauces, Dressings and Condiments category includes, but is not limited to tomato pastes and purees, bouillon/stock cubes, herbs and spices, monosodium glutamate (MSG), table sauces, based sauces, pasta sauces, wet/cooking sauces, dry sauces/powder mixes, ketchup, mayonnaise, mustard, salad dressings, vinaigrettes, dips, pickled products, and other sauces, dressings and condiments.
  • MSG monosodium glutamate
  • table sauces based sauces
  • pasta sauces pasta sauces
  • wet/cooking sauces dry sauces/powder mixes
  • ketchup mayonnaise, mustard, salad dressings, vinaigrettes, dips, pickled products, and other sauces, dressings and condiments.
  • the Baby Food category includes, but is note limited to milk- or bean-based formula; and prepared, dried and other baby food.
  • the Spreads category includes, but is not limited to jams and preserves, honey, chocolate spreads, nut based spreads, and yeast based spreads.
  • the Dairy Product category generally refers to edible product produced from mammal's milk.
  • dairy product include, but are not limited to drinking milk products, cheese, yoghurt and sour milk drinks, and other dairy products.
  • comestible compositions include one or more confectioneries, chocolate confectionery, tablets, countlines, bagged selflines/softlines, boxed assortments, standard boxed assortments, twist wrapped miniatures, seasonal chocolate, chocolate with toys, alfajores, other chocolate confectionery, mints, standard mints, power mints, boiled sweets, pastilles, gums, jellies and chews, toffees, caramels and nougat, medicated confectionery, lollipops, liquorice, other sugar confectionery, gum, chewing gum, sugarized gum, sugar-free gum, functional gum, bubble gum, bread, packaged/industrial bread, unpackaged/artisanal bread, pastries, cakes, packaged/industrial cakes, unpackaged/artisanal cakes, cookies, chocolate coated biscuits, sandwich biscuits, filled biscuits, savory biscuits and crackers, bread substitutes, breakfast cereals, rte cereals, family breakfast cereals, flakes, muesli, other
  • condiments tomato pastes and purees, bouillon/stock cubes, stock cubes, gravy granules, liquid stocks and fonds, herbs and spices, fermented sauces, based sauces, pasta sauces, wet sauces, dry sauces/powder mixes, ketchup, mayonnaise, regular mayonnaise, mustard, salad dressings, regular salad dressings, low fat salad dressings, vinaigrettes, dips, pickled products, other sauces, dressings and condiments, baby food, milk formula, standard milk formula, follow-on milk formula, toddler milk formula, hypoallergenic milk formula, prepared baby food, dried baby food, other baby food, spreads, jams and preserves, honey, chocolate spreads, nut-based spreads, and yeast-based spreads.
  • Exemplary comestible compositions also include confectioneries, bakery products, ice creams, dairy products, sweet and savory snacks, snack bars, meal replacement products, ready meals, soups, pastas, noodles, canned foods, frozen foods, dried foods, chilled foods, oils and fats, baby foods, or spreads or a mixture thereof.
  • Exemplary comestible compositions also include breakfast cereals, beverages or solid or liquid concentrate compositions for preparing food and beverages, so as to reduce or alleviate the bitter taste in the food and beverages.
  • the concentration of the present compound needed to modulate or reduce the bitter flavor of the ingestible composition will of course depend on many variables, including the specific type of the ingestible composition and its various other ingredients, the natural genetic variability and individual preferences and health conditions of various human beings tasting the compositions, and the subjective effect of the particular compound on the taste of such chemosensory compounds.
  • the present compounds may be used in pharmaceutical compositions as a taste modulator, such as a bitter taste blocker.
  • the present compounds can be used to modulate the flavor or taste of pharmaceutical compositions.
  • the pharmaceutical compositions are administered to a patient via the oral route in a dosage form of solid, semi-solid, liquid, or mixtures thereof.
  • the present compound can be mixed with other ingredients including the therapeutically active ingredient and pharmaceutically acceptable vehicles.
  • a pharmaceutically acceptable vehicle is water. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid vehicles.
