sweet flavor modifier

专利摘要:
abstract sweet taste modifier the present invention includes compounds having structural formula (i), or salts or solvates thereof. these compounds are useful as sweet taste modifiers. the present invention also includes compositions comprising the present compounds and methods for enhancing the sweet taste of the compositions.
公开号:BR112014003285B1
申请号:R112014003285
申请日:2012-08-10
公开日:2020-01-14
发明作者:Tachdjian Catherine；S Karanewsky Donald；Zhang Feng；Servant Guy；Zhang Hong；Wong Melissa；Chen Qing；Davis Timothy；Selchau Victor；Darmohusodo Vincent；Qing Tang Xiao；Li Xiaodong
申请人:Firmenich Incorporated；Senomyx Inc；
IPC主号:

专利说明:

SWEET FLAVOR MODIFIER
REMISSIVE REFERENCE TO RELATED ORDERS
This claim claims the priority benefit of US Provisional Order 61 / 522,806, filed on August 12, 2011 and entitled “SWEET FLAVOR MODIFIER”. This application is related to US Patent Application 13 / 076,632, filed on March 31, 2011 and entitled “SWEET FLAVOR MODIFIER”, which claims the priority benefit of US Provisional Patent Application 61 / 320,528, filed on April 2 2010 and entitled “SWEET FLAVOR MODIFIER”, and US Patent Application 61 / 422,341, filed on December 13, 2010 and entitled “SWEET FLAVOR MODIFIER”. The contents of these requests are hereby incorporated by reference in their entirety for all purposes.
FIELD OF THE INVENTION
The invention relates to compounds suitable for the modification of receptors and their ligands associated with the chemosensory or related sensation or reaction such as the chemosensory.
BACKGROUND OF THE INVENTION
The taste system provides sensory information about the chemical composition of the outside world. The taste transduction is one of the most sophisticated forms of chemical sensation triggered in animals. Taste signaling is found throughout the animal kingdom, from simple metazoans to the most complex of vertebrates. It is believed that mammals have five basic taste modalities: sweet, bitter, sour, salty and umami (taste of monosodium glutamate, also known as salty taste).
Obesity, diabetes and cardiovascular disease are health problems on the rise worldwide, but they are growing at alarming rates in the United States. Sugar and calories are the main components that can be limited to have a positive effect on nutritional health. High-intensity sweeteners can provide sugar sweetening, with various taste qualities. Because they are often sweeter than sugar, much less of the sweetener is needed to replace sugar.
High intensity sweeteners have a wide range of chemically distinct structures and therefore have different properties, such as, without limitation, odor, taste, mouthfeel and aftertaste. These properties, especially aftertaste and aftertaste, are well known to vary over time, so that each
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2/96 temporal profile is specific to the sweetener (Tunaley, A., Perceptual Characteristics of Sweeteners, Progress in Sweeteners, T. H. Grenby, Ed. Elsevier Applied Science, 1989).
Sweeteners such as saccharin and potassium salt of 6-methyl-1,2,3-oxatiazin-4 (3H) one-2,2-dioxide, (acesulfame potassium) are generally characterized as having residual bitter and / or metallic flavors . Products prepared with 2,4-dihydroxybenzoic acid are claimed to exhibit reduced undesirable residual flavors associated with sweeteners, and to do so in concentrations below those at which their own tastes are noticeable. In addition, high-intensity sweeteners such as sucralose and aspartame are reported to have problems with sweetening distribution, that is, delayed onset and prolongation of sweetening (SG Wiet, et al., J. Food Sci., 58 ( 3): 599-602, 666 (1993)).
It has been reported that an extracellular domain, for example, the Venus trap domain of a chemosensory receptor, especially one or more sites of interaction within the Venus trap domain, is a suitable target for compounds or other entities to modulate the chemosensory receptor and / or its binders. Certain compounds have been reported as modulators of chemosensory receptors of the T1R family and / or their ligands and are described in the four patent applications listed below.
(1) US Patent Application 11 / 760,592, entitled “Modulation of Chemosensory Receptors and Ligands Associated Therewith”, filed on June 8, 2007; (2) US Patent Application 11 / 836,074, entitled “Modulation of Chemosensory Receptors and Ligands Associated Therewith”, filed on August 8, 2007; (3) US Patent Application 61 / 027,410, entitled “Modulation of Chemosensory Receptors and Ligands Associated Therewith”, filed on February 8, 2008; and (4) International Application PCT / US2008 / 065650, entitled “Modulation of Chemosensory Receptors and Ligands Associated Therewith”, filed on June 3, 2008. The contents of these orders are incorporated by reference in their entirety for all purposes.
There is a need in the art to develop new and inventive compounds suitable for the modification of receptors and / or their ligands associated with the chemosensory or chemosensory-related sensation or reaction.
SUMMARY OF THE INVENTION
In one embodiment, the present invention provides a compound having Structural Formula (I):
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(I), or a salt, solvate and / or prodrug thereof; on what
R ¹ and R ² are, independently, hydrogen or C1 to C6 alkyl;
L is C1 to C12 alkylene or C1 to C12 substituted alkylene;
M is -NR4-C (O) - or -C (O) -NR ⁴ -;
R ⁴ is hydrogen or C1 to C6 alkyl; or alternatively, when M is -NR ⁴ -C (O) -, R ⁴ and one or more L atoms, together with the nitrogen to which they are attached, form a 5- to 8-membered heterocyclic ring containing one to three heteroatoms selected from nitrogen, oxygen, and sulfur; and
R ³ is C1 to C12 alkyl, substituted C1 to C12 alkyl, 5- to 8-membered heterocyclyl, or substituted 5- to 8-membered heterocyclyl; or alternatively, when M is -C (O) -NR ⁴ -, R ⁴ and one or more atoms of R ³ , together with the nitrogen to which they are attached, form a 5- to 8-membered heterocyclic ring containing one to three heteroatoms selected from nitrogen, oxygen, and sulfur.
In another embodiment, the present invention provides an ingestible composition comprising a compound of the present invention, and an ingestibly acceptable excipient.
In another embodiment, the present invention provides a method for increasing the sweet taste of an ingestible composition, comprising contacting the ingestible composition, with a compound of the present invention to form a modified ingestible composition. In the method, the present compound can be a chemosensory receptor modifier, a chemosensory receptor ligand modifier, or both, i.e., a partial chemosensory receptor modifier and partial chemosensory receptor ligand modifier. For example, the present compound can be a sweet receptor agonist, or a sweet enhancer, or a partial sweet receptor agonist and partial sweet enhancer.
In another embodiment, the present invention provides a candy-enhancing composition, which comprises a compound of the present invention in an amount effective to provide sweetening in combination with a first amount of sweetener, in
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4/96 that sweetening is more than the sweetening provided by the first amount of sweetener without the compound.
In another embodiment, the present invention provides a flavor concentrate formulation comprising i) as a flavor-modifying ingredient, a compound of the present invention; ii) a carrier; and iii) optionally, at least one adjuvant.
In another embodiment, the present invention provides a method of treating a condition, disease or disorder associated with a chemosensory receptor, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present invention, or a salt, solvate, and / or prodrug thereof.
DETAILED DESCRIPTION OF THE INVENTION
These and other modalities, advantages and features of the present invention are provided in the sections below. Unless otherwise stated, all technical and scientific terms used herein have the same meaning as is commonly understood by a person versed in the technique to which this invention belongs.
Definitions "Alkyl," alone or as part of another substituent, refers to a saturated or unsaturated, straight chain, branched, or cyclic monovalent hydrocarbon radical derived from the removal of a hydrogen atom from a single carbon atom of an alkane, alkene or alkyne of origin. The term "alkyl" includes "cycloalkyl" as defined here below. Typical alkyl groups include, but are not limited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-in-1-yl, prop-2-in-1-yl, etc .; butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, but-1-en-1-yl , but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3 -dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobut-1,3-dien-1-yl , but-1-in-1-yl, but-1-in-3-yl, but-3-in-1-yl, etc .; and the like. The term "alkyl" is especially intended to include groups having any degree or level of saturation, that is, groups having exclusively single carbon-carbon bonds, groups having one or more carbon-carbon double bonds, groups having one or more bonds carbon-carbon triples and groups having mixtures of single, double and triple carbon-carbon bonds. When a specific level of saturation is targeted, the expressions “alkanyl,”
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5/96 “alkenyl,” and “alkynyl” are used. In some embodiments, an alkyl group comprises 1 to 20 carbon atoms (C ₁ -C ₂₀ alkyl). In other embodiments, an alkyl group comprises from 1 to 12 carbon atoms (C ₁ -C ₁₂ alkyl). In still other embodiments, an alkyl group comprises from 1 to 6 carbon atoms (C1-C6 alkyl). It is observed that when an alkyl group is still 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 ethyl, while -CH ₂ CH ₂ - is ethylene. That is, "Alkylene," alone or as part of another substituent, refers to a divalent saturated or unsaturated, branched, linear or cyclic hydrocarbon radical derived from the removal of two hydrogen atoms from a single carbon atom or two different carbon atoms of an alkane, alkene or alkyl of origin. The term "alkylene" includes "cycloalkylene" as defined here below. The term "alkylene" is especially intended to include groups having any degree or level of saturation, that is, groups having exclusively single carbon-carbon bonds, groups having one or more carbon-carbon double bonds, groups having one or more bonds carbon-carbon triples and groups having mixtures of single, double and triple carbon-carbon bonds. When a specific saturation level is intended, the terms "alkanylene,""alkenylene," and "alkynylene" are used. In some embodiments, 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 12 carbon atoms (C ₁ -C ₁₂ alkylene). In still other embodiments, an alkylene group comprises from 1 to 6 carbon atoms (C 1 -C 6 alkylene).
"Alkyl," alone or as part of another substituent, refers to a branched, straight-chain or cyclic saturated alkyl radical derived from the removal of a hydrogen atom from a single carbon atom of an origin alkane. The term "alkanyl" includes "cycloalkyl" as defined here below. Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl, etc .; butanyls such as butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl), 2-methyl-propan-2-yl (t-butyl), cyclobutan- 1-il, etc .; and the like.
"Alkenyl," by itself or as part of another substituent, refers to a branched, straight-chain or cyclic unsaturated alkyl radical having at least one carbon-carbon double bond derived from the removal of a hydrogen atom from a single
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6/96 carbon atom of an alkene of origin. The term "alkenyl" includes "cycloalkenyl" as defined here below. The group may be in either the cis or trans configuration on the double bond (s). Typical alkenyl groups include, but are not limited to, ethylene; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1- en-1-yl; cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2 -en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl , cyclobut-1-en-3-yl, cyclobut-1,3-dien-1-yl, etc .; and the like.
"Alquinyl," alone or as part of another substituent refers to a branched, straight-chain or cyclic unsaturated alkyl radical having at least one carbon-carbon triple bond derived from the removal of a single atom hydrogen atom of carbon gives an alkaline of origin. Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-in-1-yl, prop-2-in-1-yl, etc .; butynyls such as but-1-in-1-yl, but-1-in-3-yl, but-3-in-1-yl, etc .; and the like.
"Alkoxy" alone or as part of another substituent, refers to a radical of the formula -OR ¹⁹⁹ , where R ¹⁹⁹ is alkyl or substituted alkyl as defined herein.
"Acyl" alone or as part of another substituent refers to a radical -C (O) R ²⁰⁰ , where R ²⁰⁰ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, heteroalkyl substituted, heteroarylalkyl or substituted heteroarylalkyl as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl and the like.
"Aril," alone or as part of another substituent, refers to a monovalent aromatic hydrocarbon group derived from the removal of a hydrogen atom from a single carbon atom from an original aromatic ring system, as defined here . Typical aryl groups include, but are not limited to, groups derived from aceanthrene, acenaphthene, acephenanthrene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexafene, hexalene, as-indacene, s-indacene, indane , indene, naphthalene, octacene, octafen, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentafene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaftalen and the like. In some embodiments, an aryl group comprises 6 to 20 carbon atoms (C ₆ -C ₂₀ aryl). In other modalities,
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7/96 an aryl group comprises from 6 to 15 carbon atoms (C ₆ -C ₁₅ aryl). In still other embodiments, an aryl group comprises 6 to 15 carbon atoms (C ₆ -C ₁₀ aryl).
"Arylalkyl," alone or as part of another substituent, refers to a cyclic alkyl group in which one of the hydrogen atoms attached to a carbon atom, typically a terminal carbon atom or sp ', is replaced with a aryl group, as defined here. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethane-1-yl and the like. Where specific alkyl fractions are intended, the nomenclature arylalkanyl, arylalkenyl and / or arylalkynyl is used. In some embodiments, an arylalkyl group is (C6-C30) arylalkyl, for example, 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 . In other embodiments, an arylalkyl group is (C6-C20) arylalkyl, for example, the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C ₁ -C8) alkyl and the aryl moiety is (C ₆ -C ₁₂ ) aryl. In still other embodiments, an arylalkyl group is (C ₆ -C ₁₅ ) arylalkyl, for example, the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C ₁ -C ₅ ) alkyl and the aryl fraction is (C ₆ -C ₁₀ ) aryl.
"Cycloalkyl," or "Carbocyclyl," alone or as part of another substituent, refers to a cyclic saturated or unsaturated alkyl radical, as defined herein. Similarly, "Cycloalkylene," or "Carbocyclylene," by itself or as part of another substituent, refers to a cyclic saturated or unsaturated 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. In some embodiments, the cycloalkyl group comprises 3 to 10 ring atoms (C ₃ -C ₁₀ cycloalkyl). In other embodiments, the cycloalkyl group comprises 3 to 7 ring atoms (C ₃ -C ₇ cycloalkyl). Cycloalkyl may be substituted by one or more heteroatoms including, but not limited to, N, P, O, S, and Si, which are attached to the carbon atoms of cycloalkyl via monovalent or multivalent bonding.
“Heteroalkyl,” “Heteroalkanyl,” “Heteroalkenyl” and “Heteroalkynyl,” alone 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 of the associated hydrogen atoms), are each, independently of each other, replaced with the same or different groups of heteroatoms or heteroatoms. In
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8/96 similarly, “Heteroalkylene,” “Heteroalkanylene,” “Heteroalkenylene” and “Heteroalkynylene,” by themselves or as part of other substituents, refer to alkylene, alkanylene, alkenylene and alkylene groups, respectively, in which one or more of the carbon atoms (and optionally any of the associated hydrogen atoms), are each, independently of each other, replaced with the same or different groups of heteroatoms or heteroatoms. Groups of typical heteroatoms or heteroatoms that can replace carbon atoms include, but are not limited to, -O-, -S-, -N-, -Si-, -NH-, -S (O) -, -S (O) 2-, -S (O) NH-, -S (O) 2NH- and the like and combinations thereof. The groups of heteroatoms or heteroatoms can be placed in the inner position of the alkyl, alkenyl or alkynyl groups. The heteroatomic groups that can be included in these groups include, but are not limited to, -O-, -S-, -OO-, -SS-, -OS-, -NR ²⁰¹ R ²⁰² -, = NN =, -N = N-, -N = N-NR ²⁰³ R ²⁰⁴ , -PR ²⁰⁵ -, -P (O) 2-, -POR ²⁰⁶ -, -OP (O) 2-, -SO-, -SO2-, -SnR 207 _d 208 «A * viAlkn * i + Afl D 201 τι 202 tj203 tj204 tj205 tj206 t> 207 tj208
R - and the like, where R, R, R, R, R, R, R and R are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl , substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl.
"Cycloheteroalkyl," or "Heterocyclyl," alone or as part of another substituent, refers to a cyclic saturated or unsaturated alkyl radical in which one or more carbon atoms (and optionally any of the hydrogen atoms associated) are independently substituted with the same or different heteroatom. Similarly, "Cyclo-heteroalkylene," or "Heterocyclylene," alone or as part of another substituent, refers to a cyclic saturated or unsaturated alkylene radical in which one or more carbon atoms (and optionally any of the associated hydrogen atoms) are independently substituted with the same or different heteroatom. The cycloheteroalkyl can be substituted by one or more heteroatoms including, but not limited to, N, P, O, S, and Si, which are attached to the carbon atoms of the cycloheteroalkyl through monovalent or multivalent bonding. Typical heteroatoms to replace the carbon atom (s) include, but are not limited to, N, P, O, S, Si, etc. Where a specific saturation level is intended, nomenclature “Cycloheteroalkanyl” or “cycloheteroalkenyl” is used. Typical cycloheteroalkyl groups include, but are not limited to, groups derived from epoxides, azirines, ti2699673 v1 / ST
9/96 irans, imidazolidine, morpholino, piperazine, piperidine, pyrazolidine, pyrrolidone, quinuclidine, and the like. In some embodiments, the cycloheteroalkyl group comprises 3 to 10 ring atoms (3-10 membered cycloheteroalkyl). In other embodiments, the cycloalkyl group comprises 5 to 7 ring atoms (5-7 membered cycloheteroalkyl). A cycloheteroalkyl group can be substituted on the heteroatom, for example, a nitrogen atom, with a (C ₁ -C ₆ ) alkyl group. As specific examples, N-methyl-imidazolidinyl, N-methyl-morpholinyl, N-methyl-piperazinyl, N-methyl-piperidinyl, N-methyl-pyrazolidinyl and N-methyl-pyrrolidinyl are included within the definition of “cycloheteroalkyl. " A cycloheteroalkyl group can be attached to the remainder of the molecule through a ring carbon atom or a ring heteroatom.
Compounds refer to compounds covered by the structural formulas disclosed herein, such as (I), (Ia) and (Ib), and include any specific compounds within these formulas, the structure of which is disclosed herein. The compounds can be identified either by their chemical structure and / or by their chemical name. When the chemical structure and chemical name come into 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, can exist as stereoisomers, such as double bonded isomers (i.e., geometric isomers), enantiomers or diastereomers. Accordingly, the chemical structures described here cover all possible enantiomers and stereoisomers of the compounds illustrated including the stereoisomerically pure form (for example, geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers, using separation techniques or chiral synthesis techniques well known to those skilled in the art. The compounds can also exist in various tautomeric forms, including the enol form, the keto form and mixtures thereof. Therefore, the chemical structures described here encompass all possible tautomeric forms of the illustrated compounds. The term tautomer as used herein refers to isomers that change to each other with great ease, so that they can coexist in equilibrium. In general, the compounds can be hydrated, solvated or Noxides. Certain compounds can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent to the uses contemplated herein and are intended to be within the scope of the present invention. In addition, it should be understood that when
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10/96 partial structures of the compounds are illustrated, in parentheses it indicates the point of attachment of the partial structure to the rest of the molecule.
"Halo," by itself or as part of another substituent refers to a -F, -Cl, -Br or -I radical.
"Heteroaryl," by itself or as part of another substituent, refers to a monovalent heteroaromatic radical derived from the removal of a hydrogen atom from a single atom of a parent heteroaromatic ring system, as defined herein. Typical heteroaryl groups include, but are not limited to, groups derived from acridine, β-carboline, chroman, chromene, cinoline, 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, pyrazol, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinoline, quinoline, quinoline, quinoline, quinoline thiadiazole, thiazole, thiophene, triazole, xanthene, and the like. In some embodiments, the heteroaryl group comprises 5 to 20 ring atoms (5 to 20 membered heteroaryl). In other embodiments, the heteroaryl group comprises 5 to 10 ring atoms (5 to 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" alone or as part of another substituent refers to a cyclic alkyl group in which one of the hydrogen atoms attached to a carbon atom, typically a terminal carbon atom or sp ³ , is replaced with a group of heteroaryl. Where specific alkyl fractions are intended, heteroarylalkanyl, heteroarylalkenyl and / or heteroarylalkynyl nomenclature is used. In some embodiments, the heteroarylalkyl group is a 6-21 membered heteroarylalkyl, for example, the alkanyl, alkenyl or alkynyl fraction of the heteroarylalkyl is (C1-C6) alkyl and the heteroaryl fraction is a 5-15-membered heteroaryl. In other embodiments, heteroarylalkyl is a 6-13 membered heteroarylalkyl, for example, the alkanyl, alkenyl or alkynyl fraction is (C ₁ -C ₃ ) alkyl and the heteroaryl fraction is a 5-10 membered heteroaryl.
“Protection group” refers to the grouping of atoms that when attached to a reactive functional group in a molecule masks, reduces or prevents the reactivity of the functional group. Examples of protection groups can be found in Green et al., “Protective Groups in Organic Chemistry”, (Wiley, 2 ^nd ed. 1991) and Harrison et al.,
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11/96 “Compendium of Sinthetic Organic Metods”, Vols. 1-8 (John Wiley and Sons, 1971-1996). Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylasilyl ("TMS"), 2-trimethylasilyl-ethanesulfonyl (“SES”), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl (“NVOC”) and the like. Representative 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 has 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, cyclopentanopropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo acid [2.2.2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphonic acid, salicylic acid, stearic acid, muconic acid and the like; or (2) salts formed when an acidic proton in the source compound is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion, or an aluminum ion, or if it coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like.
Solvate means a compound formed by solvation (the combination of solvent molecules, with molecules or solute ions), or an aggregate consisting of an ion or solute molecule, that is, a compound of the present invention, with one or more molecules solvent. When water is the solvent, the corresponding solvate is hydrate.
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N-oxide, also known as amine oxide or amine-N-oxide, means a compound that is derived from a compound of the present invention through the oxidation of an amine group of the compound of the present invention. An N-oxide typically contains the functional group R3N + -O- (sometimes written as R ₃ N = O or R ₃ N> O).
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 each other, replaced by the same or different substituent (s). Substituent groups useful for substituting saturated carbon atoms in the specified group or radical include, but are not limited to -R ^a , halo, -O ^- , —π m ^b çm ^b c ^- —ç xn ^c T ^c —xn ^b —wm ^b + rí = O, -OR, -SR, -S, = S, -NR R, = NR, = N-OR, trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, —XT XT C / Μλ T B X.TT br~ Q.ÍC \ OT B ríC / fVv T> b ΓίΟΎΓίλ C ~ C Q.ÍC \ OT B = N ₂ , -N ₃ , -S (O) ₂ R, -S (O) ₂ NR, -S (O) ₂ O, -S (O) ₂ OR, -OS (O) ₂ R, -OS (O) ₂ O, -OS (O) ₂ OR
TVnVCW PfAVCVD ^b VrYA PfAVCVD ^b VrVD ^b A CfA D ^b CfQ D ^b CrKTD ^b YD ^b CfAAfY, -P (O) (O) 2, -P (O) (OR) (O), -P (O) (OR) (OR), -C (O) R, -C (S) R, -C (NR) R, -C (O) O, rVnAriP ^b CÍQAm ^b CínYMP ^c P ^c CrMP ^b ANTP ^c P ^c ArYnYP ^b AfYQVP ^b ΑΡίΓΛΓΤ ΩΓ / C (O) OR, -C (S) OR, -C (O) NR R, -C (NR) NR R, -OC ( O) R, -OC (S) R, -OC (O) O, -OC (AArn ^B ACÍQArn ^B NTP ^b CÍAYP ^b NTP ^b CÍQYP ^b NrP ^b CÍAArY NTP ^b CÍAArn ^B NTP ^b rVQAA O) OR, -OC (S) OR, -NR C (O) R, -NR C (S) R, -NR C (O) O, -NR C (O) OR, -NR C (S) OR ^b , -NR ^b C (O) NR ^c R ^c , -NR ^b C (NR ^b ) R ^b and -NR ^b C (NR ^b ) NR ^c R ^c , where R ^a is selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, heteroalkyl, 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 can be taken together with the nitrogen atom to which they are attached to form a 4-, 5-, 6or 7-membered heteroalkyl which can optionally include 1 to 4 of the same additional heteroatoms or different heteroatoms selected from the group consisting of O, N and S. As specific examples, -NR ^c R ^c is intended to include -NH2, -NH-alkyl, N-pyrrolidinyl and N- morpholinyl. As another specific example, a substituted alkyl is intended to include -alkylene-O-alkyl, -alkylene-heteroaryl, -alkylene-cycloheteroalkyl, -C (O) OR ^b , -alkylene-C (O) NR ^b R ^b , and -CH ₂ -CH ₂ -C (O) -CH ₃ . The one or more substituent groups, taken together with the atoms to which they are attached, can form a cyclic ring including cycloalkyl and cycloheteroalkyl.
Similarly, substituent groups useful for replacing unsaturated carbon atoms in the specified group or radical include, but are not limited to, -R ^a , halo, -O, -OR, -SR, -S, -NR R, trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N3, -S (O) 2R ^b , -S (O) 2O ^- , -S (O) 2OR ^b , -OS ( O) 2R, -OS (O) 2O, -OS (O) 2OR, -P (O) (O) 2, -P (O) (OR) (O), -P (O) (OR) (OR ), -C (O) R, 2699673 v1 / ST
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CÍQVP ^b C / NTP ^b YP ^b ΡίΓΛΓΥ CÍAAriP ^b CÍQACVP ^b CÍAYKTP ^c P ^c C / NTP ^b ANTP ^c P ^c COíÁj C (S) R, -C (NR) R, -C (O) O, -C (U ) UK, -C (S) UK, -L (U) NK R, -C (NR) NR R, -UC (U) R ^b AfVQYP ^b Í ACÍQAm ^b NTP ^b Cín P ^b NTP ^b CÍQVP ^b NTP ^b rvnA, -UC (0) K, -UC (U) U, -UC (U) UR, -UC (0) UK, -NR C (O) R , -NR C (S) R, -NR C (O) O- xmffw / - t) b · τηbp / c / - t) b χττ> b ^ // a amct> c xmb ^ / ambx-rjb _Λ xmb ^ Amb ^^ n ^ c, -NR C (O) OR, -NR C (S) OR, -NR C (O) NR R, -NR C (NR) R and -NR C ( NR) NR R, where R ^a , R ^b and R ^c are as previously defined.
Substituting groups useful for substituting nitrogen atoms in the heteroalkyl and cycloheteroalkyl groups include, but are not limited to α T ^at m ^b Qü ^b Q NTP ^c P ^c + rí a, -R, -O, -OR, -SR, -S, -NR R, trihalomethyl, -CF3, -CN, -NO, -NO2, -S (O) 2R ^b , -S (O) 2O-, -S (O) 2OR ^b , -OS (O) 2R ^b , -OS (O) 2O-, AQfnA CVD ^b PfAVfYA PfnVCVD ^b VfYA PfAVCVD ^b VrVD ^b A CfA D ^b CfQYD ^b CrKTD ^b YD ^b -OS (O) 2OR, -P (O) (O) 2, -P (O) (OR) (O), -P (O) (OR) (OR), -C (O) R, -C (S) R, -C (NR) R
CÍAAriP ^b CÍQAriP ^b CÍAYKTP ^c P ^c C / NTP ^b ANTP ^c P ^c ArYAYP ^b AfVQYP ^b ACÍAAriP ^b , -C (O) OR, -C (S) OR, -C (O) NR R, -C (NR) NR R, -OC (O) R, -OC (S) R, -OC (O) OR, ACÍQAriP ^b NTP ^b CÍAYP ^b NTP ^b CÍQYP ^b NTP ^b CÍAAriP ^b NTP ^b CÍQAriP ^b NTP ^b CÍAYKTP ^c P ^{c c}
OC (S) OR, -NR C (O) R, -NR C (S) R, -NR C (O) OR, -NR C (S) OR, -NR C (O) NR R, NR ^b C (NR ^b ) R ^b and -NR ^b C (NR ^b ) NR ^c R ^c , where R ^a , R ^b and R ^c are as previously defined.
Substituent groups in the lists above useful for the replacement of other specified groups or atoms will be evident to those skilled in the art.
Substituents used to replace a specified group may be further substituted, typically with one or more of the same or different groups selected from the various groups specified above.
Treating or treating any condition, disease or disorder refers to ameliorating the condition, disease or disorder (i.e., interrupting or reducing the development of the condition, disorder or disease, or at least one of its clinical symptoms). In other modalities, treatment or treatment refers to the softening of at least one physical parameter, which may not be perceived by the patient. In still other modalities, treating or treating refers to the inhibition of the condition, disease or disorder, either physically (for example, stabilization of a noticeable symptom), physiologically, (for example, stabilization of a physical parameter) or both. In still other modalities, treating or treating refers to delaying the onset of the condition, disease or disorder.
Therapeutically effective amount means the amount of the compound present which, when administered to a patient to treat a condition, disease or disorder, is sufficient to effect such treatment for the condition, disease or disorder. The therapeutically effective amount will vary depending on the compound, the condition, the disease or disorder and its severity and the age, weight, etc., of the patient to be treated. In one embodiment, the therapeutically effective amount is different from the amount
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14/96 flavor modulating, such as a modulating amount of the sweet receptor, a modulating amount of sweet receptor binder, a modulating amount of sweet flavor, an amount of the sweet flavoring agent, or an intensifying amount of sweet flavor.
Vehicle refers to a diluent, adjuvant, excipient or carrier with which a compound is administered.
As used herein, an ingestible composition includes any substance that, alone or in conjunction with another substance, can be taken orally, whether for consumption or not. The ingestible composition includes both food and drink products and inedible products. Food products or beverages means any edible product intended for consumption by humans or animals, including solids, semi-solids or liquids (for example, drinks). The term inedible products or inedible composition includes any product or composition that can be taken by humans or animals for purposes other than consumption or as food or drink. For example, the inedible product or inedible composition includes supplements, nutraceuticals, functional food products (for example, all raw or processed food alleged to have health-promoting properties and / or to prevent diseases beyond the basic nutritional function of providing nutrients), pharmaceuticals and over-the-counter medications, oral care products such as toothpastes and mouthwashes, cosmetic products such as sugary lip balms and other personal care products, which may or may not contain any sweetener.
An ingestibly acceptable carrier or excipient is a medium and / or composition that is used to prepare a desired dispersed dosage form of the compound of the invention, in order to administer the compound of the invention in a diluted / dispersed form, so that the biological efficacy of the compound of the invention is maximized. The medium and / or the composition can be in any form, depending on the intended use of the product, for example, solid, semi-solid, liquid, paste, gel, lotion, cream, foamy material, suspension, solution, or any combinations thereof ( such as a liquid containing solids). Ingestibly acceptable carriers include many common food ingredients, such as water at neutral, acidic or basic pHs, fruit or vegetable juices, vinegar, marinades, beer, wine, natural water / fat emulsions, such as milk or condensed milk, edible oils and fats, fatty acids and their esters of
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15/96 alkyl, low molecular weight propylene glycol oligomers, fatty acid glyceryl esters, and dispersions or emulsions of such hydrophobic substances in aqueous media, salts such as sodium chloride, wheat flour, solvents such as ethanol , solid edible diluents, such as vegetable powders or flours, or other liquid vehicles, dispersion or suspension aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives; solid binders, lubricants and the like.
According to the present invention, a chemosensory receptor can be any receptor associated with signal transduction triggered by the chemosensory sensation or chemosensory ligand, for example, through taste receptors or taste related receptors expressed in the taste buds or internal organs of the body , such as the gastrointestinal tract, etc. In one embodiment, a chemosensory receptor is a receptor that belongs to the superfamily of transmembrane-7 receptors or G protein-coupled receptors (GPCRs). In another embodiment, a chemosensory receptor is a receptor that performs signal transduction through one or more G proteins. In yet another embodiment, a chemosensory receptor is a receptor that belongs to the C or class C family of GPCRs. In yet another embodiment, a chemosensory receptor is a receptor that belongs to the T1R family. In yet another embodiment, a chemosensory receptor is a T1R1, T1R2, T1R3 receptor, or its equivalences or variations or a combination thereof. In yet another embodiment, a chemosensory receptor is a heterodimer of T1R2 and T1R3, or their equivalences or variations.
An enhancer refers to a compound, or an ingestibly acceptable salt or solvate, that modulates (increases) the activation of a particular receptor, preferably a chemosensory, for example, T1R2 / T1R3 receptor. Here, these enhancers will enhance the activation of a chemosensory receptor by its ligand. Normally, the enhancer will be specific to a particular ligand, that is, it will not enhance the activation of a chemosensory receptor by chemosensory ligands other than the ligands or the particular chemosensory ligand closely related to it. Some intensifiers, in their concentration of ligand intensification, do not result in activation of the particular receptor by itself. That is, the ligand-enhancing concentrations of these enhancers are the concentration levels of the enhancers that increase or intensify the activation of a particular receptor by a ligand, without activating
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16/96 substantially the particular receiver by the intensifiers themselves. In some embodiments, some enhancers, when used at a higher concentration than the enhancer concentration of the ligand, can also activate a particular receptor by itself, in addition to modulating (for example, increasing or intensifying) receptor activation. For example, certain enhancers, when used at a higher concentration than the enhancer concentration of the binder, can be sweeteners (eg sweet flavoring agent / entity) as well. In other embodiments, some intensifiers can activate a particular receptor by itself, in addition to modulating (for example, increasing or intensifying) the activation of the receptor, simultaneously, with the same concentration. In other words, certain enhancers are also sweeteners (for example, sweet flavoring agent / entity) at the same time.
A flavor in this document refers to the perception of taste in a subject, which includes sweet, sour, salty, bitter and umami. The subject can be a human or an animal.
A flavoring agent here refers to an ingestibly acceptable compound or salt or solvate of which induces a taste or taste, in an animal or a human. The flavoring agent can be natural, semi-synthetic, or synthetic.
A flavor modifier or flavor modifying agent herein refers to a compound or ingestibly acceptable salt or solvate thereof, which modulates, including intensification or enhancement, and / or induction, the flavors of a flavoring agent in an animal or human.
A flavor enhancer here refers to a compound or its ingestibly acceptable salt thereof that enhances and / or multiplies the tastes of a flavoring agent, or an ingestible composition, comprising the flavoring agent.
A sweet taste refers to the sweet taste typically induced by sugar, such as sucrose, in an animal or a human.
A sweet flavoring agent, sweet-tasting entity, sweetener or sweet compound, refers to an ingestible compound or salt thereof that causes a detectable sweet taste in a subject, for example, sucrose or a compound that activates a T1R2 receptor. / T1R3 in vitro. The subject can be a human or an animal.
A sweet taste modifier, or sweet taste modifying agent, refers to a compound or ingestibly acceptable salt or solvate thereof, which modulates,
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17/96 including intensifying or enhancing, inducing, or blocking, the sweet taste of a sweet flavoring agent in an animal or a human. The sweet flavor modifier includes both the sweet flavor enhancer and the sweet flavoring agent.
A sweet flavor enhancer or sweet flavor enhancing agent refers to a sweet flavor enhancer, where the term enhancer is the same as defined above.
A candy receptor activating compound or candy receptor agonist refers to a compound that activates a candy receptor, such as a T1R2 / T1R3 receptor. An example of a sweet receptor activating compound is a sweetener, such as sucrose.
A candy receptor modulation compound refers to a compound that modulates (activates, blocks or enhances / reduces the activation of) a candy receptor, such as a T1R2 / T1R3 receptor.
A candy receptor enhancing compound refers to a compound that enhances or enhances the effect of a candy receptor activating compound, for example, sucrose.
While most sweet receptor-enhancing or sweet-tasting enhancer compounds, in their use-enhancing binder concentration, do not result in activation of the particular receptor per se, some of the sweet-tasting or sweet-tasting enhancer compounds, they can also activate a particular receiver by themselves, in addition to modulating (increasing) the activation of the receiver. For example, some of the candy receptor enhancer or sweet flavor enhancer compounds can also activate a candy receptor, such as a T1R2 / T1R3 receptor, by acting as receptor agonists.
A modulating amount of sweet taste refers to an amount of a compound of Formula (I), which is sufficient to alter (increase or decrease) the sweet taste in an ingestible composition, or a precursor to it, enough to be perceived by a human subject. In many embodiments of the invention, at least about 0.001 ppm of the present compound would need to be present for most human subjects to experience a sweet taste modulation of an ingestible composition, comprising the present compound. A wide concentration range that would typically be employed to provide a desirable degree of sweet taste modulation economically can be from about 0.001 ppm to 100 ppm, or a narrow range of about 0.1 ppm
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18/96 at about 10 ppm. The alternative ranges of sweet flavor modulation 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.
An intensifying amount of sweet flavor here refers to an amount of a compound that is sufficient to enhance the taste of flavoring agents, for example, sucrose, in an ingestible composition, as perceived by an animal or a human. A wide range of a sweetening-enhancing amount can be from about 0.001 ppm to 100 ppm, or a narrow range from about 0.1 ppm to about 10 ppm. The alternative ranges of sweetening enhancing 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. In some embodiments, the sweet flavor enhancing amount is the amount corresponding to the binder enhancing concentration (s) of a sweet flavor enhancer of the present invention.
A sweet receptor modulating amount refers to an amount of a compound that is sufficient to modulate (activate, enhance or block) a sweet-tasting receptor protein. In many embodiments of the invention, a modulating amount of the candy receptor is at least about 1 pM, or at least about 1 nM, or at least about 10 nM, or at least about 100 nM (that is, about 0.1 μΜ). A modulation or activation amount of the T1R2 / T1R3 receptor is an amount of compound that is sufficient to modulate or activate a T1R2 / T1R3 receptor. A sweet receptor is a taste receptor that can be modulated by a sweet compound. Preferably, a candy receptor is a G protein coupled receptor, and most preferably the candy receptor is a T1R2 / T1R3 receptor.
Compounds
In one embodiment, the present invention provides a compound having Structural Formula (I):
(I), or a salt, solvate and / or prodrug thereof; on what
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R ¹ and R ² are, independently, hydrogen or C1 to C6 alkyl;
L is C1 to C12 alkylene or C1 to C12 substituted alkylene;
M is -NR4-C (O) - or -C (O) -NR ⁴ -;
R ⁴ is hydrogen or C1 to C6 alkyl; or alternatively, when M is -NR ⁴ -C (O) -, R ⁴ and one or more L atoms, together with the nitrogen to which they are attached, form a 5- to 8-membered heterocyclic ring that is optionally substituted and contains one to three heteroatoms selected from nitrogen, oxygen, and sulfur; and
D C1 to C12 alkyl, C1 to C12 substituted alkyl, 5 to 8 membered heterocyclyl, or 5 to 8 membered heterocyclyl; or alternatively, when M is -C (O) -NR ⁴ -, R ⁴ and one or more atoms of R ³ , together with the nitrogen to which they are attached, form a 5- to 8-membered heterocyclic ring that is optionally substituted and contains one to three heteroatoms selected from nitrogen, oxygen, and sulfur.
In a form of Formula (I), the substituent group (s) in C1 to C12 alkylene, in heterocyclyl, in the heterocyclic ring, and in C1 to C12 alkyl is selected from the group consisting of halo, amino, N-alkyl amino, N, N-dialkyl amino, hydroxyl, alkoxy, aryl, heteroaryl, heterocyclyl, carbocyclyl, = O, = S, = NR ^a , = N-OR ^a , -CN, -OCN, -SCN, - NO, -NO2, - i i rvrrvpb rvrá rw ^a rvrá MD ^a D ^a T <n ^the cmYi ^b iD ^a c = N2, -N3, -C (O) R, -C (O) OR, -C (O) NR R, -OC (O) OH, -OC (O) OR, -NR C (O) R, -NR C (O) OR ^a , and -NR ^to C (O) NR ^to R ^a , wherein each R ^a is independently hydrogen or alkyl including linear, branched, and cyclic alkyl; or alternatively, two R ^a's , taken together with the nitrogen to which they are attached, form a heterocyclic ring; and each R ^b is alkyl including linear, branched, and cyclic alkyl.
In an embodiment of the present invention, Formula (I) does not include the species of the Compound described in US Patent Application 13 / 076,632. In a more specific embodiment, Formula (I) does not include the Compounds listed in Table X below:
TABLE X Me. uu Me. Π Ί 0 HO ₂ CT nh ₂ 0 ^ / Hho ₂ ct L II J NH ₂ o ^ / 0
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TABLE X ^Μ θ ^ ^Ν γ HOsC ^ Y 'nh ₂ CL0 Me. HO ₂ CT Or nh ₂ 0 ^^ v Me ^ 1 Me ^ N _xXj 0NH ₂ 0- ho ₂ c γ ^ V ^H μ-Ι NH 2 0. Y. .N OMe0 0 1 ^Μ6 Τ ^Ν ιΓΊ Me.  T]HO ₂ C ^x ^ y ^X ^ Y' HHO ₂ CT, O NH ₂ N. . Y./0Hnh ₂ ο ^ χΖ Η 1 0 ^Μ θγ ^Ν ιΠ Me. Η ΊΗ0 ₂ 0 ^ γ ^Χ γ( ^C HO ₂ CT JX '0 NH ₂ nh ₂ u ^ isr '' ^ '' OMeH H Me. / ThY H ^Me ^ , Ν - ^ / Τί.JL II 0 HO ₂ C ^0 nh ₂ 0H '- (Dnh ₂ oYXÍ _kl A JDMe H Me N Me._N 1 ^ z ^0Me HCbC ^ y ' 0 ho ₂ c ^ y / ⁰ X ΊΓ nh ₂ 0.'N Y H nh ₂ ο ^ _ν Λ H u Me. .N. . T T Me NHOjCty '' '' k 1 znh ₂ O. ho ₂ cyy Nnh ₂ o _x O' B.C
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TABLE X ho ₂ cVt _y h rr ^0Me nh ₂ oJCn 0 ^Me z ^N x ^ XIJ ho ₂ c '^ Vy _v h nh ₂ oJCn JV 0 Me. .N. ΊΓ Η Ί ⁰ ΗΟ ₂ Ο ' ^Λ γ ^ γ < ^χχ ' Ν ^> γ ^Χ nh ₂ I w Me. ^ N. / x ΗΟ ^^ γ ^ γ ί 0 ^nh 2 ^H LJ Me ^Η ο ₂ ο''γγ ^ / _H nh ₂ ^Me _V ^N x / ^ ho ^ 'Vt V NH ₂ 0 ^>< _n Axx ^Μ ®γ ^Ν <χ k, 0 nh ₂ οΧ < _Ν Λγ ^ ^H LJ HO ₂ C ^ V _h nh ₂ O ^ X ^ N ^ x ^Me Y ^N X HO ₂ cAfV _H NH ₂ (0CNy- Me./tk^xx ho ₂ cVt _v h nh ₂ oJK.N.AA Μθ. ^ Ι'ΕχτχΗΟ, Ο ^ ΤΤ A / Η Π] 0 I / O ΜθχχΝ ^^. XJO ^02C Μθ.υγ ^^ HOsC ^^ Y ^ Y ί 0 ^nh 2 ° .a γθ
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TABLE X Me. í Ί Ί κο ₂ σ NH ₂ O ^ > -N ο ^ζ [
-------------------------------------------------- ------------- 1 ------- 2 ---------------------------- ------------------------------------- In a Formula (I) modality, Re R are both hydrogens.
In an embodiment of Formula (I), the alkylene is linear, branched, cyclic, or a combination thereof.
In an embodiment of Formula (I), the alkyl is linear, branched, cyclic, or a combination thereof.
In a Formula (I) modality, the compound can be represented by the Structural Formula (Ia):
(Ia), where,
L is C1 to C12 alkylene or C1 to C12 substituted alkylene;
R4 is hydrogen or C1 to C6 alkyl; or alternatively, R4 and one or more L atoms, together with the nitrogen to which they are attached, form a 5- to 8-membered heterocyclic ring containing one to three selected heteroatoms of nitrogen, oxygen, and sulfur; and
R is C1 to C12 alkyl, substituted C1 to C12 alkyl, 5- to 8-membered heterocyclyl, or substituted 5- to 8-membered heterocyclyl.
In an embodiment of Formula (Ia), L is branched or cyclic C3 to C6 alkylene; R ⁴ is hydrogen; and R ³ is branched C3 to C6 alkyl or C1 to C6 linear alkyl.
In a Formula (I) modality, the compound can be represented by the Structural Formula (Ib):
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(Ib), where:
L is C1 to C12 alkylene or C1 to C12 substituted alkylene;
R ⁴ is hydrogen or C1 to C6 alkyl; and
R is C1 to C12 alkyl, C1 to C12 substituted alkyl, 5 to 8 membered heterocyclyl, 5 to 8 membered heterocyclyl; or alternatively, R ⁴ and one or more atoms of R ³ , together with the nitrogen to which they are attached, form a 5- to 8-membered heterocyclic ring containing one to three selected heteroatoms of nitrogen, oxygen, and sulfur.
In an embodiment of Formula (Ib), L is linear C1 to C6 alkylene or branched C3 to C6 alkylene; R ⁴ is hydrogen; and R ³ is C1 to C6 straight or branched alkyl or C3 to C6 cyclic alkyl.
In certain modalities of Formula (I), the compound is selected from the group consisting of:


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O




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Me
HO ₂ C
O
H N


NH ₂ O
O

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O
O.

Compositions
The present compounds can be used for one or more methods of the present invention, for example, to modify the receptors and their ligands associated with the chemosensory or chemosensory related sensation or reaction. According to the present invention, a method of modulating a chemosensory receptor and / or the
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27/96 its ligand includes modulating the activity, structure, function, expression, and / or modification of a chemosensory receptor, as well as modulating, treating, or taking prophylactic measures of a condition, for example, physiological or pathological condition, associated with a chemosensory receptor. In general, a pathological or physiological condition associated with a chemosensory receptor includes a condition, disease or disorder associated with the chemosensory receptor and / or its ligand, for example, gastrointestinal disorders, metabolic disorders, functional gastrointestinal disorders, etc. .. , the method includes increasing or intensifying the sweet taste. In another embodiment, the method includes modulating a sweet receptor and / or its ligand expressed in a location on the body other than the taste buds, such as an internal organ. In general, the compounds of the present invention, individually or in combination, can be supplied in a composition, such as, for example, an ingestible composition. In one embodiment, the present compound can impart a more similar time profile to that of sugar and / or flavor profile of a sweetener composition, combining one or more of the present compounds with one or more sweeteners in the sweetener composition. In another embodiment, the present compound can increase or intensify the sweet taste of a composition by contacting the composition thereof with one or more of the present compounds to form a modified composition. In another embodiment, the present compound can be in a composition that modulates sweet receptors and / or their ligands expressed in different organisms in the taste buds.
The compounds of Formula (I), (Ia) and (Ib) and their various species and subgenera, and their salts and / or solvates, preferably, should be edibly acceptable, for example, considered suitable for consumption in food or drink from the perspective of producing in the unmodified edible compositions an improved and / or pleasant sweet taste, and not significantly toxic or that cause unpleasant or undesirable pharmacological or toxicological effects for an animal or human in typical concentrations they are used as flavoring agents in the compositions edible.
One of the methods of demonstrating that a flavoring compound is edibly acceptable is to have the compound tested and / or evaluated by a panel of Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) and declared as Generally Recognized as Safe (GRAS). The FEMA / GRAS evaluation process for flavoring compounds is complex, but well known to those skilled in the art of
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28/96 preparation of food products, as discussed by Smith, et al. in an article entitled GRAS Flavoring Substances 21, Food Technology, 57 (5), pages 46-59, May 2003, all content of which is incorporated herein by reference. In addition to the FEMA expert panel, an independent, qualified panel of experts in relevant scientific disciplines can be formed by the manufacturer to assess the safety of a specific compound for the state of GRAS. This process is known as a self-determination of GRAS status. Another method of demonstrating that a flavoring compound is edibly acceptable is to obtain a favorable review from the WHO / FAO Joint Expert Committee on Food Additives or JECFA. There are also other evaluation methods, for example, independent review by the regulatory agency, which are generally known to those skilled in the art of preparing food products.
In one embodiment, the compounds of the present invention can be used in their binder enhancing concentrations, for example, very low concentrations in the order of a few parts per million, in combination with one or more of the known, natural or artificial sweeteners, so to reduce the concentration of the known sweetener needed to prepare an ingestible composition having the desired degree of sweetening.
In an embodiment of the present invention, the present compounds can enhance the sweetening of a sweetener over a wide pH range, for example, from a pH below neutral pH. The lowest, neutral pH includes, but is not limited to, a pH of about 2.5 to about 8.5, about 3.0 to about 8.0, about 3.5 to about 7.5, and from about 4.0 to about 7. In certain embodiments, the present compounds can enhance the perceived sweetening of a fixed concentration of a sweetener in taste tests to a compound concentration of about 50 μΜ , 40 μΜ, 30 μΜ, 20 μΜ, or 10 μΜ, in both low to neutral pH values. In certain embodiments, the intensification factor of the present compounds at a lower pH is substantially similar to the intensification factor of the compounds at neutral pH. Such consistent sweetening property over a wide pH range makes the present compounds good candidates for wide use in a wide variety of foods and beverages.
Artificial or commonly used sweeteners known for use in such sweetener combinations include, but are not limited to, common saccharide sweeteners, for example, sucrose, fructose, glucose, and sweetener compositions that
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29/96 comprise natural sugars, such as corn syrup (including high fructose corn syrup) or other sweetener concentrates or syrups derived from natural fruit and vegetable sources, semi-synthetic sugar alcohol sweeteners such as erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, maltodextrin, and the like, and artificial sweeteners such as aspartame, saccharin, acesulfame K, cyclamate, sucralose, and alitame. Sweeteners also include cyclamic acid, mogroside, tagatose, maltose, galactose, mannose, sucrose, fructose, lactose, neotame and other derivatives of aspartame, glucose, D-tryptophan, glycine, maltitol, lactitol, isomalt, hydrogenated glucose syrup ( HGS), hydrogenated starch hydrolyzate (MSM), stevioside, rebaudioside A and other glycosides based on sweet Stevia, carrelame and other sweeteners based on guanidine, etc. The term sweeteners also includes sweetener combinations, as described here.
In one embodiment, the present compound is added to an inedible or non-food composition or product, such as supplements, nutraceuticals, functional food products (for example, any fresh or processed food claimed to have some health promoting properties and / or that prevent diseases in addition to the basic nutritional function of supplying nutrients), pharmaceutical product, over-the-counter product (OTC), oral care products, cosmetic products such as sugary lip moisturizers and other personal care products.
In general, the OTC product and oral hygiene product generally refer to the product for home use and / or personal use that can be sold without a prescription and / or without a visit to a medical professional. Examples of OTC products include, but are not limited to, vitamins and dietary supplements; topical analgesics and / or anesthetics; medicines for coughs, colds and allergies; antihistamine and / or allergy remedies; and combinations thereof. Vitamins and food supplements include, but are not limited to, vitamins, food supplements, bottled / toned nutritional drinks, child-specific vitamins, food supplements, any other products from, or related to, or supply for, nutrition, and combinations thereof . Topical analgesics and / or anesthetics include any topical creams / ointments / gels used to relieve superficial or deep pain and suffering, for example, muscle pain; teething gel; dressings with analgesic ingredient, and combinations thereof. Cough, cold and allergy remedies include, but are not limited to, decongestants, cough remedies, preparations
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30/96 pharyngeal, medicated confectionery, antihistamines and children's specific cough, cold and allergy remedies, and combined products. Antihistamine and / or allergy remedies include, but are not limited to, any systemic treatments for hay fever, nasal allergies, insect bites and bites. Examples of oral care products include, but are not limited to, mouth cleaning strips, toothpaste, toothbrushes, mouthwashes / dental washes, denture care, home mouth cleansers, toothpaste, and dental floss .
In another embodiment, the present compounds are added to food or beverage products or formulations. Examples of food and beverage products or formulations include, but are not limited to, candy coatings, toppings, or glazes for edible products or any entity included in the Soup category, Dry Processed Food category, Drinks category, Ready Meal category, Canned and Preserved Food category, Frozen Processed Food category, Chilled Processed Food category, Snack category, Baked Goods category, Confectionery category, Dairy product category, Ice cream category, Meal Replacement category, Macaroni and Pasta, and Sauces, Seasonings, Condiments category, Baby Food category, and / or Dispersions category.
In general, the Soup category refers to canned / preserved, dehydrated, instant, chilled, UHT and frozen soup. For the purpose of this definition soup (s) means a food prepared from meat, poultry, fish, vegetables, cereals, fruit and other ingredients, cooked in a liquid that may include visible parts of some or all of these ingredients. It can be transparent (like a broth) or thick (like a stew), smooth, puree or thick, ready to serve, semi-condensed or condensed and can be served hot or cold, as a first dish or as the main dish of a meal or as a snack between meals (as a sip of a drink). Soup can be used as an ingredient for the preparation of other components of the meal and can vary from broths (Consommé) to sauces (cream or cheese-based soups).
The Culinary and Dehydrated Food Category usually means: (i) Cooking aids, such as: powders, granules, pastes, concentrated liquid products, including concentrated meat broth, products similar to meat broth, and diced meat broth pressed, compressed or powdered or granulated, which are
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31/96 sold separately as a finished product or as an ingredient in a product, sauces and recipe mixes (regardless of technology); (ii) meal solution products, such as: dehydrated and frozen dry soups, including dehydrated soup mixes, dehydrated instant soups, dehydrated ready-to-cook soups, ready-made dehydrated or room temperature prepared dishes, meals and starters to serve unique, including pasta, potatoes and rice dishes; and (iii) meal-beautifying products, such as: condiments, marinades, salad dressings, salad dressings, sauces, bread, whipped mixes, stable shelf dispersions, barbecue sauces, liquid recipe mixes, concentrates, sauces or dressings mixes, including salad recipe mixes, sold as a finished product or as an ingredient within a product, whether dehydrated, liquid or frozen.
The Beverages category generally means drinks, mixtures of drinks and concentrates, including, but not limited to, carbonated and non-carbonated drinks, alcoholic and non-alcoholic drinks, ready-to-drink drinks, liquid concentrate formulations for beverage preparation, such as soft drinks and dry powder drinks precursor to mixing. The Beverages category also includes alcoholic drinks, soft drinks, sports drinks, isotonic drinks, and hot drinks. Alcoholic beverages include, but are not limited to beer, cider / perry, FABs, wine and alcoholic beverages. Soft drinks include, but are not limited to carbonates, such as glue and non-glue carbonates; fruit juice, such as juices, nectars, juice drinks and flavored fruit drinks; bottled water, which includes sparkling water, spring water and table / purified water; functional drinks, which can be carbonated or even and include sports, energy or elixir drinks; concentrates, such as liquid and powder concentrates, ready to drink. Drinks, hot or cold, include, but are not limited to, coffee or coffee ice cream, such as fresh, instant, and combined coffee, tea or iced tea, such as black, green, white, oolong and flavored tea, and others beverages, including flavor, malt or herbal powders, granules, blocks or tablets mixed with milk or water.
The Snacks category generally refers to any food that may be an informal light meal, including, but not limited to, sweet and snack snacks and bar snacks. Examples of snacks include, but are not limited to, fruit snacks, chips / chips, extruded snacks, tortilla / corn chips, popcorn, snacks,
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32/96 chestnuts and other sweet and savory snacks. Examples of bar snacks include, but are not limited to, granola / muesli bars, breakfast bars, energy bars, fruit bars and other bar snacks.
The Baked Goods category generally refers to any edible product, whose preparation process involves exposure to heat or excessive sunlight. Examples of baked goods include, but are not limited to, bread, cakes, cookies, light cake, cereals, toaster pie dough, pie dough, pancakes, tortillas, cookies, pies, donuts, hot pies, quiches, cake, any baked foods, and combinations thereof.
The Ice Cream category generally refers to the frozen dessert containing cream and sugar and flavoring. Examples of ice cream include, but are not limited to: impulse ice cream; ice creams to take home; frozen yogurt and artisanal ice cream; sorbets based on soy, oats, beans (eg red beans and green beans) and rice.
The Confectionery category generally refers to the edible product that is sweet on the palate. Examples of confectionery products include, but are not limited to, candies, jellies, chocolate, confectionery, confectionery sugar, gums, and the like and any combination products.
The Meal Replacers category generally refers to any food intended to replace normal meals, particularly for people with compromised health or fitness. Examples of Meal Replacers include, but are not limited to, weight loss products and convalescence products.
The Ready Meal category generally refers to any food that can be served as a meal without extensive preparation or processing. The ready-made meal includes products that have '' recipe '' skills added to them by the manufacturer, which results in a high degree of readiness, completion and convenience. Examples of ready-made meals include, but are not limited to, canned / preserved, frozen, dried, ready-made, refrigerated meals; dinner mixes; frozen pizza; chilled pizzas, and prepared salads.
The Macaroni and Pasta category includes any macaroni and / or pasta, including, but not limited to, canned, dried and chilled / fresh pasta and simple, instant, chilled, frozen and snack noodles.
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The Canned / Canned Food category includes, but is not limited to, canned / canned meat and meat products, fish / seafood, vegetables, tomatoes, beans, fruits, ready meals, soups, pasta and other canned / canned foods .
The processed frozen food category includes, but is not limited to, frozen processed red meat, processed poultry, processed fish / seafood, processed vegetables, meat substitutes, processed potatoes, baked goods, desserts, ready meals, pizza, soup , pasta and other frozen foods.
The Dry Processed Food category includes, but is not limited to, rice, dessert mixes, dry ready meals, dehydrated soup, instant soup, dried pasta, plain pasta and instant pasta. The refrigerated Processed Food category includes, but is not limited to, refrigerated processed meats, processed fish / seafood, lunch kits, fresh fruit cuts, ready meals, pizza, prepared salads, soups, pasta and fresh noodles.
The Sauces, Seasonings and Condiments category includes, but is not limited to, tomato paste and puree, bouillon / broth cubes, herbs and spices, monosodium glutamate (MSG), table sauces, soy-based sauces, pasta sauces, wet / cooking sauces, powder mixes / dry sauces, ketchup, mayonnaise, mustard, salad dressings, vinaigrettes, dipping sauces, pickled products, and other sauces, seasonings and condiments.
The Baby Food category includes, but is not limited to, formula based on milk or soy, and prepared, dry and other baby foods.
The Dispersions category includes, but is not limited to, jams and preserves, honey, chocolate, nut-based dispersions, and yeast-based dispersions.
The Dairy Products category, in general, refers to the edible product produced from mammalian milk. Examples of dairy products include, but are not limited to, drinking dairy products, cheese, yogurt and dairy drinks and other dairy products.
Additional examples for the edible composition, particularly of food and beverage products or formulations, are provided below. Exemplary edible compositions include one or more of confectionery products, chocolate candies, tablets, ingredients, packaged in selflines / softlines, boxed assortments, standard boxed assortments, twisted rolled miniatures, seasonal chocolate, toy chocolate, alfajores, other confectionery chocolate, peppermint, peppermint
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34/96 standard, energy mints, baked sugar candies, lozenges, gums, jellies and chewing gum, caramels, caramels and walnut, medicated confectionery, lollipops, licorice, other confectionery, gum, chewing gum, sugar , sugar-free gum, functional gum, chewing gum, bread, packaged / industrial bread, unpacked / artisan bread, pastry pies, cakes, packaged / industrial cakes, packaged / artisanal cakes, cookies, chocolate filled cookies, sandwich cookies, stuffed cookies, crackers and savory donuts, bread substitutes, breakfast cereals, rte cereals, family breakfast cereals, flakes, muesli, other cereals, children's breakfast cereals, hot cereals, ice cream, ice cream impulse, single serving milk ice cream, single serving water ice cream, multi-package milk ice cream, multi-package water ice cream, take-home ice cream, dairy ice cream to take home for home, ice cream desserts, ice cream in bulk, watery ice cream to take home, frozen yogurt, artisanal ice cream, dairy products, milk, fresh / pasteurized milk, fresh / whole pasteurized milk, fresh / pasteurized semi-skimmed milk, long-life milk / uht, long life milk / whole milk, long life milk / semi-skimmed milk, long life milk / fat-free uht, goat milk, condensed / evaporated milk, simple / evaporated condensed milk, flavored condensed milk, functional and other, drinks flavored dairy products, dairy flavored drinks only with dairy products, flavored dairy drinks with fruit juice, soy milk, sour milk drinks, fermented dairy drinks, coffee creams, powdered milk, flavored powdered milk drinks, cream, cheese , processed cheese, processed dispersible cheese, processed non-dispersible cheese, unprocessed cheese, dispersible unprocessed cheese, hard cheese, packaged hard cheese, non-hard cheese packaged, yogurt, plain / natural yogurt, flavored yogurt, fruit yogurt, probiotic yogurt, drinking yogurt and regular drinking yogurt, probiotic drinking yogurt, chilled and storage-stable desserts, dairy-based desserts, dairy-based desserts soy, chilled snacks, fresh cheese and quark, simple fresh cheese and quark, fresh cheese with flavor and quark, fresh salted and quark cheese, sweet and savory snacks, fruit snacks, chips / chips, extruded snacks, tortilla chips / corn, popcorn, snacks, nuts, other sweet and savory snacks, bar snacks, granola bars, breakfast bars, energy bars, fruit bars, other bar snacks, meal replacement products, slimming products , convalescent drinks, ready meals, canned ready meals, frozen ready meals, dry ready meals, meals
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35/96 chilled ready-made, dinner mixes, frozen pizza, chilled pizza, soup, canned soup, dehydrated soup, instant soup, chilled soup, hot soup, frozen soup, pasta, canned pasta, dry pasta, chilled / fresh pasta, macaroni , plain noodles, instant noodles, instant cup / bowl noodles, instant pouch noodles, refrigerated noodles, snack noodles, canned foods, canned meat and meat products, canned fish / seafood, canned vegetables, canned tomatoes, beans canned, canned fruits, canned ready meals, canned soups, canned noodles, other canned foods, frozen foods, frozen processed red meat, frozen processed poultry, processed frozen fish / seafood, processed frozen vegetables, frozen meat substitutes, frozen potatoes , roasted french fries, other roasted potato products, frozen unroasted potatoes, produce frozen bakery products, frozen desserts, frozen ready meals, frozen pizzas, frozen soup, frozen noodles, other frozen foods, dry foods, dessert mixes, dry ready meals, dehydrated soups, instant soups, dry pastas, simple noodles, instant noodles , cup / bowl instant noodles, purse instant noodles, chilled foods, chilled processed meats, chilled fish / seafood products, chilled processed fish, chilled coated fish, chilled smoked fish, chilled lunch kit, chilled ready meals, chilled pizza, chilled soup, chilled / fresh pasta, chilled pasta, oils and fats, olive oil, vegetables and seed oil, cooking fats, butter, margarine, dispersible oils and fats, dispersible functional oils and fats, sauces, seasonings and condiments, tomato paste and purees, ca meat loaf / bouillon cubes, bouillon cubes, granule sauce, broths and liquid sauces, herbs and spices, fermented sauces, soy-based sauces, pasta sauces, wet sauces, dry sauces / powder mixes, ketchup, mayonnaise, normal mayonnaise, mustard, salad dressings, regular salad dressings, low-fat salad dressings, vinaigrettes, dipping sauces, preserved products, other sauces, seasonings and condiments, baby foods, powdered milk, standard powdered milk, accompanying powdered milk, infant powdered milk, hypoallergenic powdered milk, prepared baby food, dried baby food, other baby foods, dispersions, jams and preserves, honey, chocolate dispersions, dispersions nut-based, and yeast-based dispersions. Exemplary edible compositions also include confectionery, bakery products, ice cream, dairy products, sweet snacks and
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36/96 snacks, bar snacks, meal replacement products, ready meals, soups, pasta, noodles, canned foods, frozen foods, dry foods, refrigerated foods, oils and fats, baby foods, or dispersions or a mixture of themselves. Examples of edible compositions include breakfast cereals, sweet drinks or concentrated solid or liquid compositions for the preparation of beverages, preferably in order to allow the reduction in the concentration of saccharide sweeteners previously known, or artificial sweeteners.
Typically, at least, a sweet receptor modulating amount, a sweet receptor modulating amount, a sweet flavor modulating amount, a sweet flavoring agent amount, a sweet flavor enhancing amount, or a therapeutically effective amount of one or more of the present compounds will be added to the ingestible composition, optionally in the presence of known sweeteners, for example, so that the modified ingestible sweet-tasting composition has an increased sweet taste when compared to the ingestible composition prepared without the compounds of the present invention, as assessed by humans or animals in general, or in the case of test formulations, as assessed by a majority of a panel of at least eight human taste testers, by procedures generally known in the art.
The concentration of sweet flavoring agent required to modulate or improve the taste of the ingestible composition will, of course, depend on several variables, including the specific type of the ingestible composition and its various other ingredients, in particular, the presence of other known sweet flavoring agents and the their concentrations, the natural genetic variability and individual preferences and the health conditions of the various human beings who taste the compositions and the subjective effect of the particular compound on the taste of such chemosensory compounds.
One application of the present compounds is to modulate (induce, increase or inhibit) the sweet taste or other taste properties of other natural or synthetic sweet flavors, and ingestible compositions made from them. In one embodiment, the compounds of the present invention are used or supplied in their binder enhancing concentration (s). For example, a wide range, but also a lower range of concentrations of the compounds or entities of the present invention would normally be required, for example, from about 0.001 ppm to 100 ppm, or more alternative narrower ranges of about 0.1 ppm at about 10 ppm, from about
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0.01 ppm to about 30 ppm, about 0.05 ppm to about 10 ppm, about 0.01 ppm to about 5 ppm, or about 0.02 ppm to about 2 ppm, or about 0.01 ppm and about 1 ppm.
In one embodiment, the present invention provides a candy-enhancing composition. The sweetening intensifier composition comprises a compound of the present invention in an amount effective to provide sweetening, for example, sweetening enhancing amount, in combination with a first amount of sweetener, wherein the sweetening is greater than the sweetening provided by the first amount of sweetener without the compound.
In one embodiment, the present invention provides an ingestible composition comprising the sweetener-enhancing composition of the present invention. In certain embodiments, the present composition is ingestible in the form of a food or drink product, a pharmaceutical composition, a nutritional product, a dietary supplement, over-the-counter medication, or an oral hygiene product.
In one embodiment, the present invention provides a sweetener substitution composition that comprises one or more compounds of the present invention in an amount effective to provide sweetening, for example, at a concentration greater than its binder enhancing concentration, in the absence of a sweetener, for example, sucrose other than the present compound (s).
According to another aspect of the invention, the compounds of the present invention are provided in a flavor concentrate formulation, for example, suitable for subsequent processing to produce a ready-to-use (i.e., ready-to-serve) product. By a flavor concentrate formulation, we mean a formulation that must be reconstituted with one or more dilution media to become a ready-to-use composition. The term ready-to-use composition is used interchangeably with ingestible composition here, which means any substance that, by itself, or in conjunction with another substance, can be made orally, whether for consumption or not. In one embodiment, the ready-to-use composition includes a composition that can be consumed directly by a human or animal. The flavor concentrate formulation is normally used by mixing with or diluted by one or more dilution means, for example, any consumable or ingestible product or ingredient, to induce or modify one or more flavors for the dilution medium. Such a process of use is often referred to as reconstitution. Reconstitution can be performed in a
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38/96 home environment or an industrial environment. For example, a frozen fruit juice concentrate can be reconstituted with water or another aqueous medium, by a consumer in a kitchen to obtain the ready-to-use fruit juice drink. In another example, a soda syrup concentrate can be reconstituted with water or other aqueous medium by manufacturing on a large industrial scale to produce ready-to-use soft drinks. Since the flavor concentrate formulation has the flavoring agent or flavor modifying agent, in a higher concentration than the ready-to-use composition, the flavor concentrate formulation is normally not suitable for consumption directly without reconstitution. There are many benefits of using and producing a flavor concentrate formulation. For example, an advantage is the reduction in weight and volume for transport since the flavor concentrate formulation can be reconstituted at the time of use by adding a suitable solvent, solid or liquid.
In one embodiment, the flavor concentrate formulation comprises: i) as a flavor-modifying ingredient, a compound of the present invention, ii) a carrier, and iii) optionally, at least one adjuvant. The term flavor-modifying ingredient indicates that the compound of the present invention acts as a flavoring agent or a flavor-modifying agent (e.g., a flavor enhancer) in the formulation. The term carrier carries a normally inactive accessory substance, such as solvents, binders, or other inert medium, which is used in combination with the present compound and one or more optional adjuvants to form the formulation. For example, water or starch can be a carrier for a flavor concentrate formulation. In some embodiments, the carrier is the same as the dilution medium for reconstituting the flavor concentrate formulation; and in other modalities, the carrier is different from the dilution medium. The term carrier as used herein includes, but is not limited to, an ingestibly acceptable carrier.
The term adjuvant denotes an additive that complements, stabilizes, maintains, or enhances the intended function, or the effectiveness of the active ingredient, such as the compound of the present invention. In one embodiment, at least one adjuvant comprises one or more flavoring agents. The flavoring agent can be of any flavor known to a person skilled in the art, or consumers, such as the taste of chocolate, coffee, tea, mocha, French vanilla, peanut butter, chai, or combinations thereof. In another embodiment, at least one adjuvant comprises one or more sweeteners. The one or
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39/96 most sweeteners can be any of the sweeteners described in this application. In another embodiment, at least one adjuvant comprises one or more ingredients selected from the group consisting of an emulsifier, a stabilizer, an antimicrobial preservative, an antioxidant, vitamins, minerals, fats, starches, concentrates and protein isolates, salts and combinations of the same. Examples of emulsifiers, stabilizers, antimicrobial preservatives, antioxidants, vitamins, minerals, fats, starches, concentrates and protein isolates, and their salts are described in US 6,468,576, the contents of which are incorporated herein by reference in their entirety for all purposes .
In one embodiment, the flavor concentrate formulation present may be in a form selected from the group consisting of liquid, including solution and suspension, solid, foam material, paste, gel, cream, and a combination thereof, such as a liquid containing a certain amount of solids content. In one embodiment, the flavor concentrate formulation is in the form of a liquid including both aqueous and non-aqueous bases. The present flavor concentrate formulation can be carbonated or non-carbonated.
The flavor concentrate formulation can further comprise a freezing point depressant, a nucleating agent, or both, as at least one adjuvant. The freezing point depressant is an ingestibly acceptable compound or agent that can decrease the freezing point of a liquid or solvent to which the compound or agent is added. That is, a liquid or solution containing the freezing point depressant has a lower freezing point than the liquid or solvent without the freezing point depressant. In addition to depressing the onset of the freezing point, the freezing point depressant can also reduce the water activity of the flavor concentrate formulation. Examples of the freezing point depressant include, but are not limited to, carbohydrates, oils, ethyl alcohol, polyol, for example, glycerol, and combinations thereof. The nucleating agent denotes an ingestibly acceptable compound or agent that is capable of facilitating nucleation. The presence of the nucleating agent in the flavor concentrate formulation can improve the mouthfeel of frozen sludge from a frozen paste and help maintain the physical properties and performance of the paste at freezing temperature, increasing the number of crystallization centers in the freeze. desirable ice. Examples of nucleating agents include, but are not limited to, calcium silicate, calcium carbonate, titanium dioxide, and combinations thereof.
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In one embodiment, the flavor concentrate formulation is formulated to have low water activity for extended shelf life. Water activity is the relationship between water vapor pressure in a formulation to the pressure of pure water vapor at the same temperature. In one embodiment, the flavor concentrate formulation has a water activity of less than about 0.85. In another embodiment, the flavor concentrate formulation has a water activity of less than about 0.80. In another embodiment, the flavor concentrate formulation has a water activity of less than about 0.75.
In one embodiment, the flavor concentrate formulation has the compound present in a concentration that is at least 2 times the concentration of the compound in a ready-to-use composition. In one embodiment, the flavor concentrate formulation has the compound present in a concentration that is at least 5 times the concentration of the compound in a ready-to-use composition. In one embodiment, the flavor concentrate formulation has the compound present in a concentration that is at least 10 times the concentration of the compound in a ready-to-use composition. In one embodiment, the flavor concentrate formulation has the compound present in a concentration that is at least 15 times the concentration of the compound in a ready-to-use composition. In one embodiment, the flavor concentrate formulation has the compound present in a concentration that is at least 20 times the concentration of the compound in a ready-to-use composition. In one embodiment, the flavor concentrate formulation has the compound present in a concentration that is at least 30 times the concentration of the compound in a ready-to-use composition. In one embodiment, the flavor concentrate formulation has the compound present in a concentration that is at least 40 times the concentration of the compound in a ready-to-use composition. In one embodiment, the flavor concentrate formulation has the compound present in a concentration that is at least 50 times the concentration of the compound in a ready-to-use composition. In one embodiment, the flavor concentrate formulation has the compound present in a concentration that is at least 60 times the concentration of the compound in a ready-to-use composition. In one embodiment, the flavor concentrate formulation has the compound present at a concentration that is greater than 100 times the concentration of the compound in a ready-to-use composition.
Therapeutic Utilities
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In one aspect of the present invention, the present compounds can be used for therapeutic purposes. That is, the present compounds can be used in methods to modulate a chemosensory receptor and / or its ligand to achieve the therapeutic effect. For example, the present method includes modulation of a chemosensory receptor and / or its ligand expressed in the body other than the taste buds.
In one embodiment, the method of the present invention, for example, modulation of a chemosensory receptor and / or its ligand includes modulation of the expression, secretion and / or functional level of cells expressing T1R associated with the hormone, peptide, production of the enzyme. In one example, the method of the present invention includes modulating the level of glucose, for example, inhibitors of a chemosensory receptor such as T1R2 can be used to decrease the level of glucose (for example, glucose absorption) in a subject. In another example, the method of the present invention includes modulating the level of incretins, for example, a chemosensory receptor agonist such as T1R2 can be used to increase glucagon-like peptide 1 (GLP-1) and thereby increase production insulin. In yet another example, the method of the present invention includes modulating the level of expression, secretion, and / or activity of hormones or peptides produced by cells that express T1R or cells producing gastrointestinal hormone, for example, ligands for the receptors of 5HT (for example, serotonin), incretins (for example, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP)), gastrin, secretin, pepsin, cholecystokinin, amylase, ghrelin, leptin, somatostatin, etc. In yet another example, the method of the present invention includes the modulation of pathways associated with hormones, peptides and / or enzymes secreted by cells that express T1R.
In another embodiment, the method of the present invention, for example, modulation of a chemosensory receptor and / or its ligand includes modulation of the activity of cells that express T1R (for example, T1R1, T1R2, or T1R3), for example, liver cells (eg, hepatocytes, endothelial cells, Kupffer cells, Starred cells, bile duct epithelial cells, etc.), heart cells (eg smooth, cardiac and muscle endothelial cells, etc.), pancreatic cells (e.g. alpha cell, beta cell, delta cell, neurosecretory PP cell, D1 cell, etc.), nipple cells (e.g., ductal epithelial cells, etc.), stomach cells (e.g., mucosal cells, parietal cells, main cells, G cells, P / D1 cells), intestinal cells (for example, enteroendocrine cells, brush cells,
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42/96 etc.), salivary gland cells (for example, seromucosal cells, mucosal cells, myoepithelial cells, intercalated duct cells, striated duct cells, etc.), L cells (for example, expressing GLP-1, etc.), enterochromaffin cells (for example, expressing serotonin), cells similar to enterochromaphine, G cells (for example, expressing gastrin), D cells (delta cells, for example, expressing somatostatin), I cells (for example, expressing cholescystokinin (CCK), K cells (for example, expressing gastric inhibitor polypeptide), P / D1 cells (for example, expressing ghrelin), chief cells (for example, expressing pepsin) and S cells (for example, expressing secretin). In one example, the method of the present invention includes increasing the level of expression of T1R in cells that express T1R In another example, the method of the present invention includes increasing the level of secretion of cells that express T 1R.
In yet another embodiment, the method of the present invention, for example, modulation of a chemosensory receptor and / or its ligand includes the modulation, treatment, and / or prophylactic measure of a condition associated with the gastrointestinal system, including, without any conditions of limitation associated with esophageal motility (eg cricopharyngeal achalasia, hysterical globus, achalasia, diffuse esophageal spasm and related motor disorders, scleroderma involving the esophagus, etc.), inflammatory disorders (eg, gastroesophageal reflux and esophagitis, infectious esophagitis, etc.), peptic ulcer, duodenal ulcer, gastric ulcer, gastrinoma, stress and erosion ulcers, ulcers and erosions associated with the drug, gastritis, cancer, esophageal, stomach tumors, absorption disorders (for example, absorption of specific nutrients, such as carbohydrates, protein, amino acid, fat, and cholesterol-soluble vitamins, water and sodium, calcium, iron, water-soluble vitamins, etc.), malabsorption disorders, mucosal defects (eg, inflammatory or infiltrative disorders, biochemical or genetic abnormalities, endocrine and metabolic, protein-losing enteropathy, etc. .), autoimmune diseases of the digestive tract (eg celiac disease, Crohn's disease, ulcerative colitis, etc.), irritable bowel syndrome, inflammatory bowel disease, complications of inflammatory bowel disease, extraintestinal manifestations of inflammatory bowel disease , bowel motility disorders, bowel vascular disorders, anorectal disorders (eg, hemorrhoids, anal inflammation, etc.), colorectal cancer, tumors of the small intestine, cancers of the anus, liver metabolism disorders, hyperbilirubinemia, hepatitis, liver disease
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43/96 alcoholic and cirrhosis, biliary cirrhosis, liver neoplasms, metabolic and infiltrative diseases affecting the liver (eg, fatty liver, Reye's syndrome, diabetic glycogenosis, glycogen storage disease, Wilson's disease, hemochromatosis), diseases gallbladder and bile ducts, disorders of the pancreas (eg pancreatitis, pancreatic exocrine insufficiency, pancreatic cancer, etc.), endocrine tumors of the pancreas and gastrointestinal tract, etc.
In yet another embodiment, the method of the present invention, for example, a chemosensory modulation receptor and / or its ligand includes the modulation, treatment, and / or prophylactic measure of a condition associated with metabolic disorders, for example, appetite, weight body, food or fluid intake or a subject's reaction to food or fluid intake, or a subject's state of satiety or perception of a state of satiety, intake and regulation of nutrition (for example, energy malnutrition- protein content, physiological impairments associated with protein-energy malnutrition, etc.), obesity, secondary obsesity (eg, hypothyroidism, Cushing's disease, insulinoma, hypothalamic disorders, etc.), eating disorders (eg, anorexia nervosa, bulimia , etc.), vitamin deficiency and excess, insulin metabolism, diabetes (type I and type II) and complications (for example, circulatory conditions, retinopathy, diabetic nephropathy, diabetic neuropathy, diabetic foot ulcers, etc.), glucose metabolism, fat metabolism, hypoglycemia, hyperglycermia, hyperlipoproteinemias, etc.
In yet another embodiment, the method of the present invention, for example, modulation of the chemosensory receptor and / or its ligand includes the modulation, treatment and / or prophylactic measure of a condition associated with functional gastrointestinal disorders, for example, in the absence of any special pathological condition such as peptic ulcer and cancer, a subject having abdominal dyspepsia, for example, feeling of abdominal distension, nausea, vomiting, abdominal pain, anorexia, gastric acid reflux, or abnormal evacuation (constipation, diarrhea and the like), optionally, based on the retention of the contents in the gastrointestinal tract, especially in the stomach. In one example, functional gastrointestinal disorders include a condition without any organic disease of the gastrointestinal tract, but with one or more reproducible gastrointestinal symptoms that affect a subject's, for example, human, quality of life.
Exemplary functional gastrointestinal disorders include, without limitation, functional dyspepsia, gastroesophageal reflux condition, diabetic gastroparesis, esophagitis
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44/96 reflux, postoperative gastrointestinal dysfunction and the like, nausea, vomiting, sick feeling, heartburn, feeling of abdominal distension, heavy stomach, belching, chest twitching, chest pain, gastric discomfort, anorexia, dysphagia, reflux of gastric acid, abdominal pain, constipation, diarrhea, shortness of breath, feeling of suffocation, low energy or encouragement, obstruction of the pharynx, foreign body sensation, easy tiredness, stiff neck, myotonia, dry mouth (dry mouth, thirst, etc.) tachypnea, burning sensation in the gastrointestinal tract, feeling cold in the extremities, difficulty concentrating, impatience, sleep disturbance, headache, general malaise, palpitations, night sweats, anxiety, dizziness, vertigo, hot flash, excessive sweating, depression, etc.
In yet another embodiment, the method of the present invention, for example, modulation of the chemosensory receptor and / or its ligand includes increasing or promoting digestion, absorption, level of nutrients in the blood, and / or motility of the gastrointestinal tract in a subject, for example, promotion of gastric emptying (eg, clearance of stomach contents), reduction of abdominal distention in the early postprandial period, improvement of anorexia, etc. In general, such promotion can be obtained either directly or through the increased secretion from a regulatory body, eg hormones, etc.
In yet another embodiment, the method of the present invention, for example, modulation of the chemosensory receptor and / or its ligand includes enhancing one or more gastrointestinal functions of a subject, for example, to improve the quality of life or health status of an individual.
In one embodiment, the present invention provides a pharmaceutical composition containing a therapeutically effective amount of one or more compounds of the present invention, or a salt, solvate, and / or prodrug thereof, optionally with an appropriate amount of a pharmaceutically acceptable carrier. . In another embodiment, the pharmaceutical composition comprises a therapeutically effective amount of one or more compounds of the present invention, or a salt, solvate, and / or prodrug thereof, and a suitable amount of a pharmaceutically acceptable carrier, in order to provide the form for administration to a patient.
In one embodiment, when administered to a patient, the compounds of the present invention and optional pharmaceutically acceptable carriers are sterile. In one embodiment, water is a preferred vehicle when a compound of the present invention
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45/96 is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be used as liquid vehicles, particularly for injectable solutions. Suitable pharmaceutical carriers also include excipients, such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, limestones, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dry skimmed milk, glycerol, propylene, glycol, water, ethanol and the like. The present pharmaceutical compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents can be used.
Pharmaceutical compositions comprising a compound of the present invention can be manufactured by conventional mixing, dissolving, granulating, drug making, levigation, emulsification, encapsulation, trapping or lyophilization processes. The pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries, which facilitate the processing of the compounds of the present invention into preparations that can be used pharmaceutically. The appropriate formulation depends on the chosen route of administration.
The present pharmaceutical compositions can take the form of solutions, suspensions, emulsions, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. In some embodiments, the pharmaceutically acceptable carrier is a capsule (see, for example, Grosswald et al., US Patent 5,698,155). Other examples of suitable pharmaceutical vehicles have been described in the art (see Remington: The Science and Practice of Pharmacy, Philadelphia College of Pharmacy and Science, 20 ^th Edition, 2000).
For topical administration, a compound of the present invention can be formulated as solutions, gels, ointments, creams, suspensions, etc., as is well known in the art.
Systemic formulations include those designed for injection, for example, subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal, as well as those designed for transdermal, transmucosal, oral or pulmonary administration. Systemic formulations can be made in combination with another active agent that improves mucociliary clearance of mucus from the airways or reduces viscoside
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46/96 of the mucus. These active agents include, but are not limited to, sodium channel blockers, antibiotics, N-acetyl cysteine, homocysteine and phospholipids.
In some embodiments, the compounds of the present invention are formulated according to routine procedures as a pharmaceutical composition adapted for intravenous administration to humans. Typically, the compounds of the present invention for intravenous administration are solutions in sterile isotonic aqueous buffer. For injection, a compound of the present invention can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer. The solution may contain formulation agents, such as suspending agents, stabilizers and / or dispersants. When necessary, pharmaceutical compositions can also include a solubilizing agent.
Pharmaceutical compositions for intravenous administration can optionally include a local anesthetic such as lignocaine to relieve pain at the injection site. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a freeze-dried powder or water-free concentrate in a hermetically sealed container, such as an ampoule or sachet indicating the amount of active agent. When the compound of the present invention is administered by infusion, it can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. When the compound of the present invention is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed before administration.
For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
Pharmaceutical compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example. Pharmaceutical compositions administered orally may contain one or more agents, optionally, for example, agents such as fructose, aspartame or saccharin, sweetening agents, flavoring agents, such as peppermint, oil of wintergreen, or cherry coloring agents and preservative agents to provide a pharmaceutically palatable preparation.
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In addition, when in tablet or pill form, pharmaceutical compositions can be coated to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained action over an extended period of time. The permeable membranes selectively involving an osmotically active driving compound are also suitable for orally administered compounds of the present invention. On these rear platforms, the fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to move the agent or agent composition through an opening. These distribution platforms can provide a distribution profile essentially of zero order, as opposed to reinforcement profiles of immediate release formulations. A time-delayed material, such as glycerol monostearate or glycerol stearate can also be used. Oral compositions can include standard vehicles, such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Such vehicles are preferably pharmaceutical grade.
For liquid oral preparations, such as, for example, suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, saline, alkylene glycols (eg propylene glycol), polyalkylene glycols (eg polyethylene glycol) oils , alcohols, slightly acidic buffers between pH 4 and pH 6 (for example, acetate, citrate, ascorbate, between about 5.0 mM to about 50.0 mM), etc. In addition, flavoring agents, preservatives, coloring agents, bile salts, acylcarnitines and the like can be added.
For oral administration, pharmaceutical compositions can take the form of tablets, lozenges, etc. conventionally formulated.
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 carrier. Preferably, the pharmaceutically acceptable carrier is a liquid, such as alcohol, water, polyethylene glycol or a perfluorocarbon. Optionally, another material can be added to alter the aerosol properties of the solution or suspension of compounds of the invention. Preferably, this material is liquid, such as an alcohol, glycol, polyglycol or a fatty acid. Other methods for formulating liquid drug or suspension solutions suitable for use in aerosol devices are known
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48/96 for those skilled in the art (see, for example, Biesalski, US Patent 5,112,598, Biesalski, US Patent 5,556,611).
A compound of the present invention can also be formulated in rectal or vaginal pharmaceutical compositions, such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides.
In addition to the formulations described above, a compound of the present invention can also be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, a compound of the present invention can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as poorly soluble derivatives, for example, as a low salt soluble.
A compound of the present invention, and / or a pharmaceutical composition thereof, will generally be used in an amount effective to achieve the intended purpose. For use to treat or prevent diseases or disorders, the compounds of the present invention and / or the pharmaceutical compositions thereof, are administered or applied in a therapeutically effective amount.
The amount of a compound of the present invention that will be effective in treating a particular disorder or condition diluted here will depend on the nature of the disorder or condition and can be determined by standard clinical techniques known in the art. In addition, in vitro or in vivo assays can optionally be employed to help identify the optimal dosage ranges. The amount of a compound of the present invention administered will, of course, be dependent, among other factors, on the subject being treated, the subject's weight, the severity of the affliction, the mode of administration and the judgment of the prescribing physician.
For example, the dosage can be delivered in a pharmaceutical composition by a single administration, by multiple applications or by controlled release. In some embodiments, the compounds of the present invention are delivered by oral sustained release administration. The dosage may be repeated intermittently, may be provided alone or in combination with other drugs and may continue as long as necessary for the effective treatment of the condition or disorder of the disease.
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Dosage ranges suitable for oral administration depend on the potency, but are generally between about 0.001 mg to about 200 mg of a compound of the present invention per kilogram of body weight. Dosage ranges can be easily determined by methods known to the person skilled in the art.
Dosage ranges suitable for intravenous (i.v) administration are about 0.01 mg to about 100 mg per kilogram of body weight. Dosage ranges suitable for intranasal administration are generally about 0.01 mg / kg body weight to about 1 mg / kg body weight. Suppositories generally contain about 0.01 milligram to about 50 milligrams of a compound of the present invention per kilogram of body weight and comprise an active ingredient in the range of about 0.5% to about 10% by weight. The recommended dosages for intradermal, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual or intracerebral administration are in the range of about 0.001 mg to about 200 mg per kilogram of body weight. Effective doses can be extrapolated from dose-response curves derived from in vitro test systems or animal models. Such animal models and systems are well known in the art.
In one embodiment, a therapeutically effective dose of a compound of the present invention described herein will provide therapeutic benefits, without causing substantial toxicity. The toxicity of the compounds of the present invention can be determined using conventional pharmaceutical procedures and can be easily determined by one skilled in the art. The dose ratio between the toxic and therapeutic effect is the therapeutic index. A compound of the present invention will preferably exhibit particularly high therapeutic indexes in the treatment of diseases and disorders. The dosage of a compound of the present invention described herein will preferably be within a range of concentrations that includes an effective dose with little or no toxicity.
In certain embodiments of the present invention, the compounds of the present invention and / or their pharmaceutical compositions can be used in combination therapy with at least one other agent. The compound of the present invention and / or the pharmaceutical composition thereof and the other agent can act additively or, more preferably, synergistically. In some embodiments, a compound of the present invention and / or a pharmaceutical composition thereof is administered simultaneously with the administration of another agent, which may be part of the same pharmaceutical composition, such as the compound of the present invention or a different pharmaceutical composition. In others
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In 50/96 embodiments, a pharmaceutical composition of the present invention is administered before or after administration of the other agent.
Preparations
The starting materials used in the preparation of the compounds of the invention, that is, the various subclasses and structural 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 literature, or are commercially available from various sources well known to those skilled in the art, such as, for example, Sigma-Aldrich Corporation of St. Louis, Missouri, USA and its subsidiaries Fluka and Riedel-de Haen, in their several other offices worldwide, and other well-known chemical suppliers such as Fisher Scientific, TCI America of Philadelphia, PA, ChemDiv of San Diego, CA, Chembridge of San Diego, CA, Asinex of Moscow, Russia, SPECS / BIOSPECS from the Netherlands, Maybridge from Cornwall, England, Acros, TimTec from Russia, ComGenex from South San Francisco, CA, and ASDI Biosciences of Newark, DE.
It is recognized that the person skilled in the organic chemistry technique can easily perform the synthesis of various starting materials and subsequent manipulations without any direction, that is, it is well within the scope and practice of the person skilled in the art to perform many desired manipulations. These include the reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherifications, esterification, saponification, nitrations, hydrogenation, reducing animation, and the like. These manipulations are discussed in standard texts such as March's Advanced Organic Chemistry (3d Edition, 1985, Wiley-Interscience, New York), Feiser and Feiser's Reagents for Organic Synthesis, and in various volumes and editions oiMetoden der Organischen Chemie (Houben-Weyl) , and the like. Many general methods for the preparation of starting materials comprising variously substituted heterocyclic, heteroaryl, and aryl rings (the precursors of Ar, hAr, and / or hAr) can be found in Metoden der Organischen Chemie (Houben-Weyl), whose various volumes and editions are available from Georg Thieme Verlag, Stuttgart. The full disclosures of the aspects cited above are hereby incorporated by reference in their entirety for your teachings regarding methods for the synthesis of organic compounds and their precursors.
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The person skilled in the art will also easily appreciate that certain reactions are best performed when another functionality is masked or protected in the molecule, thus avoiding any undesirable side reactions and / or increasing the reaction yield. Often the person skilled in the art uses protective groups to achieve such increased yields or to avoid unwanted reactions. These reactions are found in the literature and are also well within the scope of those skilled in the art. Examples of many of these manipulations can be found for example in T. Greene and P. Wuts, Protecting Groups in Organic Synthesis, 3 ^st Ed., John Wiley & Sons (1999).
Some examples of synthetic methods for the preparation of the present compounds are illustrated in Schemes 1 to 3 below.
Scheme 1: Preparation of substituted 4-aminoquinoline-3-carboxylate derivatives (VI) from substituted anilines (I)
HoN
ROCO ₂ R
X, OR 'ii R ²
III
OH
IV
POCI ₃ or
R ³ R ⁴ NH
VII
SOCI ₂
RO ·
Cl
As shown in Scheme 1, substituted 4-aminoquinoline-3-carboxylate (VI) derivatives can be prepared by reacting the corresponding anilines I with 2 (alkoxymethylene) malonates II followed by cyclization of intermediates III, under elevated temperature, to provide the hydroxyl intermediates IV, which can be treated with POCl ₃ or SO ₂ Cl ₂ to provide the corresponding chloride derivatives V, which can be further treated with ammonia or amines to obtain the desired amino quinolines VI. (Kamal, A. et al. Bioorg. Med. Chem. 2005, 13, 2021-2029; Fryer, RI et al. J. Med. Chem. 1993, 36, 1669-1673; Bi, Y. et al. Bioorg Med. Chem. Lett. 2004, 14, 1577-1580; Li, SY et al. Bioorg. Med. Chem. 2006, 14, 7370-7376. Koga, H. et al. J. Med. Chem. 1980, 23, 1358-1363.).
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Scheme 2: Preparation of substituted 4-aminoquinoline-3-carboxylate derived from (VI) from derivatives of substituted 2-aminobenzoic acid (VIII) h ₂ n ho ₂ c
VIII
H
The IX
R r ²
X r ²
RO ₂ C
Ti- R ¹
OH IV
R ²
RO ₂ C
-ί— R ¹
R ³ ' ^N ' R ⁴
SAW
Substituted 4-aminoquinoline-3-carboxylate derivatives (VI) can also be prepared by reacting corresponding 2-aminobenzoic acids VIII with phosgene or equivalent, to provide isatoic anhydride IX which can be further reacted with X to produce the IV derivatives ( Mai, A. et al. J. Med. Chem. 2006, 49, 6897-6907. Beutner, GL et al. J. Org. Chem. 2007, 72, 7058-7061, and references cited therein.), Which can be converted to VI as described in Scheme 1.
Scheme 3: Preparation of substituted 4-aminoquinoline-3-carboxylate (VI) derivatives from substituted 2-amino benzonitrile derivatives (XI)
CO2R

