HK1121644A - Aromatic amides and ureas and their uses as sweet and/or umami flavor modifiers,tastants and taste enhancers - Google Patents

Description

Aromatic amides and ureas and their use as sweet and/or umami taste modifiers, flavouring agents and flavour enhancers

This application claims priority from U.S. utility patent application serial No. 11/051,567, filed on 4.2.2005, the entire disclosure of which is incorporated herein by reference.

Disclosure of Invention

The present invention relates to the discovery of flavor or taste modifiers, such as flavors or seasonings and flavor or flavor enhancers, and more particularly, to savory ("umami") or sweet flavor modifiers, savory or sweet flavors, and savory or sweet taste enhancers for food, beverages, and other edible or oral pharmaceutical products or compositions.

Background

For centuries, various natural and non-natural compositions and/or compounds have been added to edible (eatable) foods, beverages and/or oral pharmaceutical compositions to improve their taste. Although only a few basic types of "tastes" have been known for a long time, the biological or biochemical basis of taste perception is poorly understood, and most taste modifiers or taste modifiers are essentially found by simple trial and error methods.

There has been significant recent progress in identifying useful natural flavoring agents, for example, sweeteners such as sucrose, fructose, glucose, erythritol, isomalt (isomalt), lactitol, mannitol, sorbitol, xylitol, certain known natural terpenoids, flavonoids, or protein sweeteners. See, for example, Kinghorn et al (Med Res Rev 18(5) 347) 360-. Similarly, recent advances have been made in the identification and commercialization of new artificial sweeteners such as aspartame, saccharin, acesulfame-K, cyclamate, sucralose, and alitame, see, the latest article by Ager et al (Angew Chem int. Ed.1998, 37, 1802-. The entire disclosures of the two references mentioned above are hereby incorporated by reference in order to describe, at least in part, the knowledge of those skilled in the art about known sweeteners.

However, there remains a need in the art for new and improved flavoring agents. For example, one of the five known basic tastes is the "savory" or "umami" taste of monosodium glutamate ("MSG"). MSG is known to produce adverse effects in certain populations, but little progress has been made in identifying artificial alternatives to MSG. A small number of naturally occurring substances are known to enhance or enhance the efficacy of MSG as a savory flavoring agent, thus making less MSG required for a given flavoring application. For example, inosinic acid (IMP) or guanylic acid (GMP), which are naturally occurring nucleotide compounds, are known to have a multiplicative effect on the savory taste of MSG, but it is very difficult and expensive to isolate and purify IMP and GMP from natural sources or to synthesize IMP and GMP, and thus most commercial demands on food or pharmaceutical compositions have only limited practical uses. Novel flavor compounds that can provide the savory flavor of MSG itself as a savory flavor alternative to MSG, or that can enhance the efficacy of MSG as a MSG flavor enhancer alternative to IMP or GMP, would be of great value.

Similarly, the discovery of compounds that are novel "high intensity" sweeteners (i.e., sweeteners that are many times sweeter than sucrose) is valuable, as well as having high utility and value for any compound that can significantly increase the sweetness of known natural or artificial sweeteners, thereby reducing the required amount of these caloric or non-caloric sweeteners.

Substantial progress has been made in recent years throughout the biotechnology field, and the fundamental biological and biochemical phenomena of taste perception are better understood. For example, taste receptor proteins have recently been identified in mammals that are involved in taste perception. Specifically, two distinct families of G protein-coupled receptors believed to be involved in taste have been identified T2R and T1R (see, e.g., Nelson et al, Cell (2001)106 (3): 381-390; Adler et al, Cell (2000)100 (6): 693-702; Chandrashekar et al, Cell (2000) 100: 703-711; Matsunami et al, Number (2000) 404: 601-604; Li et al, Proc. Natl. Acad. Sci. USA (2002) 99: 4962-494966; Montmayur et al, Nature Neuroscience (2001)4 (S): 492-498; U.S. Pat. No. 6,462,148; and PCT publications WO 02/06254, WO 00/63166, WO 02/064631 and WO 03/001876; and U.S. Pat. No. 023-2407A 1). The articles, patent applications, and published patents cited immediately above are incorporated by reference in their entirety for all purposes, including the disclosure of the recognition and structure of T2R and T1R mammalian taste receptor proteins, as well as methods for artificially expressing these receptors in cell lines and using the resulting cell lines to screen compounds for potential "savory" or "sweet" flavors.

However, the T2R family includes more than 25 families of genes involved in bitter taste, and T1R includes only three members T1R1, T1R2 and T1R3 (see Li et al, Proc. Natl. Acad. Sci. USA (2002) 99: 4962-. It has recently been disclosed in WO 02/064631 and/or WO 03/001876 that specific T1R members can assemble to form functional taste receptors when co-expressed in a suitable mammalian cell line. In particular, it was found that co-expression of T1R1 and T1R3 in a suitable host cell results in a functional T1R1/T1R3 savory ("umami") taste receptor that responds to savory taste stimuli, including monosodium glutamate. Similarly, it was found that co-expression of T1R2 and T1R3 in a suitable host cell results in a functional T1R2/T1R3 "sweet" taste receptor that responds to different taste stimuli, including natural and artificial sweeteners. (see Li et al (supra)). The references cited above also disclose assays and/or high throughput screening methods for measuring T1R1/T1R3 or T1R2/T1R3 receptor activity by fluorescence imaging in the presence of a target compound. We used the above assays and/or high throughput screening methods to identify initial "lead" compounds that modulate the activity of T1R1/T1R3 "savory" taste receptors or T1R2/T1R3 "sweet" taste receptors, followed by long, complex and iterative research, evaluation, and optimization procedures, to complete the inventions described below.

Disclosure of Invention

The present invention has a number of aspects, all of which relate to methods of using or compositions comprising non-naturally occurring amide compounds and/or amide derivative compounds having the general structure shown in formula (I):

wherein R is¹、R²And R³The following detailed description may be further defined in various ways independently. In all embodiments of the amide compounds of formula (I), R¹The radicals being packetsAn organic residue containing at least three carbon atoms, and for R¹There are various optional limitations to the size and/or chemical nature of the groups, as will be further described below. In many, but not all embodiments, the amide compound of formula (I) is a "primary" amide, i.e., R²And R³Is an organic group containing at least three carbon atoms, and R²And R³Is hydrogen.

The amide compounds of formula (I) also include certain sub-classes of amide derivatives or classes of amide-related derivatives, such as ureas, carbamates, oxalamides, acrylamides, and the like, as further described below.

Some of the amide compounds of formula (I) have previously been synthesized by methods known in the art for a variety of purposes. However, many of the amide compounds of formula (I) disclosed herein are novel compounds that have not been synthesized previously at all. In any event, to the knowledge of the present inventors, it has not previously been recognized that the amides can be used in very low concentrations as savory or sweet flavoring agents, or savory or sweet taste enhancers, in edible compositions.

Unexpectedly, we demonstrate hereinafter that many subgeneric compounds and various compounds of the "amide" compounds of formula (I) can bind to or activate the T1R1/T1R3 "savory" ("umami") receptor and/or the T1R2/T1R3 sweet receptor in vitro at relatively low concentrations, on the micromolar scale or less, as shown below. Moreover, it is believed that the amide compounds may also interact similarly in vivo with savory or sweet taste receptors in animals or humans, as demonstrated by human taste testing of certain compounds of formula (I).

Thus, most subgeneric and most diverse compounds of the "amide" compounds of formula (I) described further below can be used in edible compositions in effective and surprisingly low concentrations as savory or sweet flavoring agents, or savory or sweetener enhancers. Thus, in some embodiments, the present invention relates to a method of modulating the savory or sweet taste of a food or pharmaceutical product, the method comprising:

a) providing at least one edible or pharmaceutical product, or more than one precursor of an edible or pharmaceutical product, and

b) combining the food or pharmaceutical product or one or more precursors thereof with at least a savory or sweet modulating amount of at least one non-naturally occurring amide compound or edible salt thereof to form an improved food or pharmaceutical product;

Wherein the amide compound is included within any compound of formula (I) as shown below, or each subgeneric compound or each compound of formula (I) as further described below:

wherein R is¹Comprising an organic or hydrocarbon residue having at least three carbon atoms and optionally one or more heteroatoms independently selected from oxygen, nitrogen, sulfur, halogen, or phosphorus; and

wherein R is²And R³Is optionally H, and wherein R is²And R³At least one of the remaining groups in (a) includes an organic or hydrocarbon residue having at least three carbon atoms, and the organic or hydrocarbon residue optionally has one or more heteroatoms independently selected from oxygen, nitrogen, sulfur, halogen, or phosphorus.

The pair R will be described below¹、R²And R³Other optional definitions of groups in terms of chemical and physical properties.

The present invention also relates to a food or pharmaceutical product made by the above method and/or process, and to a food or pharmaceutical product or a food or pharmaceutical composition or a precursor thereof comprising an amide compound of formula (I), including but not limited to food products, beverages, pharmaceuticals and pharmaceutical compositions for oral administration and precursors thereof.

In many embodiments, one or more amide compounds of formula (I) or edible salts thereof, further identified, described and/or claimed herein, can be used in the form of a mixture, or in combination with other known savory or sweet compounds, or as a flavor enhancer in food, beverages and pharmaceutical compositions for human or animal consumption.

In some embodiments, while the amide compound of formula (I) has little or possibly no sweet or savory taste when tasted alone, the amide compound of formula (I) can be used in very low concentrations, thereby very significantly enhancing the efficacy of other savory or sweet flavors or precursors thereof in a comestible or pharmaceutical composition. The invention described herein also relates to a flavored edible or pharmaceutical product comprising a modulating amount of one or more of the amide compounds disclosed herein.

Many amide compounds of formula (I) and/or subgeneric compounds of the amide compounds, when used with MSG or alone, can enhance or modulate in vitro responses and salty-fresh taste in humans at surprisingly low concentrations. Many of the amide compounds of the present invention are T1R1/T1R3 receptor agonists and therefore at surprisingly low concentrations, on the micromolar scale, can themselves induce salty fresh taste in humans regardless of the presence of MSG in the edible composition. In addition, many amide compounds of formula (I) can enhance, potentiate, modulate or induce other natural and synthetic savory flavoring agents, such as MSG.

In related embodiments of the compounds of formula (I) and uses thereof, some of the amide compounds of formula (I) are potent T1R2/T1R3 receptor agonists below micromolar, but in many cases, they do not independently induce the sweet taste of humans in the absence of other sweeteners. In other words, some amide compounds of formula (I) are not recognized by the human body as sweet flavors when isolated from other sweeteners. However, many of the congeners of amide compounds of formula (I) can strongly enhance, potentiate, modulate or induce the sweet taste perception in humans of other natural, semisynthetic or synthetic sweet flavors, such as sucrose, fructose, glucose, erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, certain known natural terpenes, flavonoid or protein sweeteners, aspartame, saccharin, acesulfame potassium, cyclamate, sucralose, alitame, and the like, or mixtures thereof.

Unexpectedly, it has been found that in many embodiments of the compounds of formula (I), there is significant structural similarity and/or overlap between amide compounds that can produce or enhance both the sweet and savory tastes of a comestible or pharmaceutical composition, even though the relevant biological taste receptor proteins are believed to be significantly different. More unexpectedly, it has now been found that at least a portion of the amide compounds of formula (I) disclosed herein can induce or enhance both the sweet and savory tastes of edible or pharmaceutical products. Thus, some aspects of the invention relate to compounds of formula (I) or subgenera and compounds thereof that can modulate (e.g., induce, enhance or potentiate) the flavor of known natural or synthetic sweeteners.

In some embodiments, the present invention relates to novel compounds, flavors, odorants, flavor compounds, and/or compositions comprising a compound of formula (I) and its respective subgenera and compounds.

In other embodiments, the invention relates to compounds of formula (I) or subgenera and compounds thereof that modulate (e.g., induce, enhance or potentiate) the flavor of monosodium glutamate (MSG) or synthetic savory flavoring agents.

In some embodiments, the present invention relates to a dietary or pharmaceutical composition suitable for human or animal consumption comprising at least one compound of formula (I) or a dietary or pharmaceutically acceptable salt thereof, or a precursor thereof. These compositions preferably include edible products such as foods or beverages, pharmaceutical or pharmaceutical compositions and oral hygiene products for oral administration, and additives that modulate the flavor or taste thereof, particularly by enhancing (enhancing) their savory and/or sweet taste, when added to these products.

The invention also relates to novel classes and species of amide compounds and derivatives within the scope of the compounds of formula (I), to flavouring agents, to edible or pharmaceutical preparations or compositions containing them, including savory or sweet flavouring agents and to flavour enhancers.

The above discussion merely summarizes certain aspects of the present invention and is not intended, nor should it be construed, as limiting the invention in any way.

Detailed Description

The present invention may be understood more readily by reference to the following detailed description of various embodiments of the invention and the examples included therein, and to the chemical diagrams and preceding and following description thereof. Before the present compounds, compositions, and/or methods are disclosed and described, it is to be understood that this invention is not limited to particular foods or food preparation methods, particular food or pharmaceutical carriers or formulations, or to particular manners of formulating the present compounds into food products or compositions or pharmaceutical products or compositions for oral administration, unless otherwise specifically defined by the claims, as one of ordinary skill in the relevant art will certainly appreciate that such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. Definition of

The term "pharmaceutical product" as used herein includes both solid and liquid compositions which are ingestible, non-toxic materials which have pharmaceutical value or which contain pharmaceutically active agents such as cough syrups, cough drops, aspirin and chewable tablets.

Oral hygiene products include solids and liquids, such as toothpaste or mouthwash.

An "edible, biological, or pharmaceutical carrier or excipient" is a solid or liquid medium and/or composition used to prepare a desired dosage form of a compound of the invention for the purpose of administering the compound of the invention in a dispersed/diluted form to maximize the biological effectiveness of the compound of the invention. Edible, biological or pharmaceutical carriers include many common food ingredients such as water, fruit or vegetable juices, vinegar, vinegars, beer, wine, natural water/fat emulsions such as milk or condensed milk, edible oils and shortenings, fatty acids, low molecular weight oligomers of propylene glycol, glycerol esters of fatty acids and dispersions or emulsions of these 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 carriers at neutral, acidic or basic pH; a dispersion or suspension aid; a surfactant; an isotonic agent; thickeners or emulsifiers, preservatives; a solid binder; lubricants, and the like.

As used herein, "flavor" refers to the perception of taste and/or odor by a subject, and includes sweet, sour, salty, bitter, umami, and the like. The subject may be a human or an animal.

As used herein, "flavoring agent" refers to a compound or biologically acceptable salt thereof that is capable of inducing flavor or taste in an animal or human.

By "flavor modifier" herein is meant a compound or biologically acceptable salt thereof that modulates (including enhances or potentiates and induces) the taste and/or odor of a natural or synthetic flavoring agent in an animal or human.

By "flavoring agent" is meant a compound or biologically acceptable salt thereof that is capable of enhancing the taste or odor of a natural or synthetic flavoring agent.

By "savory flavor" herein is meant the salty savory ("umami") taste sensation typically induced by MSG (monosodium glutamate) in the human or animal body.

By "savory flavoring agent", "savory compound" or "savory receptor-activating compound" herein is meant a compound or biologically acceptable salt thereof, such as MSG (monosodium glutamate), that is capable of eliciting a perceptible savory flavor in a subject, or a compound that can activate the T1R1/T1R3 receptor in vitro. The subject may be a human or an animal.

By "sweet flavoring agent," "sweet compound," or "sweet receptor activating compound," herein is meant a compound or biologically acceptable salt thereof that elicits a detectable sweet taste in a subject, such as known natural sugar sweeteners, e.g., sucrose, fructose, glucose, or the like, or known artificial sweeteners, e.g., saccharin, cyclamate, aspartame, and the like, as further discussed herein, or a compound that activates the T1R2/T1R3 receptor in vitro. The subject may be a human or an animal.

By "savory flavor modifier" herein is meant a compound or biologically acceptable salt thereof that modulates (including enhances or potentiates, induces and blocks) the savory flavor of a natural or synthetic savory flavor, such as monosodium glutamate (MSG), in an animal or human.

As used herein, "sweet taste improving agent" refers to a compound or biologically acceptable salt thereof that modulates (including enhancing or potentiating, inducing and blocking) the sweet taste of a natural or synthetic sweetener, such as sucrose, fructose, glucose, etc., known natural sugar sweeteners, or such as saccharin, cyclamate, aspartame, etc., known artificial sweeteners.

By "savory flavoring agent" is meant herein a compound or biologically acceptable salt thereof that enhances or potentiates the savory taste of a natural or synthetic savory flavoring agent, such as monosodium glutamate (MSG), in an animal or human.

By "sweet taste enhancer" is meant a compound or biologically acceptable salt thereof that enhances or potentiates the sweet taste of a natural or synthetic sweet taste flavoring agent in an animal or human, such as known natural sugar sweeteners such as sucrose, fructose, glucose, or known artificial sweeteners such as saccharin, cyclamate, aspartame, and the like, as further discussed herein.

As used herein, "umami receptor activating compound" refers to a compound capable of activating an umami receptor such as the T1R1/T1R3 receptor.

As used herein, "sweet taste receptor activating compound" refers to a compound capable of activating a sweet taste receptor such as the T1R2/T1R3 receptor.

Herein, "umami receptor modulating compound" refers to a compound capable of modulating (activating, enhancing or blocking) an umami receptor.

Herein, "sweet taste receptor modulating compound" refers to a compound capable of modulating (activating, enhancing or blocking) a sweet taste receptor.

By "umami receptor-enhancing compound" herein is meant a compound that is capable of enhancing or potentiating the effect of a natural or synthetic umami receptor-activating compound, such as monosodium glutamate (MSG).

By "sweet receptor enhancing compound" herein is meant a compound that is capable of enhancing or potentiating the effect of a natural or synthetic sweet receptor activating compound, such as known natural sugar sweeteners, e.g., sucrose, fructose, glucose, etc., or known artificial sweeteners, e.g., saccharin, cyclamate, aspartame, etc., and the like, as discussed further herein.

By "savory flavoring amount" herein is meant an amount of a compound (including a compound of formula (I), as well as known savory flavoring agents, such as MSG) sufficient to induce savory flavor in a comestible or medicinal product or a comestible or medicinal composition or precursor thereof. A relatively broad range of savoury flavour dosage for the compounds of formula (I) may be from about 0.001ppm to 100ppm, or a narrow range of from about 0.1ppm to about 10 ppm. An optional range for the amount of savory flavoring may be from about 0.01ppm to about 30ppm, from about 0.05ppm to about 15ppm, from about 0.1ppm to about 5ppm, or from about 0.1ppm to about 3 ppm.

As used herein, "sweet flavoring amount" refers to an amount of a compound (including a compound of formula (I), as well as known sweet flavors) sufficient to induce sweetness in a comestible or medicinal product or a comestible or medicinal composition or precursor thereof. The relatively broad range of sweet flavor amounts for the compounds of formula (I) can be from about 0.001ppm to 100ppm, or a narrow range of from about 0.1ppm to about 10 ppm. An optional range of sweet flavor amounts can be from about 0.01ppm to about 30ppm, from about 0.05ppm to about 15ppm, from about 0.1ppm to about 5ppm, or from about 0.1ppm to about 3 ppm.

As used herein, "savory flavor modulating amount" refers to an amount of a compound of formula (I) sufficient to alter (increase or decrease) savory flavor as perceived by a human subject in a comestible or medicinal product or comestible or medicinal composition or precursor thereof. A relatively wide range of savory flavor formulation amounts may be from about 0.001ppm to about 100ppm, or a narrow range of from about 0.1ppm to about 10 ppm. An optional range of savory flavor modulator amounts can be from about 0.01ppm to about 30ppm, from about 0.05ppm to about 15ppm, from about 0.1ppm to about 5ppm, or from about 0.1ppm to about 3 ppm.

As used herein, "sweet taste modulating amount" refers to an amount of a compound of formula (I) sufficient to alter (increase or decrease) the sweet taste perceived by a human subject in a comestible or medicinal product or comestible or medicinal composition or precursor thereof. The relatively wide range of sweetness modulation amounts may be from about 0.001ppm to 100ppm, or a narrow range of from about 0.1ppm to about 10 ppm. An optional range of sweetness modulation amounts may be from about 0.01ppm to about 30ppm, from about 0.05ppm to about 15ppm, from about 0.1ppm to about 5ppm, or from about 0.1ppm to about 3 ppm.

By "savory taste enhancing amount" herein is meant an amount of a compound of formula (I) that is sufficient to enhance the taste sensation of a natural or synthetic flavoring agent, such as monosodium glutamate (MSG), when both are present in a comestible or medicinal product or composition. A relatively broad range of savory flavor enhancing amounts can be from about 0.001ppm to 100ppm, or a narrow range of from about 0.1ppm to about 10 ppm. An optional range of savory flavor enhancing amount can be from about 0.01ppm to about 30ppm, from about 0.05ppm to about 15ppm, from about 0.1ppm to about 5ppm, or from about 0.1ppm to about 3 ppm.

By "sweet taste enhancing amount" herein is meant an amount of a compound of formula (I) sufficient to enhance the sweet taste of a natural or synthetic flavoring agent, such as a known natural sugar sweetener, e.g., sucrose, fructose, glucose, etc., or a known artificial sweetener, e.g., saccharin, cyclamate, aspartame, etc., and the like as discussed further herein, in a comestible or medicinal product or composition. A relatively wide range of sweetness enhancing amounts can be from about 0.001ppm to 100ppm, or a narrow range of from about 0.1ppm to about 10 ppm. An optional range of sweetness enhancing amounts may be from about 0.01ppm to about 30ppm, from about 0.05ppm to about 15ppm, from about 0.1ppm to about 5ppm, or from about 0.1ppm to about 3 ppm.

Herein, "umami receptor modulating amount" refers to an amount of a compound sufficient to modulate (activate, enhance or block) an umami receptor. The amount of umami receptor preparation is preferably in the range of 1pM to 100mM, more preferably 1nM to 100. mu.M, and most preferably 1nM to 30. mu.M. A relatively broad range of umami enhancing amounts can be from about 0.001ppm to 100ppm, or a narrow range of from about 0.1ppm to about 10 ppm. An optional range of umami enhancing amount may be from about 0.01ppm to about 30ppm, from about 0.05ppm to about 15ppm, from about 0.1ppm to about 5ppm, or from about 0.1ppm to about 3 ppm.

A "T1R 1/T1R3 receptor modulating or activating amount" is an amount of a compound sufficient to modulate or activate the T1R1/T1R3 receptor. These amounts are preferably the same as the umami receptor modulating amounts.

An "umami receptor" is a taste receptor that can be modulated by savory compounds. The umami receptor is preferably a G protein-coupled receptor, more preferably the umami receptor is the T1R1/T1R3 receptor.

The compounds of the invention may modulate umami receptors and are preferably agonists of the T1R1/T1R3 receptor. Agonists of this receptor have the effect of activating the G protein signaling cascade. In many cases, this agonist effect of the compounds on the receptor also produces a perceived savory taste in taste testing. Thus, it is desirable that the compounds of the present invention can be used as a substitute for MSG, since the presence of MSG is not allowed in, for example, certain food products.

Furthermore, when the compounds of the present invention are used in combination with other savory flavoring agents, such as MSG, the agonist effect may also produce a synergistic savory effect. Nucleotides, i.e., IMP or GMP, are typically added to MSG to enhance the savory taste of MSG so that only a relatively small amount of MSG is required to provide the same savory taste as compared to MSG alone. Thus, it is expected that combining the compounds of the present invention with other savory flavoring agents, such as MSG, may advantageously eliminate the need to add expensive nucleotides, such as IMP, as flavoring agents, while concomitantly reducing or eliminating the amount of savory compounds, such as MSG, needed to provide the same savory flavor, as compared to the use of the savory compound or MSG alone.

As used herein, "sweet taste receptor modulating amount" refers to an amount of a compound sufficient to modulate (activate, enhance or block) a sweet taste receptor. The preferable range of the amount of the sweet taste receptor preparation is 1pM to 100mM, more preferably 1nM to 100. mu.M and most preferably 1nM to 30. mu.M.

A "T1R 2/T1R3 receptor modulating or activating amount" is an amount of a compound sufficient to modulate or activate the T1R2/T1R3 receptor. These amounts are preferably the same as the sweet taste receptor modulating amounts.

"sweet taste receptors" are taste receptors that can be modulated by sweet compounds. The sweet taste receptor is preferably a G protein-coupled receptor, more preferably the sweet taste receptor is the T1R2/T1R3 receptor.

Many compounds of formula (I) may modulate sweet taste receptors and are preferably agonists of the T1R2/T1R3 receptor. Agonists of this receptor have the effect of activating the G protein signaling cascade. In many cases, this agonist effect of the compounds on the receptor also produces a detectable sweet taste in taste tests. Thus, it is expected that the compounds of the present invention will be useful as substitutes for known natural sugar sweeteners such as sucrose, fructose, glucose, and the like, or for known artificial sweeteners such as saccharin, cyclamate, aspartame, and the like, as well as similar materials discussed further herein, or mixtures thereof.

By "synergistic effect" is meant an enhanced savory and/or sweet taste resulting from the combination of savory and/or sweet compounds or receptor activating compounds as compared to the sum of taste effects or flavor-related effects associated with each individual compound. In the case of savoury flavour enhancer compounds, compounds of formula (I) having an EC50 ratio (defined below) above 2.0 may indicate a synergistic effect on the potency of MSG, or the EC50 ratio is preferably above 5.0, or above 10.0, or above 15.0. The EC50 test for sweetness enhancement has not been developed, but in the case of savory-sweet flavor enhancer compounds, the synergistic effect can be demonstrated by human taste testing, as described elsewhere herein.

When the compounds described herein include one or more chiral centers, the stereochemistry of the chiral centers may independently be in the R or S configuration, or a mixture of the two. The chiral center may be further designated as R or S, or R, S or D, D, L, L or D, L, D, L. Accordingly, if an amide compound of the present invention can exist in an optically active form, it can actually exist in the form of a racemic mixture of enantiomers, or in the form of any individual enantiomer in substantially isolated and purified form, or as a mixture containing enantiomers in any relative ratio.

For the compounds described herein, the suffix "ene" added to any of the terms refers to a substituent that connects two other moieties in the compound. For example, "alkylene" is (CH)₂)_n"alkenylene" is such a moiety that contains a double bond, and "alkylylene" is such a moiety that contains a triple bond.

As used herein, "hydrocarbon residue" refers to a chemical subunit located in a larger compound having only carbon and hydrogen atoms. The hydrocarbon residue may be an aliphatic or aromatic, straight-chain, cyclic, branched, saturated or unsaturated hydrocarbon residue. In many embodiments, the hydrocarbon residue is limited in size and molecular weight and can contain 1 to 18 carbon atoms, 1 to 16 carbon atoms, 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.

When described as "having"when substituted, the hydrocarbon residue contains or is substituted on the carbon and hydrogen atoms of the residue with one or more substituents independently selected from heteroatoms such as O, S, N, P or halogens (fluorine, chlorine, bromine and iodine), or one or more substituents containing heteroatoms (OH, NH)₂、NO₂、SO₃H, etc.). The hydrocarbon residue having a substituent may further contain a carbonyl group, an amino group, a hydroxyl group, or the like, or a hetero atom inserted into the "skeleton" of the hydrocarbon residue.

As used herein, an "inorganic" group or residue refers to a substituent on an organic molecule disclosed or claimed herein that contains from 1 to 16 other heteroatoms from the periodic Table, other than carbon, such as neutral molecules, cationic or anionic groups, preferably including one or more atoms independently selected from the group consisting of H, O, N, S, one or more halogens, or alkali or alkaline earth metal ions. Examples of inorganic groups include, but are not limited to H, Na +, Ca + +, and K +; halogen including fluorine, chlorine, bromine and iodine; OH, SH, SO₃H、SO₃ ^-、PO₃H、PO₃ ^-、NO、NO₂Or NH₂And the like.

The terms "alkyl", "alkenyl" and "alkynyl" as used herein include straight and branched chain and cyclic monovalent substituents which are saturated groups, unsaturated groups having at least one double bond, and unsaturated groups having at least one triple bond, respectively.

"alkyl" refers to a hydrocarbon group that can be conceptually formed from an alkane by removing hydrogen from the structure of a non-cyclic hydrocarbon compound having a straight or branched carbon chain, and replacing the hydrogen atom with another atom or an organic or inorganic substituent. In some embodiments of the invention, alkyl is "C1-C6 alkyl," such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl, and the like. Many embodiments of the present invention comprise a "C1-C4 alkyl" group (alternatively termed a "lower alkyl" group), said "C1-C4 alkyl" group being methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Some preferred alkyl groups of the present invention have more than three carbon atoms, preferably 3 to 16 carbon atoms, 4 to 14 carbon atoms, or 6 to 12 carbon atoms.

The term "alkenyl" refers to a hydrocarbon group or residue that contains at least one carbon-carbon double bond. In some embodiments, alkenyl is "C₂～C₇Alkenyl "includes vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, and straight-chain or branched-chain dienes and trienes. In other embodiments, alkenyl groups are defined as having two to four carbon atoms.

The term "alkynyl" refers to a hydrocarbon residue containing at least one carbon-carbon triple bond. Preferred alkynyl groups are "C2-C7 alkynyl" such as ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl, and straight or branched chain di-and tri-alkynes including ene-alkynes.

The terms "substituted alkyl", "substituted alkenyl", "substituted alkynyl" and "substituted hydrocarbylene" denote alkyl, alkenyl, alkynyl and hydrocarbylene groups or residues as described above, the hydrogen atoms of one or more of which groups or residues are substituted by one or more (preferably one or two) organic or inorganic substituent groups or residues which may include halogen, hydroxy, C₁～C₇Alkoxy, alkoxy-alkyl, oxy, C₃～C₇Cycloalkyl, naphthyl, amino, (mono) amino, (di-substituted) amino, guanidino, heterocycle, substituted heterocycle, imidazolyl, indolyl, pyrrolidinyl, C₁～C₇Acyl radical, C₁～C₇Acyloxy, nitro, carboxyl, carbamoyl, formamide, N-(C₁～C₆Alkyl) carboxamides, N-di (C)₁～C₆Alkyl) carboxamides, cyano, methylsulfonylamino, thiols, C₁～C₄Alkylthio or C₁～C₄An alkylsulfonyl group. The alkyl group having a substituent may be substituted one or more times, preferably once or twice, with the same or different substituent. In many embodiments of the invention, preferred groups of substituents include hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃SEt (i.e. SCH)₂CH₃)、SCH₃Methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups. In many embodiments of the present invention containing the substituents listed above, more preferred substituents include hydroxy, SEt, SCH₃Methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy and trifluoromethoxy.

Examples of the above-mentioned alkyl group having a substituent include 2-oxo-propan-1-yl, 3-oxo-butan-1-yl, cyanomethyl, nitromethyl, chloromethyl, trifluoromethyl, hydroxymethyl, tetrahydropyranyloxymethyl, trityloxymethyl, propionyloxymethyl, aminomethyl, carboxymethyl, allyloxycarbonylmethyl, allyloxycarbonylaminomethyl, methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl, chloromethyl, trifluoromethyl, 6-hydroxyhexyl, 2, 4-dichloro (n-butyl), 2-aminopropyl, 1-chloroethyl, 2-chloroethyl, 1-bromoethyl, 2-chloroethyl, 1-fluoroethyl, 2-fluoroethyl, 1-iodoethyl, 2-iodoethyl, 1-chloropropyl, 2-chloropropyl, 3-chloropropyl, 1-bromopropyl, 2-bromopropyl, 3-bromopropyl, 1-fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 2-aminoethyl, 1-aminoethyl, N-benzoyl-2-aminoethyl, N-acetyl-2-aminoethyl, N-benzoyl-1-aminoethyl, N-acetyl-1-aminoethyl, and the like.

Examples of the above alkenyl group having a substituent include styryl, 3-chloro-propen-1-yl, 3-chloro-buten-1-yl, 3-methoxy-propen-2-yl, 3-phenyl-buten-2-yl, 1-cyano-buten-3-yl and the like. The geometric isomerism is not critical and all geometric isomers can be used for a given double bond with substituents.

Examples of the above-mentioned alkynyl group having a substituent include phenylacetylene-1-yl, 1-phenyl-2-propyn-1-yl and the like.

Haloalkyl is an alkyl group having a substituent in which one or more hydrogens on the corresponding alkyl group are replaced with halogen atoms (fluorine, chlorine, bromine, and iodine). Preferred haloalkyl groups may have one to four carbon atoms. Examples of preferred haloalkyl groups include trifluoromethyl and pentafluoroethyl.

Haloalkoxy is an alkoxy group having a substituent in which hydrogen of one or more of the R groups derived from the alkoxy group is replaced with a halogen atom (fluorine, chlorine, bromine and iodine). Preferred haloalkoxy groups may have one to four carbon atoms. Examples of preferred haloalkoxy groups include trifluoromethoxy and pentafluoroethoxy.

The term "oxo" denotes a carbon atom bonded to two other carbon atoms substituted with an oxygen double bonded to that carbon atom, thereby forming a ketone group or residue.

"alkoxy (alkoxy OR alkxyl)" means a-OR residue OR group, wherein R is alkyl. In some embodiments the alkoxy group may be C₁～C₈Alkoxy, in other embodiments may be C₁～C₄Alkoxy, wherein R is lower alkyl, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and the like. The term "substituted alkoxy" means that the R group is a substituted alkyl group or residue. Examples of the substituted alkoxy group include trifluoromethoxy group, hydroxymethyl group, hydroxyethyl group, hydroxypropyl group, and alkoxyalkyl group such as methoxymethyl group, methoxyethyl group, polyoxyethylene group, polyoxypropylene group, and the like.

"alkoxyalkyl" means a radical or residue of-R-O-R', wherein R andr' is an alkyl group. In some embodiments, the alkoxyalkyl group may be C₁～C₈And may be C in other embodiments₁～C₄. In many embodiments, R and R' are both lower alkyl groups, such as alkoxy groups like methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, and the like. Examples of alkoxyalkyl groups include methoxymethyl, ethoxyethyl, methoxypropyl, and methoxybutyl, and the like.

"hydroxyalkyl" refers to the group or residue-R-OH, where R is alkyl. In some embodiments, the hydroxyalkyl group may be C₁～C₈And may be C in other embodiments₁～C₄. In many embodiments, R is lower alkyl. Examples of hydroxyalkyl groups include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, and the like.

"acyloxy" refers to RCO₂-an ester group, wherein R is an alkyl, cycloalkyl, aryl, heteroaryl, substituted alkyl, substituted cycloalkyl, substituted aryl or substituted heteroaryl group or residue, wherein said R residue comprises one to seven or one to four carbon atoms. In many embodiments, R is an alkyl residue, and such acyloxy residues include formyloxy, acetoxy, propionyloxy, butyryloxy, pivaloyloxy, valeryloxy, hexanoyloxy, heptanoyloxy, and the like. In other embodiments, the R group is C₁～C₄An alkyl group.

As used herein, "acyl" includes the definition of alkyl, alkenyl, alkynyl and related heteroforms coupled to another organic residue through a carbonyl group to form a keto residue or group. Preferred acyl is "C ₁～C₇Acyl "such as formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl, hexanoyl, heptanoyl, benzoyl and the like. More preferred acyl groups are acetyl and benzoyl.

The term toolThe "substituted acyl group" means an acyl group in which the R group is substituted with one or more (preferably one or two) of the following groups as a substituent: halogen, hydroxy, oxy, alkyl, cycloalkyl, naphthyl, amino, (mono) amino, (di-substituted) amino, guanidino, heterocycle with substituents, imidazolyl, indolyl, pyrrolidinyl, C₁～C₇Alkoxy, alkoxy-alkyl, C₁～C₇Acyl radical, C₁～C₇Acyloxy, nitro, C₁～C₆Alkyl ester, carboxyl, alkoxycarbonyl, carbamoyl, formamide, N- (C)₁～C₆Alkyl) carboxamides, N-di (C)₁～C₆Alkyl) carboxamides, cyano, methylsulfonylamino, thiols, C₁～C₄Alkylthio or C₁～C₄An alkylsulfonyl group. The acyl group having a substituent may be substituted with the same or different substituent once or more, preferably once or twice.

C₁～C₇Examples of the acyl group having a substituent include a 4-phenylbutyryl group, a 3-phenylpropionyl group, a 2-cyclohexylacetyl group, a cyclohexanecarbonyl group, a 2-furoyl group and a 3-dimethylaminobenzoyl group.

A cycloalkyl residue or group is structurally related to a cyclic mono-or bicyclic hydrocarbon compound in which one or more hydrogen atoms are replaced by an organic or inorganic substituent. The cycloalkyl groups of the present invention contain at least 3 to 12 ring carbon atoms, or more preferably 3 to 8 ring carbon atoms, or more preferably 4 to 6 ring carbon atoms. Examples of such cycloalkyl residues include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl ring, and saturated bicyclic or fused polycyclic cycloalkanes such as decalinyl, polycyclic norbornyl or adamantyl groups and the like.

Preferred cycloalkyl groups include "C3-C7 cycloalkyl", such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings. Similarly, the term "C5-C7 cycloalkyl" includes cyclopentyl, cyclohexyl, or cycloheptyl rings.

"substituted cycloalkyl" refers to a cycloalkyl ring as defined above having one to four (preferably one or two) substituents independently selected from the group consisting of: halogen, hydroxy, C₁～C₄Alkylthio radical, C₁～C₄Alkyl sulfoxide, C₁～C₄Alkylsulfonyl radical, C₁～C₄Alkylthio group having substituent, C₁～C₄Alkyl sulfoxide having substituent, C₁～C₄Alkylsulfonyl group having substituent(s), C ₁～C₄Alkyl radical, C₁～C₄Alkoxy radical, C₁～C₆Alkyl having substituent, C₁～C₄Alkoxy-alkyl, oxy, (mono) amino, (di-substituted) amino, trifluoromethyl, carboxyl, phenyl, substituted phenyl, phenylthio, phenylsulfoxide, phenylsulfonyl, amino. In many embodiments of substituted cycloalkyl groups, the substituted cycloalkyl group can have 1, 2, 3, or 4 substituents independently selected from hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SEt、SCH₃Methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.

The term "cycloalkylene" refers to a cycloalkyl group as defined above, and which is bonded at two positions to two separate other groups. Similarly, the term "substituted cycloalkylene" refers to a cycloalkylene group wherein a cycloalkyl group is bonded at two positions to two separate other groups together and further bears at least one other substituent.

The term "cycloalkenyl" preferably denotes a 1-, 2-or 3-cyclopentenyl ring, a 1-, 2-, 3-or 4-cyclohexenyl ring or a 1-, 2-, 3-, 4-or 5-cycloheptenyl ring, while the term "cycloalkenyl with substituents" denotes a cycloalkenyl ring as defined above with substituents, preferably C ₁～C₆Alkyl, halogen, hydroxy, C₁～C₇Alkoxy, alkoxy-alkyl, trifluoromethyl, carboxyl, alkoxycarbonyl, oxy, (mono) amino, (di-substituted) amino, phenyl, substituted phenyl, amino or protected amino.

The term "cycloalkenylene" is a cycloalkenyl ring as defined above, and the cycloalkenyl group is bonded at two positions to two separate other groups. Similarly, the term "cycloalkenylene group having a substituent" means the above-mentioned cycloalkenylene group further having a substituent, preferably halogen, hydroxy, C₁～C₄Alkylthio radical, C₁～C₄Alkyl sulfoxide, C₁～C₄Alkylsulfonyl radical, C₁～C₄Alkylthio group having substituent, C₁～C₄Alkyl sulfoxide having substituent, C₁～C₄Alkylsulfonyl group having substituent(s), C₁～C₆Alkyl radical, C₁～C₇Alkoxy radical, C₁～C₆Alkyl having substituent, C₁～C₇Alkoxy-alkyl, oxy, (mono) amino, (di-substituted) amino, trifluoromethyl, carboxyl, alkoxycarbonyl, phenyl, substituted phenyl, phenylthio, phenylsulfoxide, phenylsulfonyl, amino or substituted amino.

The term "heterocyclic ring" means an optionally substituted 3-8 membered ring having one or more carbon atoms attached to the ring and having 1-5 heteroatoms, such as oxygen, sulfur and/or nitrogen, inserted into the ring. These heterocycles may be saturated, unsaturated or partially unsaturated, but are preferably saturated. "amino-substituted heterocycle" refers to any of the heterocycles described above having at least one amino substituent. Preferred unsaturated heterocycles include furyl, thienyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, quinolinyl, and similar heteroaryl rings. Preferred saturated heterocycles include piperidinyl, aziridinyl, piperidino (piperidinyl), piperazinyl, tetrahydrofuranyl, pyrrolyl and tetrahydrothienyl rings.

The term "heterocyclic ring having substituent(s)" means that the above-mentioned heterocyclic ring is substituted with, for example, one or more (preferably one or two) same or different substituent(s), preferably halogen, hydroxy, thio, alkylthio, cyano, nitro, C₁～C₄Alkyl radical, C₁～C₄Alkoxy radical, C₁～C₄Alkoxy, alkoxy-alkyl, C with substituents₁～C₄Acyl radical, C₁～C₄Acyloxy, carboxyl, alkoxycarbonyl, carboxymethyl, hydroxymethyl, alkoxy-alkylamino, (mono-substituted) amino, (di-substituted) amino, carboxamide, N- (C)₁～C₆Alkyl) carboxamides, N-di (C)₁～C₆Alkyl) carboxamides, trifluoromethyl, N- ((C)₁～C₆Alkyl) sulfonyl) amino, N- (phenylsulfonyl) amino, or substituted with fused rings such as benzo rings. In many embodiments of substituted heterocyclyl groups, the substituted cycloalkyl group can have 1, 2, 3, or 4 substituents independently selected from hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SEt、SCH₃Methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy substituents.

"aryl" means a monocyclic residue or group, a linked bicyclic residue or group, or a fused bicyclic residue or group comprising at least one six-membered aromatic "benzene" ring. The aryl group preferably contains 6 to 12 ring carbon atoms, and examples thereof include phenyl, biphenyl, naphthyl, 2, 3-indanyl and tetrahydronaphthyl. The aryl group is optionally substituted with various organic and/or inorganic substituents, wherein the substituted aryl group together with all substituents thereof contains 6 to 18 carbon atoms in total, or preferably 6 to 16 carbon atoms. Preferred optional substituents include 1, 2, 3 or 4 substituents independently selected from hydroxy, fluoro, chloro, NH ₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SEt、SCH₃Methyl, ethyl, isopropyl, ethylAlkenyl, trifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy substituents.