  • Suitable pharmaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the present pharmaceutical compositions can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • auxiliary, stabilizing, thickening, lubricating and coloring agents may be used.
  • compositions comprising a compound of the present invention may be manufactured by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries, which facilitate processing of compounds of the present invention into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. In one
  • the pharmaceutical compostion is a herbal composition, such as the traditional Chinese medicine (TCM).
  • TCM Chinese medicine
  • the present pharmaceutical compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders,
  • the pharmaceutically acceptable vehicle is a capsule (see e.g., Grosswald et ah, United States Patent No. 5,698,155).
  • suitable pharmaceutically acceptable vehicle is a capsule (see e.g., Grosswald et ah, United States Patent No. 5,698,155).
  • compositions for oral delivery may be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example.
  • Orally administered pharmaceutical compositions may contain one or more optionally agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry coloring agents and preserving agents, to provide a pharmaceutically palatable preparation.
  • suitable carriers, excipients or diluents include water, saline, alkyleneglycols ⁇ e.g., propylene glycol), polyalkylene glycols ⁇ e.g., polyethylene glycol) oils, alcohols, slightly acidic buffers between pH 4 and pH 6 ⁇ e.g., acetate, citrate, ascorbate at between about 5.0 mM to about 50.0 mM) etc.
  • flavoring agents, preservatives, coloring agents, bile salts, acylcarnitines and the like may be added.
  • the pharmaceutical compositions may take the form of tablets, lozenges, etc. formulated in conventional manner.
  • Liquid drug formulations suitable for use with nebulizers and liquid spray devices and EHD aerosol devices will typically include a compound of the present invention with a pharmaceutically acceptable vehicle.
  • the pharmaceutically acceptable vehicle is a liquid such as alcohol, water, polyethylene glycol or a perfluorocarbon.
  • another material may be added to alter the aerosol properties of the solution or suspension of compounds of the invention.
  • this material is liquid such as an alcohol, glycol, polyglycol or a fatty acid.
  • Other methods of formulating liquid drug solutions or suspension suitable for use in aerosol devices are known to those of skill in the art (see, e.g. , Biesalski, United States Patent No. 5,112,598; Biesalski, United States Patent No. 5,556,611).
  • At least a bitter flavor/taste modulating amount or a bitter flavor/taste enhancing amount of one or more of the present compound will be added to the ingestible composition so that the bitter flavor modified ingestible composition has a reduced bitter taste as compared to the ingestible composition prepared without the compounds of the present invention, as judged by human beings or animals in general, or in the case of formulations testing, as judged by a majority of a panel of at least eight human taste testers, via procedures commonly known in the field.
  • a broad but also low range of concentrations of the compounds or entities of the present invention would typically be required, i.e., from about 0.001 ppm to 100 ppm, or narrower alternative ranges from about 0.1 ppm to about 10 ppm, from about 0.01 ppm to about 30 ppm, from about 0.05 ppm to about 10 ppm, from about 0.01 ppm to about 5 ppm, or from about 0.02 ppm to about 2 ppm, or from about 0.01 ppm to about 1 ppm.
  • the present invention provides a method of preparing a compound of Formula (I):
  • R , R ⁇ Ar 1 , A , A X, Y , Y , a, b, and Z are the same as defined above.
  • Formula (I) also includes all the subgenus, such as Formua (II), Formula (III), and Formula
  • the method of preparing the compound of Formula (I) comprises:
  • reaction mixture a solution of compound of Formula (la) with an aqueous solution of compound of Formula (lb) and a first base at a temperature of about 25°C or lower to form a reaction mixture:
  • the mixing step comprises adding a portion of the solution of compound of Formula (la) to the aqueous solution of compound of Formula (lb) and a first base via infusion; and adding the remaining of the solution of compound of Formula (la) to the aqueous solution of compound of Formula (lb) and a first base in bolus.
  • the portion is about two third of the solution of compound of Formula (la), and the remaining is about one third of the solution of compound of Formula (la).