XI r2 ^cO 2 ^R '
X
---- ►
r ² XIII or
co ₂ R ^X XIV
X = Cl, Br, I or
R ⁵ ---— CO ₂ R
RO ₂ C ' ^X ''''^>|' ^
R ²
XV XVI
Alternatively, substituted 4-aminoquinoline-3-carboxylate (VI) derivatives can be prepared by the reaction of corresponding benzonitrile amino XI with X to provide amino XII derivatives (Sestili, I. et al. Eur. J. Med. Chem. 2004, 39, 10471057. Doucet-Personeni, C. et al. J. Med. Chem. 2001, 44, 3203-3215. Veronese, AC et al. Tetrahedron 1995, 51, 12277-12284, and the references cited therein .) that can be further alkylated to produce the substituted aminoquinolines VI as shown in Scheme 3. Amino quinolines XII can also be prepared through a Michael addition of 2-amino benzonitriles XI to various α, β unsaturated XIII, XIV or carboxylate derivatives XV to supply XVI adducts (MacNab, H. et al. Synthesis 2009, 2171-2174. Vicario, JL Synthesis 2007, 2065-2092, and references cited in
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53/96 same.) That can be further cyclized to produce amino quinolines XII (Han, GF et al. Synth. Commun. 2009, 39, 2492-2505. Tabarrini, O. et al. Bioorg. Med. Chem. 2001 , 9, 2921-2928. Shutske, GM et al. J. Med. Chem. 1989, 32, 1805-1813, and references cited therein.).
Examples
Having now generally described the invention, it will be more easily understood by reference to the following examples, which are provided by way of illustration and are not intended to be limiting. It is understood that several modifications and alterations can be made to the exemplary modalities described here, without departing from the spirit and scope of the invention.
Example A: 4-amino-6-methoxyquinoline-3-carboxylic acid
To a stirred solution of ethyl 4-amino-6-methoxyquinoline-3-carboxylate (Example Aa, 1.23 g, 5.0 mmol) in EtOH (20.0 mL) was added aqueous NaOH (2.0 N, 5 , 0 mL) at room temperature. The reaction mixture was then refluxed for 3 hr. The solution was then filtered and washed with water. The filtrate was cooled to 0 ° C and carefully neutralized with 1 N HCl to pH 7. Most of the EtOH was removed under reduced pressure, and the precipitate was collected by filtration, washed with cold water, and dried under vacuum to produce the title compound as an off-white solid (1.01 g, 93%). ¹ H NMR (400 MHz, DMSOd) δ 3.89 (s, 3H), 7.40 (dd, J = 2.8, 9.4 Hz, 1H), 7.73 (d, J = 9.4 Hz, 1H), 7.77 (d, J = 2.8 Hz, 1H), 8.77 (s, 1H). MS 219 (MH +).
Example Aa: ethyl 4-amino-6-methoxyquinoline-3-carboxylate
A mixture of ethyl 4-chloro-6-methoxyquinoline-3-carboxylate (Example Ab, 796 mg, 3.0 mmol) and ammonia (25% aqueous solution, 10 mL) in isopropanol (40 mL) was stirred at 110 ° C in a pressure reactor overnight. Most of the solvent was then removed under reduced pressure, and the reaction mixture was diluted with water. The precipitate was collected by filtration, washed with cold water, and dried in vacuo to produce the title compound as an off-white solid (680 mg, 92%). ¹ H NMR (400 MHz, DMSOd) δ 1.33 (t, J = 7.0 Hz, 3H), 3.88 (s, 3H), 4.32 (q, J = 7.0 Hz, 2H) , 7.36 (dd, J = 2.8, 8.8 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 2.8 Hz, 1H), 8.23 (bs, 2H), 8.77 (s, 1H). MS 247 (MH ⁺ ).
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Example Ab: ethyl 4-chloro-6-methoxyquinoline-3-carboxylate
A solution of ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate (Example Ac, 1.24 g, 5.0 mmol) in POCl ₃ was refluxed under nitrogen for 3 hours. The solution was cooled to room temperature and evaporated under reduced pressure. The residue was carefully quenched with ice, and neutralized with 2.0 N NaOH to pH 7. The precipitate was collected by filtration, washed with cold water, and dried in vacuo to yield the title compound as an opaque yellow solid (1 , 29 g, 97%). ¹ H NMR (400 MHz, DVISO-U) δ 1.36 (t, J = 7.0 Hz, 3H), 3.96 (s, 3H), 4.41 (q, J = 7.0 Hz, 2H), 7.57 (d, J = 2.8 Hz, 1H), 7.61 (dd, J = 2.8, 8.8 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 8.97 (s, 1H). MS 266, 268 (MH ⁺ ).
Example Ac: ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate
A mixture of 4-methoxyaniline (12.3 g, 100 mmol) and diethyl 2 (ethoxymethylene) malonate (21.6 g, 100 mmol) was stirred at 120 ° C under nitrogen for 4 hours. The solution was cooled to room temperature and Ph2O (100 ml) was added. The reaction mixture was refluxed at 260 ° C under nitrogen for 8 hours. The solution was cooled to room temperature and diluted with hexanes. The resulting precipitate was collected by filtration, washed with 25% ethyl acetate in hexanes, and dried under vacuum to produce ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate as an opaque yellow solid (4.21 g, 17% ). ¹ H NMR (400 MHz, DVISO-U) δ 1.26 (t, J = 7.0 Hz, 3H), 3.83 (s, 3H), 4.19 (q, J = 7.0 Hz, 2H), 7.32 (dd, J = 3.2, 9.6 Hz, 1H), 7.55 (d, J = 3.2 Hz, 1H), 7.56 (d, J = 9.6 Hz, 1H), 8.47 (s, 1H), 12.27 (s, 1H). MS 248 (MH +).
Example B: 4-amino-5- (2,2-dimethyl-3-oxo-3- (propylamino) propoxy) -2methyl-quinoline-3-carboxylic acid
Prepared as in Example A from ethyl 4-amino-5- (2,2-dimethyl-3-oxo-3 (propylamino) -propoxy) -2-methylquinoline-3-carboxylate (Example Ba) as an off-white solid (41%). ¹ H NMR (400 MHz, DVISO-U) δ 0.73 (t, J = 7.6 Hz, 3H), 1.25 (s, 6H), 1.33-1.42 (m, 2H), 2.76 (s, 3H), 3.00-3.05 (m, 2H), 4.16 (s, 2H), 7.01 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.89 (t, J = 5.8 Hz, 1H), 8.85 (bs , 1H), 12.28 (bs, 1H), 12.78 (bs, 1H). MS 360 (MH +).
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Example______Ba: Ethyl 4-amino-5- (2,2-dimethyl-3-oxo-3- (propylamino) propoxy) -2-methylquinoline-3-carboxylate
To a solution of 3- (3-amino-2-cyanophenoxy) -2,2-dimethyl-N-propylpropan-amide (Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221, 1.38 g, 5.0 mmol) and ethyl acetoacetate (0.66 g, 5.0 mmol) in dry toluene (150 mL) SnCl ₄ (2.61 g, 10.0 mmol) was added dropwise via syringe at temperature nitrogen environment. After 1 hr at room temperature, the reaction mixture was refluxed for an additional 5 hours. The solution was cooled to room temperature and the solvent removed under reduced pressure. The residue was diluted with EtOAc, and aqueous NaOH (2N) was added at room temperature to pH> 8. The solution was filtered and the organic layer was separated. The aqueous layer was extracted with EtOAc (5X). The combined organic layers were washed with brine, and dried over Na ₂ SO ₄ . After evaporation of the solvent, the residue was purified by silica gel chromatography (0.5% MeOH in EtOAc) to produce the title compound as an off-white solid (1.63 g, 84%). ¹ H NMR (400 MHz, DMSO-A) δ 0.73 (t, J = 7.6 Hz, 3H), 1.25 (s, 6H), 1.32 (t, J = 7.4 Hz, 3H), 1.35-1.42 (m, 2H), 2.54 (s, 3H), 3.00-3.05 (m, 2H), 4.12 (s, 2H), 4.31 (q, J = 7.4 Hz, 2H), 6.87 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.50 (t , J = 8.0 Hz, 1H), 7.80 (t, J = 5.6 Hz, 1H), 8.08 (s, 2H). MS 388 (MH ⁺ ).
Example C: 4-amino-5- (2-ethylbutoxy) -2-methylquinoline-3-carboxylic acid
Prepared as in Example A from ethyl 4-amino-5- (2-ethylbutoxy) -2methylquinoline-3-carboxylate (Example Ca) as a white solid (45%). Mp: 145-151 ^o C. ¹ H NMR (400 MHz, DMSO-A) δ 0.90 (t, J = 8 Hz, 6H), 1.48-1.41, (m, 4H), 1, 84-1.78 (m, 1H), 2.73 (s, 3H), 4.11 (d, J = 8 Hz, 2H), 6.99 (d, J = 8 Hz, 1H), 7, 32 (d, J = 8 Hz, 1H), 7.59 (t, J = 8 Hz, 1H), 8.40 (brs, 1H), 11.09 (brs, 1H), 13.91 (brs, 1H). MS 303 (MH ⁺ ).
Example Ca: ethyl 4-amino-5- (2-ethylbutoxy) -2-methylquinoline-3-carboxylate
Prepared as in Example Ba from 2-amino-6- (2-ethylbutoxy) benzonitrile (Example Cb) and ethyl 3-oxobutanoate as a white solid (89%). ¹ H NMR (400 MHz, DMSO-A) δ 0.90 (t, J = 8 Hz, 6H), 1.32 (t, J = 8 Hz, 3H), 1.48-1.41 (m, 4H), 1.79
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1.73 (m, 1H), 2.54 (s, 3H), 4.08 (d, J = 4 Hz, 2H), 4.31 (q, J = 8 Hz, 2H), 6.92 ( dd, J = 2, 8 Hz, 1H), 7.23 (dd, J = 2, 8 Hz, 1H), 7.50 (t, J = 8 Hz, 1H), 8.04 (brs, 1H) . MS 331 (MH +).
Example Cb: 2-amino-6- (2-ethylbutoxy) benzonitrile
To a solution of 2-ethylbutan-1-ol (1.02 g, 10.0 mmol) in dry THF (60 mL) was carefully added NaH (60% in mineral oil, 480 mg, 12.0 mmol) in small portions at 0 ° C under nitrogen. The reaction mixture was stirred at 0 ° C under nitrogen for 2 hours. To this solution, 2-amino-6-fluorobenzonitrile (1.36 g, 10.0 mmol) was added, and the reaction solution was stirred at 0 ° C - RT for 2 hours, then at 65 ° C overnight under nitrogen. The reaction was cooled to below room temperature then quenched with brine, and extracted with EtOAc (3X). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ . Filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: 20% EtOAc in hexanes) to give the title compound as a colorless oil (1.29 g, 59%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.93 (t, J = 8 Hz, 6H), 1.55-1.43 (m, 4H), 1.73-1.65 (m, 1H) , 3.90 (d, J = 4 Hz, 2H), 4.10 (brs, 2H), 6.25 (d, J = 8 Hz, 1H), 6.34 (d, J = 8 Hz, 1H ), 7.20 (t, J = 8 Hz, 1H).
Example D: 4-amino-5- (2- (isonicotinamido) -2-methylpropoxy) -2-methylquinoline-3-carboxylic acid
Prepared as in Example A from ethyl 4-amino-5- (2- (isonicotinamido) -2methylpropoxy) -2-methylquinoline-3-carboxylate (Example Da) as a white solid (67%). Mp: 195-198 ^o C. ¹ H NMR (400 MHz, DVISO-V) δ 1.51 (s, 6H), 2.75 (s, 3H), 4.48 (s, 2H), 7.07 (d, J = 8 Hz, 1H), 7.31 (d, J = 8 Hz, 1H), 7.67 (t, J = 8 Hz, 1H), 7.70 (dd, J = 1, 8 Hz, 2H), 8.50 (s, 1H), 8.67 (dd, J = 1.8 Hz, 2H), 8.76 (brs, 1H), 12.19 (brs, 1H), 12, 85 (brs, 1H). MS 395 (MH +).
Example Da: ethyl 4-amino-5- (2- (isonicotinamido) -2-methylpropoxy) -2-methylquinoline-3-carboxylate
To a solution of ethyl 4-amino-5- (2-amino-2-methylpropoxy) -2-methylquinoline-3-carboxylate (Example Db, 1.0 g, 3.15 mmol) in dry DMF (20 mL) isonicotinic acid (504 mg, 4.10 mmol), followed by EDCI (783 mg, 4.10 mmol), HOBt
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Example Db: ethyl 4-amino-5- (2-amino-2-methylpropoxy) -2-methylquinoline-3 carboxylate
Prepared as in Example Ba from benzyl 1- (3-amino-2-cyanophenoxy) -2methylpropan-2-ylcarbamate (Example Dc) and ethyl 3-oxobutanoate as a yellowish brown solid (91%). ¹ H NMR (400 MHz, DMSO-d ^) δ 1.15 (s, 6H), 1.31 (t, J = 4 Hz, 3H), 2.54 (s, 3H), 3.87 (s , 2H), 4.31 (q, J = 4 Hz, 2H), 6.85 (d, J = 4 Hz, 1H), 7.21 (d, J = 4 Hz, 1H), 7.49 ( t, J = 8 Hz, 1H), 8.38 (brs, 2H). MS 318 (MH +).
Example Dc: benzyl 1 - (3-amino-2-cyanophenoxy) -2-methylpropan-2-ylcarbamate
To a solution of 2-amino-6- (2-amino-2-methylpropoxy) benzonitrile (Example Dd, 30.5 g, 148.6 mmol) in THF / H2O (1: 1, 400 mL) was added NaHCO ₃ (24.7 g, 294 mmol), followed by benzyl (2,5-dioxopyrrolidin-1-yl) carbonate (44.0 g, 176 mmol) at room temperature. The reaction was stirred at room temperature for 4 h then the organic layer was separated and the aqueous layer was extracted with EtOAc (2X). The combined organic layers were washed with brine and dried over MgSO ₄ . After filtration, the solvent was evaporated and the crude oil was purified by chromatography on silica gel (eluent: 0-60% EtOAc in hexane) to yield the title compound as yellow oil (44.8 g, 89%). ¹ H NMR (400 MHz, DVISO-A) δ 1.30 (s, 6H), 4.02 (s, 2H), 4.96 (s, 2H), 5.98 (s, 2H), 6, 14 (d, J = 8.0 Hz, 1H), 6.32 (dd, J = 0.8, 8.4 Hz, 1H), 7.12 (t, J = 8.4 Hz, 1H), 7.38-7.21 (m, 6H). MS 340 (MH +).
Example Dd: 2-amino-6- (2-amino-2-methylpropoxy) benzonitrile
To a solution of 2-amino-2-methylpropan-1-ol (14.4 g, 161 mmol) in anhydrous THF (150 mL) was added NaH (6.8 g, 161 mmol, 60% in mineral oil) in small
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Example E: 4-amino-5- (3- (cyclohexylamino) -2,2-dimethyl-3-oxopropoxy) 2-methyl-quinoline-3-carboxylic acid
Me
HO
Prepared as in Example A from ethyl 4-amino-5- (3- (cyclohexylamino) 2,2-dimethyl-3-oxopropoxy) -2-methylquinoline-3-carboxylate (Example Ea) as an off-white solid ( 13%). MS 400 (MH ⁺ ).
Example Ea: Ethyl 4-amino-5- (3- (cyclohexylamino) -2,2-dimethyl-3-oxopropoxy) -2-methylquinoline-3-carboxylate
Prepared as in Example Da from 3 - ((4-amino-3- (ethoxycarbonyl) -2methylquinolin-5-yl) oxy) -2,2-dimethylpropanoic acid (Example Eb) and cyclohexanamine as a yellowish brown solid (46%). MS 428 (MH ⁺ ).
Example Eb: 3 - (((4-amino-3- (ethoxycarbonyl) -2-methylquinolin-5-yl) oxy) -2,2-dimethyl-propanoic acid
Prepared as in Example Ba from benzyl 3- (3-amino-2-cyanophenoxy) -2,2dimethyl-propanoate (Example Ec) and ethyl 3-oxobutanoate as a brown solid (80%). MS 192 (MH +).
Example Ec: 3- (3-amino-2-cyanophenoxy) -2,2-dimethylpropanoate
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To a solution of benzyl 3- (2-cyano-3-nitrophenoxy) -2,2-dimethylpropanoate (Example Ed, 200 mg, 0.56 mmol) in AcOH (5 mL) was added iron powder (158 mg, 2 , 82 mmol) at room temperature. The reaction mixture was then stirred at 90 ° C for 1 h. The reaction mixture was cooled to room temperature then diluted with AcOEt. The precipitate was filtered and the filtrate was successively washed with 1 N NaOH and brine, then dried over Na ₂ SO4, filtered and evaporated. The residue was purified by chromatography on silica gel (eluent: 40% EtOAc in hexanes) to produce a title compound as a colorless oil (187 mg, 100%). MS 325 (MH +).
Example Ed: Benzyl 3- (2-cyano-3-nitrophenoxy) -2,2-dimethylpropanoate
To a solution of benzyl 3-hydroxy-2,2-dimethylpropanoate (Yang, D. et al. J. Am. Chem. Soc. 2002, 124, 9966. 6.68 g, 32.1 mmol) in dry THF ( 200 mL) NaH (60% in mineral oil, 3.5 g, 87.5 mmol) was added carefully in small portions at 0 ° C under nitrogen. The reaction mixture was stirred at 0 ° C under nitrogen for 2 hours. To this solution, 2,6-dinitrobenzonitrile (6.19 g, 32.1 mmol) was added, and the reaction solution was stirred at 0 ° C - RT under nitrogen overnight. The reaction mixture was heated briefly with brine, and extracted with EtOAc (3X). The combined organic layers were washed with brine, dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluting (Eluent: 20% EtOAc in hexanes) to yield the title compound as a brown solid (10.0 g, 87%). MS 355 (MH ⁺ ).
Example F: 4-amino-5- (cyclohexyloxy) -2-methylquinoline3-carboxylic acid hydrochloride
nh ₂ o
HCI
To a suspension of 4-amino-5- (cyclohexyloxy) -2-methylquinoline-3-carboxylic acid (Example H, 1.0 g, 3.33 mmol) in ethanol (10 mL) was added M 1.25 solution of HCl in ethanol (2.93 mL, 3.66 mmol). The clear solution was stirred for 30 minutes and evaporated to dryness to provide 4-amino-5- (cyclohexyloxy) -2-methylquinoline-3-carboxylic acid hydrochloride (1.12 g, 100%) as a white solid. ¹ H NMR (400 MHz, DVISO-Á) δ 1.30 (m, 1H), 1.39-1.47 (m, 2H), 1.53-1.72 (m, 5H), 2.01 -2.05 (m,
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2H), 2.82 (s, 3H), 4.78-4.82 (m, 1H), 7.29-7.31 (d, J = 8.0 Hz, 1H), 7.61-7 , 63 (d, J = 8.0 Hz, 1H), 7.82 (t, J = 8.4 Hz, 1H), 9.30 (bs, 1H), 9.93 (bs, 1H). MS 301 (MH + -HCl).
Example G: Sodium 4-amino-5- (cyclohexyloxy) -2-methylquinoline-3-carboxylate
NaO ₂ C
NH ₂ O
Me N