The term "heteroaryl" refers to a heterocyclic aryl derivative preferably comprising a 5-or 6-membered conjugated aromatic ring system having 1 to 4 heteroatoms inserted into the unsaturated conjugated heterocycle and independently selected from oxygen, sulfur and/or nitrogen. Heteroaryl includes monocyclic heteroaromatic moieties, linked bicyclic heteroaromatic moieties, or fused bicyclic heteroaromatic moieties. Examples of heteroaryl groups include pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, phthalimidyl, thiazolyl, quinolinyl, isoquinolinyl, indolyl, or furan or thiophene bonded directly to an unsaturated conjugated heteroaromatic ring such as a phenyl, pyridyl or pyrrolyl ring. Any monocyclic, linked bicyclic or fused bicyclic heteroaromatic ring system having aromatic character in terms of electron distribution throughout the ring system is included in this definition. Typically, the heteroaromatic ring system contains from 3 to 12 ring carbon atoms and from 1 to 5 ring heteroatoms independently selected from oxygen, nitrogen and sulfur atoms.

The term "substituted heteroaryl" means that the above-mentioned heteroaryl has, for example, one or more (preferably one or two) same or different substituents, preferably halogen, hydroxy, protected hydroxy, thio, alkylthio, cyano, nitro, C₁～C₆Alkyl radical, C₁～C₇Alkyl having substituent, C₁～C₇Alkoxy radical, C₁～C₇Alkoxy, alkoxy-alkyl, C with substituents₁～C₇Acyl radical, C₁～C₇Acyl having substituent, C₁～C₇Acyloxy, carboxyl, alkoxycarbonyl, carboxymethyl, hydroxymethyl, amino, (mono-substituted) amino, (di-substituted) amino, carboxamide, N- (C)₁～C₆Alkyl) carboxamides, N-di (C)₁～C₆Alkyl) carboxamides, trifluoromethyl, N- ((C)₁～C₆Alkyl) sulfonyl) amino or N- (phenylsulfonyl) amino. In at least one position ofIn many embodiments of substituted heteroaryl, the substituted heteroaryl can have 1, 2, 3, or 4 substituents independently selected from hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SEt、SCH₃Methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy substituents.

Similarly, "aralkyl" and "heteroaralkyl" refer to aromatic or heteroaromatic systems coupled to other residues through carbon chains, including substituted or unsubstituted, saturated or unsaturated carbon chains, typically 1 to 6 carbons. These carbon chains may also contain a carbonyl group, thereby enabling them to provide substituents as acyl moieties. Preferably, aralkyl or heteroaralkyl is alkyl substituted at any position with the following groups: an aryl group, a substituted aryl group, a heteroaryl group or a substituted heteroaryl group. Preferred groups also include benzyl, 2-phenylethyl, 3-phenyl-propyl, 4-phenyl-n-butyl, 3-phenyl-n-pentyl, 3-phenyl-2-butyl, 2-pyridylmethyl, 2- (2-pyridyl) ethyl and the like.

The term "substituted aralkyl" denotes an aralkyl group having one or more (preferably one or two) substituents on the alkyl moiety, preferably said substituents are selected from the group consisting of halogen, hydroxy, oxy, amino, (monosubstituted) amino, (disubstituted) amino, guanidino, heterocycle, substituted heterocycle, C₁～C₆Alkyl radical, C₁～C₆Alkyl having substituent, C₁～C₇Alkoxy radical, C₁～C₇Alkoxy, alkoxy-alkyl, C with substituents₁～C₇Acyl radical, C₁～C₇Acyl having substituent, C₁～C₇Acyloxy, nitro, carboxyl, alkoxycarbonyl, carbamoyl, carboxamide, N- (C)₁～C₆Alkyl) carboxamides, N-di (C)₁～C₆Dialkyl) formamide, cyano, N- (C)₁～C₆Alkylsulfonyl) amino, thiol, C₁～C₄Alkylthio radical, C₁～C₄An alkylsulfonyl group; and/or the phenyl group may have one or more (preferably one or two) substituents, preferably selected from halogen, hydroxy, protected hydroxy, thio, alkylthio, cyano, nitro, C₁～C₆Alkyl radical, C₁～C₆Alkyl having substituent, C₁～C₇Alkoxy radical, C₁～C₇Alkoxy, alkoxy-alkyl, C with substituents₁～C₇Acyl radical, C₁～C₇Acyl having substituent, C₁～C₇Acyloxy, carboxyl, alkoxycarbonyl, carboxymethyl, hydroxymethyl, amino, (mono-substituted) amino, (di-substituted) amino, carboxamide, N- (C) ₁～C₆Alkyl) carboxamides, N-di (C)₁～C₆Alkyl) carboxamides, trifluoromethyl, N- ((C)₁～C₆Alkyl) sulfonyl) amino, N- (phenylsulfonyl) amino, Ring C₂～C₇An alkylene group or a substituted or unsubstituted phenyl group, and a phenyl group as a substituent, a biphenyl group can be obtained. The alkyl group or the phenyl group having a substituent may have one or more (preferably one or two) same or different substituents.

Examples of the term "aralkyl group having a substituent" include groups such as 2-phenyl-1-chloroethyl, 2- (4-methoxyphenyl) ethyl, 4- (2, 6-dihydroxyphenyl) -n-hexyl, 2- (5-cyano-3-methoxyphenyl) -n-pentyl, 3- (2, 6-dimethylphenyl) propyl, 4-chloro-3-aminobenzyl, 6- (4-methoxyphenyl) -3-carboxy-n-hexyl, 5- (4-aminomethylphenyl) -3- (aminomethyl) -n-pentyl, 5-phenyl-3-oxo-n-pent-1-yl and the like.

The term "aralkylene" refers to an aralkyl group as defined above, and the aralkyl group is bonded at two positions to two separate other groups. The definition includes groups of the formula: -phenyl-alkyl-and-alkyl-phenyl-alkyl-. The substitution position on the phenyl ring may be 1, 2, 1, 3 or 1, 4 substitution. The term "substituted aralkylene" is arylene as defined above And the aralkylene group further has the following preferable substituents on the benzene ring or on the alkyl group: halogen, hydroxy, protected hydroxy, C₁～C₄Alkylthio radical, C₁～C₄Alkyl sulfoxide, C₁～C₄Alkylsulfonyl radical, C₁～C₄Alkylthio group having substituent, C₁～C₄Alkyl sulfoxide having substituent, C₁～C₄Alkylsulfonyl group having substituent(s), C₁～C₆Alkyl radical, C₁～C₇Alkoxy radical, C₁～C₆Alkyl having substituent, C₁～C₇Alkoxy-alkyl, oxy, (mono) amino, (di-substituted) amino, trifluoromethyl, carboxyl, alkoxycarbonyl, phenyl, substituted phenyl, phenylthio, phenylsulfoxide, phenylsulfonyl, amino or protected amino.

The term "substituted phenyl" refers to a phenyl group having as a substituent one or more (preferably one or two) moieties, preferably selected from: halogen, hydroxy, protected hydroxy, thio, alkylthio, cyano, nitro, C₁～C₆Alkyl radical, C₁～C₆Alkyl having substituent, C₁～C₇Alkoxy radical, C₁～C₇Alkoxy, alkoxy-alkyl, C with substituents₁～C₇Acyl radical, C₁～C₇Acyl having substituent, C₁～C₇Acyloxy, carboxyl, alkoxycarbonyl, carboxymethyl, hydroxymethyl, amino, (mono-substituted) amino, (di-substituted) amino, carboxamide, N- (C) ₁～C₆Alkyl) carboxamides, N-di (C)₁～C₆Alkyl) carboxamides, trifluoromethyl, N- ((C)₁～C₆Alkyl) sulfonyl) amino, N- (phenylsulfonyl) amino, or phenyl, wherein the phenyl is substituted or unsubstituted, such that a biphenyl group can be formed. In many embodiments of substituted phenyl, the substituted cycloalkyl group can have 1, 2, 3, or 4 substituents independently selected from hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SEt、SCH₃Methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy substituents.

The term "phenoxy" denotes a phenyl group bonded to an oxygen atom. The term "substituted phenoxy" means a phenoxy group having one or more (preferably one or two) moieties as substituents, preferably, the moieties are selected from the group consisting of: halogen, hydroxy, protected hydroxy, thio, alkylthio, cyano, nitro, C₁～C₆Alkyl radical, C₁～C₇Alkoxy radical, C₁～C₇Alkoxy, alkoxy-alkyl, C with substituents₁～C₇Acyl radical, C₁～C₇Acyloxy, carboxyl, alkoxycarbonyl, carboxymethyl, hydroxymethyl, amino, (mono-substituted) amino, (di-substituted) amino, carboxamide, N- (C)₁～C₆Alkyl) carboxamides, N-di (C) ₁～C₆Alkyl) carboxamides, trifluoromethyl, N- ((C)₁～C₆Alkyl) sulfonyl) amino and N- (phenylsulfonyl) amino.

The term "substituted phenylalkoxy" denotes a phenylalkoxy group in which the alkyl moiety has one or more (preferably one or two) groups as substituents, preferably selected from: halogen, hydroxy, protected hydroxy, oxo, amino, (mono) amino, (di-substituted) amino, guanidino, heterocycle, substituted heterocycle, C₁～C₇Alkoxy, alkoxy-alkyl, C₁～C₇Acyl radical, C₁～C₇Acyloxy, nitro, carboxyl, alkoxycarbonyl, carbamoyl, carboxamide, N- (C)₁～C₆Alkyl) carboxamides, N-di (C)₁～C₆Alkyl) carboxamides, cyano, N- ((C)₁～C₆Alkyl) sulfonyl) amino, thiol, C₁～C₄Alkylthio radical, C₁～C₄An alkylsulfonyl group; and/or benzeneThe radicals may have one or more (preferably one or two) substituents, preferably selected from halogen, hydroxy, protected hydroxy, thio, alkylthio, cyano, nitro, C₁～C₆Alkyl radical, C₁～C₇Alkoxy, alkoxy-alkyl, C₁～C₇Acyl radical, C₁～C₇Acyloxy, carboxyl, alkoxycarbonyl, carboxymethyl, hydroxymethyl, amino, (mono-substituted) amino, (di-substituted) amino, carboxamide, N- (C) ₁～C₆Alkyl) carboxamides, N-di (C)₁～C₆Alkyl) carboxamides, trifluoromethyl, N- ((C)₁～C₆Alkyl) sulfonyl) amino, N- (phenylsulfonyl) amino, or substituted or unsubstituted phenyl, with phenyl as a substituent, to give biphenyl. The alkyl group or the phenyl group having a substituent may have one or more (preferably one or two) same or different substituents.

The term "substituted naphthyl" refers to a naphthyl group having one or more (preferably one or two) moieties as substituents on the same ring or on different rings, said moieties being selected from the group consisting of: halogen, hydroxy, protected hydroxy, thio, alkylthio, cyano, nitro, C₁～C₆Alkyl radical, C₁～C₇Alkoxy, alkoxy-alkyl, C₁～C₇Acyl radical, C₁～C₇Acyloxy, carboxyl, alkoxycarbonyl, carboxymethyl, hydroxymethyl, amino, (mono-substituted) amino, (di-substituted) amino, carboxamide, N- (C)₁～C₆Alkyl) carboxamides, N-di (C)₁～C₆Alkyl) carboxamides, trifluoromethyl, N- ((C)₁～C₆Alkyl) sulfonyl) amino, N- (phenylsulfonyl) amino.

The terms "halo" and "halogen" refer to a fluorine, chlorine, bromine or iodine atom. May be one or more of the same or different halogens. Preferred halogens are chlorine and fluorine. Although many of the compounds of the present invention having halogen atoms as substituents are very effective in binding to the relevant taste receptors, the halogenated organic compounds often have poor toxicological properties when administered in the animal body. Thus, in many embodiments of the compounds of formula (I), if a halogen atom (including a fluorine atom or a chlorine atom) is listed as a possible substituent, then the preferred substituents for the substituents specifically contemplated therefore will not include a halogen group.

The term "(monosubstituted) amino" refers to an amino group (NHR) having one substituent selected from phenyl, C₆～C₁₀Phenyl having a substituent, C₁～C₆Alkyl radical, C₁～C₆Alkyl having substituent, C₁～C₇Acyl radical, C₁～C₇Acyl having substituent, C₂～C₇Alkenyl radical, C₂～C₇Alkenyl having substituent, C₂～C₇Alkynyl, C₂～C₇Alkynyl having substituent(s), C₇～C₁₂Phenylalkyl, C₇～C₁₂Substituted phenylalkyl and heterocycle. The (monosubstituted) amino group may additionally have an amino protecting group and is thus included within the term "protected (monosubstituted) amino group".

The term "(disubstituted) amino" refers to an amino group having two substituents (NR)₂) The substituents are independently selected from phenyl and C₆～C₁₀Phenyl having a substituent, C₁～C₆Alkyl radical, C₁～C₆Alkyl having substituent, C₁～C₇Acyl radical, C₂～C₇Alkenyl radical, C₂～C₇Alkynyl, C₇～C₁₂Phenylalkyl and C₇～C₁₂A substituted phenylalkyl group. The two substituents may be the same or different.

The term "amino protecting group" as used herein refers to a substituent on an amino group that is typically used to block or protect the functionality of the amino group when other functional groups of the molecule are reacted. The term "protected (monosubstituted) amino" refers to an amino protecting group on the nitrogen atom of the monosubstituted amino group. In addition, the term "protected carboxamides "means that there is an amino protecting group on the nitrogen of the carboxamide. Similarly, the term "protected N- (C)₁～C₆Alkyl) formamide "means that there is an amino protecting group on the nitrogen of the formamide.

The term "alkylthio" refers to the-SR radical, where R is optionally substituted C₁～C₇Or C₁～C₄An organic group (preferably an alkyl, cycloalkyl, aryl or heterocyclic group), -an SR group such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio and the like.

The term "alkyl sulfoxide" refers to-SO₂R group, wherein R is C optionally having a substituent₁～C₇Or C₁～C₄An organic group, preferably an alkyl, cycloalkyl, aryl or heterocyclic group, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio and the like, -SO₂R groups are, for example, methyl sulfoxide, ethyl sulfoxide, n-propyl sulfoxide, isopropyl sulfoxide, n-butyl sulfoxide, sec-butyl sulfoxide, and the like.

The term "alkylsulfonyl" refers to the group-S (O) R, wherein R is optionally substituted C₁～C₇Or C₁～C₄Organic groups, -S (O) R groups include groups such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, t-butylsulfonyl, and the like.

The terms "phenylthio", "phenylsulfoxide" and "phenylsulfonyl" refer to sulfoxide (-S (O) — R), or sulfone (-SO)₂R), wherein the R group is phenyl. The terms "phenylthio group having a substituent", "phenylsulfoxide group having a substituent" and "phenylsulfonyl group having a substituent" mean that the phenyl group of these groups may have a substituent as described above in connection with the "phenyl group having a substituent".

The term "alkoxycarbonyl" refers to an "alkoxy" (-C (O) -OR) attached to a carbonyl group, wherein R is alkyl,preferably C₁-C₄An alkyl group. The term "substituted alkoxycarbonyl" denotes a substituted alkoxy group attached to a carbonyl group, which may have a substituent as described above in connection with the substituted alkyl group.

The term "phenylene" refers to a phenyl group in which the phenyl group is bonded together at two positions with two separate other groups. Examples of "phenylene" include 1, 2-phenylene, 1, 3-phenylene, and 1, 4-phenylene.

The term "substituted alkylene" refers to an alkyl group wherein the alkyl group is bonded at two positions to two separate other groups and further bears other substituents. Examples of the "alkylene group having a substituent" include aminomethylene, 1- (amino) -1, 2-ethyl, 2- (amino) -1, 2-ethyl, 1- (acetylamino) -1, 2-ethyl, 2-hydroxy-1, 1-ethyl, 1- (amino) -1, 3-propyl.

The term "substituted phenylene" refers to a phenyl group in which a phenyl group is bonded together at two positions with two separate other groups, wherein the phenyl group has a substituent as described above in connection with "substituted phenyl".

The terms "cycloalkylene," "substituted cycloalkylene," "cycloheteroalkylene," and "substituted cycloheteroalkylene" are defined as a cyclic group or residue bonded ("fused") to a phenyl group to form a fused bicyclic group or residue. The non-fused portion of the cycloalkylene or cycloheteroalkylene ring may contain one or two double bonds, or is generally saturated. Furthermore, the non-fused part of the cycloalkylene or cycloheteroalkylene ring may have one or two oxygen, nitrogen or sulfur atoms, or NH, NR, S (O) or SO₂One or two methylene or methine groups replaced by a group wherein R is lower alkyl.

The cycloalkylene or cycloheteroalkylene groups may be substituted once or twice by identical or different substituents, preferably selected from the group consisting ofThe method comprises the following steps: hydroxy, protected hydroxy, carboxy, protected carboxy, oxo, protected oxo, C₁～C₄Acyloxy, formyl, C ₁～C₇Acyl radical, C₁～C₆Alkyl radical, C₁～C₇Alkoxy radical, C₁～C₄Alkylthio radical, C₁～C₄Alkyl sulfoxide, C₁～C₄Alkylsulfonyl, halogen, amino, protected amino, (mono) amino, protected (mono) amino, (di-substituted) amino, hydroxymethyl or protected hydroxymethyl. The cycloalkylene or cycloheteroalkylene fused to the phenyl group may contain 2 to 10 ring members, but preferably contains 3 to 6 ring members. Examples of saturated cycloalkylene groups are 2, 3-dihydro-indanyl and tetralin ring systems. When the cyclic group is unsaturated, examples include a naphthalene ring or an indolyl group. When phenyl is fused to pyridyl, pyranyl, pyrrolyl, pyridino, dihydropyrrolyl or dihydropyridino are examples of fused cyclic groups each comprising one nitrogen atom and one or more double bonds, preferably one or two double bonds. When a benzene ring is fused to the ring of a furyl, pyranyl, dihydrofuryl or dihydropyranyl group are examples of fused cyclic groups each containing one oxygen atom and one or two double bonds. When phenyl is fused to the ring of thienyl, thiopyranyl, dihydrothienyl or dihydrothiopyranyl is an example of a fused cyclic group each having one sulfur atom and containing one or two double bonds. When a benzene ring is fused to the ring of thiazolyl, isothiazolyl, dihydrothiazolyl or dihydroisothiazolyl is an example of a cyclic group comprising two heteroatoms selected from sulphur and nitrogen and one or two double bonds. When a benzene ring is fused to the ring of an oxazolyl, isoxazolyl, dihydrooxazolyl, or dihydroisoxazolyl group is an example of a cyclic group containing two heteroatoms selected from oxygen and nitrogen and one or two double bonds. Examples of cyclic groups comprising two nitrogen heteroatoms and one or two double bonds are produced when a phenyl ring is fused to a ring of pyrazolyl, imidazolyl, dihydropyrazolyl or dihydroimidazolyl or to a pyrazinyl group.

The term "carbamoyl" refers to aminoFormate groups or residues, usually derived from organic isocyanate compounds R₁-NCO with alcohol R₂OH to form a compound having R₁-NH-C(O)-OR₂Reaction of a carbamate compound of structure (la) wherein R₁And R₂The nature of the group depends on the circumstances.

One or more of the compounds of the present invention may exist in the form of a salt. The term "salt" includes salts formed from carboxylate anions and amine nitrogens, as described below, and includes salts formed from organic and inorganic anions and cations, as discussed below. In addition, the term includes salts formed by standard acid-base reactions of basic groups (e.g., nitrogen-containing heterocyclic groups or amino groups) with organic or inorganic acids. The acid includes hydrochloric acid, hydrofluoric acid, trifluoroacetic acid, sulfuric acid, phosphoric acid, acetic acid, succinic acid, citric acid, lactic acid, maleic acid, fumaric acid, palmitic acid, cholic acid, pamoic acid (pamoic acid), mucic acid, D-glutamic acid, D-camphoric acid, glutaric acid, phthalic acid, tartaric acid, lauric acid, stearic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, sorbic acid, picric acid, benzoic acid, cinnamic acid, and the like.

The term "organic or inorganic cation" refers to a positively charged counterion which can form a salt with the carboxylate anion of a carboxylate salt. Inorganic positively charged counterions include, but are not limited to, alkali and alkaline earth metals (e.g., lithium, sodium, potassium, calcium, magnesium, and the like) as well as other divalent and trivalent metal cations such as barium, aluminum, and the like, and ammonium (NH) ₄)⁺A cation. Organic cations include ammonium cations resulting from acid treatment or alkylation of primary, secondary or tertiary amines such as trimethylamine, cyclohexylamine, and the like; and organic cations of cations such as dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, bis (2-hydroxyethyl) ammonium, phenethylbenzylammonium, dibenzylethylenediamine, and the like. See, for example, "Pharmaceutical Salts," (Berge et al, J.pharm.Sci. (1977) 66: 1-19), which is incorporated herein by reference, other cations encompassed by the above terms include protonated forms of procaine, quinine, and N-methylglucamine, and basic amino acids such as glycine, ornithine, histidine, phenylglycine, lysine, and arginineProtonated form of the acid. Furthermore, the term also refers to any zwitterionic form of the transient compound formed from a carboxylic acid and an amino group. For example, when R is²Or R³With a (quaternary) ammonium methyl substituent, there will be a cation that can form a salt with the carboxylate anion. The preferred cation for salt formation with the carboxylate anion is a sodium cation.

The compounds of the invention may also exist in the form of solvates and hydrates. Thus, these compounds can be crystallized, for example, with water of hydration, or with one, many, or any portion of one molecule of the mother liquor solvent. Solvates and hydrates of the compounds are included within the scope of the invention.

The term "amino acid" includes any of the 20 naturally occurring amino acids or the D-form of any of the naturally occurring amino acids. Furthermore, the term "amino acid" includes other non-naturally occurring amino acids in addition to the D-amino acid that is functionally equivalent to a naturally occurring amino acid. Such non-naturally occurring amino acids include those such as norleucine ("Nle"), norvaline ("Nva"), L-or D-naphthylalanine (D-naphthanine), ornithine ("Om"), homoarginine (homoArg), and other amino acids well known in the peptide art, such as those described in M.Bodanzsky, "Principles of peptide Synthesis" (first and second revisions, Springer-Verlag, New York, N.Y., published 1984 and 1993, respectively), and Stewart and Yong, "Solid phase peptide Synthesis" (second edition, Pierce Chemical Co., Rokford, Ill., 1984), both of which are incorporated herein by reference. Amino acids and amino acid analogs are commercially available (Sigma Chemical Co.; Advanced Chemtech) or synthesized using methods known in the art.

"amino acid side chain" refers to any side chain derived from the above-mentioned "amino acid".

"substituted" as used herein refers to a substituted moiety, such as a hydrocarbon, for example, a substituted alkyl or benzyl group, wherein at least one element or residue (e.g., hydrogen) is replaced by another element or residue, for example, hydrogen is replaced by a halogen in a chlorobenzyl group.

The residues of a chemical species described in the specification and claims that follow refer to a structural fragment or moiety that is the resulting product of the chemical species in a particular chemical reaction or subsequent formulation or chemical product, regardless of whether the structural fragment or moiety is actually derived from the chemical species. Thus, an ethylene glycol residue in a polyester refers to one or more-OCH's in the polyester₂CH₂O-repeating units regardless of whether ethylene glycol is used to prepare the polyester.

The term "organic residue" or "organic group" defines a carbon-containing residue or group, i.e., a residue comprising at least one carbon atom. The organic residue may contain various heteroatoms, including oxygen, nitrogen, sulfur, or phosphorus, or may be attached to another molecule through a heteroatom. Examples of organic residues include, but are not limited to, alkyl or substituted alkyl, alkoxy or substituted alkoxy, mono-or di-substituted amino, amido, CN, CO ₂H、CHO、COR⁶、CO₂R⁶、SR⁶、S(O)R⁶、S(O)₂R⁶Alkenyl, cycloalkyl, cycloalkenyl, aryl and heteroaryl: wherein R is⁶Is an alkyl group. More specific examples of the kind of organic group or residue include, but are not limited to, NHCH₃、N(CH₃)₂、CO₂CH₃、SEt、SCH₃、S(O)CH₃、S(O)₂CH₃Methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy, CH₂OCH₃、CH₂OH、CH₂NH₂、CH₂NH₂CH₃Or CH₂N(CH₃)₂A group or residue. The organic residue may contain 1 to 18 carbon atoms, 1 to 15 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms.

The term "effective amount" of a compound as provided herein refers to a sufficient amount of one or more compounds in a composition that is sufficient to provide the desired modulation of a desired biological function, such as gene expression, protein function, or more specifically, to induce umami or sweet taste in an animal or human. As will be noted below, the exact amount required will vary from subject to subject, depending on the species, age, general condition of the subject, the specific nature and formulation of the edible composition, and the like. Therefore, it is not possible to specify an exact "effective amount". However, one of ordinary skill in the art can determine an appropriate effective amount by only routine experimentation.

It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," "the," and "the" include plural and multiple referents unless the context clearly dictates otherwise. Thus, for example, "an aromatic compound" includes mixtures of aromatic compounds.

Ranges are generally expressed herein as from "about" one particular value, and/or to "about" another particular value. When ranges are so expressed, another embodiment includes from the previous particular value and/or to the next particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

"optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs or instances where it does not. For example, the phrase "optionally substituted lower alkyl" means that the lower alkyl may or may not have a substituent, and the description includes both unsubstituted lower alkyl and substituted lower alkyl.

Amide compounds of the present invention

The compounds of the present invention are all organic (carbon-containing) compounds which each have at least one "amide" group therein, said compounds having the following general structure, which is hereinafter referred to as amide compound having the formula (I) shown below:

the amide compounds of formula (I) do not include amide compounds known to occur naturally in biological systems or food products, such as peptides, proteins, nucleic acids, certain amino sugars and/or amino polysaccharides, glycopeptides or glycoproteins, and the like. The amide compounds of formula (I) according to the invention are man-made and artificially synthesized amide compounds, although the applicant does not exclude the possibility that one could conceivably purposefully prepare the compounds of formula (I) in their specific form or in the form of peptide-or protein-modified "prodrugs" by means of one or more methods of modern biotechnology.

For the various embodiments of the compounds of formula (I), R will now be described further¹、R²And R³Groups may be further defined and/or qualified independently in various ways to form and/or include a substantial number of subgenera and/or species of compounds of formula (I). Thus, it is specifically contemplated that any subgenus and/or species of compounds of formula (I) described herein can be combined with a comestible or medicinal product or precursor thereof in an effective amount to form a savory or sweet modified comestible or medicinal product or precursor thereof, in the form of its particular form or an edible salt thereof, by processes and/or methods described elsewhere herein, or by any other method that will be apparent to one of ordinary skill in the preparation of the comestible or medicinal product or precursor thereof.

In some embodiments of compounds of formula (I), R¹Is a hydrocarbon residue which may contain one or more heteroatoms or is an inorganic residue, and R²And R³Each independently is H or a hydrocarbon residue which may contain one or more heteroatoms; more preferably, R¹、R²And R³Independently selected from aralkenyl, heteroaralkenyl, aralkyl, heteroaralkyl, alkyl, alkoxy-alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, -R⁴OH、-R⁴CN、-R⁴CO₂H、-R⁴CO₂R⁵、-R⁴COR⁵、-R⁴CONR⁵R⁶、-R⁴NR⁵R⁶、-R⁴N(R⁵)COR⁶、-R⁴SR⁵、-R⁴SOR⁵、-R⁴SO₂R⁵、-R⁴SO₂NR⁵R⁶and-R⁴N(R⁵)SO₂R⁶Or the above group optionally having a substituent, and preferably R²Or R³Is H; wherein R is⁴Each independently being a hydrocarbon residue which may contain one or more heteroatoms, preferably independently selected from small (C)₁～C₆) Alkylene or (C)₁～C₆) An alkoxy alkylene group; and wherein R⁵And R⁶Each independently being H or a hydrocarbon residue which may contain one or more heteroatoms, preferably independently selected from small (C)₁～C₆) Alkyl or (C)₁～C₆) An alkoxyalkyl group.

In many embodiments of the compounds of formula (I), R¹Comprising an organic or hydrocarbon residue having at least three carbon atoms and optionally 1 to 20, 1 to 15, 1 to 10, 1 to 8, 1 to 7, 1 to 6 or 1 to 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, halogen or phosphorus.

In many embodiments of the compounds of formula (I), R ²And R³Is optionally H, and R²And/or R³Comprising an organic or hydrocarbon residue having at least three carbon atoms and optionally from 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, halogen or phosphorus.

In contrast to many biomolecules, the compounds of formula (I) are relatively "small molecules" and can often impose various limitations on their overall absolute physical size, molecular weight and physical properties, such that they are at least slightly soluble in aqueous media and of suitable size to effectively bind to the relevant heterodimeric T1R1/T1R3 or T1R2/T1R3 taste receptors, which share a common T1R3 protein subunit.

While not wishing to be bound by any theory, it is believed that MSG binds to the T1R1 subunit of the T1R1/T1R3 "savory" taste receptor and that a variety of known sweeteners bind to the T1R2 subunit of the T1R2/T1R3 sweet taste receptor. Thus, amide compounds of formula (I) may share many overlapping physical and chemical characteristics and may sometimes bind to savory and/or sweet taste receptors, and this surprising and surprising finding by the inventors may be justifiable and/or justifiable from a chemical/biochemical/biological point of view.

As an example of the overlapping physical and chemical properties and/or physical/chemical limitations of the savory and/or sweet amides of formula (I), in most embodiments of the compounds of formula (I), the molecular weight of the compounds of formula (I) should be less than about 800 g/mole, or in further related embodiments, less than or equal to about 700 g/mole, 600 g/mole, 500 g/mole, 450 g/mole, 400 g/mole, 350 g/mole, or 300 g/mole.

Similarly, the molecular weight range of the compound of formula (I) is preferably, for example, from about 175 to about 500 g/mole, from about 200 to about 450 g/mole, from about 225 to about 400 g/mole, from about 250 to about 350 g/mole.

In a related series of embodiments, R¹Having 3 to 16 carbon atoms or 4 to 14 carbon atoms or 5 to 12 carbon atoms and 0, 1, 2, 3, 4 or 5 heteroatoms selected from oxygen, nitrogen, sulphur, fluorine or chlorine, and/or R²Or R³Has 3 to 16 carbon atoms and 0, 1, 2, 3, 4 or 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, fluorine or chlorine; or preferably R²Or R³Has 4 to 14 carbon atoms and 0, 1, 2, 3, 4 or 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, fluorine; or more preferably, R ²Or R³Has 5 to 12 carbon atoms and 0, 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur.

In addition to the general physical and chemical characteristics and/or limitations described above that may be shared by various subgenera of sweet and savory compounds of formula (I), the compounds of formula (I) may also share chemical structural features or chemical groups or residues that may be more specifically defined, as described further below.

For example, in some embodiments, R¹、R²And R³May be independently selected from aralkenyl, heteroaralkenyl, aralkyl, heteroaralkyl, alkyl, alkoxy-alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, -R⁴OH、-R⁴OR⁵、-R⁴CN、-R⁴CO₂H、-R⁴CO₂R⁵、-R⁴COR⁵、-R⁴SR⁵and-R⁴SO₂R⁵And optionally substituted derivatives thereof comprising 1, 2, 3 or 4 carbonyl, amino, hydroxy or halogen groups, and wherein R is⁴And R⁵Is C₁～C₆A hydrocarbon residue.

In other related embodiments of the amide compounds of formula (I), R¹、R²And R³May be independently selected from aralkenyl, heteroaralkenyl, aralkyl, heteroaralkyl, alkyl, alkoxy-alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycle, aryl and heteroaryl, and optionally substituted derivatives thereof containing 1, 2, 3 or 4 carbonyl, amino, hydroxyl or chloro or fluoro groups. In both of the embodiments just mentioned, an alternative and preferred series of optional substituents may be independently selected from hydroxy, fluoro, chloro, NH ₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SEt、SCH₃Methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy substituents.

R²And/or R³Radical (I)

In many embodiments of the compounds of formula (I), R²And R³One radical in (A) is hydrogen, and R²Or R³Is an organic residue or an organic group. It is therefore to be understood that the following description "R" is provided²And R³"means an embodiment, i.e., R²And R³One radical in (A) is hydrogen, and R is²And R³Has the structure described below, and another embodiment, R²And R³All have the structure.

In many embodiments, R²And R³At least one of which is a branched or cyclic organic residue having carbon atoms directly bonded to both (a) the amide nitrogen atom and (b) two other carbon atoms from other organic residues, which may be branched or cyclic organic residues comprising other hydrogen atoms and up to 10 optional other carbon atoms and optionally 0 to 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, fluorine and chlorine. The branched R²And R³Groups include organic groups having the formula:

Wherein na and nb are independently selected from 1, 2 and 3, and R^2aOr R^2bThe substituted residues are each independently selected from hydrogen, halogen, hydroxyl, or optionally a carbon-containing residue having 0-5 heteroatoms independently selected from oxygen, nitrogen, sulfur, and halogen. In some such embodiments, R^2aOr R^2bAre independent substituents, but in other embodimentsIn the embodiment, one or more R^2aOr R^2bThe groups may be bonded together to form a cyclic structure.

In some such embodiments of the compounds of formula (I), R²And R³At least one of which is a branched alkyl group having 5 to 12 carbon atoms, or R²And R³At least one of which is a cycloalkyl ring or a cycloalkenyl ring containing 5 to 12 ring carbon atoms. At R²And R³In said embodiment of (a), the branched alkyl or cycloalkyl or cycloalkenyl ring may be optionally substituted with 1, 2, 3 or 4 substituents independently selected from hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SEt、SCH₃Methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy substituents.

In other embodiments of the amide compound of formula (I), R²And R³Is a "benzylic" group having the structure:

wherein Ar is an aromatic or heteroaromatic ring, such as phenyl, pyridyl, furyl, thienyl, pyrrolyl or similar aromatic ring systems, m is 0, 1, 2 or 3, and R is ²' each is independently selected from hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SEt、SCH₃Methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy, and R^2aThe substituents are each independently selected from alkyl, alkoxy-alkyl, alkenyl, cycloalkenyl, cycloalkyl, -R⁴OH、-R⁴OR⁵、-R⁴CN、-R⁴CO₂H、-R⁴CO₂R⁵、-R⁴COR⁵、-R⁴SR⁵and-R⁴SO₂R⁵A group.

In many embodiments of the compounds of formula (I), R²Or R³Is at least one of C₃～C₁₀A branched alkyl group. In many such embodiments, R²Or R³Is hydrogen. These have found that₃～C₁₀Branched alkyl is highly effective R for both savoury and sweet amide compounds²A group. In some embodiments, R³Is C₄～C₈A branched alkyl group. Examples of such branched alkyl groups include the following structures.

In other embodiments, the branched alkyl group optionally contains one or two heteroatoms, such as nitrogen, oxygen or sulfur atoms, inserted into the otherwise alkyl chain to form an amine, ether and/or thioether, sulfoxide or sulfone, respectively, or one or two heteroatom substituents independently selected from hydroxyl, fluorine, chlorine, bromine, NH bonded to the alkyl chain₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SCH₃SEt, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy and the like.

In other embodiments of the compounds of formula (I), R²Or R³At least one of which is an alpha-substituted carboxylic acid or a lower alkyl ester of an alpha-substituted carboxylic acid. Preferably, R is²Or R³At least one of which is a lower alkyl (especially methyl) ester of an alpha-substituted carboxylic acid. In some such preferred embodiments, the α -substituted carboxylic acid or α -substituted carboxylic acid ester residue corresponds to that of a naturally occurring optically active α -amino acid or ester thereof or the reverse enantiomer thereofAnd (c) a residue.

In many embodiments of the compounds of formula (I), R²Or R³Is a 5-or 6-membered aryl or heteroaryl ring, optionally substituted by 1, 2, 3 or 4 substituents selected from hydroxy, NH₂SH, halogen or C₁-C₄A substituent of an organic group. In related embodiments, the substituent for the aryl or heteroaryl ring is selected from alkyl, alkoxy-alkyl, OH, CN, CO₂H、CHO、COR⁶、CO₂R⁶、SR⁶Halogen, alkenyl, cycloalkyl, cycloalkenyl, aryl and heteroaryl; and R is⁶Is C₁～C₆An alkyl group. Preferably the aryl or heteroaryl ring is substituted with 1, 2, 3 or 4 substituents selected from hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SCH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.

In some embodiments of compounds of formula (I), R²Or R³Is a phenyl, pyridyl, furyl, thienyl or pyrrolyl ring, said phenyl, pyridyl, furyl, thienyl or pyrrolyl ring optionally being substituted with one or two substituents independently selected from hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SCH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.

In many embodiments of the compounds of formula (I), R²Or R³At least one of which is a cycloalkyl, cycloalkenyl or saturated heterocyclyl ring having from 3 to 10 ring carbon atoms, optionally substituted with 1, 2 or 3 substituents independently selected from NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SEt、SCH₃、C₁～C₄Alkyl radical, C₁～C₄Haloalkyl, C₁～C₄Alkoxy radical, C₁～C₄Haloalkoxy, hydroxy and halogen. In some other embodiments, R²Or R³Is a cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl ring or piperidinyl ring, said cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl ring or piperidinyl ring optionally being substituted with 1, 2 or 3 substituents independently selected from hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SEt、SCH₃Methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.

In some preferred embodiments, R²Or R³Is a cyclohexyl ring, which is optionally substituted by 1, 2 or 3 substituents selected from NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SEt、SCH₃、C₁～C₄Alkyl radical, C₁～C₄Haloalkyl, C₁～C₄Alkoxy radical, C₁～C₄Substituted by substituents of haloalkoxy, hydroxy and halogen groups, and R²Or R³Is hydrogen. For example, in some such embodiments, R³Is hydrogen and R²May have one of the following structures:

wherein R is²' and R²Independently selected from hydroxyl, fluorine, chlorine, bromine and NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethylOxy, or preferably methyl. Such methyl-substituted cyclohexyl rings have the formula:

in many embodiments of the compounds of formula (I), in particular compounds having flavour enhancing activity towards other sweeteners or compounds having flavour enhancing activity towards other savoury compounds such as MSG, R³Is hydrogen and R²Is a cyclopentyl or cyclohexyl ring fused with a benzene ring, i.e., a 1- (1, 2, 3, 4) -tetrahydronaphthalenyl or 2, 3-dihydro-1H-indene ring group having the following structure:

wherein n is 0, 1, 2 or 3, and R²Each of which may be bonded to an aromatic or non-aromatic ring.

In other embodiments, R is as follows²' each bonded to the aromatic ring:

in the tetrahydronaphthyl and indanyl embodiments shown above, R²' may be independently selected from hydroxyl and NH₂SH, halogen or C₁-C₄An organic group. In an alternative but related embodiment, R²' may be independently selected from hydroxyl and NH₂SH, halogen, C₁～C₄Alkyl radical, C₁～C₄Haloalkyl, C₁～C₄Haloalkoxy, C₁～C₄Alkoxy radical,C₁～C₄Alkoxy-alkyl, C₁～C₄Hydroxy-alkyl, OH, NH₂、NHR⁶、NR⁶ ₂、CN、CO₂H、CO₂R⁶、CHO、COR⁶、SH、SR⁶And halogen, wherein R⁶Is C₁～C₄An alkyl group. In some preferred embodiments, R²' may each be independently selected from hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SCH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.

In some embodiments, R²Or R³Is a 1- (1, 2, 3, 4) -tetrahydronaphthalene ring with a particularly preferred substitution pattern. In particular, in some embodiments of the compounds of formula (I), R²Or R³Is a cyclohexyl ring having one of the following formulas:

wherein R is²' may each be independently selected from the groups described above. Similarly, in some preferred embodiments, R ²Or R³May comprise one of the following structures:

in some embodiments, R²Or R³Is a 1- (1, 2, 3, 4) tetrahydronaphthalene ring having no substituent in a racemic or optically active form, as shown below:

similarly, in the indanyl series, R²May have the following structure:

or said R is²' substituents may be bonded to the aromatic ring as shown below,

or in some more specific embodiments, R²Having one of the exemplary structures shown below:

in some embodiments of the amide compounds of the present invention, R is as described above²The tetralin ring or indene ring system of groups may be modified to contain one or more heteroatoms or heteroatom groups in the bicyclic ring system to form new heterocyclic and bicyclic analogs of the tetralin ring and indene ring systems to form new R²A group. For example, one of the aromatic rings of a tetrahydronaphthyl radical can be substituted with a nitrogen atom to form a novel tetrahydroquinolinyl or tetrahydroisoquinolinyl radical having the structure shown below:

wherein R is²The' group may be bonded to an aromatic or non-aromatic ring and may be defined as being attached to the tetrahydronaphthyl group in any of the ways described above. It will be apparent to one of ordinary skill in the art that at least one additional nitrogen atom may be similarly inserted to form additional isomeric heteroaryl groups, such as the exemplary R below ²Group (b):

the above indanyl group R²The radicals may likewise be modified by one or more nitrogen atoms to form further bicyclic heteroaryls R²Examples of the substituent include the following structures:

in addition, one or more heteroatoms or heteroatom groups may be inserted into the cyclopentyl or cyclohexyl groups of the tetrahydronaphthyl or indanyl groups described above to form additional fused bicyclic heteroaryl groups, including, but not limited to, the exemplary structures listed below:

wherein n is 0, 1, 2 or 3, R²' may each be defined in any of the ways described above, and X_hIs O, S, SO₂NH or NR_hWherein R is_hIs C₁-C₄An organic group. Such R²Examples of radicals are listed below:

it will also be appreciated by those of ordinary skill in the art that R is as defined above²Unsaturated five and six membered rings of the radical, as well as many other Rs disclosed herein¹、R²And R³In the base, optical isomers and/or diastereomers may occur, and the different optical isomers (enantiomers) and/or diastereomers may have differing biological activities for the relevant sweet and savory taste receptors. Predicting a specific R²It will be difficult to identify which diastereomer or enantiomer of a group is most likely to be biologically active, and finding a particular isomer more effective for a given ring system does not necessarily mean that similar isomers with different substituents are similarly effective.