  • the mixing step is maintained at a temperature of about 20°C or lower, a temperature of about 15°C or lower, a temperature of about 10°C or lower, temperature of about 5°C or lower, a temperature of about 0°C or lower, a temperature of about -5°C or lower, or a temperature of about -10°C or above.
  • the reaction mixture obtained from the mixing step is maintained at the temperature of about 25°C or lower for about 15 minutes to about 180 minutes, about 30 minutes to about 120 minutes, about 45 minutes to about 90 minutes, or about 60 minutes.
  • the solvent for the solution of compound of Formula (la) can be any organic solvent or mixtures of organic solvents.
  • the solvent is an aprotic organic solvent miscible with water or an aqueous solution, such as dioxane.
  • the obtaining step comprises removing the first organic solvent from the washed organic extract to obtain a first crude material of compound of Formula (I); and purifying the first crude material of compound of Formula (I) without using chromatographic purification to obtain the compound of Formula (I) in a purified form.
  • the purifying step comprises crystallizing or recrystallizing the first crude material of compound of Formula (I).
  • the purifying step comprises dissolving the first crude material of compound of Formula (I) in a second organic solvent to obtain an organic solution;
  • the obtaining step comprises removing the fourth organic solvent from the second organic extract to obtain a second crude material of compound of Formula (I); and purifying the second crude material of compound of Formula (I) without using chromatographic purification to obtain the compound of Formula (I) in a purified form.
  • the purification of the second crude material of compound of Formula (I) is carried out by crystallizing or recrystallizing the second crude material of compound of Formula (I).
  • the first and second bases can be the same or different.
  • the first and second bases are
  • inorganic base examples of which include, but are limited to, sodium hydroxide, sodium carbonate, sodium hydrocarbonate, potasium hydroxide, potasium carbonate, potasium hydrocarbonate, and combinations thereof.
  • the acids used for acidification or washing the organic extract can be the same or different.
  • the acids are independently any inorganic acid, examples of which include, but are limited to, hydrochloride, sulfuric acid, nitric acid, and combinations thereof.
  • the first, second, third, and fourth organic solvents can be the same or different.
  • the first, second, third, and fourth organic solvents are independently aprotic solvents immiscible with water, the examples of which include, but are not limited to, diethyl ether, ethyl acetate,
  • the compound of Formula (la) is prepared by mixing a compound of Formula (Ic) Ar 1 ⁇ ⁇ OH wl th thionyl chloride in the absence of a solvent to form a reaction mixture; and obtaining the compound of Formula (la) without purifying the reaction mixture.
  • the present invention provides a method of preparing a compound of Formula (Ic):
  • R 1 is hydrogen, alkyl, or substituted alkyl
  • M is an alkali metal when n is 1; or M is an alkaline earth metal when n is 2;
  • Ar 1 is aryl, substituted aryl, heteroaryl, or substituted heteroaryl
  • a 1 is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl;
  • a 2 is a covalent bond, Ci to C 3 alkylene, substituted Ci to C 3 alkylene, -C(0)OCR 3 R 4 -
  • X is a covalent bond, S, O, CH 2 , NR 3 , -S(O)-, -S(0) 2 -, -C(O)-, or -C(S)-;
  • Y 1 and Y 2 are independently Ci to C 3 alkylene or substituted Ci to C 3 alkylene;
  • a and b are independently 0 or 1, but are not both 0;
  • Z is -S(O)-, -S(0) 2 -, -C(O)-, or -C(S)-;
  • R 3 and R 4 are independently hydrogen, alkyl or substituted alkyl; or R 3 and R 4 together with the atoms to which they are bonded, form a cycloheteroalkyl or substituted cycloheteroalkyl ring.
  • Z is -S(0) 2 - or -C(O)-.
  • a 2 is a covalent bond; and M is an alkali metal when n is 1.
  • a 2 is Ci to C 3 alkylene; and M is an alkali metal when n is 1.
  • a 2 is -C(0)NHCR 3 R 4 -; and M is an alkali metal when n is 1.