To a solution of 4-amino-5- (cyclohexyloxy) -2-methylquinoline-3-carboxylic acid (Example H, 1.0 g, 3.33 mmol) in ethanol (20 mL) was added a solution of NaHCO ₃ (294 mg, 3.50 mmol) in water (15 mL). The mixture was stirred and heated to 60 ° C until the solution became clear then it was evaporated to dryness to provide sodium 4-amino-5 (cyclohexyloxy) -2-methylquinoline-3-carboxylate (1.07 g, 100%) as a white solid. ¹ H NMR (400 MHz, DVISO-Y) δ 1.25-1.45 (m, 3H), 1.50-1.70 (m, 5H), 1.53-1.72 (m, 5H) , 1.98-2.00 (m, 2H), 2.64 (s, 3H), 4.59-4.63 (m, 1H), 6.87-6.89 (d, J = 7, 6 Hz, 1H), 7.20-7.22 (d, J = 8.0 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H). MS 301 (MH ++ H-Na).
Example H: 4-amino-5- (cyclohexyloxy) -2-methylquinoline-3-carboxylic acid
To a solution of ethyl 4-amino-5- (cyclohexyloxy) -2-methylquinoline-3-carboxylate (Example Ha, 110 g, 0.335 mol) in EtOH (450 mL) was added a solution of NaOH (33, 5 g, 0.837 mol) in water (200 mL) at room temperature. The reaction mixture was then refluxed overnight. The reaction solution was cooled to 0 ° C and carefully neutralized with 4N HCl to pH 7. The resulting solution was concentrated under reduced pressure to remove most of EtOH. The precipitate was collected by filtration, and redissolved in EtOH (4 L) at 65 ° C and treated with activated carbon (5 g) for
O, 5 h. The charcoal was removed by filtration over celite, and the filtrate was concentrated. The precipitate was collected by filtration, washed with cold water, and dried under vacuum at 60 ° C overnight to produce the title compound as a white solid (100 g, 99%).
M.p .: 220.0-221.5 ° C. ¹ H NMR (400 MHz, DVISO-Y) δ 1.28-1.72 (m, 8H), 2.00-2.04 (m, 2H), 2.75 (s, 3H), 4.69 -4.71 (m, 1H), 7.10-7.12 (d, J = 8.0 Hz, 1H), 7.24-7.26 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 12.80 (brs, 1H). MS 301 (MH +). Elementary Analysis
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Calculated (Calculated) for C17H20N2O3: C, 67.98% (67.74%); H, 6.71% (7.01%); N, 9.33% (9.40%).
Example Ha: ethyl 4-amino-5- (cyclohexyloxy) -2-methylquinoline-3-carboxylate
A solution of ethyl 3-oxobutanoate (29.9 g, 0.230 mol) in anhydrous toluene (200 mL) was added to a solution of 2-amino-6- (cyclohexyloxy) benzonitrile (Example Hb, 49.8 g , 0.230 mol) in anhydrous toluene (1000 mL) under nitrogen in a 3 L round bottom flask sitting in an oil bath at room temperature. SnCl ₄ (53.9 mL, 0.461 mol) was added slowly over a period of approximately 1 h. The temperature of the oil bath was raised to 110 ° C and the reaction mixture was stirred at that temperature for 2.5 h. It was cooled to 5 ° C, still under nitrogen, and the toluene was decanted from the immiscible viscous oil at the bottom of the flask. The viscous oil was concentrated under vacuum at 60 ° C, redissolved in boiling ethyl acetate (1 L), and transferred to a 4 liter Erlenmeyer flask. The solution was diluted with more EtOAc (1.5 L), cooled to -15 ° C, and neutralized with NaOH (3 N, 500 mL). The organic layer was separated, and the aqueous emulsion was extracted once more with ethyl acetate. The insoluble salts were filtered from the aqueous layer, so both salts and the aqueous filtrate were washed once more with ethyl acetate. The combined organic layers were dried over MgSO ₄ , concentrated, and passed through a silica column using 0% to 60% ethyl acetate in hexanes. The product was purified by recrystallization from EtOAc to produce the title compound as an off-white solid (64.3 g, 85%). ¹ H NMR (400 MHz, DVISO-A) δ 1.28-1.34 (m, 1H), 1.32 (t, 3H), 1.37-1.45 (m, 2H), 1.51 -1.63 (m, 3H), 1.67-1.71 (m, 2H), 1.99-2.03 (m, 2H), 2.54 (s, 3H), 4.28-4 , 33 (q, J = 6.8 Hz, 2H), 4.64 (m, 1H), 6.95-6.97 (d, J = 7.6 Hz, 1H), 7.19-7, 21 (d, J = 8.4 Hz, 1H), 7.65 (t, J = 8.4 Hz, 1H), 8.15 (brs, 2H). MS 329 (MH +).
Example Hb: 2-amino-6- (cyclohexyloxy) benzonitrile
To a solution of cyclohexanol (19.1 g, 0.191 mol) in anhydrous THF (500 mL) was added NaH (7.6 g, 40% in mineral oil, 0.191 mol) in small portions at 0 ° C under nitrogen . The mixture was stirred at room temperature for 1 h and a solution of 2 amino-6- fluorobenzonitrile (20.0 g, 0.15 mol) in anhydrous THF (150 ml) was added gradually at room temperature. The reaction mixture was heated to reflux overnight then cooled to room temperature and most of the THF was removed under reduced pressure. Ice water (100 ml) was added to the concentrated reaction mixture followed by EtOAc (500 ml). The organic layer was separated and
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Example Hb: 2-amino-6- (cyclohexyloxy) benzonitrile
Alternative method a): To a solution of 2- (cyclohexyloxy) -6-nitrobenzonitrile (Example Hc, 50.0 g, 0.20 mol) in THF / AcOH (1: 1 by volume, 500 mL) was added powdered iron (34.0 g, 0.61 mol) in one serving at room temperature under nitrogen. The reaction mixture was refluxed for 40 min under nitrogen and cooled to room temperature and EtOAc (2 L) was added. The formed precipitate was filtered and washed with EtOAc. The organic layer was separated and washed successively with water (2 X 300 ml), aqueous NaOH (1.0 N, 2 X 300 ml), saturated Na ₂ CO _{3 solution} (300 ml), brine (300 ml), dried over filtered Na ₂ SO ₄ and evaporated under reduced pressure. The residue was purified by chromatography on silica gel eluting with 25% EtOAc in hexanes to produce 2 amino-6- (cyclohexyloxy) benzonitrile as an opaque yellow oil (45.0 g, 94%), which solidified after storage during night at room temperature.
Alternative method b): A 3 L 3-neck round-bottom flask was first purged with nitrogen. 10% Pd / C (2.81 g) was then added under nitrogen, followed successively by 2- (cyclohexyloxy) -6-nitrobenzonitrile (Example Hc, 43.2 g, 0.175 mol), anhydrous methanol (389 mL) , and acetic acid (80.4 ml). A reflux condenser, a drip funnel containing an ammonium-shaped solution (49.8 g, 0.790 mol) in anhydrous methanol (498 mL), thermometer, nitrogen inlet and nitrogen outlet were connected. Ammonium formate solution (75 mL) was added at room temperature, then the reaction was heated slowly to a maximum of 42 ° C. The Mixture was monitored carefully until the beginning of the reaction was observed (the evolution of the gas occurred around the exotherm of 10 ° C). The initiation of the reaction often took up to 40 minutes before starting. The remainder of the ammonium formate solution was then added at a rate that maintained the internal reaction temperature from 40 ° C to 48 ° C. After the addition was complete, a reaction mixture was stirred for another 10 minutes at 45 ° C, then cooled to room temperature. The Pd / C was removed by filtration using a Teflon filter, and the solvent was evaporated. Ice water (1 L) was added to the residue,
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Example Hc: 2- (cyclohexyloxy) -6-nitrobenzonitrile
To a solution of cyclohexanol (46.8 grams, 0.467 mol) in anhydrous THF (1 L) was added sodium hydride (20.3 grams, 0.508 mol) at -40 ° C under nitrogen. The reaction mixture was allowed to warm slowly to room temperature and stir for an additional hour. It was then cooled to -55 ° C and 2,6-dinitrobenzonitrile (78.4 g, 0.406 mol) was added. The reaction was stirred at room temperature overnight, then cooled to -20 ° C, and citric acid (23.4 grams, 0.122 mol) was added. The mixture was then poured into ice water (5 L) containing citric acid (7.8 g, 0.041 mol), stirred for 15 minutes, and the precipitated product was collected by filtration. The crude product was recrystallized from isopropanol (750 ml, heated to a boil, then cooled to 0 ° C), filtered, washed with isopropanol (300 ml), then air dried to produce 84.4 g of a yellow solid. The solid was dissolved in dichloromethane (169 ml) and filtered through an alumina plug to produce the title compound as an opaque yellow solid (83.2 g, 83.2%). ¹ H NMR (400 MHz, DVISO-Á) δ 1.4 (m, 4H), 1.6 (m, 2H), 1.7 (m, 2H), 1.9 (m, 2H), 4, 75 (m, 1H), 7.79 (dd, J = 2.0, 8.0 Hz, 1H), 7.84-7.91 (m, 2H).
Example 1: 4-amino-5- (3- (isopropylamino) -2,2-dimethyl-3-oxopropoxy) -2methylquinoline-3-carboxylic acid
To a solution of ethyl 4-amino-5- (3- (isopropylamino) -2,2-dimethyl-3-oxopropoxy) -2methylquinoline-3-carboxylate (Example 1a, 14.0 g, 36.2 mmol) in EtOH (140 ml) aqueous NaOH solution (2.0 N, 46 ml) was added at room temperature. The reaction mixture was stirred at 90 ° C for 4 hours. The resulting solution was neutralized at 0 ° C to pH 7 with 6 N HCl, and concentrated under reduced pressure. The residue was redissolved in EtOH (400 ml) and water (25 ml), and treated with charcoal (200 mg) at 65 ° C for 30 minutes. After removing the charcoal by filtration, the filtrate was concentrated, and the solid
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The resulting white 64/96 was purified by recrystallization from EtOH / H ₂ O and dried under vacuum at 70 ° C to yield the title compound as a white solid (11.5 g, 89%). Mp: 216-218 ° C. ¹ H NMR (400 MHz, DVISO-U) δ 1.01 (d, J = 6.4 Hz, 6H), 1.24 (s, 6H), 2.75 (s, 3H), 3.86- 3.93 (m, 1H), 4.17 (s, 2H), 7.01 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 8.83 (brs, 1H), 12.34 (brs, 1H), 12.78 (brs, 1H). MS 360 (MH +).
Example_____1a: Ethyl 4-amino-5- (3- (isopropylamino) -2,2-dimethyl-3-oxopropoxy) -2-methylquinoline-3-carboxylate
Method A: to a solution of 3- (3-amino-2-cyanophenoxy) -N-isopropyl-2,2-dimethylpropanamide (Example 1b, 11.35 g, 41.27 mmol) and ethyl 3-oxobutanoate (5 , 2 ml, 41.27 mmol) in anhydrous 1,2-dichloroethane (110 ml) and toluene (110 ml) was added dropwise SnCl ₄ (9.66 ml, 82.55 mmol) at room temperature under nitrogen. The reaction mixture was heated to reflux for 3 hours. The solution was cooled to room temperature and the solvent removed under reduced pressure. The residue was dissolved in EtOAc (600 ml) and neutralized at 0 ° C to pH 8 with 6 N NaOH. The organic layer was separated and the aqueous layer was further extracted with EtOAc (100 ml). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by Biotage SP-1, 40S x4 column chromatography eluting with 05% MeOH in dichloromethane, and recrystallized from EtOAc to yield the title compound as a creamy white solid (14.0 g, 88%). ¹ H NMR (400 MHz, DVISO-U) δ 1.01 (d, J = 6.4 Hz, 6H), 1.24 (s, 6H), 1.32 (t, J = 7.2 Hz, 3H), 2.55 (s, 3H), 3.87-3.93 (m, 1H), 4.12 (s, 2H), 4.31 (q, J = 7.2 Hz, 2H), 6.87 (d, J = 7.2 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.49-7.53 (m, 3H), 8.09 (s , 2H). MS 388 (MH +).
Method B: to a solution of 3- (3-amino-2-cyanophenoxy) -N-isopropyl-2,2-dimethylpropanamide (Example 1b, 10.0 g, 36.4 mmol) in ethyl 3-oxobutanoate (110 mL, 874 mmol, 24 eq.) Anhydrous FeCl ₃ (6.5 g, 40 mmol, 1.1 eq.) was added at room temperature under nitrogen. The black reaction mixture was stirred for 2 h at 110 ° C. Excess ethyl 3-oxobutanoate was rotary evaporated at 80 ° C. The resulting thick mixture was dissolved in EtOAc (200 ml). An aqueous solution of NaOH (15%) (80 ml) was added slowly at 0 ° C. The mixture was stirred for 15 min. The organic layer was separated and the aqueous solution was extracted again with EtOAc (100 ml). The combined organic layers were washed with brine, dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography on silica
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Example 1b: 3- (3-amino-2-cyanophenoxy) -N-isopropyl-2,2-dimethylpropanamide
To a solution of 3-hydroxy-N-isopropyl-2,2-dimethylpropanamide (Example 1c, 5.12 g, 32.15 mmol) in dry THF (100 mL) was gradually added NaH (60% in mineral oil, 1 , 41 g, 35.37 mmol) at 0 ° C under nitrogen. The reaction mixture was stirred at 0 ° C for about 30 minutes until the bubbling stopped. 2-Amino-6 fluorobenzonitrile (4.38 g, 32.15 mmol) was added and the solution stirred at 80 ° C overnight. The reaction mixture was cooled slowly with water to 0 ° C, and concentrated under reduced pressure. The residue was absorbed in EtOAc and washed consecutively with brine and water, dried over Na ₂ SO _{4 and} concentrated. The residue was purified by recrystallization from EtOAc / hexane to yield the title compound as a white crystalline solid (4.4 g, 50%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.18 (d, J = 6.8 Hz, 6H), 1.32 (s, 6H), 3.94 (s, 2H), 4.04-4 , 12 (m, 1H), 4.43 (s, 2H), 5.98 (d, J = 6.8 Hz, 1H), 6.21 (d, J = 8.0 Hz, 1H), 6 , 32 (d, J = 8.0 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H). MS 276 (MH +).
Example 1c: 3-hydroxy-N-isopropyl-2,2-dimethylpropanamide
Method A: To a Parr reactor, methyl 3-hydroxy-2,2dimethylpropanoate (66.0 g, 0.5 mol) and propan-2-amine (59.1 g, 1.0 mol) were added at room temperature. The reaction mixture was then stirred at 190 ° C overnight. The reaction was cooled to room temperature and the solution concentrated under reduced pressure. The residue was dissolved in EtOAc and the solution was successively washed with brine (5X), dried over Na2SO4, and evaporated under reduced pressure. The residue was coevaporated with dry toluene (100 ml X 2) to produce the title compound as a colorless oil (38.76 g, 49%). ¹ H NMR (400 MHz, DVISO-N) δ 0.98 (s, 6H), 1.02 (d, J = 6.4 Hz, 6H), 3.32 (d, J = 5.2 Hz, 2H), 3.79-3.88 (m, 1H), 4.83 (t, J = 5.2 Hz, 1H), 7.11 (d, J = 7.2 Hz, 1H). MS 160 (MH +).
Method B: to a solution of propan-2-amine (9.7 mL, 113.0 mmol) and 3-hydroxy-2,2-dimethylpropanoic acid (11.1 g, 94.2 mmol) in dichloromethane (500 mL) 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (22.0 g, 113 mmol), 1-hydroxybenzotriazole monohydrate (17.3 g, 113 mmol), and triethylamine (16 mL , 113 mmol). The reaction was stirred at room temperature overnight. The crude mixture was concentrated on the rotavapor. The residue was taken up in EtOAc and washed with NaHCO ₃
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Example 2: 4-amino-5- (3- (cyclopropylamino) -2,2-dimethyl-3-oxopropoxy) 2-methyl-quinoline-3-carboxylic acid
Prepared as in Example A from ethyl 4-amino-5- (3- (cyclopropylamino) 2,2-dimethyl-3-oxopropoxy) -2-methylquinoline-3-carboxylate (Example 2a) as a white solid (60% ). Mp: 227-229 ° C. ¹ H NMR (400 MHz, DVISO-V) δ 0.40-0.44 (m, 2H), 0.58-0.62 (m, 2H), 1.24 (s, 6H), 2.62 (m, 1H), 2.77 (s, 3H), 4.15 (s, 2H), 7.01 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8, 0 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.86 (d, J = 4.0 Hz, 1H), 8.75 (brs, 1H), 12.25 (brs, 1H), 12.77 (brs, 1H). MS 358 (MH +).
Example 2a: Ethyl 4-amino-5- (3- (cyclopropylamino) -2,2-dimethyl-3-oxopropoxy) -2-methylquinoline-3-carboxylate
Prepared as in Example Da from 3 - ((4-amino-3- (ethoxycarbonyl) -2methylquinolin-5-yl) oxy) -2,2-dimethylpropanoic acid (Example 47b) and cyclopropanamine as an opaque yellow solid (64 %). ¹ H NMR (400 MHz, DVISO-V) δ 0.14-0.45 (m, 2H), 0.57-0.62 (m, 2H), 1.25 (s, 6H), 1.35 (t, J = 8.0 Hz, 3H), 2.58 (s, 3H), 2.62-2.65 (m, 1H), 4.13 (s, 2H), 4.35 (q, J = 8.0 Hz, 2H), 6.90 (d, 1H), 7.27 (d, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.79 (d, J = 4.0 Hz, 1H), 8.09 (s, 2H). MS 386 (MH +).
Example 3: 4-amino-5- (3- (cyclobutylamino) -2,2-dimethyl-3-oxopropoxy) -2methylquinoline-3-carboxylic acid
Prepared as in Example A from ethyl 4-amino-5- (3- (cyclobutylamino) -2,2-dimethyl-3-oxopropoxy) -2-methylquinoline-3-carboxylate (Example 3a) as a white solid (45% ). Mp: 183-187 ° C. ¹ H NMR (400 MHz, DVISO-V) δ 1.24 (s, 6H), 1.52-1.63 (m, 2H), 1.87-1.98 (m, 2H), 2.03 -2.12 (m, 2H), 2.75 (s, 3H), 4.16 (s, 2H), 4.17
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4.26 (m, 1H), 7.01 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.67 (t, J = 8 , 0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 8.78 (brs, 1H), 12.35 (brs, 1H), 12.70 (brs, 1H). MS 372 (MH +).
Example 3 a: Ethyl 4-amino-5- (3- (cyclobutylamino) -2,2-dimethyl-3-oxopropoxy) -2-methylquinoline-3-carboxylate
Prepared as in Example Da from 3 - ((4-amino-3- (ethoxycarbonyl) -2methylquinolin-5-yl) oxy) -2,2-dimethylpropanoic acid (Example 47b) and cyclobutanamine as an off-white solid (71% ). MS 400 (MH *).
Example 4: 4-amino-5 - ((((1,4) -trans-4-isobutyramidocyclohexyl) oxy) -2-methylquinoline-3-carboxylic acid
nh ₂ 0 ,,, ..
Prepared as in Example A from ethyl 4-amino-5 - ((((1,4) -trans-4isobutyramidocyclohexyl) oxy) -2-methylquinoline-3-carboxylate (Example 4a) as a white solid (86 %). Mp: 183-185 ° C. ¹ H NMR (400 MHz, DVISO-Λ) δ 0.95 (s, 3H), 0.97 (s, 3H), 1.34-1.38 (m, 2H), 1.65-1.68 (m, 2H), 1.81-1.84 (m, 2H), 2.13-2.15 (m, 2H), 2.29-2.34 (m, 1H), 2.75 (s , 3H), 3.57-3.59 (m, 1H), 4.64 (m, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.53 (s, 1H), 7.65 (m, 2H). MS 386 (MH *).
Example______4a: Ethyl 4-amino-5 - ((((1,4) -trans-4-isobutyramidocyclohexyl) oxy) -2-methylquinoline-3-carboxylate
Prepared as in Example Ba from N - ((1,4) -trans-4- (3-amino-2-cyanophenoxy) cyclohexyl) isobutyramide (Example 4b) and ethyl acetoacetate as an off-white solid (88%). MS 414 (MH *).
Example 4b: N - ((1,4) -trans-4- (3-amino-2-cyanophenoxy) cyclohexyl) isobutyramide
Prepared as in Example Ca from N - ((1,4) -trans-4-hydroxycyclohexyl) isobutyramide (Example 4c) and 2-amino-6-fluorobenzonitrile as an off-white solid (91%). MS 302 (MH +).
Example 4c: N - ((1,4) -trans-4-hydroxycyclohexyl) isobutyramide
Prepared as in Example Da from isobutyric acid and (1,4) -trans-4aminocyclohexanol as a colorless oil (51%). MS 186 (MH +).
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Example 5: 4-amino-2-methyl-5- (2-methyl-2- (3-methylbutanamido) propoxy) quinoline-3-carboxylic acid ^Me XjO / ⁰ I nh ₂ oJ < _n AA H
Prepared as in Example A from ethyl 4-amino-2-methyl-5- (2-methyl-2- (3-methylbutan-starch) propoxy) quinoline-3-carboxylate (Example 5a) as a white solid (47% ). Mp: 195-198 ° C. ¹ H NMR (400 MHz, DVISO-A) δ 1.50 (d, J = 4.0 Hz, 6H), 1.37 (s, 6H), 1.90-2.0 (m, 3H), 2.73 (s, 3H), 4.32 (s, 2H), 6.92 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 8.45 (s, 1H), 11.14 (brs, 1H), 12.94 (brs, 1H). MS 374 (MH +).
Example 5a: Ethyl 4-amino-2-methyl-5- (2-methyl-2- (3-methylbutanamido) propoxy) -quinoline3-carboxylate
Prepared as in Example Da from ethyl 4-amino-5- (2-amino-2-methylpropoxy) -2-methylquinoline-3-carboxylate (Example Db) and 3-methylbutanoic acid as an off-white solid (100%). MS 402 (MH +).
Example 6: 4-amino-5- (2-isobutyramido-2-methylpropoxy) -2methylquinoline-3-carboxylic acid
Prepared as in Example A from ethyl 4-amino-5- (2-isobutyramido-2 methylpropoxy) -2-methylquinoline-3-carboxylate (Example 6a) as a white solid (38%). Mp: 184-186 ° C. ¹ H NMR (400 MHz, DVISO-A) δ 0.89 (d, J = 8.0 Hz, 6H), 1.35 (s, 6H), 2.41 (m, 1H), 2.79 ( s, 3H), 4.35 (s, 2H), 7.01 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.65 ( t, J = 8.0 Hz, 1H), 7.82 (s, 1H), 8.83 (brs, 1H), 12.10 (brs, 1H), 13.10 (brs, 1H). MS 360 (MH +).
Example 6a: Ethyl 4-amino-5- (2-isobutyramido-2-methylpropoxy) -2-methylquinoline-3carboxylate
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Prepared as in Example Da from ethyl 4-amino-5- (2-amino-2-methylpropoxy) -2-methylquinoline-3-carboxylate (Example Db) and isobutyric acid as a white solid (58%). MS 388 (MH +).
Example 7: 4-amino-2-methyl-5- (2-methyl-2- (tetrahydro-2H-pyran-4carboxamido) -propoxy) quinoline-3-carboxylic acid
Prepared as in Example A from ethyl 4-amino-2-methyl-5- (2-methyl-2- (tetrahydro-2H-pyran-4-carboxamido) propoxy) quinoline-3-carboxylate (Example 7a) as a white solid (65%). Mp: 170-173 ° C, 1H NMR (400 MHz, DVISO-A) δ 1.35 (s, 6H), 1.44-1.49 (m, 4H), 2.40 (m, 1H), 2.76 (s, 3H), 3.19-3.25 (m, 2H), 3.75-3.79 (m, 2H), 4.34 (s, 2H), 6.99 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.84 (s, 1H) . MS 402 (MH +).
Example________7a: Ethyl 4-amino-2-methyl-5- (2-methyl-2- (tetrahydro-2H-pyran-4carboxamido) propoxy) quinoline-3-carboxylate
Prepared as in Example Da from ethyl 4-amino-5- (2-amino-2-methylpropoxy) -2-methylquinoline-3-carboxylate (Example Db) and tetrahydro-2H-pyran-4-carboxylic acid as a yellow solid opaque (63%). MS 430 (MH +).
Example 8: 4-amino-2-methyl-5- (2-methyl-2propionamidopropoxy) quinoline-3-carboxylic acid
Prepared as in Example A from ethyl 4-amino-2-methyl-5- (2-methyl-2propionamido-propoxy) quinoline-3-carboxylate (Example 8a) as a white solid (31%). Mp: 189-193 ° C. ¹ H NMR (400 MHz, DVISO-A) δ 0.89 (t, J = 8.0 Hz, 6H), 1.34 (s, 6H), 2.05 (q, J = 8.0 Hz, 2H), 2.72 (s, 3H), 4.31 (s, 2H), 6.90 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.80 (s, 1H), 8.41 (brs, 1H), 11.02 (brs, 1H), 13.17 ( brs, 1H). MS 346 (MH +).