Applicants have discovered, however, that in many embodiments, when R is²The compounds of formula (I) are particularly effective as sweet taste enhancers when the substituted or unsubstituted tetrahydronaphthyl, indanyl, tetrahydroquinolinyl, tetrahydronaphthyl, or related heterocyclic analogs described above contain an enantiomeric excess of the absolute optical configuration depicted in the following figures:

one of ordinary skill will appreciate that whether "R" or "S" under the Cahn-Ingold-Prelog nomenclature system designating a particular compound as being useful for an optically active compound may depend on the exact nature and number of substituents, but with a bicyclic R²Ligand and just aboveThe compounds of formula (I) in the absolute optically active configuration shown in the diagram are typically "R" at the optically active carbon shown above, and these compounds generally bind very well to T1R2/T1R3 sweet taste receptors. It should be noted, however, that the "S" isomer as opposed thereto typically has some (although typically lower) activity in binding the T1R2/T1R3 sweet taste receptor and/or activity as a sweet taste enhancer compound.

The applicant has found that said T1R1/T1R3 savory taste receptors often show a strong binding to R having the "S" configuration (as opposed to the one shown above) ²Trend of compounds of formula (I) said "S" configuration R²The base is as follows:

it is again stated that while the T1R1/T1R3 savory taste receptors often show a clear preference for the "S" isomer of compounds containing the R2 group as shown above, the "R" isomer may also retain a biological activity that is also clear, although reduced, as a savory taste flavor or as a savory taste enhancer compound for MSG. To illustrate this, the following data sheet provides a relevant example of data for the binding of the relative enantiomer to the savory taste receptor of T1R1/T1R 3.

When the specification, claims and/or drawings herein indicate that a compound is present in an optically active form, as is indicated immediately above in the discussion and drawings, it is to be understood that reference to a compound of formula (I) is made at least in a small enantiomeric excess (i.e., more than about 50% of the molecules in the molecule have the optical configuration indicated). Further embodiments preferably comprise an enantiomeric excess of at least 75%, or 90%, or 95%, or 98%, or 99%, or 99.5% of the designated isomer. Depending on the biological activity, differences in production costs, and/or any differences in toxicity between the two enantiomers, it may be advantageous for a given compound to manufacture and sell a racemic mixture of said enantiomers for human consumption, or to have one of the enantiomers of a given compound in small or large enantiomeric excess.

In other embodiments of the amide compounds of formula (I), such as the savory oxalamide compounds of formula (V) disclosed below, R²And R³One group is hydrogen and the other group is an alkylene substituted pyridyl group having the structure:

wherein p is 1 or 2; n is 0, 1 and 2, R²' may be any substituent defined above.

In other embodiments of the amide compounds of formula (I), in some embodiments of the compounds of formula (I), R²And R³The groups are not hydrogen, and combine with each other to form a heterocyclic amine ring optionally having a substituent, examples of which are shown below:

n is 0, 1 and 2, R²' may be any substituent defined above. As further described below, urea, as a subgenus of amide compounds of formula (I), may preferably have such R²/R³Cyclic embodiments of the invention, and such compounds are particularly useful as sweet taste enhancer compounds and/or flavoring agents.

Comprising aryl or heteroaryl radicals R¹Amide compounds of the group

Among the many preferred subgenera of amide compounds of formula (I) having savory and/or sweet receptor agonist activity, in preferred subgenera of said amide compounds, R is¹Is an optionally substituted aryl or heteroaryl group. More specifically, many subgenera of amide compounds of formula (I) have the following formula (II):

Wherein a comprises a 5-or 6-membered aryl or heteroaryl ring; m is 0, 1, 2, 3 or 4.

In such compounds of formula (I) and/or formula (II), R¹' may be independently selected from hydroxyl and NH₂SH, halogen and C₁～C₄An organic group. In related embodiments, R¹' independently of each other are selected from alkyl, alkoxy-alkyl, hydroxyalkyl, OH, CN, CO₂H、CO₂R⁶、CHO、COR⁶、SR⁶Halogen, alkenyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, and heteroaryl; and R is⁶Is C₁～C₆An alkyl group. In some related but alternative embodiments of the compounds of formula (I) and/or formula (II), each R¹' and/or each R²' may be independently selected from hydroxyl, NH₂SH, halogen, C₁～C₄Alkyl radical, C₁～C₄Haloalkyl, C₁～C₄Haloalkoxy, C₁～C₄Alkoxy radical, C₁～C₄Alkoxy-alkyl, C₁～C₄Hydroxy-alkyl, OH, NH₂、NHR⁶、NR⁶ ₂、CN、CO₂H、CO₂R⁶、CHO、COR⁶、SH、SR⁶And halogen, wherein R⁶Is C₁～C₄An alkyl group. In formulae (I) and-In many preferred embodiments of compounds of formula (II), R¹' each is independently selected from hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃SEt, methyl, ethyl, isopropyl, n-propyl, n-butyl, 1-methyl-propyl, isobutyl, tert-butyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy. In such compounds of formula (II), R ²Any of the above contemplated configurations, and the like.

In some embodiments, the a group of formula (II) comprises an aryl ring, i.e., it comprises at least one six-membered aromatic benzene ring located somewhere within its structure. The aryl group includes at least a benzene ring and a naphthalene ring, which may be unsubstituted, but in many embodiments is substituted with at least 1, 2 or 3R¹' substituent further substituted, R¹' may be defined as any of the alternative configurations described above. In such embodiments, the benzylidene and naphthyl rings may, but need not, be directly bonded to the carbonyl carbon atom of the amide compound.

In many embodiments of the compounds of formula (II), the A group is a benzene ring directly bonded to the carbonyl carbon atom of the amide group, and R is³Is H to form a benzamide compound having the formula shown below:

in these compounds of the formula (II), R²Any of the above contemplated configurations, and the like. Such branched alkyl radicals R²The compounds of the group are preferred savory flavoring agents and/or savory flavor enhancers. Such a tetralinyl, indanyl or structurally related heterocycle R as disclosed above having optionally substituted groups²Is a highly effective sweet taste enhancer compound.

In which A isIn some preferred embodiments of the compounds which are benzylic rings, as exemplified by the preferred subgenera (IIa) and (IIb) below, one or both R¹' substituents may be bonded together to form a saturated alkylene dioxy ring on the phenyl ring;

wherein R is_1aAnd R_1bIndependently hydrogen or lower alkyl, or alternatively, R_1aAnd R_1bIndependently hydrogen or methyl, or alternatively, R_1aAnd R_1bBoth of which are hydrogen.

In many embodiments of the amide compounds of formula (II), a is a heteroaromatic ring, and typically a monocyclic or fused bicyclic heteroaromatic ring. Fused bicyclic heteroaryls are represented by the following benzofurans (formula (IIc)) and benzothiophenes (formula (IId)):

wherein m is 0, 1, 2 or 3, and R¹' may each be bonded to a benzene ring or a heteroaromatic ring, and R¹' each is independently selected from hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SCH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.

Other examples of fused bicyclic heteroaryl groups as a group a are represented by the following benzoxazole compounds (formula (IIe)) and (formula (IIf)):

wherein R is_1aOr R_1bIndependently hydrogen or lower alkyl.

In many embodiments of the amide compounds of formula (II), a is a monocyclic heteroaryl ring. Monocyclic heteroaryl groups useful as a groups in formula (II) include the following structures:

Wherein m is 0, 1, 2 or 3. In such compounds of formula (II), R¹' may be independently selected from hydroxyl and NH₂SH, halogen and C₁-C₄An organic group. In some related but alternative embodiments of the compounds of formula (II), R¹' may be independently selected from hydroxyl and NH₂SH, halogen, C₁～C₄Alkyl radical, C₁～C₄Haloalkyl, C₁～C₄Haloalkoxy, C₁～C₄Alkoxy radical, C₁～C₄Alkoxy-alkyl, C₁～C₄Hydroxy-alkyl, OH, NH₂、NHR⁶、NR⁶ ₂、CN、CO₂H、CO₂R⁶、CHO、COR⁶、SH、SR⁶And halogen, wherein R⁶Is C₁～C₄An alkyl group. In many preferred embodiments, R¹' each is independently selected from hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃SEt, methyl, ethyl, isopropyl, n-propyl, n-butyl, 1-methyl-propyl, isobutyl, tert-butyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy. In such compounds of formula (II), R²Any of the above contemplated configurations, and the like.

In some preferred embodiments of the monocyclic heteroaryl amide compounds, a is a substituted furan, thiophene, or oxazole ring, thereby forming compounds having formulas (IIg), (IIh), and (IIi):

wherein m is 0, 1, 2 or 3. In some such embodiments, m is 1 or 2, and R is¹' may each be independently selected from hydroxy, fluoro, chloro, NH ₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃SEt, methyl, ethyl, isopropyl, n-propyl, n-butyl, 1-methyl-propyl, isobutyl, tert-butyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy.

In many embodiments of each subgeneric compound of formula (II) mentioned immediately above, R²Or R³May be C₃～C₁₀A branched alkyl group; an alpha-substituted carboxylic acid or a lower alkyl ester of an alpha-substituted carboxylic acid; a 5-or 6-membered aryl or heteroaryl ring, optionally substituted with 1, 2, 3 or 4 substituents selected from hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SCH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy; cyclohexyl optionally substituted with 1, 2 or 3 methyl groups.

When R is¹Is' a C₁-C₈When organic radicals, e.g. C₁-C₈Alkyl (normal or branched), C₁-C₈Alkoxy radical, C₁-C₈Alkoxy-alkyl, C₁-C₈Hydroxy-alkyl, C₁-C₈Amino-alkyl or C₁-C₈When the five-or six-membered aromatic ring-containing aryl or heteroaryl group optionally having a substituent(s), of the formula (IIi)Isoxazole compounds are unexpectedly good as sweet flavor enhancer compounds, and in other embodiments, the R of the isoxazole ring ¹' is hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃SEt, methyl, ethyl, isopropyl, n-propyl, n-butyl, 1-methyl-propyl, isobutyl, tert-butyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy, CH₂OCH₃、CH₂OH、CH₂NH₂、CH₂NHCH₃Or CH₂N(CH₃)₂A group.

In some embodiments, the isoxazole compound of formula (IIi) comprises R²Group R²The group is one of a 1- (1, 2, 3, 4) tetrahydronaphthalene ring or a 2, 3-dihydro-1H-indene ring or their heterocyclic analogs having the formula shown below:

wherein n is 0, 1, 2 or 3, preferably 1 or 2, and R²' may each be bonded to an aromatic or non-aromatic ring and is independently selected from hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SCH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy; this is described above in relation to the general amide compounds of formula (I). In its use as sweet taste enhancer, comprising a bicyclic ring R as described above²The compounds of the formula (IIa-i) of the radicals generally preferably comprise at least enantiomeric per-isomersThe amount of "R" in the optically active configuration described below.

In contrast, when having a bicyclic ring R such as above ²When the compounds of formula (IIa-i) of the group are used as "umami" flavourings or as agents for enhancing the umami taste of MSG, it has been found that use of bicyclic indanyl or tetrahydronaphthyl R comprising the relative "S" configuration as exemplified below²The radicals are advantageously:

the subgenus of aromatic or heteroaromatic amide compounds of formula (II) described immediately above contain many excellent agonists of the T1R1/T1R3 savory ("umami") taste receptor and/or T1R2/T1R3 sweet taste receptor at micromolar or lower, very low amide compound concentrations and are capable of inducing a significant perception of savory flavor in humans and/or can be used as a taste enhancer to enhance the savory flavor of MSG or to significantly enhance the potency of a variety of known sweeteners, particularly carbohydrate sweeteners.

Thus, as described elsewhere herein, many of the aromatic or heteroaromatic amide compounds of formula (II) can be used as savory or sweet flavoring agents or savory or sweet taste enhancers to produce taste-modified edible or pharmaceutical compositions when contacted with various edible articles and/or compositions or precursors thereof.

In another subgenus of compounds of formula (I), the amide compound has formula (III):

wherein a comprises a 5-or 6-membered aryl or heteroaryl ring; m is 0, 1, 2, 3 or 4; r ¹' independently of each other are selected from alkyl, alkoxy-alkyl, hydroxyalkyl, OH, CN, CO₂H、CHO、COR⁶、CO₂R⁶、SH、SR⁶Halogen, alkenyl, cycloalkyl, cycloalkenyl, aryl and heteroaryl, and R⁶Is C₁～C₆An alkyl group; b is a 5 or 6 membered aryl or heteroaryl ring; m' is 0, 1, 2, 3 or 4; r²' is selected from alkyl, alkoxy-alkyl, OH, CN, CO₂H、CHO、COR⁶、CO₂R⁶、SR⁶Halogen, alkenyl, cycloalkyl, cycloalkenyl, aryl and heteroaryl, and R⁶Is C₁～C₆An alkyl group.

In the compounds of formula (III), optionally R¹' and R²' substituents may also be independently selected from hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SCH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.

In the compound of formula (III), both a and B rings comprise a 5-or 6-membered aryl or heteroaryl ring. For the a ring, any of the various embodiments described above for the a ring of the compounds of formula (II), including phenyl and monocyclic and bicyclic heteroaryl, are suitable. In some bicyclic embodiments, the a ring of the compound of formula (III) has the following structure:

wherein R is_1aAnd R_1bIndependently hydrogen or lower alkyl.

In the compounds of formula (III), the B ring is typically a monocyclic 5-or 6-membered aryl or heteroaryl ring, optionally substituted, for example a monocyclic phenyl, pyridyl, furyl, thienyl, pyrrolyl and the like. In some embodiments of the compounds of formula (III) wherein B is phenyl, i.e., embodiments wherein the amide compound is readily derived from an aniline precursor having a substituent, as shown in the following subgenus of compounds (IIIa):

Aniline derivatives of formula (IIIa) have previously appeared to have been synthesized in a number of ways, but it is believed that it was not previously known in the art that these compounds can be used as very effective umami and/or sweet tasting flavorant compounds in concentrations below the millimolar or micromolar range, see for example compound a1 in table 1 below.

Urea compounds

In another subgenus of amide compounds of formula (I), the amide compound is a urea compound having formula (IV):

wherein R is⁷、R⁸And R⁹Each is a hydrocarbon residue or an inorganic residue which may contain one or more heteroatoms and is preferably independently selected from aralkenyl, heteroaralkenyl, aralkyl, heteroaralkyl, alkyl, alkoxy-alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl and heteroaryl, each of which may optionally have a substituent, or R⁷Or R⁸One ofThe radicals can and often are H. It will be appreciated by those of ordinary skill in the art that these urea compounds are subgenera of amide compounds of formula (I) wherein R is⁷And R⁸And the nitrogen atom bonded thereto is equivalent to R of the formula (I) as an organic residue¹Group, and R⁹Is equivalent to R in formula (I) and/or formula (II)²And/or R³And (4) a base.

In some embodiments of the urea compound of formula (IV), R ⁷And R⁸May be taken together to form a heterocyclic or heteroaromatic ring having 5, 6 or 7 ring atoms, optionally having 1, 2 or 3 ring atoms independently selected from hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy substituents. Examples of such urea compounds are of formulae (IVa) and (IVb):

wherein m and n are independently 0, 1, 2 or 3, and R¹' and R²' each independently may be defined in any way as hereinbefore described for the compounds of formula (I). In many embodiments, R¹' and R²' may be each independently selected from fluorine, chlorine, NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SEt、SCH₃Methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups. In some embodiments, n is preferably 0.

However, it has been unexpectedly found that if m is 1, 2 or 3 and one or two small R's of the indoline ring²' substituents are arranged in a certain advantageous geometric configuration, certain embodiments of the urea compounds of formula (IVa) shown above (said urea compounds comprising a dihydro hydrogen)Indole rings) are particularly effective as taste enhancers that enhance the sweet taste of known sweeteners. Thus, in some preferred embodiments, the urea compound of formula (IVa) has the structure shown below:

Wherein m is 1, 2 or 3, and R¹' and R²' may each be independently selected from fluorine, chlorine, bromine, NH₂、NHCH₃、N(CH₃)₂、SEt、SCH₃Methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy, or two R¹' the groups together form a methylene dioxy ring. In preferred embodiments of these compounds, R²' is methyl or methoxy.

In some embodiments, the anilino group of the indoline urea compound has the structure:

wherein R is¹′、R¹"and R¹"' is independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl and methoxy (provided that R is¹′、R¹"and R¹At least one of "") is not hydrogen. Preferably the anilino group has the formula:

wherein R is¹' and R¹"is independently selected from the group consisting of fluoro, chloro, bromo, methyl and methoxy. In certain other preferred embodiments, the anilino group has the formula:

in other embodiments of the urea compounds of formula (IV), R⁷And R⁸With R⁹Independently selected from the group consisting of aralkenyl, heteroaralkenyl, aralkyl, heteroaralkyl, alkyl, alkoxy-alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, and heteroaryl, wherein each carbon-containing group optionally has 1, 2, or 3 carbon-containing groups independently selected from the group consisting of hydrogen, hydroxy, fluoro, chloro, NH, and mixtures thereof ₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy substituents.

In other embodiments of the urea compounds of formula (IV), R⁷And R⁸With R⁹Independently selected from aralkyl, heteroaralkyl, alkyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which may optionally contain 1 to 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, chlorine, and fluorine.

In other embodiments of the urea compounds of formula (IV), R⁷And R⁸With R⁹Independently selected from alkyl, phenyl, cyclohexyl or pyridyl, each of which optionally comprises 1 to 4 substituents independently selected from hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SEt、SCH₃Methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy substituents.

In other embodiments of the urea compounds of formula (IV), R⁷And R⁸At least one group of (a) has one of the following heteroaromatic chemical formulas:

wherein m is 0, 1, 2 or 3, and R¹' are each independently selected from hydrogen, hydroxy, fluorine, chlorine, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy. In this embodiment, R ⁹Preferably C₃～C₁₀Branched alkyl, aralkyl or cycloalkyl radicals, said C₃～C₁₀The branched alkyl, aralkyl or cycloalkyl group optionally has 1, 2 or 3 substituents independently selected from hydrogen, hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy substituents. Amide compounds of formula (II) can be readily synthesized from well-known and/or readily commercially available aryl or heteroaryl carboxylic acid precursors.

In other embodiments of the urea compounds of formula (IV), R⁷And R⁸Is a benzene ring, optionally having 1, 2 or 3 substituents independently selected from hydrogen, hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy substituents. In this embodiment, R⁹Preferably C₃～C₁₀Branched alkyl, aralkyl or cycloalkyl radicals, said C₃～C₁₀The branched alkyl, aralkyl or cycloalkyl group optionally has 1, 2 or 3 substituents independently selected from hydrogen, hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃SEt, methyl, ethyl, isoPropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy.

In other embodiments of the urea compounds of formula (IV), R⁹Is C₃～C₁₀A branched alkyl group. In other embodiments of the urea compounds of formula (IV), R⁹Has the structure:

wherein B is a phenyl, pyridyl, furyl, thienyl, pyrrolyl, cyclopentyl, cyclohexyl or piperidinyl ring, m is 0, 1, 2 or 3, and R is²' are each independently selected from hydrogen, hydroxy, fluorine, chlorine, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy, and R^9aSelected from alkyl, alkoxy-alkyl, alkenyl, cycloalkenyl, cycloalkyl, -R, each containing 1 to 12 carbon atoms⁴OH、-R⁴OR⁵、-R⁴CN、-R⁴CO₂H、-R⁴CO₂R⁵、-R⁴COR⁵、-R⁴SR⁵and-R⁴SO₂R⁵。

It has been found that certain subgenera of the urea compounds of formula (IV) are unexpectedly effective umami flavoring agents and/or MSG flavor enhancers. Related urea compounds have the formula (IVc) shown below:

wherein

i)R⁷Is a benzene ring, which may be selected fromHas 1, 2 or 3 substituents independently selected from hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy substituents, or two of said substituents form a methylenedioxy ring, and

ii)R⁹Is C selected from branched alkyl, aralkyl or cycloalkyl₃-C₁₀Wherein said C is₃-C₁₀The radicals optionally containing 1, 2 or 3 radicals independently selected from hydroxyl, fluorine, chlorine, bromine, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy substituents.

In some embodiments of compounds of formula (IVc), R⁹Has one of the following structures:

wherein R is_9’And R_9”Independently selected from hydroxy, fluorine, chlorine, bromine, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy groups, and preferably R_9’And R_9”Is methyl.

In other embodiments of the umami urea of formula (IVc), R⁹Is C₄-C₈Branched alkyl groups, for example, may include the following structures:

in other embodiments of the umami urea of formula (IVc), R⁹Has one of the following structures:

in some embodiments of the umami urea of formula (IVc), R⁷Has the structure:

wherein R is_7’And R_7”Independently selected from hydroxy, fluorine, chlorine, bromine, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy groups, and in preferred embodiments, R is ⁷Has one of the following structures:

ethanediamide compound

In another subgenus of amide compounds of formula (I), the amide compound is an oxalamide compound having formula (V):

wherein R is¹⁰And R³⁰Each independently selected from hydrocarbon residues which may contain one or more heteroatoms, or preferably, R¹⁰And R³⁰Independently selected from aralkyl, heteroaralkyl, heterocycloalkyl or such groups optionally having substituents, and

R²⁰and R⁴⁰Each independently is H or a hydrocarbon residue which may contain one or more heteroatoms; preferably R²⁰And R⁴⁰Is H or C₁～C₃Alkyl, or C optionally having a substituent₁～C₃An alkyl group. More preferably R²⁰And R⁴⁰Is H. Furthermore, R¹⁰And R³⁰There may be 0, 1, 2, 3 or 4 independently selected from hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SCH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.

In a preferred embodiment of the oxalamide compound of formula (V), R¹⁰And R³⁰Each independently selected from hydrocarbon residues having at least three carbon atoms and optionally 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, halogen or phosphorus, and wherein R is²⁰And R⁴⁰Independently selected from hydrogen and hydrocarbon residues having at least three carbon atoms and optionally from 1 to 10 heteroatoms independently selected from oxygen, nitrogen, sulfur, halogen or phosphorus.

In many preferred embodiments of the oxalamide compounds of formula (V), R²⁰And R⁴⁰Is hydrogen. In this embodiment, R¹⁰And R³⁰May be each independently selected from aralkyl, heteroaralkyl, cycloalkyl-alkyl and heterocycle-alkyl groups each containing 5 to 15 carbon atoms, wherein R is¹⁰And R³⁰Each optionally containing 1 to 4 substituents independently selected from hydrogen, hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SEt、SCH₃Methyl, ethyl, isopropyl, vinyl, trifluoroMethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy substituents.

In many embodiments of the oxalamide compound of formula (V), the oxalamide compound has formula (Va):

wherein A and B are independently aryl, heteroaryl, cycloalkyl or heterocycle each containing 5 to 12 ring atoms; m and n are independently 0, 1, 2, 3 or 4-8; r²⁰And R⁴⁰Is hydrogen, R⁵⁰Is hydrogen or an alkyl group having 1 to 4 carbon atoms or an alkyl residue having a substituent; r⁶⁰Is absent or is C₁～C₅Alkylene or C₁～C₅An alkylene group having a substituent; r⁷⁰And R⁸⁰Independently selected from hydrogen, alkyl, alkoxy-alkyl, OH, SR⁹Halogen, CN, NO₂、CO₂R⁹、COR⁹、CONR⁹R¹⁰、NR⁹R¹⁰、NR⁹COR¹⁰、SOR⁹、SO₂R⁹、SO₂NR⁹R¹⁰、NR⁹SO₂R¹⁰Alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycle; r⁹And R¹⁰Independently selected from H, C ₁～C₆Alkyl radical, C₃～C₆Cycloalkyl and C₁～C₆An alkenyl group.

In a preferred embodiment of the oxalamide compound of formula (Va), R⁶⁰is-CH₂CH₂-a group, a and B are independently selected from phenyl, pyridyl, furyl, thienyl and pyrrole rings, and R⁷⁰And R⁸⁰Independently selected from hydroxy, fluorine, chlorine, NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SEt、SCH₃Methyl, ethyl, isoPropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy.

In some embodiments of the oxalamide compound of formula (Va), a and B are independently a phenyl, pyridyl, furyl, benzofuryl, pyrrolyl, benzothienyl, piperidinyl, cyclopentyl, cyclohexyl, or cycloheptyl ring; m and n are independently 0, 1, 2 or 3; r²⁰And R⁴⁰Is hydrogen; r⁵⁰Is hydrogen or methyl; r⁶⁰Is C₁～C₅Or preferably C₂An alkylene group; r⁷⁰And R⁸⁰Independently selected from hydrogen, hydroxyl, fluorine, chlorine, NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SEt、SCH₃Methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.

In many embodiments of the oxalamide compound of formula (V), the oxalamide compound has formula (Vb):

wherein A is a phenyl, pyridyl, furyl, pyrrolyl, piperidinyl, cyclopentyl, cyclohexyl or cycloheptyl ring; m and n are independently 0, 1, 2 or 3; r ⁵⁰Is hydrogen or methyl; p is 1 or 2; and R is⁷⁰And R⁸⁰Independently selected from hydrogen, hydroxyl, fluorine, chlorine, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy groups, or two R⁷⁰Together form a methylene dioxy ring. In some embodiments of the oxalamide compounds of formula (Vb), the pyridyl-R⁸⁰The group has the structure:

in certain preferred embodiments of the amide compound of formula (V), the oxalamide compound has formula (Vc):

wherein Ar is¹Is a substituted aryl or heteroaryl ring containing 5 to 12 carbon atoms; r⁵⁰Is hydrogen or methyl; n is 0, 1, 2 or 3; r⁸⁰Each independently selected from hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SEt、SCH₃Methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups. In some embodiments of the oxalamide compounds of formula (Vc), Ar¹Is 2-, 3-or 4-monosubstituted phenyl, 2, 4-, 2, 3-, 2, 5-, 2, 6-, 3, 5-or 3, 6-disubstituted phenyl, 3-alkyl-4-substituted phenyl, trisubstituted phenyl, wherein the substituents are independently selected from hydrogen, hydroxy, fluorine, chlorine, NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SEt、SCH₃Methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy groups, or two adjacent substituents together form a methylenedioxy ring on the phenyl ring. In some embodiments of the oxalamide compounds of formula (Vc), Ar ¹Is a substituted heteroaromatic ring containing 5 to 12 carbon atoms, wherein the substituents are independently selected from hydrogen, hydroxyl, fluorine, chlorine, NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SEt、SCH₃Methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.

In certain preferred embodiments of the amide compound of formula (V), the oxalamide compound has formula (Vd):

wherein A is an aryl or heteroaryl ring having a substituent group containing 5 to 12 carbon atoms; r⁵⁰Is hydrogen or methyl; n is 0, 1, 2 or 3; r⁸⁰Each independently selected from hydrogen, hydroxy, fluorine, chlorine, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy. Preferably, a is a phenyl, pyridyl, furyl, pyrrolyl, piperidinyl, cyclopentyl, cyclohexyl or cycloheptyl ring, a optionally having 1, 2 or 3 rings independently selected from hydrogen, hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.

In certain preferred embodiments of the amide compound of formula (V), the oxalamide compound has formula (Ve):

Wherein m and n are independently 0, 1, 2 or 3; r⁷⁰And R⁸⁰Independently selected from hydrogen, alkyl, alkoxy-alkyl, OH, SR⁹Halogen, CN, NO₂、CO₂R⁹、COR⁹、CONR⁹R¹⁰、NR⁹R¹⁰、NR⁹COR¹⁰、SOR⁹、SO₂R⁹、SO₂NR⁹R¹⁰、NR⁹SO₂R¹⁰Alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycle; and R is⁹And R¹⁰Independently selected from H, C₁～C₆Alkyl radical, C₃～C₆Cycloalkyl and C₁～C₆An alkenyl group. Preferably, R is⁷⁰And R⁸⁰Independently selected from hydrogen, hydroxyl, fluorine, chlorine, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy. Preference is given to pyridyl-R of oxalamide compounds of the formula (Ve)⁸⁰The group has the following structure:

examination of the attached examples below will note that the oxalamide compounds of formulas (Ve) to (Ve) are excellent agonists of the T1R1/T1R3 savory ("umami") taste receptor at very low concentrations below the micromolar level, can induce a significant perception of savory flavor in humans, and/or can be used as flavor enhancers to enhance the savory flavor of MSG. Thus, the oxalamide compounds of formulae (Vc), (Vd), and (Ve) are useful as savory or savory flavoring agents when contacted with various edible articles and/or compositions, or precursors thereof, as described elsewhere herein.

Acrylamide compound

In another subgenus of amide compounds of formula (I), the amide compound is an acrylamide compound having the formula (VI):

wherein a is a 5-or 6-membered aryl or heteroaryl ring; m is 0, 1, 2, 3 or 4; r¹' independently of each other are selected from alkyl, alkoxy-alkyl, OH, CN, CO₂H、CO₂R⁶、CHO、COR⁶、SR⁶Halogen, alkenyl, cycloalkyl, cycloalkenyl, aryl and heteroaryl, and R²R which may be an amide of formula (I) as defined above²Any of the various embodiments of (1).

In some acrylamide compounds of formula (VI), A is a phenyl ring and m is 1, 2, 3, or 4, or preferably m is 1 or 2, and R is¹' may be independently selected from hydrogen, hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SEt、SCH₃Methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups. In some acrylamide compounds of formula (VI), R²Is C₃～C₁₀Alkyl or lower alkyl esters of alpha-substituted carboxylic acids.

Edible or medicinal compounds

Many of the amide compounds of formula (I), or a multiple-enumerated subgenus thereof, contain acidic or basic groups such that, depending on the acidic or basic ("pH") of the edible or pharmaceutical composition in which they are formulated, they may be present as salts, preferably edible (i.e., labeled as generally recognized as safe, or GRAS) or pharmaceutically acceptable salts, many of which have been identified by the Federal Food and Drug Administration.

Amide compounds of formula (I) having an acidic group such as a carboxylic acid tend to exist in solution (at near neutral physiological pH) as anionic carboxylate salts, and thus in preferred embodiments have associated edible and/or pharmaceutically acceptable cations, many of which are known to those of ordinary skill in the art. The edible or medicinal cationThe cation includes alkali metal cation (lithium, sodium and potassium cation), alkaline earth metal cation (magnesium, calcium, etc.) or ammonium (NH)₄)⁺Or an organically substituted ammonium cation such as (R-NH)₃)⁺A cation.

Amide compounds of formula (I) having basic substituents such as amino or nitrogen-containing heterocyclic groups tend to exist in solution (at near neutral physiological pH, or typically acidic pH in many food products) as cationic ammonium groups and thus in preferred embodiments have associated edible or pharmaceutically acceptable anions, many of which are known to those of ordinary skill in the art. The edible or pharmaceutically acceptable anionic groups include anionic forms of various carboxylic acids (acetate, citrate, tartrate, anionic salts of fatty acids, etc.), halides (particularly fluorides or chlorides), nitrates, and the like.

The amide compounds of formula (I) and each subgenus thereof should preferably be edible, i.e. considered suitable for consumption in food or beverages, and also pharmaceutically acceptable. A typical method of proving a Flavor compound as an edible compound is to test and/or evaluate the compound by the specialist group of the american Association of Flavors and Extracts Manufacturers (FEMA) and declare it "generally recognized as safe (" GRAS "). The FEMA/GRAS evaluation method for flavor compounds is complex but well known to those of ordinary skill in the art of Food production, and is discussed by Smith et al in an article entitled "GRAS flavor sustances 21" (Food Technology, 57(5), pages 46-59, month 5 2003), the entire contents of which are incorporated herein by reference.

When evaluated by the FEMA/GRAS method, the rats are typically fed with the novel flavor compound for at least about 90 days at a concentration that is 100-fold or 1000-fold or even higher than the maximum allowable concentration of the compound suggested in a particular classification of food to be approved to test any adverse toxic effects of the novel flavor compound on laboratory rats. For example, these tests of the amide compounds of the present invention may include combining the amide compound with rat chow, feeding laboratory rats such as Crl: CD (SD) IGS BR rats for 90 days at a concentration of about 100 mg/kg body weight/day, then killing the rats and evaluating the rats by various medical testing procedures to demonstrate that the amide compound of formula (I) does not have an adverse toxic effect on the rats.

Compounds of the invention as savory or sweet taste enhancers

As described above, the amide compounds of formula (I) and their respective subgenuses and species of compounds are useful as savory or sweet flavor compounds or flavor modifiers for edible or pharmaceutical products. It is apparent from the teachings and examples herein that many of the compounds of formula (I) are agonists of the hT1R1/hT1R3 "savory" receptor or hT1R2/hT1R3 sweet receptor at least relatively high concentrations of the amide compound, and thus many of the amide compounds of formula (I) may have utility as savory or sweet flavoring or taste enhancers themselves, at least at relatively high concentrations.

However, it is preferred to use as little of the artificial flavour as possible to minimise the cost and any undesirable health side effects of administering the compound of formula (I) at high concentration levels. Thus, there is a need to test the efficacy of compounds of formula (I) as taste receptor agonists at lower concentration levels to identify the best and most effective amide compounds among the compounds of formula (I). As disclosed in WO03/001876 and US 2003-0232407A1 and described below, there are currently experimental methods for measuring agonist activity of compounds at hT1R1/hT1R3 "savory" receptors and hT1R2/hT1R3 sweet taste receptors. The measurement method generally measures "EC ₅₀", i.e., the concentration at which the compound causes 50% activation of the relevant receptor.

Preferably, the amide compounds of formula (I) as savory taste modifiers have an EC of less than about 10 μ M at the hT1R1/hT1R3 receptor₅₀. More preferably, the amide compounds have an EC of less than about 5. mu.M, 3. mu.M, 2. mu.M, 1. mu.M or 0.5. mu.M for the hT1R1/hT1R3 receptor₅₀。

Preferably, the amide compounds of formula (I) as sweetness modifiers or sweetness enhancers have an EC of less than about 10 μ M at the hT1R2/hT1R3 receptor₅₀. More preferably, the amide compounds have an EC of less than about 5. mu.M, 3. mu.M, 2. mu.M, 1. mu.M or 0.5. mu.M for the hT1R2/hT1R3 receptor₅₀。

In some embodiments, the amide compound of formula (I) is a savory modulator or flavor enhancer that modulates or enhances the agonist activity of monosodium glutamate to the hT1R1/hT1R3 receptor. Hereinafter, the method for obtaining the so-called EC will be described₅₀Specific assay method, i.e. dissolving a compound of formula (I) in water containing MSG and measuring the extent to which the amide compound reduces the amount of MSG required to activate 50% of the available hT1R1/hT1R3 receptors. Preferably, the amide compound of formula (I) results in an apparent EC of monosodium glutamate for hT1R1/hT1R3 receptors expressed in the HEK 293-G.alpha.15 cell line when dissolved in an aqueous solution comprising about 1. mu.M of the amide compound ₅₀By at least 50%, i.e., the amide compound has an EC of at least 2.0₅₀Or preferably 3.0, 5.0 or 7.0.

Although no specific EC has been developed for sweet taste enhancers₅₀Compared to analytical methods, it is believed that amide compounds of formula (I) (more specifically, many amides of formula (II)) can modulate the binding of hT1R2/hT1R3 receptors by known sweeteners such as sucrose, fructose, glucose, erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, known natural terpenes, flavonoids or protein sweeteners, aspartame, saccharin, acesulfame, cyclamate, sucralose, alitame, or erythritol. One of ordinary skill in the art can readily develop appropriate assays for such sweetness-enhancing properties by using appropriate hT1R2/hT1R3 receptor expressing cell lines.

The above identification analysis is useful in identifying the compounds of formula (I) which are most effective for savory and/or sweet taste improving or flavour enhancing properties, and the results of the analysis are believed to correlate well with the actual savory or sweet taste sensation in animals or humans, but ultimately the results of the analysis, at least the results of the analysis of the most effective compounds of formula (I), can be confirmed by human taste testing. The human taste test experiment can be well quantified and controlled by tasting the candidate compound in an aqueous solution and comparing it to a blank aqueous solution, or alternatively by tasting the amide compound of the invention in an actual edible composition.

Thus, to identify savory flavor modifiers or improvers or flavor enhancers that are more effective for MSG savory flavor in a comestible or medicinal composition, the aqueous solution comprising a savory flavor modulating amount of an amide compound should have a savory flavor as determined by most of a taste tester panel of at least 8 people.

Accordingly, in order to identify a more effective savory flavor enhancer of formula (I), an aqueous solution comprising a savory flavor modulating amount of an amide compound of formula (I) and 12mM monosodium glutamate should have an increased savory flavor as determined by most of a taste tester panel of at least 8 people compared to a control aqueous solution comprising 12mM monosodium glutamate. Preferably, in order to identify a more potent savory taste enhancer, an aqueous solution comprising a savory taste modulating amount (preferably about 30, 10, 5 or 2ppm) of an amide compound of formula (I) and 12mM monosodium glutamate should have an increased savory taste as determined by most of at least 8 people in a taste tester panel compared to a control aqueous solution comprising 12mM monosodium glutamate and 100 μ M inosinic acid.

Similar human taste testing methods can be used to identify which of the compounds of formula (I) are the more potent sweet flavoring or sweet taste enhancer. A preferred sweet taste modifier of formula (I) is identified when the modified comestible or medicinal product has a sweeter taste, as determined by most of a taste tester panel of at least 8 people, than a control comestible or medicinal product that does not contain the amide compound.

Preferred sweet taste enhancers of formula (I) are identified when an aqueous solution comprising a sweet taste-modifying amount of a known sweetener selected from the group consisting of sucrose, fructose, glucose, erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, known natural terpenoids, flavonoid or protein sweeteners, aspartame, saccharin, acesulfame k, cyclamate, sucralose, and alitame has a sweeter taste as determined by most of a taste tester panel of at least 8 people when compared to a control aqueous solution comprising a sweet taste-modifying amount of a known sweetener selected from the group consisting of sucrose, fructose, glucose, erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, known natural terpenoids, flavonoid or protein sweeteners, aspartame. In this taste test experiment, sucrose is preferably present at a concentration of about 6g/100ml, a 50: 50 mixture of glucose and fructose is preferably present at a concentration of about 6g/100ml, aspartame is preferably present at a concentration of about 1.6mM, acesulfame K is preferably present at a concentration of about 1.5mM, cyclamate is preferably present at a concentration of about 10mM, sucralose is preferably present at a concentration of about 0.4mM, or alitame is preferably present at a concentration of about 0.2 mM.

Preparation of edible compositions using compounds of formula (I)

Flavors, flavor modifiers, flavoring agents, taste enhancers, savory ("umami") flavoring agents and/or flavor enhancers, compounds of formula (I) and its various subgeneric compounds and various compounds can be used in foods, beverages and pharmaceutical compositions in which savory or sweet compounds are typically used. These compositions include compositions for human and animal consumption. This includes foods consumed by agricultural animals, pets and zoo animals.

Each class, subclass, and variety of such edible compositions are well known to those of ordinary skill in the art of the preparation and sale of edible compositions (i.e., edible foods or beverages, or precursors or flavor modifiers thereof), and in an attempt to prepare and sell a wide variety of such compositions, those edible compositions may be referred to using terms well known and recognized in the art. A list of such terms in the art is set forth below whereby it is expressly contemplated that each subgenus of compounds of formula (I) and each compound, individually or in reasonable combinations or mixtures thereof, may be used to modify or enhance the savory and/or sweet taste of the edible compositions set forth below:

one or more confectionery products, chocolate candies, chocolate tablets, countlines, bagged sellinines/softlines, boxed assorted chocolates, standard boxed assorted chocolates, kinked packaged mini chocolates, seasonal chocolates, toy-bearing chocolates, alfajors, other chocolate confections, mints, standard mints, hard candies (boiled sweet), lozenges, chewing gums, gummies, fudge and gummies, taffy, caramel and nougat, medicated candies, lollipops, licorice, other sugar confections, chewing gum (chewing gum), sugared chewing gum, sugarless chewing gum, functional chewing gum, bubble gum, bread, packaged/supplied bread, bulk/hand (artissanal) bread, pastry, biscuits, packaged/supplied cakes, hand cake, cookie, cake, cookie, coated with chocolate, sugar, functional gum, and other confectionery, Sandwich biscuit, filled biscuit, savory biscuit and cracker, bread substitute, breakfast cereal, ready-to-eat (RTE) cereal, breakfast cereal for home, slice, breakfast milk (muesli), other ready-to-eat cereal, breakfast cereal for children, hot cereal, ice cream, impule ice cream, single cream ice cream, single water ice cream, multi-pack ice cream, combined water ice cream, external cream ice cream, after meal ice cream dessert, bulk ice cream, external water ice cream, frozen yogurt, handmade ice cream, dairy product, milk, fresh/sterilized (pasteurized) milk, whole fresh/sterilized milk, semi-skimmed fresh/sterilized milk, normal temperature shelf/ultra high temperature sterilized milk, whole normal temperature shelf life/ultra high temperature sterilized milk, Semi-skimmed ambient/ultra-high temperature sterilized milk, nonfat ambient/ultra-high temperature sterilized milk, goat milk, concentrated/condensed milk, regular concentrated/condensed milk, flavored, functional and other milk concentrates, flavored milk beverages, plain milk flavored milk beverages, fruit juice flavored milk beverages, soy milk, yogurt beverages, fermented milk beverages, cafe e butter, milk powder, flavored milk powder beverages, cream, cheese, processed cheese, spreadable processed cheese, non-spreadable processed cheese, unprocessed cheese, spreadable unprocessed cheese, hard cheese, packaged hard cheese, bulk hard cheese, yogurt, regular/natural yogurt, flavored yogurt, fruit yogurt, probiotic (probiotic) yogurt, beverage yogurt, regular drinking yogurt, probiotic (probiotic) yogurt beverages, frozen and shelf-stable dessert, Cream desserts, soy desserts, frozen snacks, salubrious cheeses (fromage frais and quark), regular salubrious cheeses, flavored salubrious cheeses, savory salubrious cheeses, desserts and savory desserts, fruit desserts, cracker/crispies, extruded desserts, tortillas/corn crackers, popcorn, pretzels, nut desserts, other sweet and savory desserts, snack bars, granola bars, breakfast bars, energy bars, fruit bars, other snack bars, meal substitutes, snacks, rehabilitation beverages, ready-to-eat meals, canned ready-to-eat meals, frozen ready-to-eat meals, dry ready-to-eat meals, snack bars, frozen pizza, soups, canned purees, dry soup powders, instant soup powders, quick-frozen soups, ultra-high temperature sterilized soups, frozen soups, edible batters, canned pasta, frozen soups, Dried pasta, quick frozen/fresh pasta, noodles, plain noodles, instant noodles, cup/bowl instant noodles, bagged instant noodles, quick frozen noodles, snack noodles, canned foods, canned meat and meat products, canned fish/seafood, canned vegetables, canned tomatoes, canned beans, canned fruits, canned ready meals, canned soups, canned pasta, other canned foods, frozen processed red meat, frozen processed poultry, frozen processed fish/seafood, frozen processed vegetables, frozen meat substitutes, frozen potatoes, baked potato chips, other baked potato products, non-baked frozen potatoes, frozen baked products, frozen desserts, frozen ready meals, frozen pizzas, frozen soups, frozen noodles, other frozen foods, dried foods, assorted snacks, dried ready meals, dried soup meals, instant soup powders, Dry pasta, regular noodles, instant noodles, cup/bowl instant noodles, bagged instant noodles, quick frozen food, quick frozen processed meat, quick frozen fish/seafood products, quick frozen processed fish, quick frozen packaged fish (chicken coated fish), quick frozen smoked fish, quick frozen lunch set, quick frozen ready-to-eat meals, quick frozen pizza, quick frozen soups, quick frozen/fresh pasta, quick frozen noodles, oils and fats, olive oil, vegetable and seed oils, cooking fats, butter, margarine, spreadable fats, functional spreadable fats, soy sauce, condiments and condiments, tomato paste and puree, bouillon/concentrated solid soup bases, gravy pellets, liquid stock and fonds, vanilla and aroma, fermented sauces, soy sauce, pasta sauce, wet sauce, sauce/powder mix, sauce mix, sauce, mayonnaise, regular mayonnaise, mustard, salad dressings, regular salad dressings, low fat salad dressings, savoury tart sauces (vinaigrettes), dips, salted foods, other sauces, dressings and dressings, baby foods, formula powders, standard formula powders, follow-on formula powders, toddler formula powders, hypoallergenic formula powders, refined baby foods, dried baby foods, other baby foods, spreads, jams and preserves, honey, chocolate spreads, nut spreads and yeast spreads.