  • Ar 1 is monocyclic aryl, substituted monocyclic aryl, monocyclic heteroaryl, substituted monocyclic heteroaryl, fused-bicyclic aryl, substituted fused-bicyclic aryl, fused-bicyclic heteroaryl, or substituted fused-bicyclic heteroaryl.
  • Ar 1 examples include, but are not limited to, phenyl, substituted phenyl, naphthyl, substituted naphthyl, furanyl, substituted furanyl, benzofuran, substituted benzofuran, indole, substituted indole, benzothiophene, substituted benzothiophene, benzooxazole, substituted benzooxazole, pyrazolopyridine, substituted pyrazolopyridine, dihydrobenzofuran, substituted dihydrobenzofuran, thienopyridine, substituted
  • thienopyridine thienopyrazole, substituted thienopyrazole, thienopyrazine, substituted thienopyrazine, chromen-2-one, substituted chromen-2-one, quinolin-2-one, and substituted quinolin-2-one.
  • a 1 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, monocyclic aryl, substituted monocyclic aryl, monocyclic heteroaryl, substituted monocyclic heteroaryl, fused-bicyclic aryl, substituted fused-bicyclic aryl, fused-bicyclic heteroaryl, or substituted fused-bicyclic heteroaryl.
  • a 1 is selected from the group consisting of Ci to C 6 alkyl, substituted Ci to C 6 alkyl, C 3 to C 7 cycloalkyl, substituted C 3 to C 7 cycloalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, furanyl, substituted furanyl, benzofuran, substituted benzofuran, indole, substituted indole, benzothiophene, substituted benzothiophene, benzooxazole, substituted benzooxazole, pyrazolopyridine, substituted pyrazolopyridine, dihydrobenzofuran, substituted dihydrobenzofuran, thienopyridine, substituted thienopyridine, thienopyrazole, substituted thienopyrazole, thienopyrazine, substituted thienopyrazine, chromen-2-one, substituted chrome
  • Y 1 and Y 2 are independently Ci to C 3 alkylene or substituted Ci to C 3 alkylene; a and b are 1; and X is S, O, CH 2 ,NR 3 , -S(O)-, - S(0) 2 -, -C(O)-, or -C(S)-.
  • Y 1 is Ci to C 3 alkylene or substituted Ci to C 3 alkylene; a is 1; b is 0; and X is a covalent bond.
  • the compound of structural Formula (Ic) has a structural Formula (He):
  • Ar 1 and Ar 2 are independently aryl, substituted aryl, heteroaryl, or substituted heteroaryl; X is a covalent bond; and a and b are independently 0 or 1, but are not both 0.
  • the compound of structural Formula (Ic) has a structural Formula (IIIc):
  • Ar 1 and Ar 2 are independently aryl, substituted aryl, heteroaryl, or substituted heteroaryl; and X is S, O, CH 2 , or NR 3 .
  • the compound of structural Formula (Ic) has a structural Formula (IVc):
  • Ar 1 and Ar 2 are independently aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
  • the compound has a structure of the following: or a mixture thereof.
  • Ar 1 and Ar 2 are independently monocyclic aryl, substituted monocyclic aryl, monocyclic heteroaryl, substituted monocyclic heteroaryl, fused-bicyclic aryl, substituted fused-bicyclic aryl, fused- bicyclic heteroaryl, or substituted fused-bicyclic heteroaryl.
  • M is alkali metal or alkaline earth metal. In one embodiment of
  • the alkali metal is selected from the group consisting of lithium, sodium, potassium, rubidium, caesium, and francium.
  • the alkaline earth metal is selected from the group consisting of beryllium, magnesium; calcium, strontium, barium, and radium.
  • the compounds of Formula (Ic) include the M salt of the specific compounds described herein.
  • the compounds of Formula (Ic) include the sodium salt of the specific compounds described herein.
  • the method of preparing a compound of Formula (la) comprises
  • the mixing step comprises adding a portion of the solution of compound of Formula (la) to the aqueous solution of compound of Formula (le) and a first base via infusion; and adding the remaining of the solution of compound of Formula (la) to the aqueous solution of compound of Formula (le) and a first base in bolus.