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Example 8a: Ethyl 4-amino-2-methyl-5- (2-methyl-2-propionamidopropoxy) quinoline-3 carboxylate
Prepared as in Example Da from ethyl 4-amino-5- (2-amino-2-methylpropoxy) -2-methylquinoline-3-carboxylate (Example Db) and propionic acid as an opaque yellow solid (23%). MS 374 (MH +).
Example 9: 4-amino-5- (2- (cyclobutanecarboxamido) -2-methylpropoxy) -2 methylquinoline-3-carboxylic acid
Prepared as in Example A from ethyl 4-amino-5- (2 (cyclobutanecarboxamido) -2-methylpropoxy) -2-methylquinoline-3-carboxylate (Example 9A) as a white solid (65%). Mp: 186-190 ° C. ¹ H NMR (400 MHz,
DVISO-V) δ 1.34 (s, 6H), 1.56-1.66 (m, 1H), 1.73-1.84 (m, 1H), 1.87-2.03 (m, 4H), 2.78 (s, 3H), 3.00-3.08 (m, 1H), 4.36 (s, 2H), 7.01 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.73 (s, 1H), 8.76 (brs, 1H), 12.01 (brs, 1H), 13.05 (brs, 1H). MS 372 (MH ⁺ ).
Example_____9a: Ethyl 4-amino-5- (2- (cyclobutanecarboxamido) -2-methylpropoxy) -2methylquinoline-3-carboxylate
Prepared as in Example Da from ethyl 4-amino-5- (2-amino-2-methylpropoxy) -2-methylquinoline-3-carboxylate (Example Db) and cyclobutanecarboxylic acid as an off-white solid (61%). MS 400 (MH +).
Example 10: 4-amino-5 - (((1-isobutyrylpiperidin-4-yl) oxy) -2-methylquinoline3-carboxylic acid
Prepared as in Example A from ethyl 4-amino-5 - ((1-isobutyrylpiperidin-4yl) oxy) -2-methylquinoline-3-carboxylate (Example 10a) as a white solid (88%). Mp: 184-186 ° C. ¹ H NMR (400 MHz, DVISO-N) δ 0.95 (s, 3H), 0.99 (t, 6H), 1.68
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1.82 (m, 2H), 2.02-2.11 (m, 2H), 2.74 (s, 3H), 2.89 (m, 1H), 3.01 (m, 1H), 3 , 35 (m, 1H), 3.84 (m, 1H), 4.04 (m, 1H), 4.94 (m, 1H), 7.16 (d, J = 8.4 Hz, 1H) , 7.26 (d, J = 7.6 Hz, 1H), 7.67 (t, J = 8.4 Hz, 1H). MS 372 (MH +).
Example 10a: Ethyl 4-ammo-5 - ((1-isobutyrylpiperidin-4-yl) oxy) -2-methylqumolma-3carboxylate
Prepared as in Example Ba from 2-amino-6 - ((1-isobutyrylpiperidin-4yl) oxy) benzonitrile (Example 10b) and ethyl acetoacetate as an off-white solid (82%). MS 400 (MH +).
Example 10b: 2-ammo-6 - ((1-isobutyrylpiperidm-4-yl) oxy) benzomtryl
Prepared as in Example Ca from 1- (4-hydroxypiperidin-1-yl) -2methylpropan-1-one (Example 10c) and 2-amino-6-fluorobenzonitrile as an off-white solid (87%). MS 288 (MH +).
Example 10c: 1- (4-hydroxypiperidin-1-yl) -2-methylpropan-1-one
Prepared as in Example Da from isobutyric acid and piperidin-4-ol as a colorless oil (43%). MS 172 (MH +).
Example 12: 4-amino-5- (3- (ethylamino) -2,2-dimethyl-3-oxopropoxy) -2methylquinoline-3-carboxylic acid
Prepared as in Example A from ethyl 4-amino-5- (3- (ethylamino) -2,2-dimethyl-3oxopropoxy) -2-methylquinoline-3-carboxylate (Example 12a) as a white solid (75% ). Mp: 168-170 ° C. ¹ H NMR (400 MHz, DVISO-Á) δ 0.96 (t, J = 8 Hz, 3H), 1.24 (s, 6H), 3.06 (s, 3H), 3.09 (dq, J = 1.6, 8.0 Hz, 2H), 4.14 (s, 2H), 7.00 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.90 (t, J = 8.0 Hz, 1H), 8.85 (brs, 1H), 12.32 ( brs, 1H), 12.70 (brs, 1H). MS 346 (MH +).
Example 12a: Ethyl 4-amino-5- (3- (ethylamino) -2,2-dimethyl-3-oxopropoxy) -2-methylquinoline-3-carboxylate
Prepared as in Example Da from 3 - ((4-amino-3- (ethoxycarbonyl) -2methylquinolin-5-yl) oxy) -2,2-dimethylpropanoic acid (Example Eb) and ethylamine hydrochloride as an off-white solid ( 61%). MS 374 (MH +).
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Example 13: 4-amino-2-methyl-5- (2-methyl-2- (2- (tetrahydro-2H-pyran-4yl) acetamido) -propoxy) quinoline-3-carboxylic acid ^Me XjO nh ₂ OJK _n A / UH
Prepared as in Example A from ethyl 4-amino-2-methyl-5- (2-methyl-2- (2- (tetrahydro-2H-pyran-4-yl) acetamido) propoxy) quinoline-3-carboxylate (Example 13a) as a white solid (28%). Mp: 175-178 ° C. ¹ H NMR (400 MHz, DVISO-N) δ 1,061.13 (m, 2H), 1.35-1.38 (m, 8H), 1.79 (m, 1H), 1.98 (d, J = 4.0 Hz, 2H), 2.77 (s, 3H), 3.10 (t, J = 4.0 Hz, 2H), 3.60 (m, 2H), 4.34 (s, 2H ), 7.01 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.88 (s, 1H), 8.76 (brs, 1H), 12.43 (brs, 1H), 12.71 (brs, 1H). MS 416 (MH ⁺ ).
Example______13a: Ethyl 4-amino-2-methyl-5- (2-methyl-2- (2- (tetrahydro-2H-pyran-4yl) acetamido) propoxy) quinoline-3-carboxylate
Prepared as in Example Da from ethyl 4-amino-5- (2-amino-2-methylpropoxy) -2-methylquinoline-3-carboxylate (Example Db) and 2- (tetrahydro-2H-pyran-4-yl ) acetic acid as a yellow solid (37%). ¹ H NMR (400 MHz, DVISO-Y) δ 1.05-1.08 (m, 2H), 1.30-1.38 (m, 11H), 1.79 (m, 1H), 1.97 (d, J = 4.0 Hz, 2H), 2.56 (s, 3H), 3.07 (t, J = 8.0 Hz, 2H), 3.61 (d, J = 8.0 Hz , 2H), 4.28-4.34 (m, 4H), 6.87 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7 , 49 (t, J = 8.0 Hz, 1H), 7.73 (s, 1H), 8.21 (s, 2H). MS 444 (MH +).
Example 14: 4-amino-5- (3 - ((cyclopropylmethyl) amino) -2,2-dimethyl-3oxopropoxy) -2-methylquinoline-3-carboxylic acid
O
Prepared as in Example A from ethyl 4-amino-5- (3 - ((cyclopropylmethyl) amino) 2,2-dimethyl-3-oxopropoxy) -2-methylquinoline-3-carboxylate (Example 14a) as a solid white (39%). Mp: 177-179 ° C. ¹ H NMR (400 MHz, DVISO-Y) δ 0.12-0.13 (m, 2H), 0.30-0.31 (m, 2H), 0.89 (m, 1H), 1.28 (s, 6H), 2.76 (s, 3H), 2.98 (t, J = 4.0 Hz, 2H), 4.17 (s, 2H), 7.03 (d, J = 8, 0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.98 (t, J = 8.0 Hz , 1H), 8.80 (brs, 1H), 12.26 (brs, 1H), 12.76 (brs, 1H). MS 372 (MH +).
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Example 14a: Ethyl 4-amino-5- (3 - ((cyclopropylmethyl) amino) -2,2-dimethyl-3-oxopropoxy) 2-methylquinoline-3-carboxylate
Prepared as in Example Da from 3 - ((4-amino-3- (ethoxycarbonyl) -2methylquinolin-5-yl) oxy) -2,2-dimethylpropanoic acid (Example Eb) and cyclopropylmethanamine as an opaque yellow solid (80 %). ¹ H NMR (400 MHz, DVISO-tA) δ 0.12-0.13 (m, 2H), 0.29-0.31 (m, 2H), 0.90 (m, 1H), 1.27 (s, 6H), 1.33 (t, J = 8.0 Hz, 3H), 2.56 (s, 3H), 2.97 (t, J = 8.0 Hz, 2H), 4.14 (s, 2H), 4.32 (q, J = 8.0 Hz, 2H), 6.88 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 4.0 Hz , 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.91 (t, J = 4.0 Hz, 1H), 8.11 (s, 2H). MS 400 (MH ⁺ ).
Example 15: 4-amino-5- (3- (butylamino) -2,2-dimethyl-3-oxopropoxy) -2methylquinoline-3-carboxylic acid
Prepared as in Example A from ethyl 4-amino-5- (3- (butylamino) -2,2-dimethyl3-oxopropoxy) -2-methylquinoline-3-carboxylate (Example 15a) as an off-white solid (59% ). Mp: 195-199 ° C. ¹ H NMR (400 MHz, DVISO-Á) δ 0.74 (t, J = 8.0 Hz, 3H), 1.11-1.21 (m, 2H), 1.27 (s, 6H), 1.32-1.39 (m, 2H), 2.77 (s, 3H), 3.09 (q, J = 8.0 Hz, 2H), 4.17 (s, 2H), 7.03 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.88 (t , J = 8.0 Hz, 1H), 8.87 (brs, 1H), 12.41 (brs, 1H), 12.74 (brs, 1H). MS 374 (MH ⁺ ).
Example_______15a: Ethyl 4-amino-5- (3- (butylamino) -2,2-dimethyl-3-oxopropoxy) -2 methylquinoline-3-carboxylate
Prepared as in Example Da from 3 - (((4-amino-3- (ethoxycarbonyl) -2methylquinolin-5-yl) oxy) -2,2-dimethylpropanoic acid (Example Eb) and n-butylamine as an opaque yellow solid (91%). ¹ H NMR (400 MHz, DVISO-U) δ 0.74 (t, J = 8.0 Hz, 3H), 1.15-1.20 (m, 2H), 1.27 (s, 6H), 1.32-1.38 (m, 5H), 2.57 (s, 3H), 3.06-3.11 (q, J = 8.0 Hz, 2H), 4.14 (s, 2H) , 4.35 (q, J = 8.0 Hz, 2H), 6.90 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7 , 53 (t, J = 8.0 Hz, 1H), 7.81 (t, J = 8.0 Hz, 1H), 8.10 (s, 2H). MS 402 (MH +).
Example 16: 4-amino-5- (2,2-dimethyl-3-oxo-3- (pentan-3-ylamino) propoxy) 2-methyl-quinoline-3-carboxylic acid
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Prepared as in Example A from ethyl 4-amino-5- (2,2-dimethyl-3-oxo-3- (pentan3-ylamino) propoxy) -2-methylquinoline-3-carboxylate (Example 16a) as a white solid (72%). Mp: 172-174 ° C. ¹ H NMR (400 MHz, DVISO-A) δ 0.69 (t, J = 8.0 Hz, 6H), 1.29 (s, 6H), 1.32-1.42 (m, 4H), 2.76 (s, 3H), 3.59-3.64 (m, 1H), 4.21 (s, 2H), 7.03 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 8.79 (brs , 1H), 12.35 (brs, 1H), 12.73 (brs, 1H). MS 388 (MH +).
Example 16a: Ethyl 4-amino-5- (2,2-dimethyl-3-oxo-3- (pentan-3-ylamino) propoxy) -2-methylquinoline-3-carboxylate
Prepared as in Example Da from 3 - (((4-amino-3- (ethoxycarbonyl) -2methylquinolin-5-yl) oxy) -2,2-dimethylpropanoic acid (Example Eb) and pentan-3-amine as a solid opaque yellow (78%). ¹ H NMR (400 MHz, DVISO-N) δ 0.68 (t, J = 8.0 Hz, 6H), 1.27 (s, 6H), 1.31 (t, J = 8.0 Hz, 3H), 1.37-1.42 (m, 4H), 2.54 (s, 3H), 3.56-3.61 (m, 1H), 4.16 (s, 2H), 4.30 (q, J = 8.0 Hz, 2H), 6.87 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.32 (d , J = 8.0 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 8.06 (s, 2H). MS 416 (MH +).
Example 17: 4-amino-2-methyl-5- (2-methyl-2- (2morpholinoacetamido) propoxy) quinoline-3-carboxylic acid
ΗΟ ₂ Ο ' ^Λϊ: γ ^χ γ x, O NH ₂ O. / N. J
H
Prepared as in Example A from ethyl 4-amino-2-methyl-5- (2-methyl-2- (2morpholino-acetamido) propoxy) quinoline-3-carboxylate (Example 17a) as a white solid (32% ). Mp: 173-175 ° C. ¹ H NMR (400 MHz, DVISO-A) δ 1.39 (s, 6H), 2.35 (t, J = 4.8 Hz, 4H), 2.74 (s, 3H), 2.85 ( s, 2H), 3.47 (t, J = 4.8 Hz, 4H), 4.35 (s, 2H), 7.00 (d, J = 8.0 Hz, 1H), 7.27 ( d, J = 8.4 Hz, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.71 (s, 1H). MS 417 (MH ⁺ ).
Example_____17a: Ethyl 4-amino-2-methyl-5- (2-methyl-2- (2-morpholinoacetamido) propoxy) quinoline-3-carboxylate
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Prepared as in Example Da from ethyl 4-amino-5- (2-amino-2-methylpropoxy) -2-methylquinoline-3-carboxylate (Example Db) and 2-morpholinoacetic acid as a yellow solid (37%). MS 445 (MH +).
Example 18: 4-amino-5- (3- (isobutylamino) -2,2-dimethyl-3-oxopropoxy) -2methylquinoline-3-carboxylic acid
Prepared as in Example A from ethyl 4-amino-5- (3- (isobutylamino) -2,2dimethyl-3-oxopropoxy) -2-methylquinoline-3-carboxylate (Example 18a) as an off-white solid (60% ). Mp: 176-179 ° C. ¹ H NMR (400 MHz, DVISO-./,) δ 0.73 (d, J = 6.8 Hz, 6H), 1.27 (s, 6H), 1.65-1.75 (m, 1H ), 2.77 (s, 3H), 2.89 (t, J = 6.4 Hz, 2H), 4.17 (s, 2H), 7.01 (d, J = 8.4 Hz, 1H ), 7.31 (d, J = 8.4 Hz, 1H), 7.67 (t, J = 8.4 Hz, 1H), 7.90 (t, J = 5.8 Hz, 1H), 8.84 (brs, 1H), 12.16 (brs, 1H), 12.91 (brs, 1H). MS 374 (MH +).
Example_____18a: Ethyl 4-amino-5- (3- (isobutylamino) -2,2-dimethyl-3-oxopropoxy) -2-methylquinoline-3-carboxylate
Prepared as in Example Da from 3 - ((4-amino-3- (ethoxycarbonyl) -2methylquinolin-5-yl) oxy) -2,2-dimethylpropanoic acid (Example Eb) and isobutylamine as an off-white solid (82% ). MS 402 (MH ⁺ ).
Example 19: 4-amino-5- (3 - ((cyclobutylmethyl) amino) -2,2-dimethyl-3oxopropoxy) -2-methylquinoline-3-carboxylic acid
O
Prepared as in Example A from ethyl 4-amino-5- (3 - ((cyclobutylmethyl) amino) 2,2-dimethyl-3-oxopropoxy) -2-methylquinoline-3-carboxylate (Example 19a) white (54%). Mp: 170-172 ° C. ¹ H NMR (400 MHz, DVISO-V) δ 1.26 (s, 6H), 1.54-1.71 (m, 4H), 1.76-1.84 (m, 2H), 2.35 -2.42 (m, 1H), 2.76 (s, 3H), 3.10 (t, J = 6.0 Hz, 2H), 4.18 (s, 2H), 7.13 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.87 (t, J = 6.4 Hz, 1H), 9.21 (brs, 1H), 10.92 (brs, 1H). MS 386 (MH +).
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Example 19a: Ethyl 4-amino-5- (3 - ((cyclobutylmethyl) amino) -2,2-dimethyl-3-oxopro-poxy) -2methylquinoline-3-carboxylate
Prepared as in Example Da from 3 - ((4-amino-3- (ethoxycarbonyl) -2methylquinolin-5-yl) oxy) -2,2-dimethylpropanoic (Example Eb) and cyclobutylmethanamine as an off-white solid (67% ). MS 414 (MH +).
Example 20: 5- (2- (6-Ammonium hexanamido) -2-methylpropoxy) -3-carboxy-2methylquinolin-4-amine trifluoroacetate vN./^
T Η Ί
II J 2CF ₃ co ₂ ho ₂ c | © Xl / O ©
NH3 o. z / NH ₃ ³ N
H
A solution of 4-amino-5- (2- (6- (tert-butoxycarbonylamino) hexanamido) -2methylpropoxy) -2-methylquinoline-3-carboxylic acid (Example 20a) (59.6 mg, 0.12 mmol) in CH ₂ Cl ₂ (9.0 mL) was treated with trifluoroacetic acid (1.0 mL) at room temperature. After being stirred at room temperature for 2h the reaction mixture was evaporated to dryness. The residue was dissolved in H ₂ O (5.0 ml) and the product was isolated by preparative HPLC (RPC18, gradient H ₂ O CH ₃ CN). The appropriate fractions were collected and evaporated under reduced pressure. The residue was dried in a desiccator over phosphorus pentoxide to produce 43.6 mg (58%) of 5- (2- (6-ammonium hexanamido) -2methylpropoxy) -3-carboxy-2-methylquinolin-4-amine trifluoroacetate as a white solid. ¹ H NMR (400 MHz, DVISO-U) δ 13.56 (s, 1H), 9.98 (s, 1H), 9.40 (s, 1H), 7.88 (t, J = 8.3 Hz, 1H), 7.75 (s, 1H), 7.72-7.56 (m, 3H), 7.42 (d, J = 7.9 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 4.42 (s, 2H), 2.81 (s, 3H), 2.72-2.60 (m, 2H), 2.08 (t, J = 7, 3 Hz, 2H), 1.50-1.39 (m, 4H), 1.38 (s, 6H), 1.26-1.14 (m, 2H). MS 404 (M +).
Example 20a: 4-Amino-5- (2- (6- (tert-butoxycarbonylamino) hexanamido) -2methylpropoxy) -2-methylquinoline-3-carboxylic acid
A solution of 6- (tert-butoxycarbonylamino) hexanoic acid (0.21 g, 0.90 mmol) in dry DMF (10 mL) was treated with triethylamine (0.46 g, 4.51 mmol, 0.63 mL) and N, N, N ', N'-tetramethyl-O- (N-succinimidyl) uranium tetrafluoroborate (TSTU) (0.30 g, 0.99 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3h and then a solution of 5- (2-ammonium -2-methylpropoxy) -3-carboxy-2-methylquinolin-4-amine chloride (Example 20b) (0.33g, 0.90 mmol) and triethylamine (0.46 g, 4.51 mmol, 0.63 mL) in dry DMF were added dropwise to the
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Example 20b: 5- (2-Ammonium -2-methylpropoxy) -3-carboxy-2-methylquinolin-4-amine chloride
To a solution of ethyl 4-amino-5- (2-amino-2-methylpropoxy) -2-methylquinoline-3carboxylate (Example Db) (0.65 g, 2.05 mmol) in EtOH (35 mL) was added a solution of NaOH in H2O (2.0 M, 5.2 mL) at room temperature under a nitrogen atmosphere. The obtained reaction mixture was heated to 80 ° C for 3h and cooled to room temperature. The pH of the cold mixture was adjusted to 1 with a HCl solution (1.5 M) and the acidified solution was evaporated to dryness. The residue was dissolved in a mixture of EtOH and H ₂ O (30 ml, 1: 1) and the product was isolated by preparative HPLC (RPC18, gradient H ₂ O CH3CN). The appropriate fractions were collected and evaporated under reduced pressure. The residue was dried in a desiccator over phosphorus pentoxide to produce 0.41 g (54%) 5- (2-ammonium -2-methylpropoxy) -3-carboxy-2-methylquinolin-4-amine chloride as a white solid. ¹ H NMR (400 MHz, DVISO-óA) δ 10,059.90 (m, 1H), 9.15-9.00 (m, 1H), 8.69-8.57 (m, 3H), 7.91 (t, J = 8.3 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.3 Hz, 1H), 4.39 (s , 2H), 2.84 (s, 3H), 1.44 (s, 6H). MS 291 (M +)
Example 21: 4-amino-2-methyl-5 - (((1-propionylpiperidin-4yl) methoxy) quinoline-3-carboxylic acid
Me
HO ·
NH ₂ ° / 2
Prepared as in Example A from ethyl 4-amino-2-methyl-5 - ((1propionylpiperidin-4-yl) methoxy) quinoline-3-carboxylate (Example 21a) as a
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78/96 off-white solid (55%). Mp: 168-170 ° C. ¹ H NMR (400 MHz, DVISO-A) δ 0.96 (t, J = 7.6 Hz, 3H), 1.08-1.25 (m, 2H), 1.81 (t, J = 15 , 6 Hz, 2H), 2.19-2.26 (m, 1H), 2.30 (q, J = 7.2 Hz, 2H), 2.55 (t, J = 12 Hz, 1H), 2.75 (s, 3H), 3.01 (t, J = 12 Hz, 1H), 3.88 (d, J = 13.6 Hz, 1H), 4.1 (d, J = 5.6 Hz 2H), 4.42 (d, J = 13.2 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H ), 7.65 (t, J = 8.4 Hz, 1H). MS 372 (MH +).
Example 21a: Ethyl 4-amino-2-methyl-5 - ((1-propionylpiperidin-4-yl) methoxy) quinoline-3carboxylate
Prepared as in Example Ba from 2-amino-6 - ((1-propionylpiperidin-4yl) methoxy) benzo-nitrile (Example 21b) and ethyl acetoacetate as an off-white solid (41%). MS 400 (MH +).
Example 21b: 2-amino-6 - ((1-propionylpiperidin-4-yl) methoxy) benzonitrile
Prepared as in Example 22a from 1- (4- (hydroxymethyl) piperidin-1yl) propan-1-one (Example 21c) and 2-amino-6-fluorobenzonitrile as an opaque yellow solid (15%). MS 288 (MH +).
Example 21c: 1 - (4- (hydroxymethyl) piperidin-1-yl) propan-1-one
Prepared as in Example 24a from propionyl chloride and piperidin-4-methanol as a colorless oil (40%). MS 172 (MH ⁺ ).
Example 22: 4-amino-2-methyl-5 - ((((1,4) -trans-4- (methylcarbamoyl) cyclohexyl) oxy) quinoline-3-carboxylic acid
Me
HO
Prepared as in Example A from ethyl 4-amino-2-methyl-5 - ((((1,4) -trans-4 (methylcarbamoyl) cyclohexyl) oxy) quinoline-3-carboxylate (Example 22a) as a white solid (42%). Mp: 195-198 ° C. ¹ H NMR (400 MHz, DVISO-á) δ 1.55-1.80 (m, 6H), 2.00-2.10 (m, 2H), 2.20-2.30 (m, 1H) , 2.55 (d, J = 8.0 Hz, 3H), 2.76 (s, 3H), 4.96 (s, 1H), 7.07 (d, J = 8.0 Hz, 1H) , 7.27 (d, J = 8.0 Hz, 1H), 7.66-7.72 (m, 1H), 8.76 (brs, 1H), 12.00 (brs, 1H), 12, 83 (brs, 1H). MS 358 (MH +).
Example 22a: Ethyl 4-amino-2-methyl-5 - ((((1,4) -trans-4- (methylcarbamoyl) cyclohexyl) oxy) quinoline-3-carboxylate
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Prepared as in Example Ba from (1,4) -trans-4- (3-amino-2-cyanophenoxy) N-methylcyclohexanecarboxamide (Example 22b) and ethyl acetoacetate as a yellow solid (43%). MS 386 (MH +).
Example 22b: (1,4) -trans-4- (3-amino-2-cyanophenoxy) -N-methylcyclohexanecarboxamide
Prepared as in Example Ec from 4- (2-cyano-3-nitrophenoxy) -N-methylcyclohexane-carboxamide (Example 22c) as an opaque yellow solid (41%). MS 274 (MH ⁺ ).
Example 22c: 4- (2-cyano-3-nitrophenoxy) -N-methylcyclohexanecarboxamide
Prepared as in Example Da from 4- (2-cyano-3-nitrophenoxy) cyclohexanecarboxylic acid (Example 22d) and ethylamine hydrochloride as an orange solid (80%). MS 304 (MH ⁺ ).
Example 22d: 4- (2-cyano-3-nitrophenoxy) cyclohexanecarboxylic acid
Prepared as in Example Ed from 4-hydroxycyclohexanecarboxylic acid and 2,6-dinitrobenzonitrile as a brown solid (50%). MS 291 (MH +).
Example 23: 4-amino-5- (3- (isopropylamino) -2,2-dimethyl-3oxopropoxy) -2-methylquinoline-3-carboxylic acid phosphate
Prepared as in Example F from 4-amino-5- (3- (isopropylamino) -2,2dimethyl-3-oxopropoxy) -2-methylquinoline-3-carboxylic acid (Example 1) and H ₃ PO ₄ as a solid white (100%). ¹ H NMR (400 MHz, DVISO-óA) δ 1.01 (d, J = 6.4 Hz, 6H), 1.25 (s, 6H), 2.76 (s, 3H), 3.86- 3.95 (m, 1H), 4.17 (s, 2H), 7.04 (d, J = 8.0 Hz, 1H), 7.30 (dd, J = 8.0 Hz, 0.8 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H). MS 360 (MH ++ HH3PO4).
Example 24: sodium 4-amino-5- (3- (isopropylamino) -2,2-dimethyl-3-oxopropoxy) -2methylquinoline-3-carboxylate
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Prepared as in Example G from 4-amino-5- (3- (isopropylamino) 2,2-dimethyl-3-oxopropoxy) -2-methylquinoline-3-carboxylic acid (Example 1) and NaHCO ₃ as a white solid (100%). 1H NMR (400 MHz, DMSO-dQ δ 1.01 (d, J = 6.4 Hz, 6H), 1.23 (s, 6H), 2.56 (s, 3H), 3.86-3, 94 (m, 1H), 4.07 (s, 2H), 6.66 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 5 8.0 Hz, 1H), 7 , 32 (t, J = 8.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H) MS 360 (MH ++ H-Na).
The following compounds in Table G were synthesized following the procedures described above.
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Table G:
No. of the Compound Compound MS (MH +) G-1 ΤΪ J nh ₂ 0 ^ < _n A ^ hl 1 4-amino-5- (2- (4-hydroxycyclohexanecarboxamido) -2-methylpropoxy) -2-methylquinoline-3-carboxylic acid 416 G-2 nh ₂ 11 H 0 4-amino-5 - ((4- (ethylcarbamoyl) cyclohexyl) oxy) -2-methylquinoline-3-carboxylic acid 372 G-3 ΤΪ J _v nh ₂ cmCA 0 4-Amino-5- (2,2-dimethyl-3-oxo-3 (pyrrolidin-1-yl) propoxy) -2-methylquinoline-3-carboxylic acid 372 G-4 Me ^N XI J Ηο, ο ^ γγ o I nh ₂ ο ^ Α _ν Λ H 4-amino-5- (2- (isopropylamino) -2-oxoethoxy) -2-methylquinoline-3-carboxylic acid 318 G-5 XI J, _H ^NH 2 0Χν ^Ν _χ 4-amino-5- (2,2-dimethyl-3- (methylamino) - 3-oxopropoxy) -2-methylquinoline-3-carboxylic acid 332 G-6 ^Μθ ύ> ^ν υΧ HO ₂ c''y'Y ^ ^NH 2 acid 5 - ((1-acetylpiperidin-4-yl) oxy) -4-amino-2-methylquinoline-3-carboxylic 344 G-7 XI J nh ₂ ο ^ θΑ ^ 4-amino-5 - (((1-isobutyrylpiperidin-3-yl) oxy) -2-methylquinoline-3-carboxylic acid 372