Preferably, the compounds of formula (I) are used to modify or enhance the savory or sweet taste of one or more of the subgenera of the following edible compositions: confectionery, bakery products, ice creams, dairy products, sweet and salty snacks, snack bars, meal replacers, ready meals, soups, pasta, noodles, canned foods, frozen foods, dry foods, quick frozen foods, fats and oils, baby foods or spreads, or mixtures thereof.

Generally, ingestible compositions comprising a sufficient amount of at least one compound within the scope of formula (I) or each subgenus thereof described above can be prepared to produce a composition having a desired flavor or taste profile, such as a "savory" or "sweet" taste profile.

One or more compounds of formula (I) in at least a savory flavor modulator amount, a sweet flavor modulator amount, a savory flavor enhancer amount, or a sweet enhancing amount can be added to the food or pharmaceutical product, typically in the optional presence of a savory flavor such as MSG, or a known sweetener, such that the food or pharmaceutical product with improved savory or sweet taste has an increased savory and/or sweet taste as compared to a food or pharmaceutical product prepared without the amide compound, as determined by methods described elsewhere herein, typically by a human or animal, or in the case of formulation testing, by a majority of a panel of at least 8 taste testers.

The concentration of savory flavoring or sweet flavoring agents required to modulate or improve the flavor of a food or pharmaceutical product or composition will, of course, vary depending upon a number of variables, including the particular type of ingestible composition, what known savory or sweet compounds are present and their concentrations, and the effect of a particular compound on the savory compound. Note that an important application of the compounds of formula (I) is for modulating (inducing, enhancing or inhibiting) the savory taste or other taste characteristics of other natural or synthetic savory flavoring agents, such as MSG. It is generally desirable that the concentration of the amide compound of formula (I) be in a wide and low range, i.e., from about 0.001ppm to about 100ppm, or a narrower alternative range, from about 0.1ppm to about 10ppm, from about 0.01ppm to about 30ppm, from about 0.05ppm to about 15ppm, from about 0.1ppm to about 5ppm, or from about 0.1ppm to about 3 ppm. In many embodiments, MSG will be present at a concentration of at least about 10ppm, or preferably 100 or 1000 ppm.

Examples of foods and beverages to which the compounds of the present invention are added include, for example, Wet soups (Wet Soup Category), Dehydrated and cooked foods (Dehydrated and Culinary foods), beverages (juice Food Category), Frozen foods (freezer foods), Snack foods (Snake Food Category), and seasonings or seasoning mixtures.

"wet soups" refers to wet/liquid soups, including frozen soups, without regard to concentration or content. For purposes of this definition, soup refers to food prepared by cooking meat, poultry, fish, vegetables, grains, fruits and other ingredients in a liquid, which may include some or all of the visible portion of these ingredients. As a first dish or as a meal entree or as a snack (sipping like a drink), it may be clear (as a broth) or thick (as a potage), mellow, purees or chunky, ready-to-eat, semi-concentrated or concentrated, and may be a hot or cold meal. The soups can be used as ingredients for preparing other dietary ingredients and can range from bouillons (consomm é) to sauces (cream or cheese-like soups).

"dehydrated and cooked food" means: (i) cooking aids, such as: powder, granule, paste, concentrated liquid preparations, including concentrated bouillon, broth and bouillon-like products in pressed cubes, tablets, powder or granulate form, sold as finished product alone or as ingredients, sauces and formulation mixtures within the product, whatever the technology; (ii) dietary solution preparations, such as: dehydrated and frozen dry soups including dehydrated soup mix, dehydrated instant soup mix, dehydrated ready-to-cook soup, dehydrated or ambient preparations of prepared dishes, meals and separately provided entrees (including pasta, potato and rice in dishes); and (iii) dietary supplements, such as: seasonings, vinegars, salad dressings, salad toppings, dips, breading (breading), custard batter, shelf-stable spreads, barbecue sauces, liquid formulation mixes, concentrates, sauces or sauce mixes, including formulation mixes for salad, which are sold as finished products or as ingredients within products, which may be dehydrated, liquid or frozen.

"beverages" refers to beverages, beverage mixes, and concentrates, including but not limited to alcoholic and non-alcoholic, ready-to-drink, and dry powdered beverages.

Other examples of foods and beverages into which the compounds of the present invention are added include, for example, carbonated beverages and non-carbonated beverages such as soda water, fruit or vegetable juices, alcoholic beverages, and non-alcoholic beverages; confectionery products such as cakes, biscuits, pies, candies, chewing gum, jellies, ice creams, sorbets, puddings, jams, jellies, salad dressings, condiments, breakfast foods such as cereals, canned fruits and fruit sauces, etc.

Furthermore, the compounds can be used in flavouring preparations which can be added to foods and beverages. Preferably, the composition will include other flavour or taste modifiers such as savoury flavours.

Method for modulating the taste of a food or pharmaceutical composition

In many embodiments, the present invention relates to a method of modulating the savory or sweet taste of a comestible or medicinal product, comprising:

a) providing at least one food or pharmaceutical product, or one or more precursors thereof, and

b) combining the food or pharmaceutical product or one or more precursors thereof with at least a savory flavor modulating sweet taste modulating amount of at least one non-naturally occurring amide compound or an edible salt of the amide compound to form a modulated food or pharmaceutical product;

Wherein the amide compound has the formula:

wherein the amide compound is an amide of formula (I), or any of the subgenera or compounds of the amide described herein, wherein R is¹、R²And R³Can be defined in a number of ways as described above. Examples of such methods include, but are not limited to, the methods specifically recited below.

In some exemplary embodiments, the present invention relates to a method for enhancing the sweetness of a comestible or medicinal product comprising:

a) providing at least one food or pharmaceutical product, or one or more precursors thereof, and

b) combining the food or pharmaceutical product or one or more precursors thereof with at least a sweetness modulating amount of at least one non-naturally occurring amide compound or edible salt of the amide compound to form a modulated food or pharmaceutical product;

wherein the amide compound has the formula:

wherein A is an aryl or heteroaryl ring having 3 to 12 ring carbon atoms;

m is 0, 1, 2, 3 or 4;

R¹' each is independently selected from C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₁-C₄Haloalkoxy, C₁-C₄Alkoxy radical, C₁-C₄Alkoxy-alkyl, C₁-C₄Hydroxy-alkyl, OH, NH ₂、NHR⁶、NR⁶ ₂、CN、CO₂H、CO₂R⁶、CHO、COR⁶、SH、SR⁶And halogen, wherein R⁶Is C₁-C₄An alkyl group;

R²having the formula

Wherein n is 0, 1, 2 or 3, and R²' may each be bonded to an aromatic or non-aromatic ring and is independently selected from hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、CO₂CH₃、SEt、SCH₃Methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy groupsAnd (4) a base.

In a related but novel embodiment, the present invention is directed to a method for enhancing the sweetness of a comestible or medicinal product comprising:

a) providing at least one food or pharmaceutical product, or one or more precursors thereof, and

b) combining the food or pharmaceutical product or one or more precursors thereof with at least one aromatic or heteroaromatic amide compound or an edible salt of such an amide compound to form a prepared food or pharmaceutical product comprising at least about 0.001ppm of the amide compound;

wherein the amide compound has the formula:

wherein A is a five or six membered aryl or heteroaryl ring;

m is 1, 2 or 3;

R¹' each is independently selected from hydroxyl, NH₂SH, halogen or C₁-C₈An organic group;

R²is a group having the structure

Wherein R is²Comprising an enantiomeric excess of a given optical configuration, n is 1, 2 or 3, R ²' may each be independently of R²Is bonded to an aromatic or non-aromatic ring, and R²' each is independently selected from hydroxyl, NH₂SH, halogen, C₁-C₄An organic radical, and

wherein the prepared edible or pharmaceutical product further comprises at least a sweet flavoring amount of one or more natural, semi-synthetic or synthetic sweet flavoring agents or mixtures thereof.

In these processes, R²Preferably having one of the following structures:

wherein R is²' each is independently selected from hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy or trifluoromethoxy. Furthermore, in these methods, the a group is preferably phenyl, or has the formula:

wherein R is¹' is hydrogen, hydroxy, NH₂SH, halogen, C₁-C₈Alkyl radical, C₁-C₈Haloalkyl, C₁-C₈Haloalkoxy, C₁-C₈Alkoxy radical, C₁-C₈Alkoxy-alkyl, C₁-C₈Hydroxy-alkyl, OH, NH₂、NHR⁶、NR⁶ ₂、CN、CO₂H、CO₂R⁶、CHO、COR⁶、SH、SR⁶And halogen, wherein R⁶Is C₁-C₄An alkyl group. In other embodiments, R¹Is' a C₁-C₈An alkyl group. In another embodiment, R of the isoxazole ring¹' is hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃SEt, methyl, ethyl, isopropyl, n-propyl, n-butyl, 1-methyl-propyl, isobutyl, tert-butyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, CH ₂OCH₃、CH₂OH、CH₂NH₂、CH₂NHCH₃Or CH₂N(CH₃)₂。

In a further embodiment, the present invention relates to a method of increasing the sweetness of a comestible or medicinal product comprising:

a) providing at least one food or pharmaceutical product, or one or more precursors thereof, and

b) combining the food or pharmaceutical product or one or more precursors thereof with at least one heteroaromatic amide compound or an edible salt of such an amide compound to form a package

Conditioned comestible or medicinal product containing at least about 0.001ppm of said amide compound

Article 1;

wherein the amide compound has the following structure:

wherein A is a five or six membered aryl or heteroaryl ring;

m is 0, 1, 2, 3 or 4;

R¹' each is independently selected from hydrogen, hydroxy, NH₂SH, halogen or C₁-C₈An organic group; r²Is a tetrahydroquinolyl or tetrahydroisoquinolyl group having the structure

Wherein n is 1, 2 or 3, R²' may each be independently of R²Is bonded to an aromatic or non-aromatic ring, and R²' each is independently selected from hydrogen, hydroxy, NH₂SH, halogen or C₁-C₄An organic group.

In these processes, wherein R²Preferred are groups having the following structure:

wherein R is²The groups exist in the optical configuration specified in enantiomeric excess.

In a further embodiment, the present invention relates to a method of increasing the sweetness of a comestible or medicinal product comprising:

a) providing at least one food or pharmaceutical product, or one or more precursors thereof, and

b) combining the food or pharmaceutical product or one or more precursors thereof with at least one aromatic or heteroaromatic amide compound or an edible salt of such an amide compound to form a prepared food or pharmaceutical product comprising at least about 0.001ppm of the amide compound;

wherein the amide compound has the following structure:

wherein A is a five or six membered aryl or heteroaryl ring;

m is 0, 1, 2, 3 or 4;

R¹' each is independently selected from hydroxyl, NH₂SH, halogen or C₁-C₄An organic group;

R²is a bicyclic heterocyclic group having the structure

Wherein n is 0, 1, 2 or 3, R²' may each be independently of R²Is bonded to an aromatic or non-aromatic ring, and R²' each is independently selected from hydrogen, hydroxy, NH₂SH, halogen or C₁-C₄Organic radical, X_hIs O, S, SO₂NH or NR_hWherein R is_hIs C₁-C₄An organic group.

In these embodiments, where R is²May preferably have the formula:

wherein R is²' each with R ²The phenyl rings of the radicals being bonded, n is 0, 1 or 2, and R²' each is independently selected from hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy, and R²It may preferably exist in the "R" configuration with an enantiomeric excess, and examples thereof include R specifically listed below²Group (b):

again, in these embodiments, the a group is preferably phenyl, or has the formula:

wherein R is¹' is hydrogen, hydroxy, NH₂SH, halogen, C₁-C₈Alkyl radical, C₁-C₈Haloalkyl, C₁-C₈Haloalkoxy, C₁-C₈Alkoxy radical, C₁-C₈Alkoxy-alkyl, C₁-C₈Hydroxy-alkyl, OH, NH₂、NHR⁶、NR⁶ ₂、CN、CO₂H、CO₂R⁶、CHO、COR⁶、SH、SR⁶And halogen, wherein R⁶Is C₁-C₄An alkyl group. In a further embodiment, R¹Is' a C₁-C₈An alkyl group. In another embodiment, R of the isoxazole ring¹' is hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃SEt, methyl, ethyl, isopropyl, n-propyl, n-butyl, 1-methyl-propyl, isobutyl, tert-butyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, CH₂OCH₃、CH₂OH、CH₂NH₂、CH₂NHCH₃Or CH₂N(CH₃)₂。

In a further embodiment, the present invention relates to a method of enhancing the sweetness of a comestible or medicinal product comprising:

a) Providing at least one food or pharmaceutical product, or one or more precursors thereof, and

b) combining the food or pharmaceutical product or one or more precursors thereof with at least one urea compound or an edible salt of the urea compound to form an improved food or pharmaceutical product comprising at least about 0.001ppm of the urea compound;

c) wherein the improved food or pharmaceutical product further comprises a known natural or artificial sweetener,

wherein the urea compound has the formula:

wherein m is 1, 2 or 3, and R¹' and R²' independently of one another are selected from fluorine, chlorine, bromine, NH₂、NHCH₃、N(CH₃)₂、SEt、SCH₃Methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy, or two R¹' the groups together form a methylene dioxy ring.

In a further embodiment, the present invention relates to a method for enhancing the savory taste of a comestible or medicinal product, comprising:

a) providing at least one food or pharmaceutical product, or one or more precursors thereof, and

b) combining the food or pharmaceutical product or one or more precursors thereof with at least one aromatic or heteroaromatic amide compound or an edible salt of the amide compound in an amount of at least about 0.001ppm to form an improved food or pharmaceutical product, and

c) Wherein the improved food or pharmaceutical product optionally comprises artificially added monosodium glutamate;

wherein the aromatic or heteroaromatic amide compound has the following structure:

wherein A is a five or six membered aryl or heteroaryl ring;

m is 1, 2, 3 or 4;

R¹' each is independently selected from hydrogen, hydroxy, NH₂SH, halogen or C₁-C₈An organic group or a monocyclic aryl or heteroaryl group,

R²is a 1-indanyl group having the structure:

wherein n is 1 or 2, and R²' each may be with R²Is bonded to an aromatic or non-aromatic ring, and R²' each is independently selected from hydrogen, hydroxy, NH₂SH, halogen or C₁-C₄An organic group.

In these embodiments, R²Is an optically active 1-indanyl group having the following structure

Wherein R is²Contains an enantiomeric excess of the specified optical configuration,

and R is²' each with R²Is bonded to the aromatic ring of (b).

In these embodiments, n is preferably 1, and/or R is preferably²' is selected from hydrogen and hydroxylFluorine, chlorine, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy. In these embodiments, the a group is preferably phenyl, exemplified by the following specific structures:

In a further embodiment, the present invention relates to a method for enhancing the savory taste of a comestible or medicinal product, comprising:

a) providing at least one food or pharmaceutical product, or one or more precursors thereof, and

b) combining said food or pharmaceutical product or one or more precursors thereof with at least one urea compound or an edible salt of said urea compound to form an improved food or pharmaceutical product comprising at least about 0.001ppm of said urea compound, and

c) wherein the improved food or pharmaceutical product optionally comprises artificially added monosodium glutamate;

wherein the urea compound has the structure:

and wherein

i)R⁷Is a benzene ring optionally having 1, 2 or 3 substituents independently selected from hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃SEt, methyl, ethyl, isopropyl, ethyleneA substituent of the group trifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy, or two of said substituents forming a methylenedioxy ring, and

ii)R⁹is C selected from branched alkyl, aralkyl or cycloalkyl₃-C₁₀Group wherein said C₃-C₁₀The radicals optionally containing 1, 2 or 3 radicals independently selected from hydroxy, fluoro, chloro, bromo, NH ₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy substituents.

The invention also relates to an improved food or pharmaceutical product made by the above disclosed method.

The present invention also relates to similar processes for the manufacture of edible or pharmaceutical products, well known to those of ordinary skill in the art. The amide compounds of formula (I) and their respective subgeneric compounds can be combined with or administered to a food or pharmaceutical product or precursor thereof in any manner known to chefs, food preparers, or producers of food or pharmaceutical products worldwide. For example, the amide compounds of formula (I) may be dissolved or dispersed in one of a number of edible liquids, solids or other carriers such as water, fruit or vegetable juices, vinegar, marinades, beer, wine, natural water/fat emulsions (e.g., milk or condensed milk), edible oils and shortenings, fatty acids, certain low molecular weight oligomers of propylene glycol, glycerol esters of fatty acids and dispersions or emulsions of these hydrophobic materials in aqueous media, salts such as sodium chloride, vegetable powders, solvents such as ethanol, solid edible diluents such as vegetable powders or flours, and the like, and then combined with precursors of the edible or medicinal products, or applied directly to the edible or medicinal products.

Preparation of amide compounds of formula (I)

The starting materials, particularly the organic carboxylic acids and benzoic acid, isocyanates and various amines, anilines, amino acids, etc., of each structural subgenus and each structural species and their synthetic precursors used to prepare the compounds of the present invention, the amide compounds of formula (I), are generally known compounds or can be prepared by methods known in the literature or can be obtained from a number of sources well known to those of ordinary skill in the art, such as Sigma-Aldrich Corporation of St.Louis, Mo., USA and their subsidiary companies Fluka and Riedel-de Ha ё n, their various other offices worldwide and other well known suppliers, such as Fisher Scientific, TCI America of St.P.F., Chemidca, St.C., Chemzda.C., Chembridge, St.C., Asinex, St.P.Y., SPECS/BIECS, Mambrege Acros, TimTec, Russian, Comgenex, St.Vancisco, Calif., and ASDI Biosciences, New York, Delaware.

It is obvious to the skilled person that the methods for preparing the precursors and the functional groups relating to the compounds claimed herein have been reviewed in the literature. The skilled person, having access to the literature and the disclosure herein, is fully enabled to prepare any desired starting materials and/or claimed compounds. In some of the examples cited below, the starting materials are not readily available commercially and are therefore synthetic, and the synthesis of the starting materials is therefore exemplified.

It is recognized that these operations can be readily performed by those skilled in the art of organic chemistry without further direction, i.e., they can be readily performed within the purview and practice of the skilled artisan. This includes reduction, oxidation, acylation, electrophilic or nucleophilic aromatic substitution, etherification, esterification, saponification, nitration, hydrogenation, reductive amination of carbonyl compounds to their corresponding alcohols, and the like. These procedures are described in standard textbooks, such as March's Advanced Organic chemistry (third edition, 1985, Wiley-Interscience, New York), Feiser and Feiser's Reagents for Organic Synthesis, Carey and Sundberg's Advanced Organic chemistry, and the like, the entire contents of which are incorporated herein by reference for their teachings on methods of Synthesis of Organic compounds.

The skilled person will readily appreciate that certain reactions may be best carried out when other functional groups are masked or protected in the molecule, thereby avoiding any undesirable side reactions and/or improving the reaction yield. The skilled artisan can generally utilize protecting groups to achieve enhanced yields or to avoid undesired reactions. These reactions are found in the literature and are within the knowledge of the skilled worker. Many examples of these operations can be found, for example, in T.Greene and P.Wuts, Protecting group protein Organic Synthesis, third edition, John Wiley & Sons (1999).

The following abbreviations have the indicated meanings:

CH₃CN is acetonitrile

CHCl₃Chloroform ═

DIC is N, N' -diisopropylcarbodiimide

DIPEA ═ diisopropylethylamine

DMAP ═ 4- (dimethylamino) -pyridine

DMF ═ N, N-dimethylformamide

EDCI ═ 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

DCM ═ dichloromethane

ESIMS mass spectrometry

Et₃N-triethylamine

EtOAc ═ ethyl acetate

EtOH ═ ethanol

Fmoc ═ N- (9-fluorenylmethoxycarbonyl)

HCl ═ hydrochloric acid

H₂SO₄Sulfuric acid

HOBt ═ 1-hydroxybenzotriazole

MeOH ═ methanol

MgSO₄Magnesium sulfate ═ magnesium sulfate

NaHCO₃Sodium bicarbonate

NaOH (sodium hydroxide)

Na₂SO₄Sodium ═ sulfate

Ph ═ phenyl

r.t. room temperature

Solid phase organic synthesis of SPOS

THF ═ tetrahydrofuran

TLC ═ thin layer chromatography

Alkyl abbreviations

Me is methyl

Et is ethyl

n-Pr ═ n-propyl

i-Pr ═ isopropyl

n-Bu ═ n-butyl

i-Bu ═ isobutyl

t-Bu ═ tert-butyl

s-Bu ═ sec-butyl

n-Pen ═ n-pentyl

i-Pen ═ isopentyl

n-Hex ═ n-hexyl

i-Hex ═ isohexyl

Abbreviations for Polymer Supported reagents

PS-Trisamine ═ polystyrene-supported tris (2-aminoethyl) amine

PS-NCO ═ polystyrene-supported methyl isocyanates

PS-TsNHNH₂Polystyrene-supported tosylhydrazones

Synthesis method

For the purpose of guidance to the reader, the following equations and examples are provided which represent various methods for preparing the amide compounds disclosed herein. These methods are by way of example only and are not limiting, and it will be apparent to those of ordinary skill in the art that many other methods known in the art can be used to prepare the amide compounds of the various embodiments of the present invention. These methods include in particular solid phase based chemical methods, including combinatorial chemistry.

Amides are generally prepared by the condensation reaction of a carboxylic acid and/or derivative thereof (such as an ester, acid halide, etc.) with a primary or secondary amine in the presence of a dehydrating agent, a coupling agent and/or a suitable catalyst. A large number of suitable starting materials, such as primary and secondary amines, and carboxylic acids and their derivatives, can be readily synthesized by methods known in the literature or are readily commercially available. In some cases, the synthesis of certain amine or carboxylic acid starting materials is as follows.

Reaction scheme 1a

The amide derivative (I) can be prepared, for example, by coupling the acid derivative (II) with the amine (III) in the presence of a coupling agent such as 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride and a base, as shown in scheme 1 a. In method a, a polymer-supported (PS) carbodiimide is used. Method B uses a non-polymer supported carbodiimide.

Alternative Process for the preparation of amides according to reaction 1b

X is halide

The amide derivative (I) is prepared by coupling an acid halide, ester or anhydride (IV) with an amine (III) in the presence of a base as shown in reaction formula 1 b.

Reaction scheme 1c Synthesis of amides by combinatorial permutation

The following methods were used and can be used to synthesize amides in combinatorial arrays.

● acetonitrile was used as the system solvent.

● the amine was weighed into an 8mL vial.

● use Tecan in DCM/CH₃CN (1: 2 from a silo (trough)) dissolved the amine to 100 mM.

● weigh the acid into an 8mL vial.

● use Tecan in DCM/CH₃CN (1: 2 from a silo) dissolved the acid to 110 mM.

● A1.2 mL Greiner plate was preloaded with 30mg of PS-carbodiimide resin using Peli 1400Case Titer plate II. Acetonitrile was used as the system solvent for the synthesis.

● to each well of the composite plate was added 200mL (20mmol, 1 eq.) of the amine.

● to each well of the composite plate was added 200mL (22mmol, 1.1 equiv.) of the acid.

● to each well of the synthesis plate was added 110mL (22mmol, 1.1 equiv.) of HOBt (0.20M in DMF) by an 8-channel pipette.

● the plates were sealed with a cap pad and shaken (normal speed) overnight at room temperature.

● Using the Titer plate Carrier thin-I20 mg/well PS-Trisamine resin was loaded into the synthetic plate. The amount of resin was adjusted based on the load.

● Add 200mL of DCM/CH to the plate₃CN。

● the plates were sealed with foil and shaken (fast) at room temperature overnight.

● used methanol as the system solvent for transfer to the storage plates.

● transfer 150mL to the storage plate and then wash 2 times with 150mL methanol (5 minutes with slow shaking). Transfer was from the top in each well. (needle height-2)

● the plates were dried in Genevac.

● the assay plate (2.5 mM theoretically) was assembled and submitted for analysis.

● dilution plates were assembled based on the results of the analysis.

Reaction scheme 1c preparation of oxalamides

As a general method, an amine is reacted with ethyloxalyl chloride in the presence of a tertiary amine in an organic solvent such as dioxane, acetonitrile, tetrahydrofuran, tetrahydropyran, and dimethylformamide at room temperature for 0.5 to 2 hours. The second amine was then added and the suspension was heated at 80 ℃ overnight using an oil bath or reacted in a microwave reactor at 160 ℃ for 5 minutes. The reaction mixture may be subjected to preparative HPLC, or to aqueous work-up, and the crude product may be readily purified, typically by recrystallization, flash column chromatography or other methods well known to those of ordinary skill in the art, to give pure oxalamide. The yields reported below were not optimized.

Reaction scheme 1d. preparation of Urea

X¹、X²And X³Each independently is an alkyl or alkoxy group.

Equation 2 describes a process for preparing pyrazine derivative (VIII). For example, the reaction of substituted or unsubstituted 2, 3-diaminopropionic acid (V) with 2, 3-diketones (VI) in the presence of a base under heating affords, after acidification, substituted pyrazine-2-carboxylic acids (VII). The acid is condensed with various amines (III) using the conditions shown in equation 1a to produce the desired amides (XIII).

Reaction formula 3

X⁴Is alkyl, halide, alkoxy or thioalkyl

Reaction scheme 3 describes a process for preparing benzofuran derivatives (XII). For example, the reaction of 2-hydroxybenzaldehyde (IX) with diethyl 2-bromo-maleate (X) in the presence of a base under heating provides substituted benzofuran-2-carboxylic acid (XI). The acid is condensed with various amines (III) using the conditions shown in equation 1a to produce the desired amides (XII).

Reaction formula 4

X₅Is H, alkyl, aryl-alkyl, heteroaryl-alkyl radical

X₆Is alkyl, alkoxyalkyl, aralkyl, heteroaralkyl

X is a halide.

Equation 4 describes a process for preparing the alkoxyalkyl amide (XX). In one process, phthalic anhydride (XIII) is heated with amino alcohol (XIV) to give alcohol (XV), which is then reacted with alkyl halide (XVI) in the presence of a base to give alkoxy group (XVII). Treatment of phthalimide (XVII) with hydrazine gives the desired amine (XVIII), which is then further condensed with acid (II) as described in scheme 1a to provide the alkoxyalkyl amide (XX). Alternatively, acid (II) is condensed with amino alcohol (XIV) using the method described in scheme 1a to provide alcohol (XIX), which is further alkylated to give (XX).

Reaction formula 5

X is a halide;

X₇is H, alkyl, alkoxyalkyl, aryl-alkyl, heteroaryl-alkyl;

X₈and X₉Each independently is H, alkyl, alkoxyalkyl, aralkyl, and heteroaralkyl.

Equation 5 describes a process for preparing amido-amides (XXIV). Treatment of the alkyl halide (IV) with an amino acid (XXI) as described in scheme 1b provides the corresponding acid (XXII), which is further condensed with an amine (XXIII) as described in scheme 1a to provide the amidoamide derivative (XXIV).

Reaction formula 6

Equation 6 describes a process for preparing benzoxazole (XXVIII). Aminophenol (XXV) can be condensed with a variety of reagents to form X having a variety of different substituents using methods described in the literature (see, e.g., J.Med. chem.28(1985)1255) and/or by methods cited in examples 39-47₉Benzoxazole (XXVI). The benzoxazole intermediate (XXVI) is then condensed with amine (V) using the method described in scheme 1a to give amide (XXVII). Alternatively, amide (XXVII) may be prepared by first condensing aminophenol (XXV) with amine (V) to give aminophenol intermediate (XXVIII), which is further converted to benzoxazole (XXVII) using a different method described above.

A wide variety of carboxylic acid derivatives, as suitable precursors for the R1 group of the amide compound of formula (I), as well as various subgenus of compounds of formula (I), are readily available by methods known in the art or readily adapted methods. In particular, aryl or heteroaryl carboxylic acid compounds having substituents as precursors of compounds of formula (II) are generally readily commercially available or obtained by using widely known synthetic methods. Similarly, many amine compounds that are suitable precursors to amide compounds of formula (I) are readily commercially available or obtained by known synthetic methods. However, disclosed in the following equations and/or examples is the synthesis of R¹And R²Methods of certain starting building block precursors of the radicals.

Reaction formula 7: preparation of racemic 1, 2, 3, 4-tetrahydronaphthalen-1-amines having substituents

3, 4-dihydronaphthalene-1 (2H) -substituted by treatment with hydroxylamine as shown in reaction formula 7Conversion of a ketone (where independently selected R substituents may be on either ring) to an oxime (XXXII) readily allows the preparation of racemic 1, 2, 3, 4-tetrahydronaphthalen-1-amines (XXXII). In MeOH-NH₃Hydrogenation of oxime in the presence of Ra/Ni, or reduction with various known reducing agents, can readily provide racemic 1, 2, 3, 4-tetrahydronaphthalen-1-amine derivatives (XXXII) having substituents. Racemic indanones having substituents can be readily prepared by a similar reaction sequence to that shown above.

Reaction formula 8: preparation of substituted 3, 4-dihydronaphthalen-1 (2H) -ones

Many dihydronaphthalenones having substituents are readily commercially available or can be prepared using a number of conventional methods, such as those described above.

Reaction formula 9: enantioselective preparation of substituted 1, 2, 3, 4-tetrahydronaphthalen-1-amines

Chiral substituted 1, 2, 3, 4-tetrahydronaphthalen-1-amine derivatives (S enantiomer, or R enantiomer) can be prepared from dihydronaphthalenones such as (XXX) using asymmetric synthesis (see Stalker, R.A., et al, Tetrahedron2002, 58, 4837-4849) as described in scheme 9. Ketones (XXX) are converted into chiral imines (Va or Vb) by condensation with S-or R-phenylglycinol, respectively. The imine is then enantioselectively reduced to an amine using sodium borohydride, followed by oxidative cleavage of a chiral auxiliary to provide the amine in the specified optical configuration with an enantiomeric excess of over 99%.

Reaction formula 10: preparation of substituted isoindolines

Equation 10 describes a process for preparing substituted isoindolines (XXXV) from substituted phthalic anhydrides by treating phthalic anhydride with concentrated ammonia solution to produce substituted phthalimides (see Noyes, w.a., Porter, p.k.org.syn., col.vol.1, 457), followed by reduction of the phthalimides using methylthioborane complex (see Gawley, r.e., Chemburkar, s.r., Smith, a.l., Anklekar, t.v.j.org.chem.1988, 53, 5381).

Reaction formula 11: preparation of substituted quinolines and isoquinolines

A variety of substituted heteroaromatic tetralins can be synthesized from pyridine carboxylic acid (XXXVa-c). The reaction of the carboxylic acid with diethylamine in the presence of HOBt and EDCI provides an activated aromatic amide which can be methylated at the ortho position of the amide upon treatment with s-BuLi, TMEDA and MeI (see Date, M.; Watanabe, M.; Furukawa, S.chem.pharm.Bull.1990, 38, 902-. The methylated diethylamide can then be cyclized to the desired dihydroquinolin-8 (5H) -one or dihydroisoquinolin-5 (6H) -one by treatment with s-BuLi, TMEDA, and ethoxydimethylvinylsilane. The conversion of the ketone to the desired racemic or enantiomerically pure quinolin-8-amine or isoquinolin-5-amine (XVa-c) may be achieved as described in equation 6 or 9.

Reaction formula 12: synthesis of unsubstituted tetrahydroquinolines and tetrahydroisoquinolines

Tetrahydroquinoline or tetrahydroisoquinoline with no substituents can be synthesized from amino-substituted quinoline or isoquinoline precursors as described by McEachem and co-workers (see Skupinska, K.A.; McEachem, E.J.; Skerlj, R.T.; bridge, G.J.J.org.chem.2002, 67, 7890-7893). Acetylation of aminoquinolines or isoquinolines followed by hydrogenation of the cyclohexyl ring in the presence of Adam's catalyst followed by deacetylation can provide racemic aminocyclohexanes which can be resolved by enantioselective acetylation of only the R isomer in the presence of EtOAc using Candida Antarctica Lipase (CALB). Isolation of the R-acetamide from the S-amine followed by deacetylation provides the desired enantiomerically pure S-amine, whereas hydrolysis of the R-acetamide can yield the R-amine (see Skupinska, K.A.; McEachern, E.J.; Baird, I.R.; Skerlj, R.T.; bridge, G.J.J.Org.Chem.2003, 68, 3546-.

Reaction formula 13: r²Synthesis of substituted 1, 2, 3, 4-tetrahydroquinolin-4-amines and 3, 4-dihydro-2H-thiochroman-4-amine precursors of

R²The synthesis of the 1, 2, 3, 4-tetrahydroquinolin-4-amine and 3, 4-dihydro-2H-thiochroman-4-amine precursors of (A) can be accomplished by the Michael addition of aniline (XXXXA) or thiophenol (XXXXB) to acrylic acid (see Ahn, Y.; Cohen, T.J.Org.Chem.1994, 59, 3142-ann, l.g.; arienti, k.l.; marschke, k.b.; davis, r.l.; farmer, l.j.; jones, t.k.bioorg.med.chem.lett.1999, 9, 1335-; kinoshita, s.; munechika, y.; iwamura, t.; watanabe, Sh. -I; kataoka, t.eur.j.org.chem.2003, 4852-. Alkylation of the aminoazone (XXXXia) provides the N-alkylated ketone (XXV), which can be obtained by the method of scheme 7 to give a racemic mixture of the desired amines (XXIVa, XXIVb and XXVI) or by using the method described in scheme 9 to give the desired amines (XXIVa, XXIVb and XXVI) in an enantioselective manner. 2, 3-dihydrothiochroman-4-one (XXXXIb) can be oxidized to the sulfoxide by treatment with a limited amount of dimethyldioxirane, whereas treatment with an excess of the oxidizing agent leads to the formation of the sulfone (cf. Patonay, T.; Adam, W.; Lee vai, A.; P.; n é meth, M.; p, e. -m.; peters, K.J.org.chem.2001, 66, 2275-. The desired enantiomerically pure amines (XXIX and XXX) can be synthesized according to the general scheme of scheme 9.

In view of the above-cited disclosures, teachings and references, all of which are incorporated herein by reference in their entirety, it is well within the ordinary skill of the art of synthetic organic chemistry to prepare the necessary and/or claimed compounds by the methods set forth in the literature and this disclosure.

Measuring the biological Activity of the Compounds of the invention

Cell-based techniques or assays, such as those disclosed in WO 02/064631 and WO 03/001876 and U.S. Pat. No. 2003-0232407A1, can be used to preliminarily screen various classes of compounds for agonist or antagonist activity of T1R1/T1R3 "savory" taste receptors or T1R2/T1R3 "sweet" taste receptors that have been expressed in appropriate cell lines. Once the initial "hits" of the amide compound is obtained in the cell line, the same assay and cell and/or receptor-specific based assays can be used as analytical tools to measure the ability of the compounds of formula (I) to enhance the savory taste of MSG or the sweet taste of known sweeteners such as sucrose, fructose, and in combination with a provisional human taste test for the compound of high interest, to provide experimental data to guide an iterative process of synthesis and testing of structural variants of the amide compound to design, test and identify species and genera of compounds with enhanced and optimized levels of desired biological activity.

Many embodiments of the present invention relate to the identification of specific compounds and classes of amide compounds of formula (I) that modulate (increase or decrease) the activity of T1R1/T1R3 (preferably hT1R1/hT1R3) savory taste receptors (umami receptors), either alone or in combination with other compounds that activate hT1R1/hT1R3, such as MSG. In particular, in many embodiments, the present invention relates to amide compounds of formula (I) capable of modulating the activity of hT1R1/hT1R3 (human umami receptor) in vivo and/or in vitro. In another aspect, the invention relates to compounds that, when added to a comestible or medicinal product or composition, can modulate the salty (umami) taste of humans, either alone or in combination with other compounds or flavoring agents.

Many embodiments of the present invention relate to the identification of classes and/or species of amide compounds of formula (I) that modulate (increase or decrease) the activity of T1R2/T1R3 (preferably hT1R2/hT1R3) sweet taste receptors, either alone or in combination with other compounds that activate hT1R2/hT1R3 or induce sweet taste, such as sucrose, glucose or fructose. In particular, the present invention relates to amide compounds of formula (I) capable of modulating the activity of hT1R2/hT1R3 (human sweet taste receptor) in vivo and/or in vitro. In another aspect, the invention relates to compounds that, when added to a comestible or medicinal product or composition, alone or in combination with other compounds or flavor compositions, modulate the sweet taste of humans.

In some embodiments of the present invention, it has been surprisingly found that at least some of the amide compounds of formula (I), when added to a comestible or medicinal product or a comestible or medicinal composition, can modulate human perception of umami and sweet taste simultaneously, alone or in combination with other compounds or flavor compositions.

In vitro hT1R1/hT1R3 umami taste receptor activation assay

To identify new savory flavoring agents and flavor enhancers, including compounds with savory agonist and flavor enhancer activity (dual activity), compounds of formula (I) were screened in both primary and secondary assays, including compound dose response and enhancement assays. In a preliminary screening for the potential ability to modulate umami taste, amide compounds of formula (I) that are themselves either savoury flavours or flavour enhancers for MSG are identified and their fraction of activity is given as a percentage (%) of the maximum MSG intensity. In compound dose response, EC was calculated₅₀To reflect the potency of the compounds as savory agonists or taste enhancers.

Compounds with savoury taste properties are identified using derivatives of the HEK293 Cell line which stably express G.alpha.15 and hT1R1/hT1R3 under induction of an inducible promoter (see, e.g., Chandrashikar et al, Cell (2000) 100: 703-711).

The compounds encompassed herein were initially selected based on their activity on hT1R1/hT1R3-HEK 293-G.alpha.15 cell lines. Activity was determined using automated fluorescence imaging analysis on a FLIPR instrument (fluorescence intensity plate reader, molecular devices, sandivol, ca, usa) (referred to as FLIPR assay). Cells from one clone, designated clone I-17, were seeded into 384-well plates (approximately 48,000 cells/well) in medium containing Dulbecco's modified Ill's medium (DMEM) supplemented with GlutaMAX (Invitrogen, Carlsbad, Calif.), 10% dialyzed fetal bovine serum (Invitrogen, Carlsbad, Calif., U.S.), 100 units/ml penicillin G, 100 μ G/ml streptomycin (Invitrogen, Carlsbad, Calif.), and 60pM of mifepristone (mifepristone) to induce expression of hT1R1/hT1R3 (see WO03/001876A 2). I-17 cells were grown at 37 ℃ for 48 hours. Then 4 μ M of calcium dye Fluo-3AM (Molecular Probes, Uygur. Oreg.) in phosphate buffered saline (D-PBS) (Invitrogen, Calsbad, Calif.) was added to the I-17 cells for 1.5 hours at room temperature. After displacement with 25 μ L D-PBS, stimulation was performed in a FLIPR instrument at room temperature by adding 25 μ L D-PBS supplemented with different stimuli at twice the concentration corresponding to the desired final level. Receptor activity was quantified by finding the maximum fluorescence enhancement (using 480nm excitation and 535nm emission wavelengths) after normalization to the baseline fluorescence intensity measured before stimulation.

For dose response analysis, stimuli were provided in duplicate at 10 different concentrations ranging from 1.5nM to 30. mu.M. Activity was normalized to the response obtained with 60mM (concentration that elicits the maximal receptor response) monosodium glutamate. Solving for EC using a non-linear regression algorithm₅₀(concentration of compound that causes 50% activation of receptor) the Hill slope, bottom asymptote and top asymptote can be varied in the algorithm. The same results were obtained when dose-response data were analyzed using commercially available software for non-linear regression analysis, such as GraphPad PRISM (san diego, ca, usa).

To determine the dependence of hT1R1/hT1R3 on different stimuli for cellular responses, a similar analysis was performed on selected compounds on I-17 cells that did not induce receptor expression with mifepristone (referred to as uninduced I-17 cells). In the FLIPR assay, uninduced I-17 cells did not show any functional response to monosodium glutamate or other savory taste tasting substances. Compounds were provided on uninduced umami cells at 10 μ M or 3 times the maximum stimulation used in the dose response assay. When uninduced umami cells are used in the FLIPR assay, the compounds encompassed herein do not show any functional response.

In some aspects of the invention, an EC of less than about 10mM₅₀Indicating that the compound can induce the activity of T1R1/T1R3 and is considered to be a salty and delicious agonist. Preferred savory agonists have lowEC at about 1mM₅₀A value; and more preferably has an EC of less than about 20. mu.M, 15. mu.M, 10. mu.M, 5. mu.M, 3. mu.M, 2. mu.M, 1. mu.M, 0.8. mu.M, or 0.5. mu.M₅₀The value is obtained.

In the umami taste enhancing activity assay experiment, this experiment produced an "EC" indicating the extent to which the amide compound of the invention effectively enhances savory flavoring agents (typically MSG) already present in the test solution₅₀Ratio "measurement result. A series of measurements of dose response were performed in a solution containing MSG alone, followed by a second dose response with MSG combined with a predetermined amount of a candidate compound of formula (I).