  • the portion is about two third of the solution of compound of Formula (la)
  • the remaining is about one third of the solution of compound of Formula (la).
  • the mixing step is maintained at a temperature of about 20°C or lower, a temperature of about 15°C or lower, a temperature of about 10°C or lower, temperature of about 5°C or lower, a temperature of about 0°C or lower, a temperature of about -5°C or lower, or a temperature of about -10°C or above.
  • the reaction mixture obtained from the mixing step is maintained at the temperature of about 25°C or lower for about 15 minutes to about 180 minutes, about 30 minutes to about 120 minutes, about 45 minutes to about 90 minutes, or about 60 minutes.
  • the second organic extract is washed and concentrated prior to the adding step.
  • the obtaining step comprises collecting the compound of Formula
  • each of the collecting steps independently comprises filtering and washing.
  • the first and second bases can be the same or different.
  • the first and second bases are
  • inorganic base examples of which include, but are limited to, sodium hydroxide, sodium carbonate, sodium hydrocarbonate, potasium hydroxide, potasium carbonate, potasium hydrocarbonate, and combinations thereof.
  • the base containing M n+ has the counter ion selected from the group consisting of hydroxide, hydrocarbonate, carbonate, and a combination thereof.
  • the base can be sodium carbonate.
  • the acids used for acidification or washing the organic extracts can be the same or different.
  • the acids are independently any inorganic acid, examples of which include, but are limited to, hydrochloride, sulfuric acid, nitric acid, and combinations thereof.
  • each of the organic solvents can be the same or different.
  • the first, second, and third organic solvents are independently aprotic solvents immiscible with water, the examples of which include, but are not limited to, diethyl ether, ethyl acetate, dichloromethane, chloroform, and combinations thereof.
  • the compound of Formula (la) is prepared by mixing a compound of Formula (Ic) Ar OH w th thionyl chloride in the absence of a solvent to form a reaction mixture; and obtaining the compound of Formula (la) without purifying the reaction mixture.
  • the starting materials used in preparing the compounds of the invention i.e. the various structural subclasses and species of the compounds of the synthetic precursors of the present compounds of Formula (I), are often known compounds, or can be synthesized by known methods described in the literature, or are commercially available from various sources well known to those of ordinary skill in the art, such as for example, Sigma- Aldrich Corporation of St. Louis, Missouri USA and their subsidiaries Fluka and Riedel-de Haen, at their various other worldwide offices, and other well known chemical suppliers such as Fisher Scientific, TCI America of Philadelphia, PA, ChemDiv of San Diego, CA,
  • compounds IV can be prepared starting by the conversion of carboxylic acids I to the acid chlorides II. Subsequently, II can be coupled, under basic conditions, with various amino acids III to yield IV, directly, or the corresponding ester intermediate which can be hydro lyzed to give IV. Alternatively, a direct condensation of I with III in the presence of a variety of well known amide coupling reagents can also yield IV, directly, or the corresponding ester intermediate followed by hydrolysis of to give IV.
  • aryl halides IVa and IVd as well as the aryl triflate IVc can be submitted to appropriate palladium catalyzed "Suzuki” coupling reactions with various organic boronic acids and boronic esters to yield compounds IVe and byaryls IVf,
  • compounds IVe and IVf may be prepared by "Suzuki” coupling of IVg and IVh with various aryl halides and aryl Inflates.
  • coumarins la can be prepared in one step by condensation of various ort/zo-hydroxybenzaldehydes of Formula V with malonic acid VI. (see Kurien, P. N.; Pandya, K. C; Surange, V. R. J. Indian Chem. Soc. (1934), 11 823-6).
  • la can be prepared by condensation of various ort/zo-hydroxybenzaldehydes of Formula V with Meldrum's acid Via. (see Bandgar, B. P.; Uppalla, L. S.; Kurule, D. S. Green Chemistry (1999), 1(5), 243-245).
  • coumarins la can be prepared in two steps starting with the condensation of ort/zo-hydroxybenzaldehydes of Formula V with dialkyl malonates VIb followed by hydrolysis of the intermediate alkyl 2-oxo-2H-chromene-3-carboxylate. (see Hori, Yuichiro; Ueno, Hideki; Mizukami, Shin; Kikuchi, Kazuya. J. Am. Chem. Soc. (2009), 131(46), 16610-16611).