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No. of the Compound Compound MS (MH +) G-8 ^Me X ^N jn s NH ₂ 4-Amino-2-methyl-5 - ((1-pivaloylpiperidin-4-yl) methoxy) quinoline-3-carboxylic acid 400 G-9 ^ (Χγ ^ γ NH ₂ 0 4-amino-5- (2- (1-isobutyrylpiperidin-4yl) ethoxy) -2-methylquinoline-3-carboxylic acid 400 G-10 ΧΤΊ I ^nh 2 ___J Ο ^ ΉΗ Ó 4-amino-5 - ((4- (cyclopentylcarbamoyl) -1isobutyrylpiperidin-4-yl) methoxy) -2methylquinoline-3-carboxylic acid 497 G-11 ^Me y ^N y ^ ^NH 2 N> ~ -N ^ 0 4-amino-5 - ((((1R, 5S) -8-isobutyryl-8azabicyclo [3,2,1] octan-3-yl) oxy) - 2-methylquinoline-3-carboxylic 398 G-12 ^Me y ^N A / Ηθ ₂ ο'η ^χ η ^# ^ ^nh 2 4-amino-5 - ((1-isobutyrylpiperidin-3yl) methoxy) -2-methylquinoline-3-carboxylic acid 386 G-13 XT J | NH ₂ 0. JAA .OH H 4-amino-5- (2- (2-hydroxyacetamido) -2-methylpropoxy) -2-methylquinoline-3-carboxylic acid 348 G-14 XT J Ηθ ₂ (τη ^ γ o nh ₂ H II 4-amino-5- (2- (cyclohexanecarboxamido) ethoxy) -2-methylquinoline-3-carboxylic acid 372
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No. of the Compound Compound MS (MH +) G-15 2θ ₂ ο ^ζ γγ 1 ο nh ₂ ^H XX 4-amino-2-methyl-5- (2-methyl-2- (1methylpiperidine-4carboxamido) propoxy) quinoline-3-carboxylic acid 415 G-16 ΤΪ J HOjC'YY _ξ 0 NH ₂ o. The. ,To. (S) -4-Amino-5- (2- (2-methoxyacetamido) propoxy) -2-methylquinoline-3-carboxylic acid 348 G-17 HOjC '^ Y ^ y. . 0 nh ₂ o ^ X _n A ^ hl JL 4-amino-5- (2 - ((1s, 4s) -4-hydroxycyclohexanecarboxamido) -2-methylpropoxy) -2-methylquinoline-3-carboxylic acid 416 G-18 Η0 ₂ 0 ^ γ ^ γ. . 0 nh ₂ o ^ X _n A ^ η 1 I 4-amino-5- (2 - ((1r, 4r) -4-hydroxycyclohexanecarboxamido) -2-methylpropoxy) -2-methylquinoline-3-carboxylic acid 416 G-19 ΗΟ, οΧ'γ nh ₂ o, ₀ H 4-amino-5 - ((((1r, 4r) -4-butyramidocyclohexyl) oxy) -2-methylquinoline-3-carboxylic acid 386 G-20 Me. X Ho ₂ c '^ r ^x r nh ₂ o ^ _c. -IX ^H 4-Amino-2-methyl-5 - ((((1r, 4r) -4 (propylcarbamoyl) cyclohexyl) methoxy) quinoline acid3 -carboxylic 400
Biological Tests
EXPERIMENT 1: Screening for sweetened intensifiers
The mammalian Ga15 cells hT1R2 / R3 were seeded in 384-well light-bottom plates (Fisher), at a density of ~ 32,000 cells / well and cultured overnight. On the day of the experiment, Ga15 from mammal hT1R2 / R3 were loaded with the
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84/96 Fluo3AM (4 mM) calcium indicator (Invitrogen, Carlsbad, CA) in D-PBS (Invitrogen, Carlsbad, CA) using a Multidrop. The cells were incubated for 1 hour at room temperature and the excess dye was washed with D-PBS using an EMBLA cell washer (Molecular Devices, Sunnyvale, CA), leaving a residual volume of 25 ml / well. The sweeteners and test compounds were prepared in a final 4X concentration and mixed 1: 1 in a 384 well Greiner plate (bringing the concentrations of the sweeteners and test compounds down to the final 2X concentration). After 30 minutes of rest time at room temperature, the cell plates loaded with Fluo3AM, and the sweetener / compound plate mixture was loaded into a Fluorometric Imaging Plate Reader (FLIPR) plate reader (Molecular Devices, Sunnyvale, CA) . Imaging was performed using an excitation of 480 nm and an emission of 535 and started with the acquisition of baseline fluorescence for a period of 7 seconds. Then, the cells were stimulated in line with the addition of 25 ml of stimuli / well. Subsequent images were acquired every second for a period of 2 minutes. The fluorescence counts of the raw material were then normalized in each well (using customized data import software) by calculating delta F / f values (maximum fluorescent count obtained after stimulation - minimum fluorescent count obtained before fluorescent counting of stimulation / minimum obtained before stimulation). EC50s were determined using a non-linear regression algorithm (GraphPad PRISM, San Diego, CA), in which the Hill slope, lower asymptote and upper asymptote were allowed to vary. The intensification properties of the test compounds were quantified by determining the magnitude of the shift to the left in the EC50 values of the sweeteners (or an EC50 ratio): the EC50 value measured in the absence of the intensifier divided by the measured EC50 value in the presence of the intensifier.
The present compounds were tested and showed sweet flavor enhancing activities for sucrose, sucralose, and / or fructose as shown in Table E (EC ₅₀ ratio for sucrose at about 10 μΜ), Table F (EC50 ratio for sucralose at about 10 μΜ), and Table H (EC50 ratio for fructose at about 50 μΜ). Specifically, the EC50 ratio of the test compounds for sucrose, sucralose, and / or fructose enhancement are greater than about 2 to about 10 μΜ or about 50 μΜ. The compounds listed in Tables E, F and H are examples described above. For example, Compound C6 listed in Tables E and F is Example 18 described above.
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Table E. Sucrose intensification by 10 μΜ
D5 5.3M5 12.4 K5 6.6 T5 10.5 Q5 65.1 G5 4.0 A6 20.6 J6 2.9 L6 9.3 F6 7.4 Y5 5.5 N5 3.5 E5 4.1 U5 9.4 E6 5.8 G6 2.9 R5 20.2 T6 2.3 M6 3.3 H6 14.8 L5 6.1 V5 4.8 B6 3.8 05 6.0 Z5 31.1 N6 2.4 Q6 3.6 16 16.5 F5 7.9 P6 2.1 S5 4.3 15 3.3 C6 11.0 U6 2.4 J5 45.8 W5 4.8 D6 2.6 06 11.4 X5 5.8 Table F. Intensification c Sucralose alO μΜ
D5 2.9S5 2.6 K5 3.4 S5 2.6 Q5 14.3 C6 3.8 A6 23.8 M5 3.5 L6 5.7 T5 8.2 Y5 3.8 G5 2.9 E5 2.1 F6 4.3 E6 3.1 N5 2.9 R5 5.8 U5 6.2 M6 3.1 H6 6.8 B6 2.7 05 4.3 Z5 8.6 N6 5.5 F5 3.0 16 4.9 X5 3.0 W5 2.4 J5 13.506 3.9
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Table H. Fructose intensification at 50 μΜ
Z5 2.9T5 3.4 Q5 3.0 F6 2.2 A6 2.9 U5 3.7 L6 2.4 H6 2.4 Y5 2.2 V5 2.4 E6 2.5 05 2.6 R5 2.1 06 2.6 L5 2.0J5 4.1 (lOuM)
EXPERIMENT 2: Measuring Sweet Flavor and Intensifying Sweet Flavor Using Human Panelists Performing a Scale Test
The test samples containing the experimental compounds were compared with a dose response curve for the perceived sweetening intensity of sweetener concentrations (sucralose, sucrose, fructose, and other sweeteners) to determine the equivalent sweetening intensity.
A group of eight or more panelists tried solutions including sweeteners in various concentrations, as well as the experimental compound, both with and without added sweetener. The panelists then rated the sweetness intensity of all samples on a structured horizontal line scale, anchored from 0 to 15, where 0 is equal to no sweetening and 15 is equal to sweetening equivalent to a 15% sample. of sucrose. The scores for the sweetening intensity were calculated through the panelists. Then, using the averages of the scores and / or line equation for the sweetener dose response curve, the equivalent sweetening concentrations were determined for samples containing experimental compounds.
The subjects were previously familiar with the taste of the key attribute and were trained to use the 0 to 15 point line scale. The subjects abstained from eating or drinking (except water) for at least 1 hour before the test. The subjects ate a cookie and drank water several times to clean their mouths.
Sweetener solutions are supplied in a wide range of concentrations, such as 100 ppm, 200 ppm, 300 ppm, 400 ppm and 500 ppm sucralose, or between 0% and 12% for sucrose or fructose, to create a dose-response curve. The samples containing the experimental compound were prepared either alone or in a 100 ppm sucralose solution or a 6% sucrose or fructose solution. Every
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87/96 samples were prepared with low sodium buffer at pH 7.1. In order to aid dispersion, solutions can be prepared in 0.1% ethanol.
The solutions were dispensed in 20 ml volumes in 1 oz sample cups and served to subjects at room temperature. All samples were presented in a randomized counterbalanced order to reduce the influence of the response. In addition, two test sessions can be used to check the accuracy of the panel.
The subjects tried each sample individually and the rate of sweetening intensity on the previous line scale to the test of the next sample. All samples were expectorated. The subjects can try the samples again, but they can only use the given sample volume. The subjects should wash their mouths with water between samples. Eating an unsalted cookie between samples may be necessary, depending on the samples tested.
The score for each sample was calculated through the subjects and the standard error was calculated. The dose-response curve has been plotted, and this can be used to ensure that the panel is grading accurately, that is, the increase in the concentration of sucralose should correspond to an increase in the average sweetening score. 2-way ANOVA (factors being samples and panelists) and multiple comparison tests (such as Tukey's Honestly Significant Difference test) can be used to determine differences between samples and / or panelists. 3-way ANOVA, with sessions as the third factor, can be used to determine if there is any difference in classifications between sessions.
The results of human experimentation tests with Compound D5 are found below. Compound D5 is one of the examples described above. Table 1 indicates that 27.8 μΜ of Compound D5 in 6% sucrose has sweetening equivalent to about 10% sucrose and 12% sucrose
Table 1. Medium sweetening, n = 30 (15 panelists x 2 rep). Tukey's value = 1.023 (a = 0.05).
Treatment Average SD St Er Tukey (5%) 6% sucrose 6.6 1.3 0.2 The 8% sucrose 8.1 1.5 0.3 B 10% sucrose 9.8 1.4 0.3 ç 6% sucrose + 27.8 pM Compound D5 10.8 1.5 0.3 CD 12% sucrose at the 1.2 0.2 d
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EXPERIMENT 3: Measuring Sweet Flavor and Intensifying Sweet Flavor Using Human Panelists Performing a Paired Comparison Test
Test samples containing experimental compounds are presented in pairs to the panelist and they are asked to determine which sample is sweeter. A group of 10-16 or more panelists participated in each test. The subjects abstained from eating or drinking (except water) for at least 1 hour before the test. The subjects rinsed their mouths several times with water to clean their mouths.
All samples are prepared with ethanol to ensure dispersion of the compound in solution. This includes samples without a compound; all solutions are balanced for 0.1% ethanol.
The samples are also prepared with low sodium buffer (pH 7.1), instead of water. The buffer contains 0.952 g of KC1, 5.444 g of Na2HPC> 4, and 0.952 g of KH2PO4 in 40 L of DIUF water. Sample volumes are typically 20 ml.
In a paired comparison test, the panelist is presented with two different samples and asked to identify which sample is sweeter. Samples within a paired comparison test are presented in a randomized counterbalanced order. Panelists had up to 1 minute delay between taste tests to clear the mouth of all flavors.
Binomial probability tables are used to determine the probability of the correct number of responses occurring for each test at alpha = 0.05
The results of human experimentation tests with Compound D5 are found below. Table 2 indicates that the panelists perceived 6% sucrose +
27.8 μΜ of Compound D5 as being significantly sweeter than a 10% sucrose solution (p> 0.05). Table 3 indicates that 27.8 μΜ of Compound D5 alone has little or no sweetening by itself.
Table 2. Sample selected as the sweetest by panelists, n = 45 (15 panelists x 3 repetitions).
Sample Total 10% sucrose 13 6% sucrose + 27.8 μΜ ofCompound D5 32 Total 45
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6% sucrose + 27.8 pM ofCompound D5 (p-value) 0.007
Table 3A indicates that 27.8 μΜ of Compound D5 alone has little or no sweetening by itself. Table 3B indicates that 111.3 μΜ of Compound D5 alone has little or no sweetening by itself.
Table 3A. Sample selected as sweetest by panelists, n = 45 (15 5 panelists x 3 repetitions).
Sample Total 1% sucrose 43 LSB + 27.8 pM of Compound D5 2 Total 45 1% sucrose (p-value) <0.001
Table 3B. Sample selected as sweetest by panelists, n = 29 (16 panelists x 1 repetition; 16 panelists x 1 repetition).
Sample Total 1% sucrose 21 LSB + 111.3 pM Compound D5 8 Total 29 1% sucrose (p-value) <0.024
The results of human experimentation tests with Compound K5 are found below. Table 4 indicates that panelists perceived 6% sucrose + 10 27.9 pM of Compound K5 as being significantly sweeter than a 10% sucrose solution (p> 0.05).
Table 4. Sample selected as sweetest by panelists, n = 45 (15 panelists x 3 repetitions).
Sample Total 10% sucrose 11 6% sucrose + 27.9 pM of Compound K5 34 Total 45 6% sucrose + 27.9 pM of compound K5 (p-value) 0.001
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The results of human experimentation tests with Compound Q5 are found below. Table 5 indicates that panelists perceived 6% sucrose + 26.9 μΜ of Compound Q5 as being significantly sweeter than a 10% sucrose solution (p> 0.05).
Table 5. Sample selected as sweetest by panelists, n = 48 (16 panelists x 3 repetitions).
Sample Total 10% sucrose 13 6% sucrose + 26.9 μΜ of Compound Q5 35 Total 48 6% sucrose + 26.9 μΜ of compound Q5 (p-value) 0.002
The results of human experimentation tests with Compound A6 are found below. Table 6 indicates that panelists perceived 6% sucrose + 26.9 μΜ of Compound A6 as being significantly sweeter than a 10% 10% sucrose solution (p> 0.05). Table 7 indicates that the panelists perceived 6% HFCS + 64.85 μΜ of Compound A6 as not being significantly different from the sweetest sweetening than an 8% solution of high fructose corn syrup (p> 0.05 ). Table 8 indicates that 64.8 μΜ of Compound A6 alone has little or no sweetening by itself.
Table 6. Sample selected as sweetest by panelists, n = 45 (15 panelists x 3 repetitions).
Sample Total 10% sucrose 9 6% sucrose + 26.9 μΜ of Compound A6 36 Total 45 6% sucrose + 26.9 μΜ of compound A6 (p-value) 0.001
Table 7. Sample selected as sweetest by panelists, n = 12 (12 panelists x 1 repetition).
Sample Total 8% High Fructose Corn Syrup 8
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6% High Fructose Corn Syrup + 64.8 pM of Compound A6 4 Total 12 8% High Fructose Corn Syrup (p-value) 0.388
Table 8. Sample selected as sweetest by panelists, n = 15 (15 panelists x 1 repetition).
Sample Total 1% High Fructose Corn Syrup 14 LSB + 64.8 pM of Compound A6 1 Total 15 1% High Fructose Corn Syrup (p-value) 0.001
The results of human experimentation tests with Compound L6 are found below. Table 9 indicates that panelists perceived 6% sucrose + 5 26.8 pM of Compound L6 as being significantly sweeter than a 10% sucrose solution (p> 0.05).
Table 9. Sample selected as sweetest by panelists, n = 45 (15 panelists x 3 repetitions).
Sample Total 10% sucrose 14 6% sucrose + 26.8 pM of Compound L6 31 Total 45 6% sucrose + 26.8 pM of Compound L6 (p-value) 0.016
The results of human experimentation tests with Compound Y5 are 10 found below. Table 10 indicates that the panelists perceived 6% sucrose +
27.8 pM of Compound Y5, as not being significantly different in sweetening than a 10% sucrose solution (p> 0.05). Table 11 indicates that 27.8 pM of Compound Y5 alone has little or no sweetening by itself.
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Table 10. Sample selected as sweetest by panelists, n = 11 (11 panelists x 2 reps).
Sample Total 10% sucrose 8 6% sucrose + 27.8 pM ofCompound Y5 14 Total 22 6% sucrose + 27.8 pM of Compound Y5 (p-value) 0.286
Table 11. Sample selected as sweetest by panelists, n = 45 (15 panelists x 3 repetitions).
Sample Total 1% sucrose 44 LSB + 27.8 pM of Compound Y5 1 Total 45 1% sucrose (p-value) <0.001
The results of human experimentation tests with Compound E5 are found below. Table 12 indicates that the panelists perceived 6% sucrose +
24.9 pM of Compound E5 as not being significantly different in sweetening than a 10% sucrose solution (p> 0.05).
Table 12. Sample selected as sweetest by panelists, n = 39 (13 panelists x 3 repetitions).
Sample Total 10% sucrose 13 6% sucrose + 24.9 pM ofCompound E5 26 Total 39 6% sucrose + 24.9 pM CompoundE5 (p-value) 0.053
The results of human experimentation tests with Compound E6 are found below. Table 13 indicates that the panelists perceived 6% sucrose +
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28.9 μΜ of Compound E6 as not being significantly different in sweetening than a 10% sucrose solution (p> 0.05).
Table 13. Sample selected as sweetest by panelists, n = 39 (13 panelists x 3 repetitions).
Sample Total 10% sucrose 18 6% sucrose + 28.9 μΜ ofCompound E6 21 Total 39 6% sucrose + 28.9 μΜ ofCompound E6 (p-value) 0.053
The results of human experimentation tests with Compound R5 are found below. Table 14 indicates that the panelists perceived 6% sucrose +
26.9 μΜ of Compound R5 as not being significantly different in sweetening than a 10% sucrose solution (p> 0.05)
Table 14. Sample selected as sweetest by panelists, n = 42 (14 panelists x 3 repetitions).
Sample Total 10% sucrose 16 6% sucrose + 26.9 μΜ of Compound R5 26 Total 42 6% sucrose + 26.9 μΜ ofCompound R5 (p-value) 0.164
EXPERIMENT 4: Measurement of Sweet Flavor and Intensification of Sweet Flavor Using Human Panelists Performing a Comparison Test with Compound D5 in the Product Prototype
Human panelists evaluated several drinks (eg tea, coffee, Kool-Aid) 15 in the paired comparison taste test procedure. These drinks or their precursors were obtained from commercially available sources in unsweetened forms and were prepared for testing by adding sucrose (sweetener) alone or
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Table 15 indicates that the panelists perceived a cherry flavored Kool-Aid sweetened with 5% sucrose + 41.7 μΜ of Compound D5 as not being significantly different in sweetness than a cherry flavored Kool-Aid sweetened with 10% sucrose (p> 0.05).
Table 15. Sample selected as sweetest by panelists, n = 33 (11 panelists x 3 repetitions).
Sample Total 10% sucrose from cherry Kool-Aid 18 5% sucrose from cherry Kool-Aid+ 41.7 μΜ Compound D5 15 Total 33 10% Kool-Aid sucrose fromcherry (p-value) 0.728
Table 16 indicates that panelists perceived Neutral Black Tea fermented 10 sweetened with 4% sucrose + 30.6 μΜ of Compound D5 as not being significantly different in sweetening than fermented Neutral Black Tea sweetened with 8% sucrose (p> 0.05).
Table 16. Sample selected as sweetest by panelists, n = 39 (13 panelists x 3 repetitions).
Sample Total 8% sucrose in Neutral Fermented Black Tea 22 4% sucrose in Neutral Fermented Black Tea + 30.6 μΜ of Compound D5 17 Total 39 4% sucrose in Neutral Fermented Black Tea + 30.6 μΜ of Compound D5 0.522
Table 17 indicates that the panelists perceived a lemonade-flavored Kool-Aid sweetened with 5% sucrose + 41.7 μΜ of Compound D5 as not being
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95/96 significantly different in sweetness than a Kool-Aid flavored with lemonade sweetened with 10% sucrose (p> 0.05).
Table 17. Sample selected as sweetest by panelists, n = 48 (16 panelists x 3 repetitions).
Sample Total 10% sucrose in Kool-Aid fromLemonade 27 5% sucrose in Kool-Aid fromLemonade + 41.7 pM Compound D5 21 Total 48 10% Lemonade Kool-Aid sucrose (p-value) 0.471
Table 18 indicates that panelists perceived a Coffee drink and 4% sucrose + 23.65 μΜ of Compound D5 as not being significantly different in sweetening than a Coffee Drink sweetened with 8% sucrose (p> 0.05 ).
Table 18. Sample selected as sweetest by panelists, n = 39 (13 panelists x 3 repetitions).
Sample Total 8% sucrose in Coffee Drink 20 4% sucrose in Coffee Drink +23.65 pM of Compound D5 19 Total 39 8% sucrose in Coffee Drink (p-value) > 0.871
All publications and patent applications are hereby incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
The previous detailed description was given only for clarity of understanding and no unnecessary limitations should be understood from it since the modifications 15 will be obvious to those skilled in the art. This is not an admission that any information provided here is state of the art or relevant to the inventions
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The embodiments of the present invention are described herein, including the best way known to the inventors for carrying out the invention. The variations of these 5 preferred modalities may become evident to those skilled in the art after reading the previous description. The inventors expect those skilled in the art to employ such variations, as the case may be, and the inventors intend that the invention be practiced in a manner different from that specifically described herein. Thus, this invention includes all modifications and equivalents of the subject recited in the appended claims, 10 as permitted by applicable law. In addition, any combination of the elements described above in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by the context.