Increasing concentrations of monosodium glutamate (ranging from 12-to 81mM) were provided in duplicate in this assay, with or without a fixed concentration of test compound. Typical concentrations of compounds tested were 30. mu.M, 10. mu.M, 3. mu.M, 1. mu.M, 0.3. mu.M, 0.1. mu.M and 0.03. mu.M. By calculating the EC of monosodium glutamate₅₀The relative potency of the compound of formula (I) in potentiating the receptor is determined by the magnitude of the shift. At such a ratio (EC) ₅₀R) to define an enhancement, the ratio corresponding to the EC of monosodium glutamate determined in the absence of test compound₅₀EC divided by monosodium glutamate determined in the presence of test compound₅₀. Show EC₅₀Compounds with R > 2.0 are considered odorants.

Put another way, the "EC" compared to MSG is calculated based on the following definition₅₀The ratio is as follows:

EC relative to MSG₅₀Ratio (EC)₅₀Ratio vs.MSG)＝EC₅₀(MSG)/EC₅₀(MSG + [ Compound)])

Wherein "[ compound ]" means the concentration of the compound of formula (I) used to elicit (or augment or potentiate) a dose response to MSG.

It should be noted that the measured EC₅₀The ratio depends to some extent on the concentration of the compound itself. Preferred savory flavor enhancers are available at low concentrationsHas higher EC relative to MSG₅₀And (4) the ratio. Preferably, the EC used to measure umami taste enhancement is₅₀The specific assay is performed at a concentration of the compound of formula (I) of about 10. mu.M to about 0.1. mu.M, or preferably at 1.0. mu.M or 3.0. mu.M.

EC greater than 1₅₀The ratio indicates that the compounds can modulate (potentiate) hT1R1/hT1R3 activity and are savory flavor enhancers. More preferably, the savoury flavour enhancer compound of formula (I) has an EC of at least 1.2, 1.5, 2.0, 3.0, 4.0, 5.0, 8.0 or 10.0 or even higher ₅₀A ratio.

In one aspect, the degree of savory taste modulation of a particular compound is assessed based on its effect on MSG activation of T1R1/T1R3 in vitro. It is anticipated that other compounds known to activate the T1R1/T1R3 receptor can be used to design similar assays.

In the detailed description, examples and claims of the present invention, the EC based on which is calculated according to the above formula is identified₅₀In contrast, specific compounds and general classes of compounds that modulate hT1R1/hT1R3 are shown.

The procedure for the human taste test of the umami/savoury compounds of formula (I) is reported below. Comparable EC against the activity of the compounds of formula (I) on sweet receptor agonism and/or sweet taste in humans are also reported below₅₀And (6) analyzing.

In vitro hT1R2/hT 3 sweet taste receptor activation assay

HEK293 Cell line derivatives (Chandrasakar, J., Mueller, K.L., Hoon, M.A., Adler, E.A., E.E., Feng, L., Guo, W., Zuker, C.S., Ryba, N.J., Cell, 2000, 100, 703-711) stably expressing G.alpha.15 and hT1R2/hT1R3(Li, X., Staszewski, L., Xu, H., Durick, K., Zoller, M.H., USA 2002, 99, 4692-4696, also see International patent WO 03/001876A2) were used to identify compounds with sweet taste enhancing properties.

The compounds encompassed herein were initially selected based on their activity on the hT1R2/hT1R3-HEK 293-G.alpha.15 cell line (Li et al, supra). Activity was determined using automated fluorescence imaging analysis on a FLIPR instrument (fluorescence intensity plate reader, Molecular Devices, sandivol, ca, usa) (referred to as FLIPR assay). Cells from one clone (designated S-9 cells) were seeded into 384-well plates (approximately 50,000 cells/well) in culture medium containing DMEM low glucose (Invitrogen, Calsbards, Calif.), 10% dialyzed fetal bovine serum (Invitrogen, Calsbards, Calif., U.S.), 100 units/ml penicillin G, and 100 μ G/ml streptomycin (Invitrogen, Calsbards, Calif. (see also International patent WO 03/001876A 2). S-9 cells were grown at 37 ℃ for 24 hours. Then 4 μ M of calcium dye Fluo-3AM (molecular probes, Uygur. Oreg.) in phosphate buffered saline (D-PBS) (Invitrogen, Calsbad, Calif.) was added to S-9 cells for 1 hour at room temperature. After displacement with 25 μ L D-PBS, stimulation was performed in a FLIPR instrument at room temperature by adding 25 μ L D-PBS supplemented with different stimuli at twice the concentration corresponding to the desired final level. Receptor activity was quantified by finding the maximum fluorescence enhancement (using 480nm excitation and 535nm emission wavelengths) after normalization to the baseline fluorescence intensity measured before stimulation.

For dose response analysis, stimuli were provided in duplicate at 10 different concentrations ranging from 60nM to 30. mu.M. The activity was normalized to the response obtained with 400mM D-fructose (concentration that elicits the maximum receptor response). EC was found using a non-linear regression algorithm (using software from senomox, inc.)₅₀The Hill slope, bottom asymptote, and top asymptote may be changed in the algorithm. The same results were obtained when dose-response data were analyzed using commercially available software for non-linear regression analysis, such as GraphPad PRISM (san diego, ca, usa).

To determine the dependence of hT1R2/hT1R3 on different stimuli for cellular responses, a similar analysis was performed on selected compounds on HEK 293-G.alpha.15 cells (which do not express the human sweet taste receptor). In the FLIPR assay, HEK 293-G.alpha.15 cells did not show any functional response to D-fructose or any other known sweetener. Similarly, when HEK293-G α 15 cells were used in the FLIPR assay, the compounds encompassed herein did not induce any functional response.

Examples

The following examples are given to illustrate various exemplary embodiments of the present invention and are not to be construed as limiting in any way.

For the purposes herein, the compounds disclosed in each of examples 1-174 and corresponding tables A-E below may be referred to by the numerals of the examples in a shorthand manner. For example, as immediately below, example 1 discloses the synthesis of a particular compound (N- (hept-4-yl) benzo [ d ] [1, 3] dioxanone-5-carboxamide), referred to herein as compound 1 and may be abbreviated as compound 1, and the results of an experimental analysis of its biological effectiveness. Similarly, the first compound shown in table a may be referred to elsewhere herein as compound a 1.

Example 1

N- (hept-4-yl) benzo [ d ] [1, 3] dioxacene-5-carboxamide

To a solution of heptan-4-amine (8.06mL, 54mmol) in triethylamine (15.3mL, 108mmol) and dichloromethane (135mL) at 0 deg.C was added dropwise benzo [1, 3] dissolved in dichloromethane (135mL)]Dioxolene-5-carbonyl chloride (10g, 54mmol) solution. The reaction mixture was stirred for 1 hour. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc. The organic layer was washed successively with 1N aqueous HCl, 1N aqueous NaOH, water, brine and dried (MgSO 2)₄) And concentrated. The residue was recrystallized from EtOAc and hexane to give 6.9g N- (heptylene) as a white solid Radical-4-yl) benzo [ d][1，3]Dioxolane-5-carboxamide (48.3%).¹H NMR(500MHz，CDCl₃)：δ0.92(t，6H)，1.38(m，6H)，1.53(m，2H)，4.11(m，1H)，5.63(m，1H)，6.01(s，2H)，7.98(d，1H)，7.27(s，d，2H)。MS(M+H，264)。

The compound activates EC of hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀Is 0.2 μ M and when present at 0.03 μ M can have an EC of 6.92₅₀The efficacy of monosodium glutamate was enhanced.

Example 2

N- (2-methylhept-4-yl) benzo [ d ] [1, 3] dioxacene-5-carboxamide

In a similar manner to example 1, benzo [ d ] was used][1，3]Dioxacene-5-carbonyl chloride and 2-methylheptan-4-amine (example 2 a).¹H NMR(500MHz，CDCl₃)：δ0.93(m，9H)，1.38(m，5H)，1.53(m，1H)，1.66(m，1H)，4.21(m，1H)，5.61(d，1H)，6.01(s，2H)，6.82(d，1H)，7.26(m，2H)。MS(278，M+H)。

Preparation of 2-methylheptyl-4-amine

To a solution of 2-methylheptan-4-one (4.24g, 33.07mmol) in methanol (60mL) was added ammonium acetate (25.50g, 330.71mmol) and sodium cyanoborohydride (2.08g, 33.07 mmol). The reaction mixture was stirred at room temperature for about 24 hours. The solvent was removed under reduced pressure, the residue diluted with water and basified with 15% aqueous NaOH and extracted with ether. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give 3.3g of 2-methylheptan-4-amine (77%). MS (M + H, 130).

The compound has an EC of 0.22 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 3

N- (2-methylhexan-3-yl) benzo [ d ] [1, 3] dioxacene-5-carboxamide

In a similar manner to example 1, benzo [ d ] was used][1，3]Dioxacene-5-carbonyl chloride and 2-methylhexan-3-amine (example 3 a).¹H NMR(500MHz，CDCl₃)：δ0.93(m，9H)，1.37(m，3H)，1.56(m，1H)，1.83(m，1H)，4.01(m，1H)，5.67(d，1H)，6.02(s，2H)，6.82(d，1H)，7.28(m，2H)。MS(M+H，264)。

a. 2-methylhexan-3-amine was prepared from 2-methylhexan-3-one using the same procedure as described in example 2 a. Yield: 40 percent.¹H NMR(500MHz，CDCl₃)：δ0.86(d，3H)，0.91(m，6H)，1.20-1.29(m，2H)，1.38-1.47(m，2H)，1.47(s，2H)，1.58(m，1H)，2.51(m，1H)。MS(M+H，116)。

The compound has an EC of 0.61 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 4

N- (2, 3-dimethylcyclohexyl) benzo [ d ] [1, 3] dioxacene-5-carboxamide

2, 3-dimethylcyclohexylamine (20. mu. mol) and benzo [ d ] [1, 3] dioxacene-5-carboxylic acid (1.1 eq.) were each dissolved in acetonitrile/dichloromethane (200. mu.L, 2: 1). The PS-carbodiimide resin (2 equiv.) was loaded into a 1.2mL 96-well Greiner plate, followed by the addition of the amine and acid solutions. Hydroxybenzotriazole (1.1 equiv.) was dissolved in DMF (100mL) and added to the reaction well. The reaction was shaken overnight at room temperature. Once the reaction was complete, PS-Trisamine resin (1.5 equivalents) was added to the reaction mixture and the solution was shaken overnight at room temperature. Acetonitrile (200mL) was added to the reaction well and the supernatant was transferred to a new plate. The solution was evaporated to give N- (2, 3-dimethylcyclohexyl) benzo [ d ] [1, 3] dioxacene-5-carboxamide. MS (M + H, 276.20).

The compound has an EC of 0.45 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀And when present at 1. mu.M, can have an EC of 8.4₅₀The efficacy of monosodium glutamate was enhanced.

Example 5

N- (5-methylhexan-3-yl) benzo [ d ] [1, 3] dioxacene-5-carboxamide

In a similar manner to example 1, benzo [ d ] was used][1，3]Dioxacene-5-carbonyl chloride and 5-methylhexan-3-amine (example 5 a). Yield: 48 percent.¹H NMR(500MHz，CDCl₃)：δ0.94(m，9H)，1.37(t，3H)，1.45(m，1H)，1.64(m，2H)，4.13(m，1H)，5.61(d，1H)，6.01(s，2H)，6.82(d，1H)，7.27(m，2H)。MS(M+H，264)。

a. 2-methylhexan-3-amine was prepared from 5-methylhexan-3-one using the same procedure as described in example 2 a. Yield: 54 percent. MS (M + H, 116).

The compound has an EC of 0.57 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 6

(R) -2- (benzo [ d ] [1, 3] dioxacene-6-carboxamido) -4-methylpentanoic acid methyl ester

In a similar manner to example 1, benzo [ d ] was used][1，3]Dioxacene-5-carbonyl chloride and D-leucine methyl ester hydrochloride. Yield: 83 percent.¹H NMR(500MHz，CDCl₃)：δ0.98(m，6H)，1.63-1.67(m，1H)，1.71-1.76(m，2H)，3.76(s，3H)，4.83(m，1H)，6.03(s，2H)，6.38(d，1H)，6.83(d，1H)，7.32(s，1H)，7.33(d，1H)。MS(M+H，294)。m.p.：89-90℃。

The compound has an EC of 0.34 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀And when present at 0.1. mu.M, can have an EC of 4.9₅₀The efficacy of monosodium glutamate was enhanced.

Example 7

N- (1, 2, 3, 4-tetrahydronaphthalen-1-yl) benzo [ d ] [1, 3] dioxacene-5-carboxamide

Prepared in a similar manner to example 4 using benzo [ d ] [1, 3] dioxacene-5-carboxylic acid and 1, 2, 3, 4-tetrahydronaphthalen-1-amine. MS (M + H, 296.6).

The compound has an EC of 0.71 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀And when present at 0.3. mu.M, can have an EC of 7.8₅₀The efficacy of monosodium glutamate was enhanced.

Example 8

(R) -N- (1-hydroxy-4-methylpent-2-yl) benzo [ d ] [1, 3] dioxacene-5-carboxamide

Prepared in a similar manner to example 4 using benzo [ d ] [1, 3] dioxacene-5-carboxylic acid and (R) -aminoleucinol. MS (M + H, 266.1).

The compound has 9 mu M EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀And when present at 3. mu.M, can be at an EC of 2₅₀The efficacy of monosodium glutamate was enhanced.

Example 9

(R) -N- (1-methoxy-4-methylpent-2-yl) benzo [ d ] [1, 3] dioxacene-5-carboxylic acid

Prepared in a similar manner to example 4 using (R) -1-methoxy-4-methyl and pentan-2-amine (example 9 a). Yield: and 55 percent.¹H NMR(500MHz，CDCl₃)：δ0.95(m，6H)，1.43(m，1H)，1.55(m，1H)，1.65(m，1H)，3.36(s，3H)，3.46(m，2H)，4.33(m，1H)，6.01(s，2H)，6.13(d，1H)，6.82(d，1H)，7.28(m，2H)。MS(M+H，280)。

a. (R) -1-methoxy-4-methylpentan-2-amine

To a solution of (R) -2- (1-methoxy-4-methylpent-2-yl) isoindoline-1, 3-dione (example 9b) (3.87g, 14.84mmol) in methanol (30mL) was added hydrazine hydrate (0.866mL, 17.81mmol) and the reaction mixture was warmed to 45 ℃ over about 3 hours. The mixture was acidified with 2N HCl and stirred at 45 ℃ for 30 min. The solution was cooled to room temperature, filtered and evaporated. The residue was taken up in 2N NaOH and extracted with diethyl ether, MgSO ₄Dried, filtered and evaporated to give 1.51g of (R) -1-methoxy-4-methylpentan-2-amine. Yield: 77 percent.¹H NMR(500MHz，CDCl₃)：δ0.91(m，6H)，1.17(m，2H)，1.58(s，2H)，1.71(m，1H)，3.02(m，1H)，3.10(m，1H)，3.32(m，1H)，3.35(s，3H)。

(R) -2- (1-methoxy-4-methylpent-2-yl) isoindoline-1, 3-dione

(R) -2- (1-hydroxy-4-methylpent-2-yl) isoindoline-1, 3-dione (example 9c) (5.88g, 23.87mmol) was dissolved in anhydrous THF (25mL) and hexamethyl-phosphoramide (30mL), and the solution was cooled to 0 ℃. Sodium hydride (60% in mineral oil, 1.15g, 28.65mmol) was added and after 10 minutes iodomethane (7.43mL, 119.35mmol) was added dropwise and the solution was slowly warmed to room temperature and stirred overnight. The reaction mixture was poured into ice/water, extracted with EtOAc, washed with brine, and MgSO₄Drying, filtering and evaporating. The residue was purified on silica gel (20% EtOAc in hexane) to give 3.92g of (R) -2- (1-methoxy-4-methylpent-2-yl) isoindoline-1, 3-dione (63%).

(R) -2- (1-hydroxy-4-methylpent-2-yl) isoindoline-1, 3-dione

Phthalic anhydride (10.30g, 69.55mmol) and D-leucinol (8.15g, 69.55mmol) were combined in THF (100mL), and the reaction mixture was heated at 85 ℃ and refluxed for 18 h. After cooling to room temperature, water was added and the solution was extracted with EtOAc, and the extract was extracted with 1N HCl, water, NaHCO ₃Aqueous solution, water and brine, over MgSO₄Dried, filtered and evaporated to give 8.1g of (R) -2- (1-hydroxy-4-methylpent-2-yl) isoindoline-1, 3-dione (47%).¹H NMR(500MHz，CDCl₃)：δ0.94(m，6H)，1.54(m，2H)，1.99(m，1H)，3.86(m，1H)，4.04(m，1H)，4.47(m，1H)，7.72(m，2H)，7.83(m，2H)。

The compound has an EC of 3.5 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 10

(R) -2- (benzo [ d ] [1, 3] dioxacene-6-carboxamido) -3-methylbutyric acid methyl ester

Prepared in a similar manner to example 4 using benzo [ d ] [1, 3] dioxacene-5-carboxylic acid and (R) -2-amino-3-methylbutanoic acid methyl ester. Yield: 50 percent. MS (M + H; 280.1).

The compound has 1.16 mu M EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 11

2- (benzo [ d ] [1, 3] dioxacene-6-carboxamido) -4-methylpentyl dihydrogen phosphate

Reacting N- (1-hydroxy-4-methylpent-2-yl) benzo [ d][1，3]Dioxole-5-carboxamide (example 11a) (0.57mmol, 151mg) was dissolved in anhydrous acetonitrile (2ml) and 1ml of a 0.45M solution of tetrazole in acetonitrile was added under a nitrogen atmosphere and stirred for 5 minutes. 0.627(1.1 equiv., 207. mu.l) of dibenzylaminodiisopropyl phosphite was then added dropwise under a nitrogen atmosphere. The mixture was stirred for 1 hour. The solvent was evaporated and the crude intermediate was dissolved in DCM and washed twice with 2% potassium carbonate and brine and dried over sodium sulfate. The material was completely dried and oxidized with 5ml of tert-butyl hydroperoxide (4M solution in nonane) for 30 minutes. The solvent was evaporated and the dibenzyl ester intermediate was purified (prep TLC). The benzyl group was hydrolyzed with trifluoroacetic acid (3ml of a mixture of 95% TFA and 5% water, 1.5 hours, room temperature). The final product was completely dried to yield 69mg (35%) of pure material. ¹H NMR(500MHz，CDCl₃)：δ0.88-0.90(t，6H)，1.23-1.27(m，2H)，1.36-1.37(m，1H)，1.53-1.62(m，2H)，3.93(s，1H)，3.98(s，1H)，4.32(s，1H)，5.90(s，2H)，6.66-6.67(d，1H)，6.98-6.99(b，2H)，7.14(s，2H)，³¹P：δ0.51(s)。MS(M+H，346.0)。

a. N- (1-hydroxy-4-methylpent-2-yl) benzo [ d ] [1, 3] dioxametallocene-5-carboxamide was obtained from piperic acid and 2-amino-4-methylpent-1-ol in the same manner as in example 4.

The compound has 10.9 mu M EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 12

N- (hex-3-yl) -4-methoxy-3-methylbenzamide

Prepared in a similar manner to example 4 using 4-methoxy-3-methylbenzoic acid and hex-3-amine (example 28 a).¹H NMR(500MHz，CDCl₃)：δ0.94(m，6H)，1.41(m，4H)，1.46(m，1H)，1.64(m，1H)，2.24(s，3H)，3.87(s，3H)，4.08(m，1H)，5.69(d，1H)，6.83(d，1H)，7.54(s，1H)，7.62(d，1H)。MS(M+H，250)。

The compound has an EC of 0.12 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 13

(R) -N- (1- (dimethylamino) -4-methyl-oxopent-2-yl) benzo [ d ] [1, 3] dioxacene-5-carboxamide

In the presence of HOBt (26mg, 1 eq.) and 1-ethyl-3- (3-di(R) -2- (benzo [ d ] in DMF (4mL) in the presence of methylaminopropyl) -carbodiimide hydrochloride (44mg, 1.2 eq) at room temperature][1，3]Dioxole-6-carboxamido) -4-methylpentanoic acid (example 13a) (52mg, 0.19mmol) and dimethylamine (2M in methanol, 36. mu.l, 2 eq.) were condensed overnight. The reaction mixture was evaporated and the residue was dissolved in ethyl acetate and successively with saturated NaHCO₃And washed with water, over MgSO₄Dried, filtered and evaporated to give 48.6mg (84%) of the product. The product was further purified by RPHPLC. ¹H NMR(500MHz，CDCl₃)：δ0.93-0.94(d，3H)，1.03-1.05(d，3H)，1.48-1.52(m，1H)，1.59-1.63(m，1H)，2.98(s，3H)，3.14(s，3H)，5.17-5.21(m，1H)，6.01(s，2H)，6.80-6.82(d，1H)，6.89-6.91(d，1H)，7.29-3.30(d，1H)，7.33-7.35(dd，1H)。MS(M+H，307.2)。

a. (R) -2- (benzo [ d ] [1, 3] dioxacene-6-formylamino) 1-4-methylpentanoic acid

Prepared in a similar manner to example 1 using benzo [ D ] [1, 3] dioxacene-5-carbonyl chloride and D-leucine. Yield: and 55 percent. MS (M + H, 280.2).

The compound has 1.06 mu M EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 14

Acetic acid 2- (benzo [ d ] [1, 3] dioxacene-6-carboxamido) pentyl ester

To a solution of N- (1-hydroxypent-2-yl) benzo [ d ] in dichloromethane (5mL)][1，3]To a solution of the dioxacene-5-carboxamide (example 14a) (59.8mg, 0.238mmol) was added triethylamine (166mL, 1.19 mmol). Acetic anhydride (112.5mL, 1.19mmol) was added slowly and the mixture was stirred under an argon atmosphere at ambient temperature overnight. The solution was successively saturated with sodium bicarbonate,Water and brine. The organic layer was dried over anhydrous sodium sulfate. Filtration and subsequent removal of the solvent under reduced pressure gave 50.8mg of acetic acid 2- (benzo [ d ]][1，3]Dioxolane-6-carboxamido) pentyl ester (73%).¹H NMR(CDCl₃)：δ0.95(t，3H，J＝7.2Hz)，1.43(m，2H)，1.57(m，2H)，2.1(s，3H)，4.11(dd，1H，J＝3.5Hz，J＝11.5Hz)，4.27(dd，1H，J＝3.5Hz，J＝11.4Hz)，4.29(m，1H)，6.02(s，2H)，6.1(m，1H)，6.82(d，1H，J＝8.4Hz)，7.27(m，2H)。MS(M+H，294)。

a. N- (1-hydroxypent-2-yl) benzo [ d ] [1, 3] dioxacene-5-carboxamide was prepared in a similar manner to example 4 using benzo [ d ] [1, 3] dioxacene-5-carboxylic acid and 2-amino-pent-1-ol. Yield: 76 percent. MS (M + H, 252).

The compound has 11.9 mu M EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀And when present at 3. mu.M, can have an EC of 4.1₅₀The efficacy of monosodium glutamate was enhanced.

Example 15

(R) -N- (4-methyl-1-oxo-1- (2- (pyridin-3-yl) ethylamino) pent-2-yl) benzo [ d ] [1, 3] dioxacene-5-carboxamide

Prepared in a similar manner to example 13 using 2- (3-pyridyl) ethylamine and (R) -2- (benzo [ d ] [1, 3] dioxanone-6-carboxamido) -4-methylpentanoic acid (example 13 a). (MS M + 384.2).

The compound has 1.7 mu M EC that activates hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 16

N- ((R) -1- (2- (hydroxymethyl) pyrrolidin-1-yl) -4-methyl-1-oxopent-2-yl) benzo [ d ] [1, 3] dioxacene-5-carboxamide

Prepared in a similar manner to example 13 using R/S propanol and (R) -2- (benzo [ d ] [1, 3] dioxanone-6-carboxamido) -4-methylpentanoic acid (example 13 a). (MS M + 363.2).

The compound has an EC of 3 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 17

N- (hept-4-yl) -6-methylbenzo [ d ] [1, 3] dioxacene-5-carboxamide

Prepared in a similar manner to example 4 using 6-methylbenzo [ d ] [1, 3] dioxacene-5-carboxylic acid and hept-4-amine. MS (M + H, 278.67).

The compound has an EC of 0.11 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 18

N- (hept-4-yl) -2-methylbenzo [ d ] [1, 3] dioxacene-5-carboxamide

N- (hept-4-yl) -3, 4-dihydroxybenzamide (example 18a) (0.5mmol) was dissolved in toluene (1.6 mL). P-toluenesulfonic acid monohydrate (0.3 eq) was added to the reaction followed by acetaldehyde (2 eq). The reaction was carried out using microwaves (180C, 300W) and was carried out for 10 minutes. The solvent was evaporated and the residue was dissolved in methanol (1ML) and purified by HPLC. Yield 20%, MS (M + H278.10).

a. N- (hept-4-yl) -3, 4-dihydroxybenzamide was obtained in a similar manner to example 4 using 3, 4-dihydroxybenzoic acid and hept-4-amine. Yield: 25 percent. MS (M + H, 252.1).

The compound has an EC of 0.1. mu.M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀And when present at 0.03. mu.M, can have an EC of 3.68₅₀The efficacy of monosodium glutamate was enhanced.

Example 19

2- (5- (hept-4-ylcarbamoyl) benzo [ d ] [1, 3] dioxan-2-yl) acetic acid ethyl ester

N- (hept-4-yl) -3, 4-dihydroxybenzamide (example 18a) (0.29mmol, 75mg) was dissolved with a 6-equivalent excess (242mg) of potassium carbonate in anhydrous acetone, then a 1.2-equivalent excess (36. mu.l) of ethyl propionate was added and the mixture was refluxed for 24 hours. The solvent was evaporated and the solid was dissolved in dichloromethane and washed with 10% NaHCO ₃And water extraction. The crude product was purified by silica gel chromatography to give 72mg of the desired product (71%).¹H NMR(500MHz，CDCl₃)：δ0.91-0.94(t，6H)，1.23-1.30(m，4H)，1.37-1.41(4H)，2.97-2.98(d，2H)，3.70-3.74(dd，2H)，4.12-4.17(m，1H)，4.2-4.24(m，3H)，5.61-5.64(d，1H)，6.58-6.60(t，1H)，6.79-6.81(d，1H)，7.23(s，1H)，7.60-7.85(b，1H)。MS(M+H，350.1)。

The compound has 14 mu M EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀And when present at 3. mu.M, can have an EC of 2.5₅₀Of the monosodium salt of glutamic acidEfficacy.

Example 20

N- (hept-4-yl) -2, 2-dimethylbenzo [ d ] [1, 3] dioxacene-5-carboxamide

In a similar manner to example 4, 2-dimethylbenzo [ d ] was used][1，3]Sodium dioxacene-5-carboxylate and 4-heptylamine (example 20 a). The yield was 30%.¹H NMR；δ0.92(t，6H，J＝7.2Hz)，1.42(m，6H)，1.53(m，2H)，1.68(s，6H)，4.12(m，1H)，5.61(d，1H，J＝8.9Hz)，6.72(d，1H，J＝8Hz)，7.16(d，1H，J＝1.5Hz)，7.22(dd，1H，J＝1.5Hz，J＝17Hz)。MS(M+H，292)。

Sodium 2, 2-dimethylbenzo [ d ] [1, 3] dioxacene-5-carboxylate and 4-heptylamine:

ethyl 2, 2-dimethylbenzo [ d ] [1, 3] dioxacene-5-carboxylate (example 20b) (461mg, 2.08mmol) was stirred at room temperature in dioxane (16mL) and 1.0N aqueous NaOH (4.16mL) for 20 hours. The solvent was removed under reduced pressure to give the desired product (449 mg). (M-H, 193).

2, 2-Dimethylbenzo [ d ] [1, 3] dioxacene-5-carboxylic acid ethyl ester

Ethyl 3, 4-dihydroxybenzoate (910.9mg, 5mmol) was combined with 2, 2-dimethoxypropane (1.23mL, 10mmol) and catalytic amounts of p-toluenesulfonic acid in toluene. The mixture was heated to reflux using a Dean-Stark trap for 20 hours. After removal of the solvent under reduced pressure, the crude product was dissolved in ethyl acetate and washed successively with a saturated aqueous solution of sodium hydrogencarbonate, water and brine. The organic layer was dried over anhydrous sodium sulfate. Purification by silica gel chromatography using a gradient of hexane: ethyl acetate from 90: 10 to 75: 25 gave a white powder (539.1mg, 49%). ¹H NMR(CDCl₃)：δ1.36(t，3H，J＝7.2Hz)，1.69(s，6H)，4.32(q，2H，J＝7.1Hz，J＝14.2Hz)，6.74(d，1H，d，J＝8.2Hz)，7.38(d，1h，J＝1.7Hz)，7.61(dd，1H，J＝1.8Hz，J＝8.3Hz)。

The compound has an EC of 2.7 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 21

N- (hept-4-yl) -2-isopropylbenzo [ d ] [1, 3] dioxacene-5-carboxamide

In a similar manner to example 4, 2-isopropylbenzo [ d ] was used][1，3]Dioxacene-5-carboxylic acid (example 21a) and 4-heptylamine. The yield was 34%.¹H NMR(CDCl₃)：δ0.92(t，6H，J＝7.2Hz)，1.04(d，6H，J＝6.9Hz)，1.40(m，6H)，1.43(m，2H)，2.15(m，1H)，4.11(m，1H)，5.62(d，1H，J＝8.9Hz)，5.96(d，1H，J＝4.4Hz)，6.75(d，1H，J＝8.0Hz)，7.19(d，1H，J＝1.8Hz)，7.22(d，1H，J＝1.9Hz)，7.23(d，1H，J＝1.6Hz)。MS(M+H，291)。

2-isopropylbenzo [ d ] [1, 3] dioxacene-5-carboxylic acid: 3, 4-Dihydroxybenzoic acid (154.12mg, 1mmol) and isobutyraldehyde (182. mu.L, 2mmol) were combined in toluene (3mL) and a catalytic amount of p-toluenesulfonic acid was added. The mixture was subjected to microwaves at 180 ℃ for 10 minutes with the power set at 275. The solution was filtered and evaporated to yield 100mg of the desired product (48%). MS (M-H, 207).

The compound has 11.5 mu M EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀And when present at 3. mu.M, can have an EC of 2.2₅₀The efficacy of monosodium glutamate was enhanced.

Example 22

2, 2-difluoro-N- (hept-4-yl) benzo [ d ] [1, 3] dioxacene-5-carboxamide

Prepared in a similar manner to example 4 using 2, 2-difluorobenzo [ d ] [1, 3] dioxacene-5-carboxylic acid and 4-heptylamine. (M + H, 300.2).

The compound has 1.51 mu M EC that activates hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line ₅₀And when present at 1. mu.M, can have an EC of 2.87₅₀The efficacy of monosodium glutamate was enhanced.

Example 23

2, 3-dihydro-benzo [1, 4] dioxin-6-carboxylic acid (1-propyl-butyl) -amide

Prepared in a similar manner to example 4 using 2, 3-dihydro-benzo [1, 4] dioxin-6-carboxylic acid and hept-4-amine. MS (M + H, 278.2).

The compound has an EC of 0.49 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 24

N- (hept-4-yl) -3, 4-dihydro-2H-benzo [ b ] [1, 4] dioxepin-7-carboxamide

Prepared in a similar manner to example 4 using 2, 3-dihydro-benzo [1, 4] dioxepin-6-carboxylic acid and hept-4-amine. MS (M + H, 292.2).

The compound has an EC of 6.4 μ M for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 25

Benzofuran-2-carboxy (1-propylbutyl) amide

Prepared in a similar manner to example 1 using benzofuran-2-carbonyl chloride and heptan-4-amine. Yield: 73 percent.¹H NMR(500MHz，CDCl₃)：δ0.93(t，6H，J＝7.2Hz)，1.41(m，8H)，3.01(s，3H)，4.18(m，1H)，6.29(d，1H，J＝9.94Hz)，7.20(d，1H，J＝8.62Hz)，7.37(m，2H)，7.44(s，1H)。MS(M+H，260)。

The compound has an EC of 0.88 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀And when present at 0.3. mu.M, can have an EC of 2.6₅₀The efficacy of monosodium glutamate was enhanced.

Example 26

N- (hept-4-yl) -5-methylbenzofuran-2-carboxamides

Prepared in a similar manner to example 4 using 5-methylbenzofuran-2-carboxylic acid (example 26a) and hept-4-amine. Yield: 46 percent.¹H NMR(500MHz，CDCl₃)：δ0.94(t，6H，J＝7.2Hz)，1.41(m，10H)，2.44(s，1H)，4.18(m，1H)，6.29(d，1H，J＝8.6Hz)，7.21(d，1H，J＝8.4Hz)，7.37(m，2H)，7.44(s，1H)。MS(M+H，274)。

5-methylbenzofuran-2-carboxylic acid: 2-hydroxy-5-methylbenzaldehyde (544.2mg, 4mmol) was combined in methyl ethyl ketone (5mL) with diethyl bromomalonate (1mL, 6mmol) and potassium carbonate (1.1g, 8mmol), and the mixture was heated at reflux overnight. The solvent was removed by rotary evaporation to give a crude oil. The oil was then taken up in 10% potassium hydroxide solution in ethanol (10mL) and heated at reflux for 45 minutes. The solvent was removed under reduced pressure and the residue was taken up in 2.0N H₂SO₄And (4) solution treatment. The free acid was then extracted with a large amount of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. Ethyl acetate was removed to give 566mg of 5-methyl-2-carboxybenzofuran as a pale yellow powder (80%).¹HNMR(500MHz，CD₃OD)：δ2.44(s，3H)，7.30(d，1H，J＝8.7Hz)，7.45(d，1H，J＝8.5Hz)，7.51(d，2H，J＝7.5Hz)。

The compound has an EC of 0.94 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 27

(R) -4-methyl-2- (5-methylbenzofuran-2-carboxamido) pentanoic acid methyl ester

Prepared in a similar manner to example 4 using 5-methylbenzofuran-2-carboxylic acid (example 26a) and D-leucine methyl ester. ¹H NMR(500MHz，CDCl₃)：δ0.98(d，3H，J＝6.26Hz)，1.00(d，3H，J＝6.17Hz)，1.56(s，3H)，1.76(m，3H)，2.48(s，3H)，3.78(s，3H)，4.86(m，1H)，6.95(m，1H)，7.23(dd，1H，J＝8.54Hz，J＝1.55Hz)，7.40(m，2H)。7.44(dd，1H，J＝1.72，J＝0.9Hz)。MS304(M+H，304)。

The compound has 0.11 mu M of hT1R1/hT1R3 umami taste receptor for activating expression in HEK293 cell lineEC of (1)₅₀。

Example 28

N- (hex-3-yl) -5-methylbenzofuran-2-carboxamides

Prepared in a similar manner to example 4 using 5-methylbenzofuran-2-carboxylic acid (example 26a) and hex-3-amine (example 28 a). Yield: 49 percent.¹H NMR(500MHz，CDCl₃)：δ0.94(m，6H)，1.40-1.68(m，6H)，2.36(s，3H)，4.07(m，1H)，5.74(d，1H，J＝8.97Hz)，7.16(d，1H，J＝7.80Hz)，7.31(dd，1H，J＝1.73Hz，J＝1.73Hz)，7.66(d，1H，J＝1.72Hz)。MS(M+H，260)。

a. Hex-3-amine was prepared from hex-3-one using the same procedure as described in example 2 a. Yield: 58 percent.¹H NMR(500MHz，CDCl₃)：δ0.94(m，6H)，1.36-1.58(m，6H)，2.83(m，1H)，3.12(s，2H)。MS：(102，M+H)。

The compound has an EC of 0.74. mu.M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 29

N- (hex-3-yl) -5-methoxybenzofuran-2-carboxamide

Prepared in a similar manner to example 4 using 5-methoxybenzofuran-2-carboxylic acid and hex-3-amine (example 28 a). Yield: 32 percent.¹H NMR(500MHz，CDCl₃)：δ0.96(m，6H)，1.40-1.67(m，6H)，3.85(s，3H)，4.09(m，1H)，6.28(d，1H)，7.01(dd，1H)，7.08(d，1H)，7.38(m，2H)。MS(276，M+H)。

The compound has an EC of 0.4 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 30

(R) -3-cyclohexyl-2- (5-methoxybenzofuran-2-carboxamido) propionic acid methyl ester

Prepared in a similar manner to example 4 using 5-methoxybenzofuran-2-carboxylic acid and methyl (R) -2-amino-3-cyclohexylpropionate. Yield: 45 percent. MS (M + H, 260.3).

The compound has 1.14 mu M EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line ₅₀。

Example 31

5-methoxy-N- (5-methylhexan-3-yl) benzofuran-2-carboxamide

Prepared in a similar manner to example 4 using 5-methoxybenzofuran-2-carboxylic acid and 5-methylhexan-3-amine (example 5 a). Yield: 67%.¹H NMR(500MHz，CDCl₃)：δ0.96(m，9H)，1.39-1.52(m，3H)，1.66(m，2H)，3.85(s，3H)，4.17(m，1H)，6.24(d，1H)，7.01(dd，1H)，7.08(d，1H)，7.38(m，2H)。MS(290，M+H)。

The compound has 1.04 mu M EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 32

Preparation of (R) -4-chloro-2- (5-methylbenzofuran-2-carboxamido) pentanoic acid methyl ester

Prepared in a similar manner to example 4 using 5-chlorobenzofuran-2-carboxylic acid and D-leucine methyl ester. MS (M + H, 324).

The compound has an EC of 0.82 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 33

(R) -4-methyl-2- (3-methylbenzofuran-2-carboxamido) pentanoic acid methyl ester

Prepared in a similar manner to example 4 using 3-methylbenzofuran-2-carboxylic acid and D-leucine methyl ester. MS (M + H, 304).

The compound has 1.18 mu M EC that activates hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 34

N- (hept-4-yl) benzo [ b ] thiophene-2-carboxamides

Prepared in a similar manner to example 4 using benzo [ b ] thiophene-2-carboxylic acid and 4-heptylamine. MS (M + H, 276).

The compound has an EC of 0.21 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 35

N- (hept-4-yl) -1H-indole-2-carboxamides

Prepared in a similar manner to example 4 using 1H-indole-2-carboxylic acid and 4-heptylamine. MS (M + H, 259).

The compound has 6.8 mu M EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 36

(R) -4-methyl-2- (5-methyl-1H-indole-2-carboxamido) pentanoic acid methyl ester

Prepared in a similar manner to example 4 using 5-methyl-1H-indole-2-carboxylic acid and D-leucine methyl ester. Yield: 50 percent.¹H NMR(500MHz，CDCl₃)：δ0.98(d，3H，J＝6.3Hz)，1.00(d，3H，J＝6.1Hz)，2.44(s，3H)，3.784(s，3H)，4.87(m，1H)，6.56(d，1H，J＝8.39Hz)，6.85(dd，1H，J＝1.94Hz，J＝0.68Hz)，7.12(dd，1H，J＝8.46Hz，J＝1.55Hz)，7.31(d，1H，J＝8.45Hz)，7.42(s，1H)。MS(M+H，303)。

The compound has 6.6 mu M EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 37

N- (hept-4-yl) -1-methyl-1H-indole-2-carboxamide

Prepared in a similar manner to example 4 using 1-methyl-1H-indole-2-carboxylic acid and 4-heptylamine. Yield: 45 percent.¹H NMR(500MHz，CDCl₃)：δ0.95(t，6H，J＝7.2Hz)，1.46(m，4H)，1.57(m，4H)，4.05(s，3H)，4.15(m，1H)，5.85(d，1H)，6.80(s，1H)，7.14(t，1H，J＝7.4Hz)，7.31(t，1H，J＝7.5Hz)，7.38(d，1H，J＝8.4Hz)，7.62(d，1H，J＝8Hz)。MS(M+H，273)。

The compound has 1.79 mu M EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 38

N- (hept-4-yl) -1H-benzo [ d ] imidazole-5-carboxamides

In a similar manner to example 4, 1H-benzo [ d ] is used]Imidazole-5-carboxylic acid and 4-heptylamine. Yield: 80 percent. ¹H NMR(500MHz，CDCl₃)：δ0.94(t，6H，J＝7.2Hz)，1.42(m，6H)，1.57(m，2H)，4.21(m，1H)，6.18(m，1H)，7.64(m，2H)，8.16(m，1H)，8.28(s，1H)。MS(M+H，260)。

The compound has 18.6 mu M EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 39

Benzoxazole-5-carboxylic acid (1-propylbutyl) amide

Prepared in a similar manner to example 4 using benzoxazole-5-carboxylic acid (example 39a) and 4-heptylamine.¹H NMR(500MHz，CDCl₃)：δ8.16(d，J＝5.4Hz，1H)，7.89(d，J＝8.6Hz，1H)，7.64(d，J＝8.6Hz，1H)，5.82(d，J＝8.6Hz，1H)，4.10-4.22(m，1H)，1.58-1.62(m，4H)，1.40-1.49(m，4H)，0.95(t，J＝7.2Hz，6H)；ESIMS：261(M+H)。

a. Benzoxazole-5-carboxylic acid: a mixture of 3-amino-4-hydroxybenzoic acid (500mg, 3.26mmol) and trimethyl orthoformate (5mL) was heated at 65 ℃ for 2 hours under an argon atmosphere. The reaction mixture was cooled to room temperature, filtered and washed with hexane. The filtrate was concentrated in vacuo to afford the product as a white solid (78mg, 15%):¹H NMR(500MHz，CDCl₃)：δ8.57(d，J＝1.5Hz，1H)，8.20(dd，J＝8.4，1.8Hz，1H)，8.20(s，1H)，7.67(d，J＝9.0Hz，1H)。MS(M+H，164)。

the compound has 1.91 muM EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 40

2-methyl-benzoxazole-5-carboxylic acid (1-propyl-butyl) -amide

Prepared in a similar manner to example 4 from 2-methylbenzoxazole-5-carboxylic acid (example 40a) and 4-heptylamine.¹H NMR(500MHz，CDCl₃): δ 8.00(d, J ═ 1.6Hz, 1H), 7.77(d, J ═ 8.5, 1.6Hz, 1H), 7.50(d, J ═ 8.5Hz, 1H), 5.79(d, J ═ 8.9Hz, 1H for NH), 4.10-4.22(m，1H)，2.66(s，3H)，1.58-1.65(m，4H)，1.38-1.55(m，4H)，0.94(t，J＝7.2Hz，6H)，MS(APCI，M+1)：275.2。

2-methylbenzoxazole-5-carboxylic acid: a mixture of 3-amino-4-hydroxybenzoic acid (1.5g, 9.79mmol) and trimethyl orthoacetate (15mL, large excess) was heated at 65 ℃ for 5 hours under an argon atmosphere. The reaction mixture was cooled to room temperature, filtered and washed with hexane. The filtrate was concentrated in vacuo to afford the product as a yellow solid (1.4g, 80%): ¹H NMR(500MHz，CD₃OD)：δ8.26(d，J＝1.7Hz，1H)，8.07(dd，J＝8.5，1.6Hz，1H)，7.67(d，J＝8.2Hz，1H)，2.67(s，1H)，MS(APCI，M+1)：178.10。

The compound has an EC of 0.33 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

EXAMPLE 41

2-ethyl-benzoxazole-5-carboxylic acid (1-propyl-butyl) -amide

3-amino-4-hydroxy-N- (1-propylbutyl) benzamide (example 41a) and trimethyl orthopropionate in N₂The mixture was heated at 65 ℃ for 5 hours under an atmosphere. The reaction mixture was cooled to room temperature and concentrated in vacuo. By preparative TLC (CH) on silica gel₂Cl₂MeOH) to afford the product as a white solid (42mg, 73%): mp 107-108 ℃; MS (APCI, M + 1): 289.10.

a. 3-amino-4-hydroxy-N- (1-propylbutyl) benzamide was obtained in a similar manner to example 4 using 3-amino-4-hydroxybenzoic acid and 4-heptylamine. Yield: 57 percent.¹H NMR(500MHz，CDCl₃)：δ0.93(t，6H)，1.26-1.51(m，8H)，4.09(m，1H)，6.74(m，1H)，7.05(s，1H)，7.43(m，2H)，7.77(m，2H)。MS：(251，M+H)。

The compound has an EC of 0.68 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 42

2-methoxy-benzoxazole-5-carboxylic acid (1-propyl-butyl) -amide

Prepared in a similar manner to example 41 using 3-amino-4-hydroxy-N- (1-propylbutyl) benzamide (example 41a) and tetramethyl orthocarbonate. Yield: 60 percent. mp 137-138 ℃; MS (M + H, 291.10).