  • compound Ilia can be prepared by O-alkylation of the N- protected serine methyl ester VII with various alkyl halides in the presence of base, (see Faul, Margaret M.; Winneroski, Leonard L.; York, Jeremy S.; Reinhard, Matt R.; Hoying, Richard C; Gritton, William H.; Dominianni, Samuel J. Heterocycles (2001), 55(4), 689-704 and Vedejs, Edwin; Naidu, B. N.; Klapars, Artis; Warner, Don L.; Li, Ven-shun; Na, Younghwa; Kohn, Harold. J. Am. Chem. Soc. (2003), 125(51), 15796-15806).
  • Ilia can be prepared by refluxing VII in an acidic methanolic solution.
  • 5-phenylfuran-2-carboxylic acid 500 mg, 2.66 mmol was suspended in dry toluene (5mL) and treated with thionyl chloride (300 mg, ⁇ 10 equiv.). The mixture was heated to 80°C for 3 h and volatiles materials were removed under vacuum to yield the desired product as yellow solid which was used in the next step without further purification.
  • the reaction was then acidified at 0°C with a 2M aq. HC1 solution and extracted with diethyl ether.
  • the organic extract was washed (x3) with a 2M aq. HC1 solution and concentrated to give a light yellow sticky material. That material was dissolved in diethyl ether (25 mL) and while stirring, a 10%> aq. Na 2 C0 3 solution (200 mL), pre-cooled to 0°C, was added. Stirring continued at 0°C while slowly removing ethyl ether with a flow of nitrogen gas. During that time a white aqueous suspension is formed. After complete dispersion of the organic into the aqueous phase, a nice homogeneous white suspension was observed.
  • Example 4a (S)-3-(benzyloxy)-2-(5-bromofuran-2-carboxamido)propanoic acid Prepared as in Example 1 from 2-bromofuran-2-carbonyl chloride (Example 4b) and (S)-2- amino-3-(benzyloxy)propanoic acid. [M+H] + 368.
  • Example 5a (S)-3-(benzyloxy)-2-(4-bromofuran-2-carboxamido)propanoic acid Prepared as in Example 1 from 4-bromofuran-2-carbonyl chloride (Example 5b) and (S)-2- amino-3-(benzyloxy)propanoic acid. [M+H] + 368.
  • 4,5-Dibromofuran-2-carboxylic acid (5.5 g, 20.6 mmol) was suspended in water (63mL). Ammonium hydroxide (18mL) was added and the mixture was stirred vigorously at room temperature followed by the addition of Zn powder (1.3 g, 20.6 mmol). The reaction was stirred for 3 h at room temperature, filtered through celite and the clear solution was acidified to pH 2-3 with a 1M HCl solution. The product was extracted using ethyl acetate and the combined organic layer was evaporated under vacuum to give the final product which was used without further purification.
  • Example 5 Compounds described in Table D were prepared as Example 5 from (S)-3-(benzyloxy)-2-(4- bromofuran-2-carboxamido)propanoic acid (Example 5 a) and the corresponding aryl boronic acids.
  • Methyl 5-hydroxybenzofuran-2-carboxylate (192 mg, 1 mmol) was dissolved in DMF and placed in ice bath. 1-Bromobutane (205 mg, 1.5 mmol) was added, followed by the addition of NaH (60 mg, 60% in mineral oil, 1.5 mmol). The reaction was stirred in ice bath for 5 minutes and was irradiated using the microwave at 165°C for 5 minutes. The mixture was dissolved in ethyl acetate and washed with water and brine. The organic layer was evaporated under vacuum to give a residue that was suspended in 1M aqueous solution of LiOH (6mL) and heated in a capped vial at 70°C for lh.
  • LiOH LiOH
  • the reaction mixture was cooled down to room temperature and acidified to pH ⁇ 3 with 1M HC1 solution.