权利要求:
Claims (24)
[1]
1. Compound, characterized by the fact that it has Structural Formula (I):
ON (K ' o L ^x r / ^x r2 ^L R ³ (I) or a salt or solvate thereof; where
R ¹ and R ² are, independently, hydrogen or C1 to C6 alkyl;
L is C1 to C12 alkylene or C1 to C12 substituted alkylene;
M is -NR ⁴ -C (O) - or -C (O) -NR ⁴ -;
R ⁴ is hydrogen or C1 to C6 alkyl; or alternatively, when M is NR ⁴ -C (O) -, R ⁴ and one or more L atoms, together with the nitrogen to which they are attached, form a 5- to 8-membered heterocyclic ring that is optionally substituted and contains one to three heteroatoms selected from nitrogen, oxygen, and sulfur; and
R ³ is C1 to C12 alkyl, substituted C1 to C12 alkyl, 5- to 8-membered heterocyclyl, or substituted 5- to 8-membered heterocyclyl; or alternatively, when M is -C (O) -NR ⁴ -, R ⁴ and one or more atoms of R ³ , together with the nitrogen to which they are attached, form a 5- to 8-membered heterocyclic ring that is optionally substituted and contains one to three heteroatoms selected from nitrogen, oxygen, and sulfur; where a substituted saturated carbon atom has one or more of its hydrogen atoms replaced by a substituent selected from the group, including but not limited to -R, halo, -O, = O, -OR, -SR, - S, = S, -NR R, = NR ^b , = N-OR ^b , trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, = N2, -N3,
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[2]
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-S (O) 2R ^b , S (O) 2NR ^b , -S (O) 2O-, -S (O) 2OR ^b , -OS (O) 2R ^b , -OS (O) 2O-, OQ / TVi AT B OQ / ΤΊλ AT B ρ / ηνΠΛ DinVrfl Byn- P / 7ÁVTÁQ ^ WlDb
OS (O) 2OR, -OS (O) 2OR, -P (O) (O) 2, -P (O) (OR) (O), -P (O) (OR) (OR), rvrwpb r / cwb CrKTPbvpb fVOW O / OAOQb CfQAAPb CfOYKTPcnc
C (O) R, -C (S) R, -C (NR) R, -C (O) O, -C (O) OR, -C (S) OR, -C (O) NR R, C /T.TPbXTpcnc nCOWb OO / QAQb ΟΓΎΟ4ΓΥ OO / OAOQb (YVCVTOb
C (NR) NR R, -OC (O) R, -OC (S) R, -OC (O) O, -OC (O) OR, -OC (S) OR, MPb ^ / fYj ^ b KTnb ^ / cYpb KTnb ^ / fY ^ fY xrpb ^ / ^ fypb xrpb ^ / cvyDb
NR C (O) R, -NR C (S) R, -NR C (O) O, -NR C (O) OR, -NR C (S) OR, MPb ^ / ^ Y rocnc xrob ^ / xrobAnb xrob ^ n TDbA xrDcnc
NR C (O) NR R, -NR C (NR) R and -NR C (NR) NR R, cffl qUe
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 can be taken together with the nitrogen atom to which they are attached to form a 4, 5, 6 cycloheteroalkyl or 7 members that can optionally include 1 to 4 of the same or different additional hetero atoms selected from nitrogen, oxygen and sulfur; and a substituted saturated nitrogen atom has one or more of its hydrogen atoms replaced by a substituent selected from πτιιήλ 1 τί / Ί111 τί / 4 / ατίΊτρ / i I '^ T' / 'x0 a ΙλοΙ / λ f ~~ —C ~~ [_P b O | _p b O - - Ο ~ Nl | _p c ip c group, including but not limited to -R, halo, -O, = O, -OR, -SR , -S, = S, -NR R, = NR ^b , = N-OR ^b , trihalomethyl, -CF ₃ , -CN, -OCN, -SCN, -NO, -NO2, = Ni, -N3, -S (O) 2R ^b , -S (O) 2NR ^b , -S (O) 2O-, -S (O) 2OR ^b , -OS (O) 2R ^b , -OS (O) 2O ^- , OS ( O) 2ORb, -OS (O) 2OR ^b , -P (O) (O ^- ) 2, -P (O) (OR ^b ) (O ^- ), -P (O) (OR ^b ) (OR ^b ) , r / O l b / VQVpb rVClSCl-C 'i / YiCTPb rvdODb f' / CiA [pmc
C (O) R, -C (S) R, -C (NR) R, -C (O) O, -C (O) OR, -C (S) OR, -C (O) NR R, rVT .n b XTpcpc ^^ / fYfpb ^ fVÇWb ^^ / fvwpb ^^ / çv pb
C (NR) NR R, -OC (O) R, -OC (S) R, -OC (O) O, -OC (O) OR, -OC (S) OR, XTPb ^ / rYfpb xrpb ^ / ÇYpb xTpb ^ / fY> fY xTpb ^ / ^ λ ^ ϋ, MP ^^^ iOpb
NR C (O) R, -NR C (S) R, -NR C (O) O, -NR C (O) OR _b , -NR C (S) OR, XTOb ^ / ^ AXTpcpc xrpb ^ zxrpbYpb ~ xTpb ^ n .rpb XTpcpc üa üb ~ nc <-, 3. ^
NR C (O) NR R, -NR C (NR) R and -NR C (NR) NR R, where R, R and R are as previously defined with the proviso that the compound of Formula (I) is not selected from among
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[3]
3/14