The compound has an EC of 0.69 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line ₅₀。

Example 43

2-ethoxy-benzoxazole-5-carboxylic acid (1-propyl-butyl) -amide

Prepared in a similar manner to example 41 using 3-amino-4-hydroxy-N- (1-propylbutyl) benzamide (example 41a) and tetraethoxymethane: mp 128-129 ℃; MS (M + H, 305.1).

The compound has 5 mu M EC that activates hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 44

N- (hept-4-yl) -2- (methylthio) benzo [ d ] oxazole-5-carboxamide

To N- (hept-4-yl) -2- (mercapto) benzo [ d ] at 0 deg.C]To a solution of oxazole-5-carboxamide (example 44a) (50mg, 0.17mmol) in DMF (3mL) was added K₂CO₃(29mg, 0.17mmol) and MeI (29mg, 0.20). The resulting reaction mixture was heated at 80 ℃ overnight. The solvent was removed under reduced pressure. The residue was diluted with dichloromethane and washed with water and dried (Na)₂SO₄) Filtered, concentrated in vacuo, and purified by PTLC (15% EtOAc in hexanes) to give the product as a white solid (50mg, 96%): mp 113-114 ℃;¹H NMR(500MHz，CDCl₃)：δ7.94(d，J＝1.8Hz，1H)，7.73(dd，J＝8.5，1.6Hz，1H)，7.46(d，J＝8.4Hz，1H)，5.76(d，J＝8.4Hz，1H)，4.15-4.25(m，1H)，2.77(s，3H)，1.58-1.65(m，2H)，1.1.38-1.55(m，6H)，0.94(t，J＝7.2Hz，6H)；MS(APCI，M+)：307.2。

a.N- (hept-4-yl) -2- (mercapto) benzo [ d ] oxazole-5-carboxamide: to a solution of 3-amino-4-hydroxy-N- (1-propylbutyl) benzamide (example 41a) (250mg, 1.0mmol) in EtOH was added KSCSOEt (160mg, 1.0 mmol). The reaction mixture was heated at 80 ℃ overnight. The solvent was removed under reduced pressure. The residue was taken up in water. The resulting mixture was acidified with HOAc to a pH of about 5 and then filtered. The residue was washed with water to give the product as a white solid (160mg, 55%). MS (M + H, 293.1).

The compound has an EC of 3.1. mu.M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 45

Chloromethyl benzoxazole-5-carboxylic acid (1-propyl-butyl) amide

Prepared in a similar manner to example 41 using 3-amino-4-hydroxy-N- (1-propylbutyl) benzamide (example 41a) and trimethyl chloroorthoacetate. Yield: 65 percent. mp 108.5-109 ℃; MS (M + H, 309.05).

The compound has an EC of 0.23 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 46

2-methyl-benzoxazole-6-carboxylic acid (1-propyl-butyl) -amide

Prepared in a similar manner to example 4 using 2-methylbenzoxazole-6-carboxylic acid (example 46a) and 4-heptylamine. Yield: 50 percent.¹H NMR(500MHz，CD₃OD)δ8.19(d，J＝1.4Hz，1H)，8.05(dd，J＝8.3，1.5Hz，1H)，7.63(d，J＝8.2Hz，1H)，2.68(s，1H)；MS(M+1，178.10)。

a. 2-methylbenzoxazole-6-carboxylic acid (50%) was prepared from 4-amino-3-hydroxybenzoic acid in a similar manner to example 40 a:¹H NMR(500MHz，CD₃OD)：δ8.19(d，J＝1.4Hz，1H)，8.05(dd，J＝8.3，1.5Hz，1H)，7.63(d，J＝8.2Hz，1H)，2.68(s，1H)，MS(M+H，178.10)。

the compound has an EC of 2.1. mu.M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 47

2-chloromethyl-benzoxazole-6-carboxylic acid (1-propyl-butyl) -amide

Prepared in a similar manner to example 41 using 3-amino-4-hydroxy-N- (1-propylbutyl) benzamide (example 47a) and trimethyl chloroorthoacetate. The product was obtained as a white solid (45mg, 73%): mp 137.0-137.5 ℃; MS (M + H, 309.05).

a. 3-amino-4-hydroxy-N- (1-propylbutyl) benzamide was obtained from 4-amino-3-hydroxybenzoic acid in a similar manner to example 41 a. Yield: 50 percent.¹H NMR(500MHz，CDCl₃)：δ0.91(t，6H)，1.41(m，6H)，1.54(m，2H)，4.13(m，1H)，5.81(d，1H)，6.63(d，1H)，6.95(d，1H)，7.82(s，1H)。MS：(251，M+H)。

The compound has an EC of 0.45 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 48

4-methyl-3-methylsulfanyl-N- (1-propylbutyl) benzamide

Prepared in a similar manner to example 4 using 4-methyl-3- (methylthio) benzoic acid (example 48a) and 4-heptamine. Yield: 50 percent.¹H NMR(500MHz，CDCl₃)：δ0.93(t，6H，J＝7.2Hz)，1.40-1.41(m，8H)，2.35(s，3H)，2.51(s，1H)，4.15(m，1H)，5.75(d，1H，J＝8.5Hz)，7.15(d，1H，J＝7.8Hz)，7.31(d，1H，J＝7.8Hz)，7.65(d，1H，J＝1.5Hz)。MS(M+H，280)。

4-methyl-3- (methylthio) benzoic acid: 3-amino-4-methylbenzoic acid was suspended in ice water (55mL) and concentrated HCl (8.56mL) was added slowly. Aqueous sodium nitrate (2.4 g in 5.5 mL) was added to the suspension over a period of 15 minutes and the mixture was stirred for a further 15 minutes.Then, an aqueous solution of sodium acetate (9.31 g in 18 mL) was added dropwise. The reaction was allowed to proceed for 45 minutes. A dark orange precipitate was obtained. The precipitate was filtered off and washed with small portions of ice-cold water. The solid was combined with a solution of potassium xanthate (11.93g) and potassium carbonate (8.22g) in 250mL of water. The reaction vessel was placed in an oil bath preheated to 70 ℃ and the mixture was stirred for 25 minutes. The reddish solution was removed from the bath and stirred for 15 minutes or until the temperature reached 30 ℃. Sodium hydroxide (0.782g) was added and stirred until dissolved. Dimethyl sulfate (5.70mL) was added. The mixture was stirred at room temperature for 1 hour and then briefly refluxed. The solvent was removed under reduced pressure to give an orange solid. With 2.0N H ₂8O₄The solid was treated with EtOAc and extracted. The extract was washed with water and anhydrous MgSO₄And (5) drying. The solvent was removed under reduced pressure to give a reddish crude solid. The solid was adsorbed on silica gel and purified by column chromatography (gradient 5-50% ethyl acetate in hexane) to give 4-methyl-3- (methylthio) benzoic acid (2g) as a pale yellow powder.¹H NMR(500MHz，CDCl₃)：δ2.39(s，3H)，2.54(s，3H)，7.24(d，1H，J＝7.8Hz)，7.79(d，1H，J＝7.8Hz)，7.86(d，1H，J＝1.5Hz)。

The compound has an EC of 0.21 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 49

(R) -4-methyl-2- (4-methyl-3- (methylthio) benzoylamino) pentanoic acid methyl ester

Prepared in a similar manner to example 4 using 3-methyl-4- (methylthio) benzoic acid (example 48a) and D-leucine methyl ester. Yield: 45 percent.¹H NMR(500MHz，CDCl₃)：δ0.97(d，3H，J＝6.36Hz)，0.99(d，3H，J＝6.1Hz)，1.64-1.77(m，2H)，2.36(s，3H)，2.51(s，3H)，3.77(s，3H)，4.85(m，1H)，6.50(d，1H，J＝8.10Hz)，7.18(d，1H，J＝7.83Hz)，7.38(dd，1H，J＝7.77Hz，J＝1.78Hz)，7.65(d，1H，J＝1.65Hz)。MS(M+H，310)。

The compound has an EC of 0.1. mu.M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 50

(R) -4-methyl-2- (4-methylthio) benzoylamino) pentanoic acid methyl ester

Prepared in a similar manner to example 4 using 4- (methylthio) benzoic acid and D-leucine methyl ester. MS (M + H, 296).

The compound has an EC of 0.16 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 51

N- (hept-4-yl) -3-methyl-4- (methylthio) benzamide

Prepared in a similar manner to example 4 using 3-methyl-4- (methylthio) benzoic acid (example 51a) and 4-heptamine.¹H NMR(500MHz，CDCl₃)：δ0.93(t，6H)，1.37-1.46(m，6H)，1.54-1.56(m，2H)，2.35(s，3H)，2.49(s，3H)，4.17(m，1H)，5.73(d，1H)，7.14(d，1H)，7.52(s，1H)，7.58(d，1H)。MS(280，M+H)。m.p：129-131℃。

a. 3-methyl-4- (methylthio) benzoic acid was obtained from 3-amino-4-methylbenzoic acid using the same method as described in example 48a) Benzoic acid. Yield: 30 percent.¹HNMR(500MHz，CDCl₃)：δ2.36(s，3H)，2.53(s，3H)，7.17(d，1H)，7.85(s，1H)，7.93(d，1H)。

The compound has an EC of 0.12 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 52

4-methoxy-3-methyl-N- (2-methylhept-4-yl) benzamide

Prepared in a similar manner to example 4 using 4-methoxy-3-methylbenzoic acid and 2-methyl-4-heptylamine (example 2 a). Yield: 45 percent.¹H NMR(500MHz，CDCl₃)：δ0.93(m，9H)，1.39(m，5H)，1.53(m，1H)，1.67(m，1H)，2.24(s，3H)，3.86(s，3H)，4.23(m，1H)，5.64(d，1H)，6.82(d，1H)，7.54(s，1H)，7.61(d，1H)。MS(278，M+H)。

The compound has an EC of 0.1. mu.M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 53

4-methoxy-3-methyl-N- (5-methylhexan-3-yl) benzamide

Prepared in a similar manner to example 4 using 4-methoxy-3-methylbenzoic acid and 5-methylhexan-3-amine (example 5 a).¹H NMR(500MHz，CDCl₃)：δ0.94(m，9H)，1.38(m，2H)，1.47(m，1H)，1.65(m，2H)，2.24(s，3H)，3.86(s，3H)，4.16(m，1H)，5.65(d，1H)，6.83(d，1H)，7.54(s，1H)，7.61(d，1H)。MS(264，M+H)。

The compound has an EC of 0.09 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 54

4-methoxy-N- (1- (4-methoxyphenyl) butyl) -3-methylbenzamide

Prepared in a similar manner to example 4 using 3-methyl-4-methoxy-benzoic acid and 1- (4-methoxyphenyl) butan-1-amine (example 54 a). The yield was 52%. ¹H NMR(500MHz，CDCl₃)：δ0.94(t，3H)，1.31-1.41(m，2H)，1.82-1.92(m，2H)，2.22(s，3H)，3.79(s，3H)，3.86(s，3H)，5.11(m，1H)，6.14(d，1H)，6.81(d，1H)，6.88(d，2H)。7.28(d，2H)，7.53(s，1H)，7.61(d，1H)。MS(328，M+H)。

a. 1- (4-methoxyphenyl) butan-1-amine was prepared from 1- (4-methoxyphenyl) butan-1-one as described in example 2 a. The yield was 90%. MS (M + H, 180).

The compound has an EC of 3.14 μ M for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 55

(R) -4-methoxy-3-methyl-N- (3-methyl-1, 2, 4-oxadiazol-5-yl) butyl) benzamide

Prepared in a similar manner to example 4 using 4-methoxy-3-methylbenzoic acid and 3-methyl-1- (3-methyl- [1, 2, 4] oxadiazol-5-yl) -butylamine (example 55 a). MS (M + H, 318).

(R) -3-methyl-1- (3-methyl-1, 2, 4-oxadiazol-5-yl) -butan-1-amine: Boc-D-Leu-OH (0.23g, 1mmol) was treated with N-hydroxyacetamidine (74mg, 1 eq.) and DIC (155. mu.L, 1 eq.) in dioxane (2mL) at room temperature overnight. Another portion of DIC (1 eq.) was added and the reaction mixture was heated at 110 ℃ for 4 hours. After removal of the solvent, the residue was treated with 50% TFA/DCM (2mL) for 1 h, then the solvent was evaporated. The crude mixture was purified by preparative HPLC (C-18 column, MeOH-H)₂Mobile phase O and formic acid as modifier) to yield 75mg of amine (45% yield).¹H NMR(500MHz，CDCl₃)：δ0.95(d，3H)，0.99(d，3H)，1.70-1.78(m，1H)，1.92-1.98(m，2H)，2.39(s，3H)，3.50(b，2H，NH₂)，4.65(t，1H)。MS(M+H，170)。

The compound has an EC of 5.4 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line ₅₀。

Example 56

4-ethoxy-N- (hept-4-yl) -3-methylbenzamide

Prepared in a similar manner to example 4 using 4-ethoxy-3-methylbenzoic acid (example 56a) and 4-heptylamine. Yield: 75 percent.¹H NMR(500MHz，CDCl₃)：δ0.93(t，6H)，1.37-1.45(m，6H)，1.53-1.59(m，2H)，2.24(s，3H)，4.07(q，2H)，4.15(m，1H)，5.67(d，1H)，6.80(d，1H)，7.54(s，1H)，7.58(d，1H)。MS(278，M+H)。

4-ethoxy-3-methylbenzoic acid: 4-hydroxy-3-methylbenzoic acid (10g) was dissolved in DMF (400mL) and sodium carbonate (3 equiv.) was added. Ethyl iodide (3 equivalents) was dissolved in DMF (50mL) and added dropwise to the reaction mixture, and the solution was stirred overnight. After completion of the reaction, the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with water. The organic layer was separated and evaporated. The residue was dissolved in 200mL of methanol/water (3: 1). Lithium hydroxide (3 equivalents) was added and stirred overnight. When the hydrolysis was complete, the solvent was removed and the product was crystallized using an ethyl acetate/hexane mixture to give 8.2g of 4-ethoxy-3-methylbenzoic acid. The yield was 70%. MS (M-H, 179.20).

The compound has an EC of 0.17 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 57

4-ethoxy-N- (1-methoxypentan-2-yl) -3-methylbenzamide

Prepared in a similar manner to example 4 using 4-ethoxy-3-methylbenzoic acid (example 56a) and 1-methoxypentan-2-amine (example 57 a). Yield: 33 percent. MS (M + H, 280.1).

a. 1-Methoxypent-2-amine was prepared in a similar manner to example 9a from 2- (1-methoxypentan-2-yl) isoindoline-1, 3-dione (example 57 b). Yield: 67%.¹H NMR(500MHz，CDCl₃)：δ0.91(t，3H)，1.24-1.45(m，4H)，1.52(s，2H)，2.94(m，1H)，3.12(t，1H)；3.33(m，1H)；3.35(s，3H)。

b. 2- (1-Methoxypent-2-yl) isoindoline-1, 3-dione is prepared in a similar manner to example 9b from 2- (1-hydroxypent-2-yl) isoindoline-1, 3-dione (example 57 c). Yield: 82 percent.¹H NMR(500MHz，CDCl₃)：δ0.91(t，3H)，1.32(m，2H)，1.64(m，1H)，2.03(m，1H)，3.31(s，3H)，3.54(m，1H)，3.98(t，1H)，4.50(m，1H)，7.70(m，2H)，7.82(m，2H)。

c. 2- (1-hydroxypentan-2-yl) isoindoline-1, 3-dione is prepared in a similar manner to example 9c, using isobenzofuran-1, 3-dione and 2-aminopentan-1-ol. Yield: 62 percent.¹HNMR(500MHz，CDCl₃)：δ0.92(t，3H)，1.33(m，2H)，1.76(m，1H)，1.95(m，1H)，3.88(m，1H)，4.06(m，1H)，4.39(m，1H)，7.72(m，2H)，7.83(m，2H)。

The compound has an EC of 0.69 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 58

4-hydroxy-3-methyl-N- (1-propyl-butyl) -benzamide

Prepared in a similar manner to example 4 using 4-hydroxy-3-methylbenzoic acid and 4-heptylamine. MS (M + H, 250.2).

The compound has an EC of 0.92. mu.M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 59

N- (hept-4-yl) -4- (2-methoxyethoxy) -3-methylbenzamide

Potassium hydroxide (4mmol) was dissolved in ethanol (5mL) and heated at 80 ℃. To the solution was added 4-hydroxy-3-methyl-N- (1-propyl-butyl) -benzamide (example 58) (1mmol) followed by chloroethanol (3 mmol). The reaction was stirred at 80 ℃ overnight. The reaction mixture was concentrated and dissolved in 5% citric acid. The mixture was stirred for 1 hour. The aqueous mixture was extracted three times with ethyl acetate. The combined ethyl acetate was washed with water and dried completely over sodium sulfate. The organic layer was concentrated and purified by HPLC to give 39% of N- (hept-4-yl) -4- (2-methoxyethoxy) -3-methylbenzamide. MS (M + H, 308.25).

The compound has an EC of 0.21 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 60

(R) -2- (3-fluoro-4-methoxybenzamido) -4-methylpentanoic acid methyl ester

Prepared in a similar manner to example 4 using 3-fluoro-4-methoxybenzoic acid and D-leucine methyl ester. MS (M + H, 298).

The compound has an EC of 0.3 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 61

3-chloro-4-methoxy-N- (pent-3-yl) benzamide

Prepared in a similar manner to example 4 using 3-pentylamine and 3-chloro-4-methoxybenzoic acid. The yield was 40%. MS (M + H, 256.20).

The compound has an EC of 0.56 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀And when present at 0.3. mu.M, can have an EC of 6.28₅₀The efficacy of monosodium glutamate was enhanced.

Example 62

(R) -2- (3-chloro-4-methoxybenzoylamino) -4-methylpentanoic acid methyl ester

Prepared in a similar manner to example 4 using 3-chloro-4-methoxybenzoic acid and D-leucine methyl ester hydrochloride. MS (M + H, 314.10).

The compound has an EC of 0.08 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line ₅₀And when present at 0.01. mu.M, can have an EC of 13.18₅₀The efficacy of monosodium glutamate was enhanced.

Example 63

(R) -3-chloro-4-methoxy-N- (1-phenylethyl) benzamide

Prepared in a similar manner to example 4 using (R) -1-phenylethylamine and 3-chloro-4-methoxybenzoic acid. MS (M + H, 290.0).

The compound has an EC of 2.5 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀And when present at 0.3. mu.M, can have an EC of 2.7₅₀The efficacy of monosodium glutamate was enhanced.

Example 64

4-chloro-3-methyl-N- (1-propyl-butyl) -benzamide

Prepared in a similar manner to example 4 using 4-chloro-3-methylbenzoic acid and hept-4-amine. MS (M + H, 268).

The compound has an EC of 0.8 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 65

3, 4-dimethoxy-N- (1-propyl-butyl) -benzamide

Prepared in a similar manner to example 4 using 3, 4-dimethoxybenzoic acid and hept-4-amine. MS (M + H, 279.37).

The compound has an EC of 0.36 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 66

(R) -2- (4-fluoro-3-methylbenzamido) -4-methylpentanoic acid methyl ester

Prepared in a similar manner to example 4 using 4-fluoro-3-methylbenzoic acid and D-leucine methyl ester. MS (M + H, 282).

The compound has an EC of 0.32. mu.M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 67

4-methoxy-3, 5-dimethyl-N- (2-methylheptan-4-yl) benzamide

Prepared in a similar manner to example 4 using 4-methoxy-3, 5-dimethylbenzoic acid and 2-methylheptan-4-amine (example 2 a). MS (M + H, 292.2).

The compound has an EC of 0.85 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 68

3, 4-dimethyl-N- (2-methylhexan-3-yl) benzamide

Prepared in a similar manner to example 4 using 3, 4-dimethylbenzoic acid and hex-3-amine (example 3 a).¹H NMR(500MHz，CDCl₃)：δ0.94(m，9H)，1.39(m，3H)，1.56(m，1H)，1.84(m，1H)，2.30(s，3H)，2.31(s，3H)，4.04(m，1H)，5.76(d，1H)，7.18(d，1H)，7.46(d，1H)，7.55(s，1H)，MS(248，M+H)。

The compound has an EC of 0.11 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 69

3, 4-dimethyl-N- (2-methylheptan-4-yl) benzamide

In a similar manner as in example 4Prepared using 3, 4-dimethylbenzoic acid and 2-methylheptan-4-amine (example 2 a).¹H NMR(500MHz，CDCl₃)：δ0.94(m，9H)，1.40(m，5H)，1.53(m，1H)，1.68(m，1H)，2.29(s，3H)，2.30(s，3H)，4.24(m，1H)，5.69(d，1H)，7.17(d，1H)，7.46(d，1H)，7.54(s，1H)。MS(262，M+H)。

The compound has an EC of 0.13 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line ₅₀。

Example 70

3, 4-dimethyl-N- (5-methylhexan-3-yl) benzamide

Prepared in a similar manner to example 4 using 3, 4-dimethylbenzoic acid and 5-methylhexan-3-amine (example 5 a).¹H NMR(500MHz，CDCl₃)：δ0.94(m，9H)，1.38(m，2H)，1.46(m，1H)，1.65(m，2H)，2.29(s，3H)，2.30(s，3H)，4.18(m，1H)，5.70(d，1H)，7.17(d，1H)，7.46(d，1H)，7.55(s，1H)。MS(248，M+H)。

The compound has an EC of 0.17 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 71

(R) -N- (1-methoxy-4-methylpent-2-yl) -3, 4-dimethylbenzamide

To a solution of (R) -N- (1-hydroxy-4-methylpent-2-yl) -3, 4-dimethylbenzamide (1.59g, 6.39mmol) (example 71a) in anhydrous DMF (20mL)Powdered NaOH (281mg, 7mmol) was added to the solution, and the solution was stirred at 0 ℃ for 2 hours. Methyl iodide (1 eq, 6.39mmol) was added dropwise to DMF (10ml) over a period of 1 hour. The temperature was kept at 0 ℃ and the mixture was stirred for 1 hour. The reaction was quenched by the addition of 300ml of water. The aqueous layer was extracted with dichloromethane and MgSO₄Dried and evaporated. The residue was purified by flash chromatography on silica gel (toluene-ethyl acetate; gradient 5-20%) to give 1.23g of (R) -N- (1-methoxy-4-methylpent-2-yl) -3, 4-dimethylbenzamide (73%).¹H NMR(500MHz，CDCl₃)：δ0.94-0.97(t，6H)，1.41-1.47(m，1H)，1.54-1.60(m，1H)，1.64-1.68(m，1H)，2.29(d，6H)，3.36(s，3H)，3.45-3.50(m，2H)，4.34-4.39(m，1H)，6.23-6.25(d，1H)，7.16-7.17(d，1H)，7.47-7.49(dd，1H)，7.56(s，1H)。MS(M+H，264.3)。

a. (R) -N- (1-hydroxy-4-methylpent-2-yl) -3, 4-dimethylbenzamide was prepared in a similar manner to that described in example 4 using 3, 4-dimethylbenzoic acid and (R) -aminoleucinol. Yield: 75 percent. MS (M + H, 250.3).

The compound has an EC of 0.2 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 72

(R) -N- (1- (methoxymethyloxy) -4-methylpent-2-yl) -3, 4-dimethylbenzamide

To a solution of (R) -N- (1-hydroxy-4-methylpent-2-yl) -3, 4-dimethylbenzamide (example 71a) (0.24mmol) dissolved in anhydrous DMF (2mL) was added powdered NaOH (0.36mmol, 14.5mg, 1.5 equiv.) at 0 deg.C and the mixture was stirred at 0 deg.C for 1 h. Then chloro-methoxy-methane (19.3 μ L, 1 eq) was added and the reaction was stirred at 0 ℃ for 1 hour. The reaction was quenched with water (30mL) and dichloroThe mixture is extracted with methane. The organic phase is MgSO₄Dried and evaporated. The crude product was purified by preparative TLC (20% ethyl acetate/hexane) to give 37.7mg of (R) -N- (1- (methoxymethoxy) -4-methylpent-2-yl) -3, 4-dimethylbenzamide (53%).¹H NMR(500MHz，CDCl₃)：δ0.98-1.00(t，6H)，1.49-1.53(m，1H)，1.58-1.64(m，1H)，1.69-1.73(m，2H)，2.32-2.33(d，6H)，3.38-3.39(t，3H)，3.64-3.72(ddd，2H)，4.41-4.44(m，1H)，4.65-4.69(dd，2H)，6.37-6.39(d，1H)，7.19-7.21(d，1H)，7.50-7.52(dd，1H)，7.60(sb，1H)。MS(M+H，294.3)。

The compound has 1.06 mu M EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 73

N- (1-methoxymethyl-2-methyl-propyl) -3, 4-dimethyl-benzamide

Prepared in a similar manner to example 71 using N- (1-hydroxy-3-methylbut-2-yl) -3, 4-dimethylbenzamide (example 73a) and iodomethane. The yield was 87%. ¹H NMR(500MHz，CDCl₃)：δ0.97-1.00(dt，6H)，1.96-2.00(m，1H)，2.29(s，3H)，2.30(s，3H)，3.35(s，3H)，3.42-3.45(dd，1H)，3.60-3.62(dd，1H)，4.01-4.05(m，1H)，6.31-6.33(d，1H)，7.16-7.18(d，1H)，7.48-7.50(dd，1H)，7.56-7.57(d，1H)。MS(M+H，250)。

a. N- (1-hydroxy-3-methylbut-2-yl) -3, 4-dimethylbenzamide was prepared in a similar manner to example 71a using 3, 4-dimethoxybenzoic acid and 2-amino-3-methylbutan-1-ol. The yield was 75%. MS (M + H, 236.2).

The compound has 0.87 mu M of hT1R1/hT1R3 umami taste for activating expression in HEK293 cell lineEC of receptor₅₀。

Example 74

(R) -2- (2-methoxy-4- (methylthio) benzoylamino) -4-methylpentanoic acid methyl ester

Prepared in a similar manner to example 4 using 2-methoxy-4- (methylthio) benzoic acid and D-leucine methyl ester. MS (M + H, 326).

The compound has 15.8 mu M EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 75

N- (2-methylhept-4-yl) benzo [ d ] [1, 3] dioxacene-5-carboxamide

Prepared in a similar manner to example 4 using 3- (4-methoxy-phenyl) -acrylic acid and 5-methylhexan-3-amine (example 5 a). Yield: 59 percent.¹H NMR(500MHz，CDCl₃)：δ0.93(m，9H)，1.33(t，2H)，1.43(m，1H)，1.58-1.67(m，2H)，3.83(s，3H)，4.11(m，1H)，5.19(d，1H)，6.25(d，1H)，6.88(d，2H)，7.44(d，2H)，7.58(d，1H)。MS(276，M+H)。

The compound has an EC of 0.24 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 76

N- (1-ethyl-propyl) -3- [4- (2-hydroxy-ethoxy) -phenyl ] -acrylamide

N- (1-Ethyl-propyl) -3- (4-hydroxy-phenyl) -acrylamide (example 76a) (0.44mmol, 103mg) and KOH (0.7mmol, 37mg) were dissolved in anhydrous ethanol. The mixture was stirred at 80 ℃ for 1 hour. 2-chloro-ethanol (1.76mmol, 118. mu.L) was then added dropwise and the mixture was refluxed overnight. It was evaporated, then the crude product was dissolved in dichloromethane and washed with water and 5% citric acid. The organic phase was evaporated and the residue was purified by silica gel chromatography to give 73mg (60%) of the desired product. ¹H NMR(500MHz，CDCl₃)：δ0.92-0.95(t，6H)，1.25(s，1H)，1.40-1.46(m，2H)，1.59-1.64(m，2H)，3.93-3.94(m，1H)，3.95-3.98(m，2H)，4.09-4.11(m，2H)，5.28-5.30(d，1H)，6.26-6.29(d，1H)，6.88-6.90(d，2H)，7.43-7.45(d，2H)，7.56-7.59(d，1H)。MS(M+H，278.1)。

a. N- (1-ethyl-propyl) -3- (4-hydroxy-phenyl) -acrylamide was prepared from 4-hydroxy-cinnamic acid and 3-pentylamine in a similar manner to that described in example 4. MS (M + H, 234.10).

The compound has an EC of 5.8 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 77

(E) -N- (hept-4-yl) -3- (thien-2-yl) acrylamide

Prepared in a similar manner to that described in example 4 from (E) -3- (thiophen-2-yl) acrylic acid and 4-heptylamine. MS (M + H, 252).

The compound has 0.44 mu M of hT1R1/hT1R3 cell line activating expression in HEK293 cell lineEC of taste receptor₅₀。

Example 78

(R, E) -4-methyl-2-oct-2-enoylaminopentanoic acid methyl ester

Prepared in a similar manner to that described in example 4 from (E) -oct-2-enoic acid and D-leucine methyl ester. MS (M + H, 270).

The compound has an EC of 0.92. mu.M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 79

3- (4-methoxy-phenyl) -N- (3-methyl-1-propyl-butyl) -acrylamide

Prepared in a similar manner to example 4 using 3- (4-methoxy-phenyl) -acrylic acid and 3-methyl-1-propyl-butylamine (example 2 a). Yield: 65 percent.¹H NMR(500MHz，CDCl₃)：δ0.90-0.95(m，9H)，1.30-1.39(m，5H)，1.49-1.50(m，1H)，1.64-1.67(m，1H)，3.82(s，3H)，4.17-4.18(m，1H)，5.18-5.20(d，1H)，6.22-6.26(d，1H)，6.86-6.89(d，2H)，7.42-7.45(d，2H)，7.56-7.59(d，1H)。MS(M+H，290.1)。

The compound has 1.84 mu M EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line ₅₀。

Example 80

N- (1-methoxymethyl-3-methyl-butyl) -3- (4-methoxy-phenyl) -acrylamide

Prepared in a similar manner to that described in example 71 from 3- (4-methoxy-phenyl) -acrylic acid and D-leucinol. Yield: 41 percent.¹H NMR(500MHz，CDCl₃)：δ0.93-0.96(t，6H)，1.38-1.42(m，1H)，1.48-1.54(m，1H)，1.63-1.66(m，1H)，3.36(s，3H)，3.41-3.46(m，2H)，3.82-3.83(s，3H)，4.29-4.31(m，1H)，5.69-5.71(d，1H)，6.24-6.27(d，1H)，6.87-6.89(d，2H)，7.43(s，1H)，7.44(s，1H)，7.56-7.59(d，1H)。MS(M+H，292.1)。

The compound has an EC of 0.90 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 81

N- (1-benzyl-2-hydroxy-ethyl) -3- (4-methoxy-phenyl) -acrylamide

Prepared in a similar manner to that described in example 4 from 3- (4-methoxy-phenyl) -acrylic acid and D-phenylalaninol. MS (M + H, 312.3).

The compound has 1.1 mu M EC that activates hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 82

3- (4-ethoxy-phenyl) -N- (1-ethyl-propyl) -acrylamide

Prepared in a similar manner to example 4 using 3- (4-ethoxy-phenyl) -acrylic acid and 3-pentylamine. MS (M + H, 262.2).

The compound has 1.35 mu M EC that activates hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 83

4-methyl-2- (3-thiophen-2-yl-acrylamido) -pentanoic acid methyl ester

Prepared in a similar manner to that described in example 4 from 3-thiophen-2-yl-acrylic acid and D-leucine methyl ester. MS (M + H, 282.2).

The compound has an EC of 0.59. mu.M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 84

4-methyl-pent-2-enoic acid (1, 2, 3, 4-tetrahydro-naphthalen-1-yl) -amide

Prepared in a similar manner to that described in example 4 from 4-methyl-pent-2-enoic acid and 1, 2, 3, 4-tetrahydro-naphthalen-1-ylamine. MS (M + H, 244.2).

The compound has 1.5 mu M EC that activates hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 85

3- (2-fluoro-phenyl) -N- (1-propyl-butyl) -acrylamide

Prepared in a similar manner as described in example 4 from 3- (2-fluoro-phenyl) -acrylic acid and 4-heptylamine. MS (M + H, 264.2).

The compound has an EC of 0.16 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 86

3- (2-methoxy-phenyl) -N- (1-propyl-butyl) -acrylamide

Prepared in a similar manner as described in example 4 from 3- (2-methoxy-phenyl) -acrylic acid and 4-heptylamine. MS (M + H, 276.2).

The compound has an EC of 0.90 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 87

3- (3, 4-dimethoxy-phenyl) -N- (1-propyl-butyl) -acrylamide

Prepared in a similar manner to that described in example 4 from 3- (3, 4-dimethoxy-phenyl) -acrylic acid and 4-heptylamine. MS (M + H, 306.2).

The compound has 0.97 mu M activation in HEK293 cell lineEC of hT1R1/hT1R3 umami taste receptor expressed in₅₀And when present at 0.3. mu.M, can have an EC of 2.4₅₀The efficacy of monosodium glutamate was enhanced.

Example 89

3- (2-methoxy-phenyl) -N- (2-methyl-cyclohexyl) -acrylamide

Prepared in a similar manner as described in example 4 from 3- (2-methoxy-phenyl) -acrylic acid and 2-methyl-cyclohexylamine. MS (M + H, 274.2).

The compound has an EC of 3.4 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 90

N- (hept-4-yl) benzofuran-5-carboxamides

Prepared in a similar manner to example 4 using benzofuran-5-carboxylic acid and hept-4-amine. The yield was 41%. MS (M + H, 260.2).

The compound has 1.19 mu M EC that activates hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 91

N- (hept-4-yl) -5, 6-dimethylpyridine-carboxamide

Prepared in a similar manner to example 4 using 5, 6-dimethylpicolinic acid (example 91a) and 4-heptylamine. The yield was 49%.¹H NMR(500MHz，CDCl₃)：δ0.91-0.94(t，6H)，1.38-1.48(m，4H)，1.49-1.61(m，4H)，2.32(s，3H)，2.52(s，3H)，4.11-4.13(m，1H)，7.52-7.53(d，1H)，7.93-7.94(d，1H)。MS(M+H，249.1)。

5, 6-dimethylpicolinic acid: 5, 6-Dimethylpyridinonitrile (example 91b) was refluxed overnight in concentrated HCl (15 mL). The solvent was evaporated and the solid residue was co-evaporated several times with EtOH. Drying gave 453mg of 5, 6-dimethylpicolinic acid (80%) as a white solid. MS (M + H, 152.1).

5, 6-dimethylpyridinenitrile: 2, 3-lutidine (13.25mmol) was refluxed with 18ml of glacial AcOH and 6ml of hydrogen peroxide overnight. The solvent was evaporated and the residue was co-evaporated twice with water and Na₂CO₃Basified and extracted with chloroform. Na for organic layer₂SO₄Drying and evaporation gave 1.45g of crystalline product. The product (615mg, 5mmol) was reacted with trimethylsilonitrile (5.5mmol) in dichloromethane (10mL) at room temperature for 5 min, then dimethylcarbamoyl chloride (5mmol) was added, and the solution was stirred at room temperature for 3 days. The reaction mixture was treated with 10% potassium carbonate (10mL), the organic layer was separated, and the aqueous layer was extracted twice with dichloromethane. Na for organic phase₂SO₄Drying and evaporation gave 495mg of 5, 6-dimethylpyridinenitrile (75%).¹H NMR(500MHz，CDCl₃)：δ2.35(s，3H)，2.53(s，3H)，7.43-7.45(d，1H)，7.51-7.52(d，1H)，¹³C：δ19.71，22.80，117.87，126.36，130.60，136.58，137.66，159.84)。MS(M+H，133.1)。

The compound has an EC of 2.8 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 92

4- (diethylamino) -N- (hept-4-yl) benzamide

Prepared in a similar manner to example 4 using 4-diethylaminobenzoic acid and 4-heptylamine. (31%).¹H NMR(500MHz，CDCl₃)：δ0.92(t，6H，J＝7.17Hz)，1.18(t，6H，J＝7.04Hz)，1.41(m，4H)，1.55(m，4H)，3.39(m，4H)，4.15(m，1H)，5.62(m，1H)，6.64(d，2H，J＝10.26Hz)，7.64(d，2H，J＝10.26Hz)。MS(M+H，291)。

The compound has an EC of 7.6 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 93

(R) -2- (2, 6-Dimethoxyisonicotinamido) -4-methylpentanoic acid methyl ester

Prepared in a similar manner to example 4 using 2, 6-dimethoxy-isonicotinic acid and D-leucine methyl ester.¹H NMR(500MHz，CDCl₃): δ 0.92(d, 3H, J ═ 7.27Hz), 0.93(d, 3H, J ═ 7.26Hz), 1.41-1.58(m, 8H), 3.95(s, 3H), 4.08(s, 3H), 4.15(m, 1H), 6.43(d, 1H, J ═ 8.32Hz), 7.47(m, broad peak, 1H), 8.41(d, 1H, J ═ 8.34 Hz). MS (M + H, 311).

The compound has 1.91 muM EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 94

N- (hept-4-yl) -6-methoxynicotinamide

Prepared in a similar manner to example 4 using sodium 6-methoxynicotinate (example 94a) and 4-heptylamine. Yield: 44 percent. MS (M + H, 251).

a. Methyl 6-methoxynicotinate (2.097g, 12.56mmol) was dissolved in dioxane (30 mL). Aqueous NaOH (1.0N, 25mL) was added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure to give 2.2g of sodium 6-methoxynicotinate.

The compound has an EC of 2.66 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 95

5, 6-dimethylpyrazine-2-carboxylic acid (1-propylbutyl) amide

Prepared in a similar manner to example 4 using 5, 6-dimethyl-pyrazine-2-carboxylic acid (example 95a) and 4-heptylamine. ¹H NMR(500MHz，CDCl₃)：δ0.91-0.94(t，6H)，1.35-1.42(m，4H)，1.48-1.51(m，2H)，1.55-1.60(m，2H)，2.57-2.60(d，6H)，4.13-4.16(m，1H)，7.52-7.53(d，1H)，9.09(s，1H)；MS(M+H，250)。

5, 6-dimethyl-pyrazine-2-carboxylic acid: to a solution of 2, 3-diaminopropionic acid (1.0g, 9.6mmol) in methanol (20mL) were added butane-2, 3-dione (728. mu.L; 11.5mmol) and NaOH (1.4 g; 56.6 mmol). The mixture was refluxed for 2 hours, then cooled to room temperature and bubbled with air for 1 hour. The white precipitate was filtered off and the gelatinous product was concentrated in vacuo. The crude product was taken up in dichloromethane, washed with 10% citric acid, MgSO₄Dried and filtered. The solvent was removed under reduced pressure to give 5, 6-dimethyl-pyrazine-2-carboxylic acid as a volatile solid. This compound was used directly in the following step.

The compound has 1.01 mu M EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 96

2-chloro-N- (hept-4-yl) -6-methylnicotinamide

Prepared in a similar manner to example 4 using 2-chloro-6-methylnicotinic acid and 4-heptylamine. MS (M + H, 269).

The compound has an EC of 3.9 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 97

2-cyano-N- (hept-4-yl) -4-methoxybenzamide

Prepared in a similar manner to example 4 using 2-cyano-4-methoxybenzoic acid and 4-heptylamine. Yield: 73 percent. ¹H NMR(CD₃OD)：δ0.94(t，6H，J＝7.3Hz)，1.38(m，4H)，1.53(m，4H)，4.02(s，3H)，4.12(m，1H)，7.27(d，1H，J＝9.40Hz)，8.11(d，2H，J＝2.21Hz)。MS(M+H，275)。

The compound has 1.39 μ M EC that activates hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀And when present at 1. mu.M, can have an EC of 4.52₅₀Than enhancing the effect of monosodium glutamateForce.

Example 98

(R) -2- (2, 3-dimethylfuran-5-carboxamido) -4-methylpentanoic acid methyl ester

Prepared in a similar manner to example 4 using 4, 5-dimethyl-furan-2-carboxylic acid and D-leucine methyl ester. Yield: 27 percent.¹H NMR(500MHz，CDCl₃)：δ0.96(t，6H)，1.66(m，3H)，1.96(s，3H)，2.26(s，3H)，3.75(s，3H)，4.78(m，1H)，6.51(d，1H)，6.89(s，1H)。MS(M+H，268)。

The compound has an EC of 0.59. mu.M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 99

N- (hept-4-yl) -1, 3-dimethyl-1H-pyrazole-5-carboxamide

Prepared in a similar manner to example 4 using 1, 3-dimethyl-1H-pyrazole-5-carboxylic acid and 4-heptylamine.¹H NMR(500MHz，CDCl₃)：δ0.90(t，6H，J＝7.2Hz)，1.41(m，4H)，1.50(m，4H)，2.27(s，3H)，3.77(s，3H)，4.09(m，1H)，6.49(d，1H)，6.53(s，1H)。MS(M+H，238)。

The compound has an EC of 7.8 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 100

N- (hept-4-yl) -2-methylthiazole-4-carboxamide

Prepared in a similar manner to example 4 using 1, 3-dimethyl-1H-pyrazole-5-carboxylic acid and 4-heptylamine. MS (M + H, 241).