  • the product was extracted by ethyl acetate and the organic solution was evaporated under vacuum to give the title compound (50 mg). The compound was used in the next step without further
  • Example 7a Prepared as in Example 1 from 7-hydroxybenzofuran-2-carbonyl chloride (Example 7a) and (S)-2-amino-3-(benzyloxy)propanoic acid.
  • Example 7b 7-hydroxybenzofuran-2-carboxylic acid
  • the obtained ester intermediate was dissolved in ethanol (lmL) and added to a 1M NaOH solution (2mL). The reaction was heated in a capped vial at 80°C for 1 h. The reaction was washed with ethyl acetate and the aqueous layer was acidified using 1M HC1 to pH ⁇ 3. The product was extracted using ethyl acetate and the organic layer was evaporated under vacuum to give the title compound (22 mg, 71%).
  • Example 12a (R)-methyl 4-(benzyloxy)-3-(5-methoxybenzofuran-2- carboxamido)butanoate
  • Example 13 Prepared as in Example 13 from (S)-3-(4-bromophenyl-2-(5-methoxybenzofuran-2- carboxamido) propanoic acid (Example 13 a) and 3-hydroxyphenyl boronic acid to furnish (S)-3-(3'-hydroxy-[l, 1 '-biphenyl]-4-yl)-2-(5-methoxybenzofuran-2-carboxamido) propanoic acid (49 mg, 45%) as a white solid. [M+H] + 432.
  • Example 15 (S)-3-(2'-hydroxy-[l, l'-biphenyl]-4-yl)-2-(5-methoxybenzofuran-2- carboxamido) propanoic acid
  • Example 13 Prepared as in Example 13 from (S)-3-(4-bromophenyl-2-(5-methoxybenzofuran-2- carboxamido) propanoic acid (Example 13 a) and 2-hydroxyphenyl boronic acid to yield (S)- 3-(2'-hydroxy-[l, 1 '-biphenyl]-4-yl)-2-(5-methoxybenzofuran-2-carboxamido) propanoic acid (56 mg, 52%) as a white solid.
  • Example 13 Prepared as in Example 13 from (S)-3-(4-bromophenyl-2-(5-methoxybenzofuran-2- carboxamido) propanoic acid (Example 13 a) and 2-(methoxymethyl) phenyl boronic acid to give (S)-2-(5-methoxybenzofuran-2-carboxamido)-3-(2'-methoxymethyl-[l, 1 '-biphenyl]-4- yl)- propanoic acid (59 mg, 51%) as a white solid. [M+H] + 460.
  • Example 13 Prepared as in Example 13 from (S)-3-(4-bromophenyl-2-(5-methoxybenzofuran-2- carboxamido) propanoic acid (Example 13a) and methyl 3-boronobenzensulfonamide to yield (S)-2-(5-methoxybenzofuran-2-carboxamido)-3-(3'-(N-methylsulfamoyl)-[l, 1 '- biphenyl]-4-yl)- propanoic acid (55 mg, 45%) as a white solid.
  • Example 19a (S)-methyl 3-(2', 6'-dimethyl-[l, 1 'biphenyl]-4-yl)-2-(5- methoxybenzofuran-2-carboxamido) propanoate
  • Example 19b (S)-methyl-2-(5-methoxybenzofuran-2-carboxamido)-3-(4- (((trifluoromethyl) sulfonyl)oxy)phenyl) propanoate
  • Example 19 Compounds described in Table G were prepared as in Example 19 from the corresponding esters which were obtained as in Example 19a from (S)-methyl 2-(5-methoxybenzofuran-2- carboxamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)propanoate (Example 19b) and the appropriate boronic acids:
  • Example 29c 1 -(bromomethyl)-2-(methoxymethoxy)benzene
  • (2-(methoxymethoxy)phenyl)methanol (1.3 g, 7.7 mmol) in dichloromethane (10 mL) and triethylamine (1.4 mL, 10.0 mmol) at 0 °C was added methanesulfonyl chloride (774 uL, 10.0 mmol). The reaction was stirred for lh at 0 °C. The reaction was quenched with 0.1 M potassium carbonate, diluted with water, extracted with dichloromethane, filtered and evaporated.