[4]
4/14

[5]
5/14
2. Compound according to claim 1, characterized by the fact that R ¹ and R ² are both hydrogens.
Compound according to claim 1 or 2, characterized in that the alkylene is linear, branched, cyclic, or a combination thereof.
Compound according to any one of claims 1 to 3, characterized in that the alkyl is linear, branched, cyclic, or a combination thereof.
5. Compound, according to claim 1, characterized by the fact that it is represented by the Structural Formula (Ia):
O (Ia), where,
L is C1 to C12 alkylene or C1 to C12 substituted alkylene;
R ⁴ is hydrogen or C1 to C6 alkyl; or alternatively, R ⁴ and one or more L atoms, together with the nitrogen to which they are attached, form a 5- to 8-membered heterocyclic ring that is optionally substituted and contains one to three selected heteroatoms of nitrogen, oxygen, and sulfur ; and
R ³ is C1 to C12 alkyl, substituted C1 to C12 alkyl, 5- to 8-membered heterocyclyl, or substituted 5- to 8-membered heterocyclyl, where a substituted saturated carbon atom has one or more of its hydrogen atoms replaced by a substituent selected from the ππιήλ 1 τίίΊ111 τί / ΊρήΊτρ λιτΙτλο a ΙλοΙ / α f ~~ - [_ ρb O | _pb O- - OI | _p c ip c group, including, among others, -r, halo, -o, = o, -or, -sr, -s, = s, -nr r, = NR ^b , = N-OR ^b , trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2 , = N2, -N3,
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[6]
6/14
-S (O) 2R ^b , S (O) 2NR ^b , -S (O) 2O-, -S (O) 2OR ^b , -OS (O) 2R ^b , -OS (O) 2O-, OQ / TVi AT B OQ / ΤΊλ AT B ρ / ηνΠΛ DinVrfl Byn- P / íXVíXQ ^ WlDb
OS (O) 2OR, -OS (O) 2OR, -P (O) (O) 2, -P (O) (OR) (O), -P (O) (OR) (OR), rvrwpb r / cwb CrKTPbvpb fVOW ΟΟΠΥ rVQVTOb CfOYKTPcnc
C (O) R, -C (S) R, -C (NR) R, -C (O) O, -C (O) OR, -C (S) OR, -C (O) NR R, C /T.TPbXTpcnc nCOWb OO / QAQb ΟΓΎΟ4ΓΥ OO / OAOQb (YVCVTOb
C (NR) NR R, -OC (O) R, -OC (S) R, -OC (O) O, -OC (O) OR, -OC (S) OR, MPb ^ / fYj ^ b KTnb ^ / cYpb KTnb ^ / fY ^ fY xrpb ^ / ^ fYpb xrpb ^ / cvyDb
NR C (O) R, -NR C (S) R, -NR C (O) O, -NR C (O) OR, -NR C (S) OR, MPb ^ / ^ Y rocnc xrob ^ fxrob nb xrob ^ n TDbA xfDcnc
NR C (O) NR R, -NR C (NR) R and -NR C (NR) NR R, cffl qUe
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 can be taken together with the nitrogen atom to which they are attached to form a 4, 5, 6 cycloheteroalkyl or 7 members that can optionally include 1 to 4 of the same or different additional hetero atoms selected from nitrogen, oxygen and sulfur; and a substituted saturated nitrogen atom has one or more of its hydrogen atoms replaced by a substituent selected from πτιιήλ 1 τί / Ί111 τί / 4 / λ ρήΊτρ ζ'χι i'Lt '/' x ο a ΙλοΙ / α f ~~ —C ~~ [_P b O | _p b O - - Ο I | _p cc group, including but not limited to -R, halo, -O, = O, -OR, -SR, -S , = S, -NR R, = NR ^b , = N-OR ^b , trihalomethyl, -CF ₃ , -CN, -OCN, -SCN, -NO, -NO2, = Ni, -N3, -S ( O) 2R ^b , -S (O) 2NR ^b , -S (O) 2O-, -S (O) 2OR ^b , -OS (O) 2R ^b , -OS (O) 2O ^- , OS (O) 2ORb , -OS (O) 2OR ^b , -P (O) (O ^- ) 2, -P (O) (OR ^b ) (O ^- ), -P (O) (OR ^b ) (OR ^b ), / V / Yfpb r / C pb C'fN.TDbVDb rVClSCl- Γ 'i / YiCfpb ^ / QA / Vob / YmMRcnc
C (O) R, -C (S) R, -C (NR) R, -C (O) O, -C (O) OR, -C (S) OR, -C (O) NR R, / VNTPbAXTpcpc ^^ / fYfpb ^ fVQVPb ^^ / fY> fxpb ^^ zçvhpb
C (NR) NR R, -OC (O) R, -OC (S) R, -OC (O) O, -OC (O) OR, -OC (S) OR, NTPb ^ // Yfpb xrpb ^ / ÇYpb xTpb ^ / fY> fY XTpb ^ / ^ λ ^ ϋ. NTPb ^ / QVYpb
NR C (O) R, -NR C (S) R, -NR C (O) O, -NR C (O) OR _b , -NR C (S) OR, NTPb ^ / ^ YKTpcpc xrpb ^ fNTDbYpb T tob ^ n .rpb D xTpcpc ^yl U "nc
NR C (O) NR R, -NR C (NR) R and -NR C (NR) NR R, where R, R and R are as previously defined.
6. Compound according to claim 5, characterized by the fact that:
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[7]
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L is branched or cyclic C3 to C6 alkylene;
R ⁴ is hydrogen; and
R ³ is branched C3 to C6 alkyl or C1 to C6 linear alkyl.
7. Compound, according to claim 1, characterized by the fact that it is represented by the Structural Formula (Ib):
H ₃ C ^ R ³
N ^R4 (Ib), where:
L is C1 to C12 alkylene or C1 to C12 substituted alkylene;
R ⁴ is hydrogen or C1 to C6 alkyl; and
R ³ is C1 to C12 alkyl, C1 to C12 substituted alkyl, 5 to 8 membered heterocyclyl, 5 to 8 membered heterocyclyl; or alternatively, R ⁴ and one or more atoms of R ³ , together with the nitrogen to which they are attached, form a 5- to 8-membered heterocyclic ring that is optionally substituted and contains one to three selected heteroatoms of nitrogen, oxygen, and sulfur, in which a substituted saturated carbon atom has one or more of its hydrogen atoms replaced by a substituent selected from γπίιήα 1 τίίΊ111 τίζΊ / x ρήΊτρ λιιΙτλο a ΙλοΙ / α f ~~ - [_ ρb O | _pb O | - - OI | _p c ip c group, including but not limited to -r, halo, -o, = o, -or, -sr, -s, = s, -nr r, = NR ^b , = N-OR ^b , trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, = N2, -N3, -S (O) ₂ R ^b , SiOiAIR, -S (O) 2O-, - S (O) 2OR ^b , -OS (O) 2R ^b , -OS (O) 2O-, AQ / TVi AT B nc / ϊϊϊ AT B ρ / ηνΠΛ DinVCWbynA
OS (O) 2OR, -OS (O) 2OR, -P (O) (O) 2, -P (O) (OR) (O), -P (O) (OR) (OR), rvrwpb r / cwb CrKTPbvpb ΓΥΓΛΛΓΥ CYrViCiftb CYQ ^ ryvb CYCí KTQct) c
C (O) R, -C (S) R, -C (NR) R, -C (O) O, -C (O) OR, -C (S) OR, -C (O) NR r, Petition 870190099899, of 10/04/2019, p. 18/25
[8]
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OWb / upcDc np / pcpb nnciftb ηπΩ Π- ΩΠίΊ / ΊβΙ ^Ί
C (NK) NR R, -UC (O) R, -UC (ü) K, -OC (O) O, -UC (U) OR, -UC (ü) UK, MPb ^ / fYj ^ b KTnb ^ / cYpb KTnb ^ / fY ^ fY xrpb ^ / ^ fypb xrpb ^ / cvyDb
NR C (O) R, -Nr C (S) R, -Nr C (O) O, -Nr C (O) OR, -Nr C (S) UK, MPb ^ / ^ Y rocnc xrob ^ fxrob nb xTDb ^ n TDbAxrocnc _nilA
Nr C (O) Nr R, -Nr C (NR) R and -Nr C (NR) Nr R, in qUe
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 can be taken together with the nitrogen atom to which they are attached to form a 4, 5, 6 cycloheteroalkyl or 7 members that can optionally include 1 to 4 of the same or different additional hetero atoms selected from nitrogen, oxygen and sulfur; and a substituted saturated nitrogen atom has one or more of its hydrogen atoms replaced by a substituent selected from ππιήλ 1 τί ίΊ 111 τί / 4ρήΊτρ / 'Xi il'T' / 'x 0 to Ixol / xf ~~ —C ~~ [_P b O | _p b O - - OI | _p c ip c group, including but not limited to -r, halo, -o, = o, -ur, -sr, -s, = s , -nr r, = NR ^b , = N-OR ^b , trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, = Ni, -N3, -S (O) 2R ^b , -SíOrNIC, -S (O) 2O-, -S (O) 2OR ^b , -OS (O) 2R ^b , -OS (O) 2O ^- , OS (O) 2ORb, -OS (O) 2OR ^b , -P (O) (O ^- ) 2, -P (O) (OR ^b ) (O ^- ), -P (O) (OR ^b ) (OR ^b ), rVíYfpb r / C pb rVXTPbYpb C (C CY C '/ fúODb Γ / Ç inpb UfLUP ^ c
C (O) R, -C (S) R, -C (NR) R, -C (O) O, -C (O) OR, -C (S) OR, -C (O) NR R, UMP ^ IP ^ c. OUfWb iWWb C C (C \ CY CirVClSCmb C rV <i. C T} b
C (NR) NR R, -OC (O) R, -OC (S) R, -OC (O) O, -OC (O) OR, -OC (S) OR, MPbfYOiPb MpbfNipb Mpbp / nin- Mpbp / n.nn MP ^^^ iOpb
NR C (O) R, -NR C (S) R, -NR C (O) O, -NR C (O) ORb, -NR C (S) OR, URbC / OiMpcpc · [pbr / XTDbYpb ~ MpbfYMpbi [pcpc. „„ „Pa pb„ nc <-, 3. ^ nr c (o) nr r, -nr c (nr) r and -nr c (nr) nr r, where r, r and r are as previously defined.
8. Compound according to claim 6, characterized by the fact that:
L is linear C1 to C6 alkylene or branched C3 to C6 alkylene;
R ⁴ is hydrogen; and
R ³ is C1 to C6 straight or branched alkyl or cyclic C3 to C6 alkyl.
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[9]
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9. Compound, according to claim 1, characterized by the fact that it is selected from the group consisting of:

[10]
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[11]
11/14

[12]
12/14
Compound according to any one of claims 1 to 9, characterized by the fact that it intensifies the sweetening of a sweetener to a pH of 2.5 to 8.5.
11. Ingestible composition, characterized by the fact that it comprises: a compound of any one of claims 1 to 10, and optionally an ingestibly acceptable excipient.
12. Ingestible composition, according to claim 11, characterized by the fact that it also comprises one or more sweeteners.
[13]
13. Ingestible composition according to claim 12, characterized by the fact that the sweetener is selected from the group consisting of sucrose, fructose, glucose, galactose, mannose, lactose, tagatose, maltose, corn syrup (including corn syrup with high fructose), Dtryptophan, glycine, erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, maltodextrin, maltitol, isomalt, isomalt, hydrogenated glucose syrup (HGS), hydrogenated starch hydrolyzate (HSH), stevia A, stevia , other glycosides based on sweet Stevia, carrelame, sweeteners based on another guanidine, saccharin, acesulfame K, cyclamate, sucralose, alitame, mogroside, neotamo, aspartame, other aspartame derivatives, and combinations thereof.
[14]
14. Ingestible composition according to claim 11, characterized by the fact that it is in the form of a food or drink product, a pharmaceutical composition, a nutritional product, a dietary supplement, over-the-counter medication, or an oral hygiene product.
[15]
15. Ingestible composition, according to claim 14, characterized by the fact that the food or drink product is for human or animal consumption.
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[16]
16. Ingestible composition, according to claim 14 or 15, characterized by the fact that the food or drink product is selected from the group consisting of the Soup category, Dry Processed Food category, Drinks category, Ready Meal category, Canned and Preserved Foods, Frozen Processed Foods category, Chilled Processed Foods category, Snacks category, Baked Goods category, Confectionery category, Dairy products category, Ice cream category, Meal Replacement category, Noodles category and Pasta, and Sauces, Seasonings, Condiments category, Baby Food category, Dispersions category, Sweet coatings, toppings, or glazes and combinations thereof.
[17]
17. Method for increasing the sweet taste of a composition, characterized in that it comprises contacting the composition of the same with a compound of any one of claims 1 to 10 to form a modified composition.
[18]
18. Method for imparting a time profile more similar to that of sugar and / or flavor profile to a sweetener composition, characterized by the fact that it comprises the combination of a compound of any one of claims 1 to 10 and one or more sweeteners in sweetener composition.
[19]
19. Concentrated aroma formulation, characterized by the fact that it comprises:
i) as a flavor-modifying ingredient, a compound of any one of claims 1 to 10;
ii) a carrier, and iii) optionally at least one adjuvant.
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[20]
20. Concentrated aroma formulation according to claim 19, characterized in that the at least one adjuvant comprises one or more flavoring agents.
[21]
21. Concentrated aroma formulation according to claim 19 or 20, characterized in that the at least one adjuvant comprises one or more sweeteners.
[22]
22. Concentrated aroma formulation according to any one of claims 19 to 21, characterized in that the at least one adjuvant comprises one or more ingredients selected from the group consisting of an emulsifier, a stabilizer, an antimicrobial preservative, an antioxidant , vitamins, minerals, fats, starches, concentrates and protein isolates, salts, a freezing point depressant, nucleating agents, and combinations thereof.
[23]
23. Concentrated aroma formulation according to any of claims 19 to 22, characterized in that it is in a form selected from the group consisting of liquid, solid, semi-solid, foamy material, paste, gel, cream, lotion, and combinations thereof.
[24]
24. Concentrated aroma formulation according to any one of claims 19 to 23, characterized in that the compound of any one of claims 1 to 10, is present in a concentration that is at least 2 times the concentration of a composition ready to use.

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BR112015017912B1|2021-08-31|COMPOUND, INGERIBLE AND SWEETNESS STRESSING COMPOSITIONS, FLAVORING CONCENTRATE FORMULATION AND METHOD TO INCREASE THE SWEET FLAVOR OF THE COMPOSITION

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BR112015002380B1|2021-09-28|COMPOUND, INGERIBLE COMPOSITIONS, PROCESSES TO INCREASE THE SWEET FLAVOR OF COMPOSITION AND CONCENTRATED FLAVORIZING FORMULATION

同族专利:

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AR087529A1|2014-04-03|

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WO2013025560A1|2013-02-21|

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JP6322673B2|2018-05-09|

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JP2014524427A|2014-09-22|

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ES2607647T3|2017-04-03|

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ZA201400106B|2015-09-30|

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法律状态:
2018-01-16| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-03-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2018-07-31| B07G| Grant request does not fulfill article 229-c lpi (prior consent of anvisa) [chapter 7.7 patent gazette]|

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2019-07-09| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|

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2019-09-03| B25A| Requested transfer of rights approved|Owner name: FIRMENICH INCORPORATED (US) |

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2019-12-10| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-01-14| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 10/08/2012, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201161522806P| true| 2011-08-12|2011-08-12|

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PCT/US2012/050461|WO2013025560A1|2011-08-12|2012-08-10|Sweet flavor modifier|

---