The compound has an EC of 7.2. mu.M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 101

N- (hept-4-yl) quinoline-6-carboxamide

Prepared in a similar manner to example 4 using quinoline-6-carboxylic acid and 4-heptylamine.¹HNMR(500MHz，CDCl₃)：δ0.96(t，J＝7.2Hz，6H)，1.42-1.58(m，6H)，1.62-1.70(m，2H)，4.18-4.20(m，1H)，5.95(d，J＝9.0Hz，1H)，7.49(br s，1H)，8.04(dd，J＝8.5，1.5Hz，1H)，8.17(d，J＝8.5Hz，1H)，8.27(d，J＝8.2Hz，1H)，8.30(s，1H)，8.99(br s，1H)，MS(M+H，271.2)。

The compound has an EC of 3.2 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 102

N- (hept-4-yl) quinoline-3-carboxamide

In a similar manner to example 4Using quinoline-3-carboxylic acid and heptylamine.¹HNMR(500MHz，CDCl₃)δ0.96(t，J＝7.3Hz，6H)，1.40-1.58(m，6H)，1.60-1.67(m，2H)，4.20-4.30(m，1H)，6.01(d，J＝8.8Hz，1H)，7.61(t，J＝7.5，1H)，7.80(t，J＝7.6Hz，1H)，7.90(d，J＝8.1Hz，1H)，8.15(d，J＝8.5Hz，1H)，8.57(d，J＝1.2Hz，1H)，9.26(br s，1H)，MS(M+H，271.2)。

The compound has 15.8 mu M EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 103

N- (hept-4-yl) isoquinoline-1-carboxamides

Prepared in a similar manner to example 4 using isoquinoline-1-carboxylic acid and heptylamine.¹HNMR(500MHz，CDCl₃)δ0.98(t，J＝7.05Hz，6H)，1.42-1.56(m，6H)，1.58-1.66(m，2H)，4.20-4.32(m，1H)，5.83(d，J＝9.1Hz，1H)，7.36(d，J＝4.2，1H)，7.60(t，J＝7.7Hz，1H)，7.75(t，J＝7.7Hz，1H)，8.11(d，J＝8.5Hz，1H)，8.18(d，J＝8.4Hz，1H)，8.88(d，J＝4.9，1H)，MS(APCI，M+)：271.2。

The compound has an EC of 14.2 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 104

4-methoxy-N- (1-methoxymethyl-3-methyl-butyl) -3-methyl-benzamide

Prepared in a similar manner to that described in example 71 from 4-methoxy-3-methyl-benzoic acid and D-leucinol. Yield: 86 percent.¹H NMR(500MHz，CDCl₃)：δ0.94-0.97(t，6H)，1.42-1.47(m，1H)，1.54-1.60(m，1H)，1.64-1.68(m，2H)，2.24(s，3H)，3.37(s，3H)，3.46-3.48(m，2H)，3.87(s，3H)，4.35-4.38(m，1H)，6.14-6.16(d，1H)，6.82-6.84(d，1H)，7.56(d，1H)，7.61-7.63(dd，1H)。MS(M+H，280.3)。

The compound has an EC of 0.24 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 105

N- (4- (trifluoromethoxy) benzyl) thiophene-2-carboxamide

Prepared in a similar manner to that described in example 4 from thiophene-2-carboxylic acid and (4- (trifluoromethoxy) phenyl) methylamine. MS (M + H, 303).

The compound has an EC of 2.4 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 106

N- (2- (furan-2-ylmethylthio) ethyl) -4-methoxy-3-methylbenzamide

Prepared in a similar manner to that described in example 4 from 4-methoxy-3-methylbenzoic acid and 2- (furan-2-ylmethylthio) ethylamine. The yield was 58%.¹H NMR(500MHz，CDCl₃)2.23(s，3H)，2.76(t，2HJ6.37 Hz), 3.59(q, 2H, J12.2 Hz), 3.76(s, 2H), 3.86(s, 3H), 6.22(dd, 1H, J3.49 Hz, J2.67 Hz), 6.30(dd, 1H, J3.04 Hz, J1.78 Hz), 6.46(m, 1H, broad peak), 6.83(d, 1H, J8.51 Hz), 7.34(dd, 1H, J1.97 Hz, J1 Hz), 7.56(d, 1H, J1.72 Hz), 7.61(dd, 1H, J8.53 Hz, J2.25 Hz). MS (M + H, 306).

The compound has an EC of 5.6 μ M for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 107

Thiophene-3-carboxylic acid 4-trifluoromethoxy-benzylamide

Prepared in a similar manner to that described in example 4 using thiophene-3-carboxylic acid and 4-trifluoromethoxy-benzylamine. MS (M + H, 302.0).

The compound has an EC of 2.2. mu.M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀And when present at 3. mu.M, can have an EC of 8.5 ₅₀The efficacy of monosodium glutamate was enhanced.

Example 108

3-methyl-thiophene-2-carboxylic acid 2, 4-dimethoxy-benzylamide

Prepared in a similar manner to that described in example 4 using 3-methyl-thiophene-2-carboxylic acid and 2, 4-dimethoxy-benzylamine. MS (M + H, 292.2).

The compound has 5.6 mu M activation in HEK293 cellsEC of hT1R1/hT1R3 umami receptor expressed in line₅₀And when present at 3. mu.M, can have an EC of 5.8₅₀The efficacy of monosodium glutamate was enhanced.

Example 109

5-pyridin-2-yl-thiophene-2-carboxylic acid 2, 4-dimethoxy-benzylamide

Prepared in a similar manner to example 4 using 5-pyridin-2-yl-thiophene-2-carboxylic acid and 2, 4-dimethoxy-benzylamine. MS (M + H, 355.2).

The compound has an EC of 2.86 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀And when present at 3. mu.M, can be at an EC of 8₅₀The efficacy of monosodium glutamate was enhanced.

Example 110

2-methyl-2H-pyrazole-3-carboxylic acid 2, 4-dimethoxy-benzylamide

Prepared in a similar manner to example 4 using 2-methyl-2H-pyrazole-3-carboxylic acid and 2, 4-dimethoxy-benzylamine. MS (M + H, 276.2).

The compound has 6 mu M EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line ₅₀And when present at 3. mu.M, can have an EC of 7.9₅₀The efficacy of monosodium glutamate was enhanced.

Example 111

4-hydroxy-3-methyl-N- (1-methyl-3-phenyl-propyl) -benzamide

Prepared in a similar manner to example 4 using 4-hydroxy-3-methyl-benzoic acid and 1-methyl-3-phenyl-propylamine. MS (M + H, 284.2).

The compound has an EC of 2.7 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀And when present at 0.3. mu.M, can have an EC of 7₅₀The efficacy of monosodium glutamate was enhanced.

Example 112

Benzo [1, 3] dioxacene-5-carboxylic acid [2- (4-ethyl-phenyl) -ethyl ] -amide

Prepared in a similar manner to example 4 using benzo [1, 3] dioxacene-5-carboxylic acid and 2- (4-ethyl-phenyl) -ethylamine. MS (M + H, 298.2).

The compound has an EC of 3.86 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 113

4-methoxy-3-methyl-N- (1-phenyl-butyl) -benzamide

Prepared in a similar manner to example 4 using 4-methoxy-3-methyl-benzoic acid and 1-phenyl-butylamine. MS (M + H, 298.2).

The compound has an EC of 2.5 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line ₅₀。

Example 114

4-methoxy-3-methyl-N- (1-pyridin-2-yl-butyl) -benzamide

Prepared in a similar manner to example 4 using 4-methoxy-3-methyl-benzoic acid and 1-pyridin-2-yl-butylamine.¹H NMR(500MHz，CDCl₃)：δ0.91-0.92(t，3H)，1.25-1.3(m，2H)，1.85-1.9(m，2H)，3.86(s，3H)，5.25-5.3(m，1H)，6.80-6.82(d，1H)，7.2-7.3(m，2H)，7.42-7.44(d，1H)，7.6-7.7(m，3H)，8.6(d，1H)。MS(M+H，299.1)。

The compound has 1.54 mu M EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 115

Benzo [1, 3] dioxacene-5-carboxylic acid [1- (4-methoxy-phenyl) -butyl ] -amide

In a similar manner to example 4, benzo [1, 3] is used]Dioxacene-5-carboxylic acid and 1- (4-methoxy-phenyl) -butylamine.¹H NMR(500MHz，CDCl₃)：δ0.93-0.95(t，3H)，1.30-1.39(m，2H)，1.80-1.90(m，2H)，3.79(s，3H)，5.08-5.09(dd，1H)，6.00(s，2H)，6.10-6.12(d，1H)，6.79-6.80(d，1H)，6.87(s，1H)，6，88(s，1H)，7.25-7.28(m，4H)。MS(M+H，328.1)。

The compound has an EC of 4.12 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 116

4-ethoxy-N- [1- (4-methoxy-phenyl) -butyl ] -3-methyl-benzamide

Prepared in a similar manner to example 4 using 4-ethoxy-3-methyl-benzoic acid and 1- (4-methoxy-phenyl) -butylamine.¹H NMR(500MHz，CDCl₃)：δ0.93-0.96(t，3H)，1.31-1.41(m，2H)，1.41-1.45(t，3H)，1.82-1.92(m，2H)，2.28(s，3H)，3.79(s，3H)，4.04-4.08(q，2H)，5.10-5.12(d，1H)，6.12-6.14(d，1H)，6.78-6.80(d，1H)，6.87(s，1H)，6.88(s，1H)，7.26-7.29(m，2H)，7.52-7.53(d，1H)，7.57-7.59(d，1H)。MS(M+H，342.1)。

The compound has an EC of 3.9 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 117

4-methoxy-N- [1- (R) - (4-methoxy-phenyl) -ethyl ] -3-methyl-benzamide

Prepared in a similar manner to example 4 using 4-methoxy-3-methyl-benzoic acid and 1- (R) - (4-methoxy-phenyl) -ethylamine. MS (M + H, 300.1).

The compound has an EC of 2.8 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 118

Benzo [1, 3] dioxacene-5-carboxylic acid indan-1-ylamides

Prepared in a similar manner to example 4 using benzo [1, 3] dioxacene-5-carboxylic acid and indan-1-ylamine. MS (M + H, 282.2).

The compound has 1.2 mu M EC that activates hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀And when present at 0.3. mu.M, can have an EC of 5.33₅₀The efficacy of monosodium glutamate was enhanced.

Example 119

4-methoxy-3-methyl-N- (pent-3-yl) benzamides

Prepared in a similar manner to that described in example 4 from 4-methoxy-3-methylbenzoic acid and pentan-3-amine. MS (M + H, 236).

The compound has an EC of 0.4 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 120

3-methyl-N- (p-tolylethyl) furan-2-carboxamide

Prepared in a similar manner to that described in example 4 from 3-methylfuran-2-carboxylic acid and 2-p-tolylethylamine. MS (M + H, 244).

The compound has 6 mu M EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀And when present at 1. mu.M, can have an EC of 3.3 ₅₀The efficacy of monosodium glutamate was enhanced.

Example 121

N- (2, 4-dimethoxybenzyl) -2- (1H-pyrrol-1-yl) benzamide

Prepared in a similar manner to example 4 using 1- (2- (1H-pyrrol-1-yl) phenyl) ethanone and 2, 4-dimethoxy-benzylamine. MS (M + H, 337.2).

The compound has 1.66 mu M EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀And when present at 1. mu.M, can be at an EC of 11₅₀The efficacy of monosodium glutamate was enhanced.

Example 121-1

(S) -N- (2, 3-dihydro-1H-inden-1-yl) -4-methoxy-3-methylbenzamide

Prepared in a similar manner to example 4 using 4-methoxy-3-methylbenzoic acid and (S) -2, 3-dihydro-1H-inden-1-amine. Yield: and 63 percent.¹H NMR(500MHz，DMSO)：δ1.94-1.99(m，1H)，2.17(s，3H)，2.41-2.46(m，1H)，2.82-2.87(m，1H)，2.96-3.01(m，1H)，3.83(s，3H)，5.53-5.57(dd，1H)，6.98-6.99(d，1H)，7.16-7.23(m，3H)，7.26-7.27(m，1H)，7.75-7.80(m，2H)，8.54-8.55(d，1H)。MS(M+H，282)。

The compound has an EC of 0.08 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 121-2

(R/S) -4-methoxy-N- (5-methoxy-2, 3-dihydro-1H-inden-1-yl) -3-methylbenzamide

In a similar manner to example 4, 4-methoxy-3-methylbenzoic acid was used with 5-methoxy-2, 3-dihydro-1H-inden-1-amine (example 121-2a) (47%). MS (M + H, 312).

The compound has an EC of 0.08 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line ₅₀。

Example 121-2 a: 5-methoxy-2, 3-dihydro-1H-inden-1-amine

To a solution of hydroxylamine hydrochloride (730mg, 10.5mmol) in 10mL of water was added 5-methoxy-2, 3-indan-1-one (1g, 6.17 mmol). The reaction mixture was warmed to 70 ℃ and a solution of sodium acetate (1.4g, 16.7mmol) in 7mL of water, 14mL of MeOH, 3mL of THF was added. After stirring for 1.5h at 70 ℃, 10ml of water was added to generate a precipitate and the suspension was stirred for 2 h. The precipitate was collected by filtration and 5-methoxy-2, 3-indan-1-one oxime was obtained almost quantitatively and used in the next step without further purification. The oxime (0.5g, 2.82mmol) was dissolved in MeOH and a catalytic amount of raney nickel and 25mL ammonia solution in MeOH (7N) were added. At H₂The reaction was stirred at room temperature under atmosphere overnight. The slurry was filtered through celite and concentrated in vacuo, diluted with EtOAc, washed with water and brine, and anhydrous MgSO₄Drying, filtration and concentration in vacuo gave the crude product of the target amine (yield, 45%). Without further purificationBut the crude amine is used directly.

Additional "amide" compounds were synthesized and tested experimentally and found to have relatively high levels of potency as activators of hT1R1/hT1R3 umami receptor expressed in the HEK293 cell line. The test results are shown in table a below.

A variety of amide compounds of formula (I) described elsewhere herein falling within the "oxamide" subgenus of compounds were also synthesized and tested experimentally for their potency as activators of hT1R1/hT1R3 umami receptors expressed in the HEK293 cell line.

Example 122

General procedure A for the preparation of oxalamides

Synthesis of N- (2-methoxy-benzyl) -N' - (2-pyridin-2-yl-ethyl) -oxalamide:

2-methoxybenzylamine (5mmol) was mixed with triethylamine (2 equivalents) in anhydrous dioxane. Ethyloxalyl chloride (1 eq) was added and the mixture was shaken at room temperature for 0.5-2 hours. 2- (2-pyridyl) ethylamine (1 eq) was then added and the suspension was heated at 80 ℃ overnight. The solution was concentrated and the residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and the solvent was evaporated to give the crude product, which was purified by flash column chromatography to give the title compound: the yield is 70%; m.p.118-119 deg.c; 314[ M +1 ] M/e]；1H NMR(CDCl₃)：δ3.02(t，2H)，3.76(dt，2H)，3.86(s，3H)，4.47(d，2H)，6.80-6.90(m，2H)，7.14-7.18(m，2H)，7.20-7.30(m，2H)，7.55-7.62(m，1H)，7.75-7.83(m，1H)，8.05-8.12(m，1H)，8.55-8.63(m，1H)。

The compound has an EC of 0.34 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀And when present at 0.3. mu.M, can have an EC of 18.85₅₀The efficacy of monosodium glutamate was enhanced.

Example 123

N- (2, 4-dimethoxy-benzyl) -N' - (2-pyridin-2-yl-ethyl) -oxalamide

Prepared in a similar manner to example 122 using 2, 4-dimethoxybenzylamine, ethyloxalyl chloride and 2- (2-pyridyl) ethylamine. The yield is 72%; m.p.123-124 ℃; 344[ M +1 ] M/e]；¹H NMR(CDCl₃)：δ3.02(t，2H)，3.73(dd，2H)，3.78(s，3H)，3.82(s，3H)，4.38(d，2H)6.40(dd，1H)，6.44(d，1H)，7.14(m，3H)，7.59(m，1H)，7.82(t，1H)，8.11(t，1H)，8.56(d，1H)，¹³C NMR：δ36.9，38.9，39.4，55.6，55.6，98.8，104.1，117.8，121.9，123.5，130.7，136.8，149.6，158.8，158.8，159.6，160.1，161.0。

The compound has an EC of 0.09 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀And when present at 0.3. mu.M, can have an EC of 6.51₅₀The efficacy of monosodium glutamate was enhanced.

Example 124

N- (3-methyl-thiophen-2-ylmethyl) -N' - (2-pyridin-2-yl-ethyl) -ethanediamide

Prepared in a similar manner to example 122 using (3-methyl-thiophen-2-yl) -methylamine, ethyloxalyl chloride and 2- (2-pyridyl) ethylamine. The yield is 40%; m.p.122-124 ℃; 304[ M +1 ] M/e]；¹H NMR(DMSO-d₆)：δ2.19(s，3H)，2.92-2.95(t，2H)，3.48-3.52(dd，2H)，4.37-4.38(d，2H)，6.79-6.80(d，1H)，7.20-7.27(m，3H)，7.67-7.71(dt，1H)，8.48-8.49(d，1H)，8.87-8.89(t，1H)，9.25-9.28(t，1H)。

The compound has an EC of 0.37 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 125

General procedure B for the Synthesis of oxalamides

N- (4-methyl-benzyl) -N' - (2-pyridin-2-yl-ethyl) -ethanediamide

4-methylbenzylamine (1mmol) was reacted with ethyloxalyl chloride (1 eq) in acetonitrile at room temperature in the presence of triethylamine (2 eq) for 0.5 to 1 hour. 2- (2-pyridyl) ethylamine (1 eq) was then added and the suspension heated in a microwave reactor at 160 ℃ for 5 minutes. The reaction mixture was purified by preparative HPLC to give the pure title oxalamide: the yield is 60%; m.p.152-154 ℃; 298[ M +1 ] M/e ]；¹H NMR(CDCl₃)：δ2.33(s，3H)，3.10(t，2H)，3.75(dt，2H)，4.43(d，2H)，7.10-7015(m，4H)，7.18-7.22(m，2H)，7.65-7.73(m，2H)，8.12(b，1H)，8.60(d，1H)。

The compound has 0.41 mu M activation in HEK293 cell lineEC of hT1R1/hT1R3 umami taste receptor expressed in₅₀。

Example 126

N- (2-methyl-4-methoxybenzyl) -N' - (2-pyridin-2-yl-ethyl) -oxalamide

Prepared in a similar manner to example 122 using 2-methyl-4-methoxybenzylamine, ethyloxalyl chloride and 2- (2-pyridyl) ethylamine. The yield is 51%; m.p.133-134 deg.C; 328[ M +1 ] M/e]；¹H NMR(CDCl₃)：δ2.29(s，3H)，3.04(t，2H)，3.74-3.77(m，2H)，3.78(s，3H)，4.40(d，2H)，6.69-6.73(m，2H)，7.13-7.18(m，3H)，7.51(t，1H)，7.60-7.63(m，1H)，8.17(t，1H)，8.58(d，1H)。

The compound has an EC of 0.11 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 127

N- (2, 4-dimethoxy-benzyl) -N' - (3-pyridin-2-yl-propyl) -oxalamide

Prepared in a similar manner to example 125 using 2, 4-dimethoxybenzylamine, ethyloxalyl chloride and 3- (2-pyridyl) propylamine. The yield is 60%; 358[ M +1 ] M/e]；¹HNMR(CDCl₃)：δ1.99-2.04(m，2H)，2.84(t，2H)，3.36(dd，2H)，3.79(s，3H)，3.82(s，3H)4.60(d，2H)，6.41-6.45(m，2H)，7.10-7.17(m，3H)，7.57-7.60(m，1H)，7.81(t，1H)，7.89(t，1H)，8.54(d，1H)。

The compound has 1.84 mu M EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 128

N- (4-methoxybenzyl) -N' - (2-pyridin-2-yl-ethyl) -ethanediamide

Prepared in a similar manner to example 125 using 4-methoxybenzylamine, ethyloxalyl chloride and 2- (2-pyridyl) ethylamine. The yield is 50%; m.p.156-158 ℃;¹H NMR：3.05(t，3H)，3.72-3.77(m，2H)，3.79(s，3H)，4.40(d，2H)，6.86(d，2H)，7.16-7.22(m，4H)，7.65-7.69(m，3H)，8.15(b，1H)，8.62(d，1H)。

the compound has an EC of 0.75 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line ₅₀。

Example 129

N- (2, 4-Dimethoxybenzyl) -N' - (2- (3-methylpyridin-2-yl) ethyl) ethanediamide

Prepared in a similar manner to example 125 using 2, 4-dimethoxybenzylamine, ethyloxalyl chloride and 2- (3-methylpyridin-2-yl) ethylamine (example 129 a). The yield is 10%; 358[ M +1 ] M/e]；¹H NMR(CDCl₃)：δ2.28(s，3H)，3.01(t，2H)，3.75-3.82(m，2H)，3.79(s，3H)，3.82(s，3H)，4.39(d，2H)，6.41(dd，1H)，6.44(d，1H)，7.10(t，1H)，7.15(d，1H)，7.45(d，1H)，7.81(bs，1H)，8.28(bs，1H)，8.40(d，1H)。

2- (3-methylpyridin-2-yl) ethylamine: to a solution of 2- (3-methylpyridin-2-yl) acetonitrile (example 129b) (95mg, 0.72mmol) in THF (0.5mL) at room temperature was added dropwise 1M BH₃THF (2.2mL, 2.2 mmol). The resulting mixture was heated in a microwave reactor at 130 ℃ for 7 minutes. Then, 6N aqueous HCl (1mL) was added dropwise at room temperature. The resulting mixture was heated in a microwave reactor at 120 ℃ for 4 minutes. The reaction mixture was washed with Et₂O (3X 3mL) was washed, then cooled to 0 ℃ and 10N aqueous NaOH (0.8mL) was added. By K₂CO₃The aqueous solution was saturated. The product was taken up in CHCl₃(6X 5mL) was extracted. Drying the organic extract (1: 1K)₂CO₃/Na₂SO₄) Filtration and concentration in vacuo afforded an oil (85mg, 86%) which was used directly in example 8. M/e 137[ M +1 ]]。

2- (3-methylpyridin-2-yl) acetonitrile: at-78 ℃ in N₂To N-butyllithium (2.5N in hexane, 7.92mL, 19.8mmol) under an atmosphere was added anhydrous THF (75mL) followed by immediate addition of a solution of anhydrous MeCN (1.15mL, 21.78mmol) in anhydrous THF (30mL) over a period of 5 minutes. The resulting reaction mixture was stirred continuously at-78 ℃ for 1 hour. 2-bromo-3-methylpyridine (516mg, 3mmol) was then added. The resulting reaction mixture was stirred at-78 ℃ for 1 hour, then warmed to room temperature and quenched with water. The organic solvent is evaporated in vacuo and dissolved in CH ₂Cl₂In (1). The organic layer was washed with brine and dried (MgSO)₄) Concentrated, purified by column chromatography (20% EtOAc in hexanes) to yield quantitatively the product: 133[ M +1 ] M/e]。

The compound has 1.64 mu M EC that activates hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 130

N- (2, 5-dimethyl-furan-3-ylmethyl) -N' - (2-pyridin-2-yl-ethyl) -ethanediamide

Prepared in a similar manner to example 122 using 2, 5-dimethyl-furan-3-ylmethylamine, ethyloxalyl chloride and 2- (2-pyridyl) ethylamine. The yield is 51%; m.p.112-115 ℃; 302[ M +1 ] M/e]；¹H NMR(DMSO-d₆)：δ2.14(s，3H)，2.18(s，3H)，2.91-2.94(t，2H)，3.47-3.51(dd，2H)，3.98-3.99(d，2H)，5.89(s，1H)，7.20-7.25(m，2H)，7.68-7.71(dt，1H)，8，48-8.49(d，1H)，8.81-8.84(t，1H)，8.97-9.00(t，1H)。

The compound has 1.01 mu M EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 131

N- (1, 5-dimethyl-1H-pyrrol-2-ylmethyl) -N' - (2-pyridin-2-yl-ethyl) -ethanediamide

Prepared in a similar manner to example 122 using 1, 5-dimethyl-1H-pyrrol-2-ylmethylamine, ethyloxalyl chloride and 2- (2-pyridyl) ethylamine. The yield is 25%; m.p.147-149 deg.C; 301[ M +1 ] M/e]；¹H NMR(DMSO-d₆)：δ2.11(s，3H)，2.92-2.95(t，2H)，3.38(s，3H)，3.48-3.52(q，2H)，4.24-4.25(d，2H)，5.64-5.65(d，1H)，5.79-5.65(d，1H)，7.20-7.25(m，2H)，7.68-7.71(dt，1H)，8.48-8.49(d，1H)，8.82-8.86(m，2H)。

The compound has an EC of 2.3 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 132

N- (2-methoxy-4-methylbenzyl) -N' - (2- (pyridin-2-yl) ethyl) ethanediamide

Prepared in a similar manner to example 125 using (2-methoxy-4-methylphenyl) methylamine (example 132a), ethyloxalyl chloride and 2- (2-pyridyl) ethylamine. The yield is 20%; m.p.128-131 ℃; 328[ M +1 ] M/e]；¹H NMR(CDCl₃)：2.33(s，3H)，3.02(t，2H)，3.73(m，2H)，3.84(s，3H)，4.42(d，2H)，6.70(m，2H)，7.14(m，3H)，7.60(m，1H)，7.86(s，1H)，8.09(s，1H)，8.56(d，1H)。

a (2-methoxy-4-methylphenyl) methylamine: to a solution of 2-methoxy-4-methylbenzamide (example 132b) (200mg, 1.21mmol) in THF (0.5mL) at room temperature was slowly added 1M BH₃THF (2.4ml, 2.42 mmol). The resulting mixture was heated in a microwave reactor at 130 ℃ for 7 minutes. Then, 6N aqueous HCl (1mL) was added dropwise at room temperature. The resulting mixture was heated in a microwave reactor at 120 ℃ for 4 minutes. The reaction mixture was washed with Et₂O (3X 3mL) was washed, then cooled to 0 ℃ and 10N aqueous NaOH (0.8mL) was added. By K₂CO₃The aqueous solution was saturated. The product was taken up in CHCl₃(6X 5mL) was extracted. Drying the organic extract (1: 1K)₂CO₃/Na₂SO₄) Filtration and concentration in vacuo afforded 180mg of (2-methoxy-4-methylphenyl) methylamine, which was used directly in example 11.

2-methoxy-4-methylbenzamide: 2-methoxy-4-methylbenzoic acid (500mg, 3.01mmol) was mixed with 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (557mg, 3.01mmol) and 1-hydroxybenzotriazole (407mg, 3.01mmol) in 25ml of dichloromethane at room temperature and stirred for 5 minutes. A2M aqueous ammonia solution in methanol (4.5ml, 9.03mmol) was added and the reaction mixture was stirred at room temperature for about 5 hours, then diluted with dichloromethane, diluted with 1N HCl, saturated (sat.) NaHCO ₃Water and brine, over MgSO₄Dried, filtered and evaporated to give 440mg of 2-methoxy-4-methylbenzamide in 88% yield.

The compound has an EC of 0.04 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 133

N- (2, 4-dimethylbenzyl) -N' - (2- (pyridin-2-yl) ethyl) ethanediamide

Prepared in a similar manner to example 125 using (2, 4-dimethylphenyl) methylamine (example 133a), ethyloxalyl chloride and 2- (2-pyridyl) ethylamine. The yield is 60%; m.p.148-149 deg.C, M/e 312[ M +1 ]]；¹H NMR(CDCl₃)：2.28(s，3H)，2.30(s，3H)，3.05(t，2H)，3.76(dd，2H)，4.43(d，2H)，6.99(m，2H)，7.11(d，1H)，7.17(m，2H)，7.54(s，1H)，7.62(m，1H)，8.17(s，1H)，8.58(d，1H)。

a (2, 4-dimethylphenyl) methylamine: a 1M solution of lithium aluminum hydride in THF (15.2ml, 15.2mmol) was placed in a pre-dried flask at 0 ℃ under an argon atmosphere; a solution of 2, 4-dimethylbenzonitrile (1.0g, 7.6mmol) in 15ml of anhydrous ether was carefully added dropwise thereto. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for 3 hours. Then cooled to 0 ℃, anhydrous sodium sulfate was added and 1ml of water was carefully added dropwise. Diluting the mixture with ethyl acetate, filtering off insoluble material, washing the filtrate with water and brine, and MgSO₄Drying, filtration and evaporation gave 1.03g of pure (2, 4-dimethylphenyl) methylamine in quantitative yield without purification.

The compound has an EC of 0.07 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 134

N- (4-ethoxy-2-methoxybenzyl) -N' - (2- (pyridin-2-yl) ethyl) ethanediamide

Prepared in a similar manner to example 125 using (4-ethoxy-2-methoxyphenyl) methylamine (example 134a), ethyloxalyl chloride and 2- (2-pyridyl) ethylamine. The yield is 10%; m.p.117-118 deg.C, M/e 358[ M +1 ]]；¹H NMR(CDCl₃)：1.40(t，3H)，3.03(t，2H)，3.74(dd，2H)，3.82(s，3H)，4.01(dd，2H)，4.39(d，2H)，6.39(d，1H)，6.44(s，1H)，7.15(m，3H)，7.61(m，1H)，7.81(s，1H)，8.10(s，1H)，8.56(d，1H)。

a (4-ethoxy-2-methoxyphenyl) methylamine: to a solution of 4-ethoxy-2-methoxybenzaldehyde (example 134b) (880mg, 4.88mmol) in 50ml of anhydrous methanol was added ammonium acetate (7.5g, 97.60mmol) and sodium cyanoborohydride (613mg, 9.76 mmol). The reaction mixture was stirred at room temperature for about 4 hours. Then concentrated in a rotary evaporator, the residue diluted with water and basified with 15% aqueous NaOH, extracted with ethyl acetate, washed with water and brine, MgSO₄Drying, filtration and evaporation of the solvent, purification of the residue by column chromatography on silica gel (DCM/MeOH 9: 1) to yield 150mg of product; yield 17% (the process was not optimized).

4-ethoxy-2-methoxybenzaldehyde: to a solution of 4-hydroxy-2-methoxybenzaldehyde (1.0g, 6.57mmol) in 10ml of acetone were added potassium carbonate (0.91g, 6.57mmol) and iodoethane (1.6ml, 19.71mmol), and the reaction mixture was stirred at room temperature overnight. Removing the acetone in a rotary evaporator; the residue was diluted with water and ethyl acetate; extracted with ethyl acetate, washed with brine, over MgSO ₄Drying, filtering and evaporating to obtain a crude product, subjecting the crude product to silica gel column chromatography (acetic acid)Ethyl ester/hexane 1: 4) to yield 943mg of product; the yield was 80%.

The compound has an EC of 0.1. mu.M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 135

N- (4-methoxy-3-methylbenzyl) -N' - (2- (pyridin-2-yl) ethyl) ethanediamide

Prepared in a similar manner to example 125 using (4-methoxy-3-methylphenyl) methylamine (example 135a), ethyloxalyl chloride and 2- (2-pyridyl) ethylamine. The yield is 12%; m.p.145-147 deg.C, M/e ═ 328[ M +1]]；¹H NMR(CDCl₃)：2.19(s，3H)，3.04(t，2H)，3.76(dd，2H)，3.81(s，3H)，4.37(d，2H)，6.76(d，1H)，7.06(m，2H)，7.16(m，2H)，7.61(m，1H)，7.66(s，1H)，8.18(s，1H)，8.58(d，1H)。

a (4-methoxy-3-methylphenyl) methylamine: prepared in a similar manner to example 134a using 4-methoxy-3-methylbenzaldehyde, ammonium acetate and sodium cyanoborohydride in MeOH; yield 22% (110 mg).

The compound has 1.04 mu M EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 136

N- (2-chlorobenzyl) -N' - (2- (pyridin-2-yl) ethyl) oxalamide:

prepared in a similar manner to example 125 using (2-chlorophenyl) methylamine, ethyloxalyl chloride and 2- (2-pyridyl) ethylamine. The yield is 45%; m/e is 318[ M +1 ].

The compound has an EC of 0.01. mu.M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 137

N- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxin-5-yl) methyl) -N' - (2- (pyridin-2-yl) ethyl) ethanediamide

Prepared in a similar manner to example 122 using (2, 3-dihydrobenzo [ b ] [1, 4] dioxin-5-yl) methylamine, ethyloxalyl chloride and 2- (2-pyridyl) ethylamine. The yield is 50%; and M/e is 342[ M +1 ].

The compound has an EC of 0.3 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 138

N- (benzo [ d ] [1, 3] dioxan-5-ylmethyl) -N' - (2- (pyridin-2-yl) ethyl) ethanediamide

Prepared in a similar manner to example 125 using benzo [ d ] [1, 3] dioxan-5-ylmethylamine, ethyloxalyl chloride and 2- (2-pyridyl) ethylamine. The yield is 35%; and M/e is 328[ M +1 ].

The compound has an EC of 0.5 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 139

N- (4-ethylbenzyl) -N' - (2- (pyridin-2-yl) ethyl) ethanediamide

Prepared in a similar manner to example 125 using 4-ethylbenzylamine, ethyloxalyl chloride and 2- (2-pyridyl) ethylamine. The yield is 38%; and M/e is 312[ M +1 ].

The compound has an EC of 0.79 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 140

N- (benzofuran-5-ylmethyl) -N' - (2- (pyridin-2-yl) ethyl) ethanediamide

Prepared in a similar manner to example 125 using benzofuran-5-ylmethylamine, ethyloxalyl chloride and 2- (2-pyridyl) ethylamine. The yield is 64%; and M/e is 324[ M +1 ].

The compound has 1.78 mu M EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 141

N- ((4-methoxycarbonylphenyl) methyl) -N' - (2- (pyridin-2-yl) ethyl) ethanediamide

Prepared in a similar manner to example 122 using 4-methoxycarbonylphenylmethylamine, ethyloxalyl chloride and 2- (2-pyridyl) ethylamine. The yield is 52%; and M/e is 342[ M +1 ].

The compound has an EC of 3.63 μ M for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 142

N- ((2-carbamoylphenyl) methyl) -N' - (2- (pyridin-2-yl) ethyl) ethanediamide

Prepared in a similar manner to example 122 using 2-carbamoylphenylmethylamine, ethyloxalyl chloride and 2- (2-pyridyl) ethylamine. The yield is 48%; and M/e is 342[ M +1 ].

The compound has an EC of 8.5. mu.M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 143

N- (2, 4-Dimethoxybenzyl) -N' - (1- (pyridin-2-yl) propan-2-yl) ethanediamide

Prepared in a similar manner to example 125 using 2, 4-dimethoxybenzylamine, ethyloxalyl chloride and 1- (pyridin-2-yl) propan-2-ylamine (example 143 a). The yield is 34%; 357[ M +1] M/e.

1- (pyridin-2-yl) propan-2-ylamine: prepared in a similar manner to example 129a using 2- (pyridin-2-yl) propionitrile (example 143 b); the crude product was used directly in example 143; the yield is 53 percent; and M/e is 137[ M +1 ].

2- (pyridin-2-yl) propionitrile: 5mmol of 2- (pyridin-2-yl) acetonitrile were dissolved in 8ml of anhydrous THF and placed in an ice bath. Potassium tert-butoxide (1 eq) was added and the reaction stirred for 30 minutes. Methyl iodide (1 eq) was dissolved in 5mL of anhydrous THF and slowly added over a period of 30 minutes.

The reaction was stirred at room temperature overnight. The solvent was evaporated, the crude mixture was dissolved in ethyl acetate and washed with water. The ethyl acetate layer was evaporated and the product was purified by preparative TLC (30% ethyl acetate/hexane); the yield is 71%; and M/e is 133[ M +1 ].

The compound has an EC of 0.4 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line ₅₀。

Example 144

N- (2, 4-Dimethoxybenzyl) -N' - (2- (pyridin-2-yl) propyl) ethanediamide

Prepared in a similar manner to example 125 using 2, 4-dimethoxybenzylamine, ethyloxalyl chloride and 2- (pyridin-2-yl) propylamine (example 144 a); the yield is 35%; 357[ M +1] M/e.

2- (pyridin-2-yl) propylamine: 10mmol of 2-methylpyridine were dissolved in anhydrous THF and kept at 0 ℃ under inert conditions. Butyllithium (1.2 eq) was added dropwise and stirred at 0 ℃ for a further 15 minutes, while the temperature was raised back to room temperature. After stirring at room temperature for 1 hour, the reaction mixture was again cooled to 0 ℃ and acetonitrile (2 equivalents) was added dropwise. The reaction was stirred at room temperature overnight. After cooling the reaction to 0 ℃, 30mL of methanol was added to the reaction mixture. Sodium borohydride (3 equivalents) was added slowly in portions at 0 ℃. The reaction was stirred for an additional 1 hour and the temperature was raised to room temperature. The reaction mixture was diluted with water and extracted thoroughly with ethyl acetate. The combined extracts were washed with water and brine and dried completely over sodium sulfate. The solution was concentrated and dissolved in ether. The product was extracted with 3N aqueous HCl, the acidic extract was washed with diethyl ether and basified with NaOH. The product was extracted thoroughly with ether, the combined ether extracts were washed with water and dried completely over sodium sulfate. Complete evaporation of the solvent gave a sufficiently pure product; the yield is 47%; and M/e is 137[ M +1 ].

The compound has 1.07 mu M EC for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 145

N- (2-methoxybenzyl) -N' - (2- (pyridin-2-yl) ethyl) ethanediamide

Prepared in a similar manner to example 125 using 2-methylbenzylamine, ethyloxalyl chloride and 2- (2-pyridin-2-yl) ethylamine. 298[ M +1] M/e]；¹H NMR(CDCl₃)δ2.32(s，3H)，3.11(t，2H)，3.78(dt，2H)，4.46(d，2H)，7.15-7.26(m，6H)，7.50-7.55(m，1H)，7.62-7.67(m，1H)，8.12-8.15(m，1H)，8.60(d，1H)。

The compound has an EC of 0.59. mu.M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 146

N- (2, 3-Dimethoxybenzyl) -N' - (2- (pyridin-2-yl) ethyl) ethanediamide

Prepared in a similar manner to example 125 using 2, 3-dimethoxybenzylamine, ethyloxalyl chloride and 2- (pyridin-2-yl) ethylamine; m/e is 343[ M +1 ].

The compound has an EC of 0.69 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 147

N- (2- (methylthio) benzyl) -N' - (2- (pyridin-2-yl) ethyl) ethanediamide

Prepared in a similar manner to example 125 using 2-methylthiobenzylamine, ethyloxalyl chloride and 2- (pyridin-2-yl) ethylamine. 330[ M +1] M/e]；¹H NMR(CDCl₃)δ2.49(s，3H)，3.08(t，2H)，3.77(dt，2H)，4.55(d，2H)，7.11-7.14(m，1H)，7.15-7.20(m，2H)，7.22-7.27(m，3H)，7.62(t，1H)，7.78-7.83(m，1H)，8.08-8.11(m，1H)，8.56(d，1H)。

The compound has an EC of 0.96 mu M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line ₅₀。

Example 148

N- (2-hydroxybenzyl) -N' - (2- (pyridin-2-yl) ethyl) ethanediamide

Prepared in a similar manner to example 125 using 2-hydroxybenzylamine, ethyloxalyl chloride and 2- (pyridin-2-yl) ethylamine; and M/e is 300[ M +1 ].

The compound has an EC of 3.11 μ M for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 149

N- (benzo [ d ] [1, 3] dioxan-4-ylmethyl) -N' - (2- (pyridin-2-yl) ethyl) ethanediamide

In a similar manner to example 125, use is made of benzo [ d ]][1，3]Dioxan-4-ylmethyl amine (example 149a), ethyloxalyl chloride and 2- (pyridin-2-yl) ethylamine; the yield is 12%; 328[ M +1] M/e]；¹H NMR(CDCl₃)：δ3.12(m，2H)，3.77-3.80(m，2H)，4.46-4.47(d，2H)，5.98(s，2H)，6.74-6.79(m，3H)，7.24(m，1H)，7.7-7.8(m，3H)，8.10-8.15(m，1H)，8.58-8.59(m，1H)。

a. Benzo [ d ] [1, 3] dioxan-4-ylmethylamines: prepared in a similar manner to example 134a from benzo [ d ] [1, 3] dioxacene-4-carbaldehyde and ammonium acetate. The crude material contained about 20% of the product (M/e ═ 152.2[ M +1]) and was used directly in example 149.