  • Example 31a 3-(biphenyl-3-ylmethoxy)-2- (tritylamino)propanoate
  • Example 13b 5-methoxybenzofuran-2-carbonyl chloride
  • Example 31a (S)-methyl 3-(biphenyl-3-ylmethoxy)-2-(tritylamino)propanoate Prepared as in Example 28a from 4-(bromomethyl)biphenyl. Yield: 26%. MS: 528 [M+H].
  • Example 28 Prepared as in Example 28 from (S)-methyl 3-(3-methoxybenzyloxy)-2- (tritylamino)propanoate (Example 32a) and 5-methoxybenzofuran-2-carbonyl chloride (Example 13b). Yield: 40 %.
  • Example 32a (S)-methyl 3-(3-methoxybenzyloxy)-2-(tritylamino)propanoate Prepared as in Example 28a from l-(bromomethyl)-3-methoxybenzene Yield: 49 %. MS: 482 [M+H]
  • Example 34a (S)-methyl 3-(4-isopropylbenzyloxy)-2-(tritylamino)propanoate Prepared as in Example 28a from l-(bromomethyl)-4-isopropylbenzene Yield: 20 %. MS: 494 [M+H].
  • Example 35a (S)-ethyl 3-(benzyloxy)-2-(5-phenylfuran-2-carboxamido)propanoate Sodium carbonate (19.00 g) in water (190 mL) was cooled down to 0°C and (S)-ethyl 2- amino-3-(benzyloxy)propanoate hydrochloride (Example 35b) (10.56 g, 40.65 mmol) was added in one portion. The mixture was stirred at 0°C until complete disappearance of solid material. At this time, an oily suspension of organic free base is observed.
  • Human T2R61 and T2R67 stable cell lines were plated onto matrigel coated 384-well plates at a concentration of 20,000 cells per well. The cells were cultured overnight in DMEM medium supplemented with 10% fetal bovine serum. Before the assay, cells were loaded with Fluo-4 calcium dye (4.5 uM in DPBS) at room temperature for 1 hour. The assay was performed on FLIPR-3. For T2R61 cell line, aristolochic acid (20 nM) was used as the activator. For T2R67, andrographolide (1 uM) was used. Compounds of the present invention were added together with the activator molecule. For inhibition dose response curves, the compounds were tested in the concentration range of 40-0.16 uM. Compounds of the invention have shown IC 50 ⁇ 30 ⁇ for either human T2R61 or human T2R67.
  • Rebaudioside A samples with the antagonists were given to the taste panelists together with the same sample without antagonists, the panelists were asked to identify the bitterer sample within the pair. As shown in Table 4, the panelists consistently identified the Rebaudioside A sample without antagonist as being bitterer than the one with antagonist, indicating that the representative antagonist, i.e., Compound B, reduced the bitter taste of Rebaudioside A (1000 ppm). Compound B is one of the Examples as described above. Table 4. Rebaudioside A taste test results with T2R61/67 antagonist

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Abstract

La présente invention comprend des antagonistes de récepteurs de goût de type 2 humains (hT2R) ayant la formule structurale (I). La présente invention concerne en outre des compositions contenant ces antagonistes, l'utilisation de ces antagonistes pour moduler la perception du goût, en particulier un goût amer, et le procédé de préparation de ces antagonistes (I).
PCT/US2011/040491 2010-06-17 2011-06-15 Modulateurs de goût amer WO2011159781A2 (fr)

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US11179383B2 (en) 2018-10-30 2021-11-23 Gilead Sciences, Inc. Compounds for inhibition of α4β7 integrin
US11224600B2 (en) 2018-10-30 2022-01-18 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
US11292801B2 (en) 2016-07-05 2022-04-05 Blade Therapeutics, Inc. Calpain modulators and therapeutic uses thereof
US11578069B2 (en) 2019-08-14 2023-02-14 Gilead Sciences, Inc. Compounds for inhibition of α4 β7 integrin

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