The compound has an EC of 0.17 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 150

N- (benzo [ b ] thiophen-2-ylmethyl) -N' - (2- (pyridin-2-yl) ethyl) ethanediamide

In a similar manner to example 125, use was made of benzo [ b ] ]Thien-2-ylmethylamine, ethyloxalyl chloride and 2- (pyridin-2-yl) ethylamine; the yield is 32%; 240[ M +1 ] M/e]；¹HNMR(DMSO-d₆)：δ2.92-2.95(t，2H)，3.48-3.53(m，2H)，4.55-4.56(d，2H)，7.20-7.25(m，2H)，7.38-7.41(m，2H)，7.50(s，1H)，7.66-7.70(m，1H)，7.95-7.99(m，2H)，8.47-8.49(d，1H)，8.88-8.90(t，1H)，9.29-9.31(t，1H)。

The compound has an EC of 0.74. mu.M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 151

N- (benzo [ d ] thiazol-2-ylmethyl) -N' - (2- (pyridin-2-yl) ethyl) ethanediamide

In a similar manner to example 125, use is made of benzo [ d ]]Thiazol-2-ylmethylamine, ethyloxalyl chloride, and 2- (pyridin-2-yl) ethylamine; the yield is 33%; 341[ M +1 ] M/e]；¹HNMR(DMSO-d₆)：δ2.95-2.98(t，2H)，3.52-3.57(m，2H)，4.72-4.73(d，2H)，7.22-7.24(m，1H)，7.25-7.27(d，1H)，7.40-7.44(t，1H)，7.48-7.51(t，1H)，7.69-7.72(dt，1H)，7.95-7.96(d，1H)，8.05-8.07(d，1H)，8.49-8.50(d，1H)，8.96-8.98(t，1H)，9.67-9.70(t，1H)。

The compound has an EC of 4.4. mu.M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 152

N- ((5-Methylfuran-2-yl) methyl) -N2- (2- (pyridin-2-yl) ethyl) ethanediamide

In a similar manner to example 125, using (5-methylfuran-2-yl) methylamine, ethyloxalyl chloride and 2- (pir-ethyl)Pyridin-2-yl) ethylamine; the yield is 38%; 288[ M +1 ] M/e]；¹HNMR(DMSO-d₆)：δ2.20(s，3H)，2.92-2.95(t，2H)，3.48-3.52(m，2H)，4.23-4.24(d，2H)，5.96-5.97(d，1H)，6.06-6.07(d，1H)，7.20-7.25(m，2H)，7.68-7.71(t，1H)，8.48-8.49(d，1H)，8.85-8.87(t，1H)，9.04-9.07(t，1H)。

The compound has an EC of 4.9 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 153

N- ((2-methylfuran-3-yl) methyl) -N' - (2- (pyridin-2-yl) ethyl) oxalamide

Prepared in a similar manner to example 125 using (2-methylfuran-3-yl) methylamine (example 153a), ethyloxalyl chloride and 2- (pyridin-2-yl) ethylamine; the yield is 50%; 288[ M +1 ] M/e ]；¹H NMR(DMSO-d₆)：δ2.23(s，3H)，2.91-2.94(t，2H)，3.48-3.52(q，2H)，4.05-4.06(d，2H)，6.30-6.31(d，1H)，7.20-7.25(m，2H)，7.38-7.39(d，1H)，7.67-7.71(dt，1H)，8.48-8.49(d，1H)，8.83-8.86(t，1H)，9.04-9.07(t，1H)。

a (2-methylfuran-3-yl) methylamine: a solution of 10mmol (1.256m) of methyl 2-methylfuran-3-carboxylate and 38.9mmol (2.1g) of NaOMe in 20ml of formamide is stirred at 100 ℃ for 30 minutes. The reaction mixture was poured into ice water (20m) and extracted with ethyl acetate (3 times). The extract is extracted with MgSO₄Dried and concentrated to give 1.05g (83%) of 2-methylfuran-3-carboxamide as an oil (M/e ═ 126.2[ M + 1%]). The amide was dissolved in anhydrous THF (10M) and added dropwise to 15ml of 1M LiAlH at 0 ℃ under an argon atmosphere₄And 15ml of THF. The mixture was then stirred at 60 ℃ for 5 hours. After cooling, 50% aqueous THF solution (is added to the mixture at 5-10 ℃30 m). The resulting precipitate was removed by filtration, and the filtered solution was dried and concentrated to give the product as an oil (0.93g, 84%).

The compound has 1.82 mu M EC that activates hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 154

N- (2, 4-Dimethoxybenzyl) -N' - (2- (4-methylpyridin-2-yl) ethyl) ethanediamide

Prepared in a similar manner to example 122 using 2, 4-dimethoxybenzylamine, ethyloxalyl chloride and 2- (4-methylpyridin-2-yl) ethylamine (example 154 a); the yield is 11%; 358[ M +1 ] M/e ]；m.p.144-145℃，¹H NMR(CDCl₃)：δ2.31(s，3H)，2.97(t，2H)，3.71(q，2H)，3.79(s，3H)，3.83(s，3H)，4.39(d，2H)，6.40(dd，1H)，6.44(d，1H)，6.97(s，1H)，6.98(d，1H)，7.15(d，1H)，7.81(br s，1H)，8.08(br s，1H)，8.41(d，1H)。

2- (4-methylpyridin-2-yl) ethylamine: prepared in a similar manner to example 129 using 2- (4-methylpyridin-2-yl) acetonitrile (example 154 b); the yield is 83%; and M/e is 137[ M +1 ].

2- (4-methylpyridin-2-yl) acetonitrile: prepared in a similar manner to example 129b using 2-bromo-4-methylpyridine, acetonitrile and n-butyllithium; the yield is 88%; and M/e is 133[ M +1 ].

The compound has 1.64 mu M EC that activates hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 155

N- (2, 4-Dimethoxybenzyl) -N' - (2- (5-methylpyridin-2-yl) ethyl) ethanediamide

Prepared in a similar manner to example 122 using 2, 4-dimethoxybenzylamine, ethyloxalyl chloride and 2- (5-methylpyridin-2-yl) ethylamine (example 155 a); the yield is 9%; 358[ M +1] M/e]；m.p.124-125℃，¹H NMR(CDCl₃)：δ2.30(s，3H)，2.97(t，2H)，3.70(q，2H)，3.79(s，3H)，3.82(s，3H)，4.38(d，2H)，6.40(dd，1H)，6.44(d，1H)，7.03(d，1H)，7.14(d，1H)，7.40(dd，1H)，7.81(br s，1H)，8.08(br s，1H)，8.38(d，1H)。

2- (5-methylpyridin-2-yl) ethylamine: prepared in a similar manner to example 129a using 2- (5-methylpyridin-2-yl) acetonitrile (155 b); the yield is 40%; and M/e is 137[ M +1 ].

2- (5-methylpyridin-2-yl) acetonitrile: prepared in a similar manner to example 129b using 2-bromo-5-methylpyridine, acetonitrile and n-butyllithium; the yield is 68 percent; and M/e is 133[ M +1 ].

The compound has an EC of 0.07 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Example 156

N- (2, 4-Dimethoxybenzyl) -N' - (2- (thien-2-yl) ethyl) ethanediamide

Prepared in a similar manner to example 122 using 2, 4-dimethoxybenzylamine, ethyloxalyl chloride and 2- (thien-2-yl) ethylamine; the yield is 72%; 349[ M +1 ] M/e]；m.p.146-147℃，¹H NMR(CDCl₃)：δ3.06(t，2H)，3.58(q，2H)，3.80(s，3H)，3.83(s，3H)，4.40(d，2H)，6.41(dd，1H)，6.45(d，1H)，6.84(dd，1H)，6.93(dd，1H)，7.15(d，1H)，7.16(d，1H)，7.61(br s，1H)，7.81(br s，1H)。

The compound has an EC of 4.87 mu M for activating hT1R1/hT1R3 umami taste receptor expressed in HEK293 cell line₅₀。

Example 157

N¹- (2-methoxy-4-methylbenzyl) -N²- (2- (5-methylpyridin-2-yl) ethyl) ethanediamide

¹H NMR(CDCl₃，500MHz)：δ2.29(3H，s)，2.33(3H，s)，2.97(2H，t，J＝6.5Hz)，3.71(2H，q，J＝6.5Hz)，3.83(3H，s)，4.40(2H，d，J＝6.2Hz)，6.68(1H，s)，6.69(1H，d，J＝7.7Hz)，7.02(1H，d，J＝7.9Hz)，7.09(1H，d，J＝7.5Hz)，7.40(1H，dd，J₁＝1.8Hz，J₂＝7.8Hz)，7.85(1H，br t)，8.06(1H，br t)，8.38(1H，s，J＝7.5Hz)。

13C NMR(CDCl₃，500MHz)：18.3，21.8，36.5，39.1，39.6，55.5，111.5，121.3，122.3，123.0，129.9，131.3，137.4，139.6，150.0，155.7，157.7，159.7，160.1。

Elemental analysis: c₁₈H₂₁N₃O₃.1/4H₂Calculated value of O: c, 65.97, H, 6.85, N, 12.15, found: c, 66.10, H, 7.34, N, 12.17.MS (342, M + 1). White powder with melting point of 133.5-134 deg.C

The compound has an EC of 0.03 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

This compound was synthesized by the reaction sequence described in the following figure, followed by details of each of the six synthetic steps.

Step 1: to a solution of 2-hydroxy-4-methylbenzoic acid in (25g, 0.164mol) acetone (350mL) was added K₂CO₃(68g, 0.492mmol), followed by MeI (41mL, 0.656mmol) and the reaction mixture heated to reflux for 48 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was evaporated to give crude methyl 2-methoxy-4-methylbenzoate. KOH (11.3g, 1.2 equiv.) was dissolved in MeOH (300mL) and the resulting crude ester was added to the mixture and the resulting solution heated to reflux for 48 h. After cooling the reaction mixture, it was acidified with aqueous HCl (1N) and extracted with ethyl acetate. The organic layer was washed with brine, over MgSO ₄Drying, filtering and evaporating. The residue was triturated with ethyl acetate/hexane to give 20g of 2-methoxy-4-methylbenzoic acid as a cream white solid (85% yield).

Step 2: to a solution of a mixture of 2-methoxy-4-methylbenzoic acid (20g, 120.4mmol), EDC (23.1g, 120.4mmol) and HOBt (16.3g, 120.4mmol) in dichloromethane (1L) was added dropwise NH₃(7N in methanol, 52mL, 3 equiv.). The reaction mixture was stirred at room temperature overnight and then successively treated with HCl (1N), NaHCO₃Washing with saturated aqueous solution, water, brine, MgSO₄Dried, filtered and evaporated. The residue was recrystallized from ethyl acetate/hexane to give 16.5g of 2-methoxy-4-methylbenzamide (83% yield).

And step 3: at 0 ℃ and N₂To a solution of 2-methoxy-4-methylbenzamide (14.55g, 88.08mmol) in anhydrous THF (50mL) was added borane-tetrahydrofuran complex (1.0M in THF, 220mL, 2.5 equiv) dropwise under an atmosphere. The reaction mixture was then heated to 60 ℃ overnight. The reaction was cooled to room temperature and carefully addedAqueous HCl (6N, 37mL) was added and the reaction mixture was then heated at 70 ℃ for 2 hours. After cooling, water was added and the resulting solution was washed with diethyl ether. Basified the aqueous layer with aqueous NaOH (10N) at 0 ℃ and treated with K ₂CO₃Saturation was performed followed by extraction with ethyl acetate. The organic layer was washed with brine, over MgSO₄Drying, filtration and evaporation gave 8.5g (2-methoxy-4-methylphenyl) methylamine (64% yield).

And 4, step 4: at-78 ℃ N₂To a solution of anhydrous acetonitrile (10.1mL, 191.83mmol, 3.3 equiv.) in anhydrous THF (500mL) was added n-butyllithium (2.5M in hexane, 69.8mL, 174.39mmol, 3 equiv.) dropwise under ambient conditions. The resulting white suspension was stirred at-78 ℃ for 1 h, then a solution of 2-bromo-5-methylpyridine (10.0g, 58.13mmol, 1 eq.) in anhydrous THF (30mL) was added. The reaction mixture was held at-78 ℃ for 1 hour and then slowly warmed to room temperature and stirred for an additional 1 hour. Ice/water was added and the layers separated. The organic layer was washed with water and brine, MgSO₄Drying, filtration and evaporation gave 18g of crude 2- (5-methylpyridin-2-yl) acetonitrile. Since the product is very volatile, it does not dry under high vacuum but remains partially solvent-containing.

And 5: at 0 ℃ and N₂To a solution of 18g of crude 2- (5-methylpyridin-2-yl) acetonitrile in anhydrous THF (100mL) was added borane-tetrahydrofuran complex (1.0M in THF, 232mL, 232.5mmol, 4 equiv.) dropwise under an atmosphere. The reaction mixture was then heated to 60 ℃ overnight. The reaction was cooled to room temperature, aqueous HCl (6N, 40mL) was added carefully, and the reaction mixture was then heated at 70 ℃ for 2 hours. After cooling, water was added and the resulting solution was washed with diethyl ether. Basified the aqueous layer with aqueous NaOH (10N) at 0 ℃ and treated with K ₂CO₃Saturation was performed followed by extraction with ether (100mL, 5 times). The organic layer was MgSO₄Drying, filtration and evaporation gave 7.6g of crude 2- (5-methylpyridin-2-yl) ethylamine. (96% crude yield)

When the ether was distilled off, the bath temperature was kept at 25 ℃ since the boiling point of the amine might be around 100 ℃.

Step 6:in N₂Under atmosphere, 2g of (2-methoxy-4-methylphenyl) methylamine (from step 3) and Et₃N (3.7mL, 2 equiv.) in anhydrous CH₃The mixture in CN (45mL) was cooled to 0 deg.C and ethyl 2-chloro-2-oxoacetate (1.47mL, 1 eq) was added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 4 hours and 2- (5-methylpyridin-2-yl) ethylamine (2.52g, 1.4 eq, from step 5) was added. The reaction was heated to reflux for 24 hours. After cooling the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and washed successively with water, brine and MgSO₄Dried, filtered and evaporated. The residue was chromatographed on silica gel (eluent: 25-35% acetone in hexane) and then recrystallized from ethyl acetate/hexane and ethanol/water to give 650mg of N¹- (2-methoxy-4-methylphenyl) -N²- (2- (5-methylpyridin-2-yl) ethyl) ethanediamide (15%)

Additional "oxamide" compounds were synthesized and tested experimentally and found to have relatively high levels of potency as activators of the hT1R1/hT1R3 umami receptor expressed in the HEK293 cell line. The test results are shown in table B below.

A number of amide compounds of formula (I) falling within the subgenus of "urea" compounds described elsewhere herein as formula (IV) were also synthesized and tested experimentally for their potency as activators of hT1R1/hT1R3 umami receptor expressed in the HEK293 cell line.

Example 158

1- (4-chlorophenyl) -3- (hept-4-yl) urea

To CH at room temperature₂Cl₂To a solution of hept-4-amine (0.18mL, 1mmol) in (5mL) was added 1-chloro-2-isocyanatobenzene (0.12mL, 1 mmol). The reaction mixture was stirred for 2 hours. A white solid precipitated. The reaction mixture was filtered. By CH₂Cl₂The solid was washed to give 1- (4-chlorophenyl) -3- (hept-4-yl) urea as a white solid (180mg, 67%). mp: 135 ℃ and 136 ℃.¹H NMR(500MHz，CDCl₃)：δ0.93(t，6H)，1.45(m，6H)，1.53(m，2H)，3.80(br s，1H)，4.33(d，1H)，6.00(s，1H)，6.95(td，1H)，7.23(dt，1H)，7.33(dd，1H)，8.13(dd，1H)。MS(M+H，269)。

The compound has an EC of 0.37 μ M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀And when present at 1. mu.M, can have an EC of 4.95₅₀The efficacy of monosodium glutamate was enhanced.

Example 159

1- (2, 4-Dimethoxyphenyl) -3- (hept-4-yl) urea

Prepared in a similar manner to example 158 using heptan-4-amine and 1-isocyanato-2, 4-dimethoxybenzene. Yield: 88 percent. mp: 172 ℃ and 173 ℃.¹H NMR(500MHz，CDCl₃)：δ0.93(t，6H)，1.45(m，8H)，3.82(s，3H)，3.83(m，1H)，3.84(s，1H)，4.32(br s，1H)，6.34(br s，1H)，6.49(d，1H)，6.50(s，1H)，7.71(d，1H)。MS(M+H，295)。

The compound has 0.98 mu M activation of expression in HEK293 cell line EC of hT1R1/hT1R3 umami taste receptor₅₀And when present at 0.3. mu.M, can have an EC of 7.61₅₀The efficacy of monosodium glutamate was enhanced.

Example 160

1- (4-ethoxyphenyl) -3- (2- (pyridin-2-yl) ethyl) urea

Prepared in a similar manner to example 158 using 2- (pyridin-2-yl) ethylamine and 1-ethoxy-4-isocyanatobenzene. Yield: 95 percent. mp: 163 ℃ and 164 ℃.¹H NMR(500MHz，CDCl₃)：δ1.43(t，3H)，3.03(t，2H)，3.68(t，2H)，4.03(q，2H)，5.69(brs，1H)，6.45(br s，1H)，6.84(m，2H)，7.14(m，3H)，7.20(d，1H)，7.64(dt，1H)，8.43(dd，1H)。MS(M+H，286)。

The compound has an EC of 4.1. mu.M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀And when present at 1. mu.M, can have an EC of 4.2₅₀The efficacy of monosodium glutamate was enhanced.

Example 161

1- (4-isopropylphenyl) -3- (2- (pyridin-2-yl) ethyl) urea

Prepared in a similar manner to example 158 using 2- (pyridin-2-yl) ethylamine and 1-isocyanato-4-isopropylbenzene. By column Chromatography (CH)₂Cl₂1% MeOH-CH in (C)₂Cl₂MeOH) to yield 1- (4-isopropylphenyl) -3- (2- (pyridin-2-yl) ethyl) urea as a white solid (130mg, 50%). mp: 72-73 ℃.¹H NMR(500MHz，CDCl₃)：δ1.25(d，6H)，2.89(m，1H)，3.06(t，2H)，3.70(t，2H)，5.80(br s，1H)，6.55(br s，1H)，7.19(m，5H)，7.24(d，1H)，7.68(dt，1H)，8.46(d，1H)。MS(M+H，284)。

The compound has an EC of 0.98. mu.M for activating hT1R1/hT1R3 umami taste receptors expressed in HEK293 cell line₅₀。

Additional "urea" compounds were synthesized and tested experimentally and found to have relatively high levels of potency as activators of hT1R1/hT1R3 umami receptors expressed in the HEK293 cell line. The test results are shown in table C below.

A number of amide compounds of formula (I) falling within the subgenus of "acrylamide" compounds described elsewhere herein were also synthesized and tested experimentally for their potency as activators of hT1R1/hT1R3 umami receptor expressed in the HEK293 cell line. The test results are shown in table D below.

Umami/savoury testing with human taster:

selection of general panelists: basic screening of sensory tasting testers: potential panelists were tested for their ability to grade and rate the strength of solutions representing five basic tastes. The panelists rated and rated the intensity of five different concentrations of the following five compounds: sucrose (sweet), sodium chloride (salty), citric acid (sour), caffeine (bitter) and monosodium glutamate (salty and fresh). In order to enroll in the test, the panelist needs to correctly grade and rate the intensity of the sample within reasonable error values.

Preliminary taste testing: the panelists selected in the above manner were deemed to be qualified to conduct the preliminary taste test. The primary taste test is used to evaluate the basic taste and aftertaste intensity of the new compounds. A panel of panelists (n-5) tasted compounds at about 5 concentrations (typically in the range of 1-100 μ M in half log cycles, e.g., 1, 3, 10, 30 and 100 μ M) in water and in a solution of 12mM MSG to evaluate potentiation. The panelists rated the five basic tastes (sweet, salty, sour, bitter, and savory) and aftertastes (e.g., chemical, metallic, and sulfur) on a label scale (labeledmagnuted scale). The samples were supplied in 10mL aliquots at room temperature. The purpose of this test was to determine the highest concentration without undesirable aftertaste, and to determine if there was significant savory or savory enhancement at any of the concentrations tested.

If the compound is potent and free of unpleasant aftertaste, it is studied on a larger scale by trained personnel (experts group).

Selection of trained panelists: trained panel of experts were used to further evaluate compounds that had been tested by initial taste.

The panelists of the trained panel were selected from a large number of qualified taste panelists. The taster may be further trained on savoury taste by a grading and rating test using a combination of MSG and IMP. The panelists completed a series of grading, rating, and reference difference tests with savory flavor solutions. In the grading and grading test, the panelists evaluated the easily recognizable MSG concentrations (0, 6, 18, 38mM) and the less recognizable MSG concentrations (3, 6, 12, 18mM MSG) in water.

Compound testing by trained panel: compounds tested by a trained panel were evaluated in a reference difference test. The panelists were given a reference sample (12mM MSG +100 μ M IMP) and asked to rate the samples according to their reference difference in savory taste in a range of values from-5 to +5 (score: -5 ═ savory taste much weaker than the reference; 0 ═ savory taste identical to the reference; and +5 ═ savory taste much heavier than the reference). The test samples were solutions with different amounts of MSG, IMP and compound. In general, each series may compare a reference sample to a plurality of test samples. The test usually consists of multiple samples with different concentrations of MSG and IMP, and a blind sample that is itself a reference to assess taste assessment accuracy. The results of the taste tests are shown in table 3 and show that the compounds of the invention have been found to provide savory taste or to enhance savory taste with 3 μ M + MSG when compared to 100 μ M IMP + MSG. Compounds were tested against a reference sample with or without 12mM MSG. All samples were present at room temperature in a volume of l0 ml. Two series of evaluations were performed for each compound tested to assess the reproducibility of the taste.

Taste testing in product prototype: this can be done in a similar manner as described above.

TABLE 3 salty and delicious taste test results

Compound numbering	Chemical name	Taste data
			Example 1	N- (hept-4-yl) benzo [ d][1，3]Dioxole-5-carboxamides	The 12mM MSG + 3. mu.M compound was comparable in strength to 12mM MSG + 100. mu.M IMP
Example 6	(R) -methyl 2- (benzo [ d ]][1，3]Dioxolene-6-carboxamido) -4-methylpentanoate	The 12mM MSG + 10. mu.M compound was comparable in strength to the 12mM MSG + 100. mu.M IMP compound
			Example 71	(R) -N- (1-methoxy-4-methylpent-2-yl) -3, 4-dimethylbenzamide	The 12mM MSG + 3. mu.M compound was comparable in strength to 12mM MSG + 100. mu.M IMP
Example 98	(R) -2- (2, 3-dimethylfuran-5-carboxamido) -4-methylpentanoic acid methyl ester	The 12mM MSG + 10. mu.M compound was comparable in strength to the 12mM MSG + 100. mu.M IMP compound

Compound numbering	Chemical name	Taste data
			Example 104	4-methoxy-N- (1-methoxymethyl-3-methyl-butyl) -3-methyl-benzamide	The 12mM MSG + 3. mu.M compound was comparable in strength to 12mM MSG + 100. mu.M IMP
Example 123	N- (2, 4-dimethoxy-benzyl) -N' - (2-pyridin-2-yl-ethyl) -oxalamide	12mMThe strength of the MSG + 1. mu.M compound was comparable to that of 12mM MSG + 100. mu.M IMP and the strength of the 1. mu.M compound was comparable to that of 12mM MSG
			Example 132	N- (2-methoxy-4-methylbenzyl) -N' - (2- (5-methylpyridin-2-yl) ethyl) ethanediamide	The 12mM MSG + 1. mu.M compound corresponds in intensity to 12mM MSG + 100. mu.M IMP and the 1. mu.M compound corresponds in intensity to 12mM MSG
Example 157	N1- (2-methoxy-4-methylbenzyl) -N2- (2- (5-methylpyridin-2-yl) ethyl) ethanediamide	The 12mM MSG + 0.3. mu.M compound corresponds in intensity to the 12mM MSG + 100. mu.M IMP 0.3. mu.M compound corresponds in intensity to the 12mM MSG
			Example 121-1	(S) -N- (2, 3-dihydro-1H-inden-1-yl) -4-methoxy-3-methylbenzamide	The 12mM MSG + 1. mu.M compound corresponds in intensity to 12mM MSG + 100. mu.M IMP and the 1. mu.M compound corresponds in intensity to 12mM MSG

Examples of sweet amides

A number of amide compounds of formula (I) were synthesized and tested experimentally for their efficacy as activators of the hT1R2/hT1R3 "sweet" receptor expressed in the HEK293 cell line. Examples of these syntheses and the EC at the sweet compound are set forth below₅₀Biological efficacy test examples in terms of measurement results. In addition, there is also an off-flavor EC₅₀And EC ₅₀A number of "sweet" amides of formula (I) were screened for activity in the assay, and some amidation of formula (I) is described belowThe compounds have significant activity and potential for use as both savory and sweet taste enhancers for edible and pharmaceutical products and compositions.

Example 162

2, 3, 5, 6-tetrafluoro-4-methyl-N- (2-methylcyclohexyl) benzamide

2, 3, 5, 6-tetrafluoro-p-toluic acid (4.00g, 19.22mmol), HOBt (5.19g, 38.44mmol) and EDCI (4.42g, 23.06mmol) were combined in 200ml of anhydrous DCM and 30ml of anhydrous DMF. The mixture was cooled to 0 ℃ under an argon atmosphere and stirred for 15 minutes. To the mixture was added 2-methylcyclohexylamine (3.05mL, 23.06mmol) and the reaction mixture was slowly warmed to ambient temperature and stirred overnight. The reaction mixture was diluted with DCM, 1N HCl, water, NaHCO₃Aqueous solution, water and brine, over MgSO₄Drying, filtration and removal of the solvent in vacuo afforded the crude product as a light yellow solid. Recrystallization (EtOH/H)₂O) and dried in vacuo to give 5.23g of the title compound (mixture of 2 diastereomers, 90%) as a white solid.¹H NMR(CDCl₃)：δ0.95，1.01(d，J＝7.0，6，6Hz，3H)1.1-2.1(m，9H)，2.29(m，3H)，3.70，4.29(m，1H)，5.65，5.92(m，1H)。MS(304.1，M+H)。m.p.202-204℃。

The compound has an EC of 0.39 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line ₅₀。

Example 163

(S) -2, 3, 5, 6-tetrafluoro-4-methyl-N- (3-methylbut-2-yl) benzamide

Prepared in a similar manner to example 162 using (S) -3-methylbutan-2-amine and 2, 3, 5, 6-tetrafluoro-p-toluic acid (93%).¹H NMR(CDCl₃)δ0.98(d，J＝6.9Hz，6H)，1.18(d，J＝6.8Hz，3H)，2.29(m，3H)，4.09(m，1H)，5.72(bs，1H)。MS(304.1，M+H)m.p.146-147℃。

The compound has an EC of 0.6 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 164

N-cycloheptyl-2, 3, 5, 6-tetrafluoro-4-methylbenzamide

Prepared in a similar manner to example 162 using cycloheptylamine and 2, 3, 5, 6-tetrafluoro-p-toluic acid (94%).¹H NMR(CDCl₃)δ1.53(m，6H)，1.57(m，4H)，2.03(m，2H)，2.28(m，3H)，4.17(m，1H)，5.85(bs，1H)。MS(304.1，M+H)。m.p.164-165℃。

The compound has an EC of 1.85 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 165

N- (2, 4-dimethylpent-3-yl) -2, 3, 5, 6-tetrafluoro-4-methylbenzamide

Prepared in a similar manner to example 162 using 2, 4-dimethylpent-3-amine and 2, 3, 5, 6-tetrafluoro-p-toluic acid (90%).¹H NMR(CDCl₃)δ0.91(d，J＝6.7Hz，6H)，1.00(d，J＝6.8Hz，6H)，1.85(m，2H)，2.29(m，3H)，3.82(m，1H)，5.52(bd，1H)。MS(306.1，M+H)。m.p.184-187℃。

This compound has an EC of 0.81 μ M for activation of hT1R2/hT1R3 sweet taste receptor expressed in HEK293 cell line₅₀。

Example 166

N- (5, 7-dimethyl-1, 2, 3, 4-tetrahydronaphthalen-1-yl) -3-methylisoxazole-4-carboxamide

To a solution of 3-methylisoxazole-4-carboxylic acid (83mg, 0.67mmol), HOBt (100mg, 0.74mmol) and EDCI · HCl (142mg, 0.74mmol) in DMF (4mL) was added 5, 7-dimethyl-1, 2, 3, 4-tetrahydronaphthalen-1-amine (example 166a) (130mg, 0.74 mmol). The reaction mixture was stirred at room temperature for 24 hours, during which time the solvent was removed under reduced pressure and the residue was purified by flash column chromatography (10: 1 hexanes: EtOAc) to give 134mg of N- (5, 7-dimethyl-1, 2, 3, 4-tetrahydronaphthalen-1-yl) -3-methylisoxazole-4-carboxamide as a white foamy solid (70%). ¹H NMR(500MHz，DMSO-d₆)：δ1.74(m，2H)，1.86(m，2H)，2.16(s，3H)，2.19(s，3H)，2.43(s，3H)，2.55(m，2H)，5.10(m，1H)，6.86(s，1H)，6.89(s，1H)，8.60(d，1H，J＝8.40Hz)，9.27(s，1H)。¹³C NMR(125MHz，DMSO-d₆)：δ10.6，19.1，19.6，20.6，25.8，29.4，46.9，115.4，126.4，129.1，132.6，134.1，135.8，136.6，158.5，159.6，159.9。MS(M+H，285)。Mp 57-58℃。

5, 7-dimethyl-1, 2, 3, 4-tetrahydronaphthalen-1-amine: a catalytic amount of raney nickel (slurry in water) was washed with anhydrous MeOH in a round bottom flask under an argon atmosphere. To the washed raney in methanolic ammonia (25mL, 7N)To the solution of internal nickel was added 5, 7-dimethyl-3, 4-dihydronaphthalen-1 (2H) -one oxime (example 166b) (420mg, 2.22mmol) and the mixture was taken up in H₂Stir in a balloon for 20 hours. After completion of the reaction, the reaction was filtered through celite, the filtrate was concentrated in vacuo, diluted with EtOAc, washed with water and brine, and MgSO₄Drying, filtration and removal of the solvent under reduced pressure gave 360mg5, 7-dimethyl-1, 2, 3, 4-tetrahydronaphthalen-1-amine (93%).¹H NMR(500MHz，CDCl₃)：δ1.66-1.83(m，4H)，1.96(m，2H)，2.19(s，3H)，2.28(s，3H)，2.55(m，1H)，2.66(m，1H)，3.97(m，1H)，6.88(s，1H)，7.09(s，1H)。

b.preparation of 5, 7-dimethyl-3, 4-dihydronaphthalene-1 (2H) -ketoxime: to a mixture of 5, 7-dimethyl-3, 4-dihydronaphthalen-1 (2H) -one (2.0g, 11.48mmol) and hydroxylamine hydrochloride (1.6g, 19.73mmol) in 10mL of water at 70 deg.C was added MeOH (14mL), THF (3mL) and sodium acetate solution (2.53g, 30.83mmol in 7mL H₂In O). Stirring was continued at 70 ℃ for 85 minutes during which time a precipitate formed and 10ml of water were added. The resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, the product was collected by filtration to give 2.12g of 5, 7-dimethyl-3, 4-dihydronaphthalen-1 (2H) -one oxime (98%). MS (M + H, 190).

The compound has an EC of 0.76 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 167

3-chloro-2-hydroxy-N- (5-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) benzamide

Prepared in a similar manner to example 166 using 5-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-amine (example 167 a). The yield was 40%.¹H NMR(500MHz，DMSO-d₆)：δ1.73(m，1H)，1.83(m，1H)，1.96(m，2H)，2.61(m，2H)，3.78(s，3H)，5.27(m，1H)，6.78(d，1H，J＝7.82Hz)，6.86(m，2H)，7.14(t，1H，J＝7.98Hz)，7.60(dd，1H，J＝7.88，1.30Hz)，7.94(dd，1H，J＝8.03，1.39Hz)，9.30(d，1H，J＝8.06Hz)，13.80(s，1H)。¹³C NMR(125MHz，DMSO-d₆)：δ19.5，22.7，28.9，47.4，55.3，108.6，115.8，118.7，119.8，121.1，125.9，126.2，126.4，133.8，137.3，156.7，156.8，168.7。MS(M+H，332)。Mp 175-176℃。

5-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-amine: prepared in a similar manner to example 166a using 5-methoxy-3, 4-dihydronaphthalen-1 (2H) -one. The yield was 94%.¹H NMR(500MHz，CDCl₃)：δ1.63-1.79(m，4H)，1.94(m，2H)，2.60(m，1H)，2.71(m，1H)，3.82(s，3H)，3.97(m，1H)，6.71(d，1H)，7.02(d，1H)，7.17(t，1H)。

The compound has an EC of 0.21 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 168

2, 6-dimethyl-N- (2-methylcyclohexyl) benzamide

Prepared in a similar manner to example 162 using 2, 6-dimethylbenzoic acid and 2-methylcyclohexylamine. The yield was 59%.¹H NMR(500MHz，CDCl₃)：δ0.88-0.94(3H，dd)，1.14-1.89(9H，m)，2.21-2.22(6H，d)，3.39-3，45(1H，m)，7.02-7.03(2H，d)，7.12-7.15(1H，t)，8.11-8.13(1H，d)。MS(M+H，246.2)。

The compound has an EC of 1.88 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 169

4-methoxy-2, 6-dimethyl-N- (2-methylcyclohexyl) benzamide

Prepared in a similar manner to example 166 using 4-methoxy-2, 6-dimethylbenzoic acid (example 169a) and 2-methylcyclohexylamine.¹H NMR(500MHz，CDCl₃)：δ0.86-0.92(3H，dd)，1.00-1.85(m，9H)，2.18-2.19(6H，d)，3.33-3.45(1H，m)，3.71-3.72(3H，d)，6.59(2H，s)，7.98-8.05(1H，m)。MS(276.2，M+H)。

4-methoxy-2, 6-dimethylbenzoic acid: 2-bromo-5-methoxy-1, 3-dimethylbenzene (example 169b) (3.38g, 15.79mmol) was dissolved in 100ml of anhydrous THF without further purification. The mixture was cooled to-78 ℃ and n-butyllithium (1.6M solution in hexane, 9.9ml, 15.8mmol) was added dropwise over a period of 15 minutes under an argon atmosphere, and the mixture was stirred at-78 ℃ for 15 minutes or more. Pieces of dry ice were then added and the mixture was stirred at-78 ℃ for 20 minutes. The cooling apparatus is then removed and the mixture is stirred as long as carbon dioxide continues to be produced. The mixture was then poured onto ice (100ml) and acidified with 6N HCl. The organic layer was separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, water, MgSO ₄Dried and concentrated in vacuo. The product, 4-methoxy-2, 6-dimethylbenzoic acid (2.7g, 95%) was obtained as a white solid. (M + H, 181).

2-bromo-5-methoxy-1, 3-dimethylbenzene: 20mmol of 1-methoxy-3, 5-dimethylbenzene (2.82ml) was dissolved in 100ml of anhydrous acetonitrile, followed by 22mmol (3.56g) of N-bromosuccinimide. The mixture was stirred at room temperature overnight. The solvent was then evaporated under reduced pressure and the solid was filtered off and washed with hexane to give 2-bromo-5-methoxy-1, 3-dimethylbenzene (3.9g, 92%) as a white solid.¹H NMR(500MHz，CDCl₃)：δ2.41(6H，s)，3.78(3H，s)，6.67(2H，s)。

The compound has an EC of 2.1. mu.M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 170

(R) -N- (1, 2, 3, 4-tetrahydronaphthalen-1-yl) furan-3-carboxamide

At 0 ℃ to CH₂Cl₂(8mL) and a solution of furan-3-carboxylic acid (100mg, 0.68mmol), HOBt (240mg, 1.78mmol) and EDCI. HCl (196mg, 1.03mmol) in DMF (1.5mL) was added (R) -1, 2, 3, 4-tetrahydronaphthalen-1-amine (160. mu.L, 1.06 mmol). The reaction was stirred at room temperature for 24 hours, then CH was added₂Cl₂. With saturated NaHCO₃、H₂O, brine, wash the resulting solution with MgSO₄Dried and concentrated in vacuo. From EtOH/H₂And recrystallizing the obtained product to obtain the (R) -N- (1, 2, 3, 4-tetrahydronaphthalene-1-yl) -2, 5-dihydrofuran-3-formamide. ¹H NMR(500MHz，CDCl₃)：δ1.89(m，3H)，2.12(m，1H)，2.84(m，2H)，5.35(m，1H)，5.96(brd，1H，J＝7.75Hz)，6.59(dd，1H，J＝1.90，0.86Hz)，7.13(m，1H)，7.19(m，2H)，7.32(m，1H)，7.43(t，1H，J＝1.73Hz)，7.93(m，1H)。MS(M+H，242)。

The compound has an EC of 6.6 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 171

(R) -5-methyl-N- (1, 2, 3, 4-tetrahydronaphthalen-1-yl) isoxazole-4-carboxamides

Prepared in a similar manner to example 170 using 5-methylisoxazole-4-carboxylic acid. Purification was performed by preparative TLC (Hexane: EtOAc ═ 5: 1).¹H NMR(500MHz，CDCl₃)：δ1.80(m，3H)，2.12(m，1H)，2.74(s，3H)，2.85(m，2H)，5.35(m，1H)，5.89(br d，1H，J＝7.75Hz)，7.10(m，1H)，7.18(m，2H)，7.32(m，1H)，8.26(s，1H)。MS(M+H，257)。

The compound has an EC of 8.1. mu.M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 172

N- (4-chloro-2-methylphenyl) isoindoline-2-carboxamide

To a solution of isoindoline (238mg, 2.0mmol) in dry 1, 4-dioxane (10mL) was added 4-chloro-2-methylphenyl isocyanate (335mg, 2.0mmol) at room temperature under an argon atmosphere. The reaction mixture was then stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was purified by recrystallization from ethanol to give the title compound as a white solid (540mg, 94%).¹H NMR(500MHz，DMSO-d₆)：δ2.24(s，2H)，4.76(s，4H)，7.20(dd，J＝2.5，8.5Hz，1H)，7.27(d，J＝2.5Hz，1H)，7.30-7.32(m，2H)，7.34-7.37(m，2H)，7.42(d，J＝8.5Hz，1H)，7.84(s，1H)，¹³CNMR(DMSO-d₆)：δ17.7，51.9，122.8，125.6，126.8，127.3，128.1，129.5，134.7，136.8，154.2；MS(MH+，287)；C₁₆H₁₅ClN₂Calculated value of elemental analysis of O: c, 67.02; h, 5.27; n, 9.77; measured value: c, 66.82; h, 5.41; n, 9.92.

The compound has an EC of 0.89 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 173

N- (4-methoxy-2-methylphenyl) isoindoline-2-carboxamide

To a solution of isoindoline (576mg, 4.0mmo1) in dry 1, 4-dioxane (20mL) was added 4-methoxy-2-methylphenyl isocyanate (815mg, 5.0mmol) at room temperature under an argon atmosphere. The reaction mixture was then stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (EtOAc/hexane: 1) to give the title compound as a white solid (1.18g, 84%).¹H NMR(500MHz，DMSO-d₆)：δ2.19(s，3H)，3.72(s，3H)，4.73(s，4H)，6.72(dd，J＝2.5Hz，8.5Hz，1H)，6.78(d，J＝2.5Hz，1H)，7.17(d，J＝8.5Hz，1H)，7.30-7.32(m，2H)，7.34-7.36(m，2H)，7.74(s，1H)，¹³C NMR(DMSO-d₆)：δ18.2，51.9，55.1，110.9，115.1，122.8，127.2，127.8，130.6，135.1，137.0，154.9，156.5；MS(MH⁺，283)；C₁₇H₁₈N₂O₂Calculated value of elemental analysis of (a): c, 72.32; h, 6.43; n, 9.92; measured value: c, 72.16; h, 6.82; and N, 9.98.

The compound has an EC of 4.5 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 174

N- (3, 4-methylenedioxyphenyl) isoindoline-2-carboxamide

To a solution of 3, 4- (methylenedioxy) aniline (150mg, 1.09mmol) in anhydrous DCM (4mL) was added phenyl chloroformate (0.138mL, 1.09mmol) and triethylamine (0.153mL, 1.09mmol) dropwise. After stirring the reaction mixture at room temperature for 8 hours, isoindoline (0.123ml, 1.09mmol) and triethylamine (0.153ml, 1.09mmol) were added and the reaction mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (EtOAc/hexane: 1: 3) to give the title compound as a white solid (185mg, 60%). m.p: 165-166 ℃. ¹HNMR(CDCl₃，500MHz)：4.82(s，4H)，5.93(s，2H)，6.20(s，1H)，6.73(s，2H)，7.17(s，1H)，7.30(m，4H)。MS(MH⁺，283)。

The compound has an EC of 1.05 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 175

3-methyl-isoxazole-4-carboxylic acid (1, 2, 3, 4-tetrahydro-naphthalen-1-yl) -amide

To a solution of 3-methyl-isoxazole-4-carboxylic acid (0.52g, 4.06mmol) in DCM (15mL) and DMF (2mL) was added HOBt (1.1g, 8.14mmol) and EDCI (0.896g, 4.67 mmol). The clear yellow solution was cooled to 0 ℃ and stirred under an argon atmosphere for 15 minutes. To the solution was added (R) -1-amino-1, 2, 3, 4-tetrahydronaphthalene (0.73mL, 5.04mmol) and the reaction mixture was slowly warmed to ambient temperature and stirred overnight. Dilute with DCM (50mL) and then NaHCO₃Aqueous solution, water, brine (50mL) and MgSO₄Dry, filter and remove the solvent in vacuo. Purification by silica gel chromatography (0-25% hexanes: EtOAc) afforded the title compound as a viscous solid (650mg, 62.5%).¹H NMR(CDCl₃)δ1.88(m，3H)，2.12(m，1H)，2.51(s，3H)，2.81(m，2H)，5.32(m，1H)，5.99(bd，1H)，7.13(m，1H)，7.20(m，2H)7.20(m，2H)，¹³C NMR(CDCl₃)δ11.22，20.15，29.41，30.35，47.93，116.73，126.72，127.88，128.88，129.65，136.25，138.00，158.45，160.28。ESIMS：257(M⁺H)。C₁₅H₁₆N₂O₂Calculated value of elemental analysis of (a): c, 70.29; h, 6.29; n, 10.93; measured value: c, 70.61; h, 6.11; and N, 11.09.

The compound has an EC of 5.8 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 176

(R) -N- (5, 7-dimethyl-1, 2, 3, 4-tetrahydronaphthalen-1-yl) -3-methylisoxazole-4-carboxamide

To a solution of 3-methylisoxazole-4-carboxylic acid (41.7mg, 0.339mmol) in 3mL DMF were added EDCI. HCl (71mg, 0.373mmol) and HOBt (50mg, 0.373 mmol). The mixture was stirred at room temperature for 20 minutes, during which time (R) -5, 7-dimethyl-1, 2, 3, 4-tetrahydronaphthalen-1-amine (example a) (65mg, 0.37mmol) was added. The reaction mixture was stirred at room temperature overnight, diluted with EtOAc and washed with 1N HCl, H₂O, saturated NaHCO₃、H₂O and brine wash. The resulting solution was over MgSO₄Drying, filtration, concentration in vacuo and separation by flash column chromatography (15-20% EtOAc in hexanes) gave (R) -N- (5, 7-dimethyl-1, 2, 3, 4-tetrahydronaphthalen-1-yl) -3-methylisoxazole-4-carboxamide (55mg, 57% as (S) -2- (R) -5, 7-dimethyl-1, 2, 3, 4-tetrahydronaphthalen-1-ylamino) -2-phenylethanol (example b).¹H NMR(500MHz，DMSO-d₆)：δ1.74(m，2H)，1.86(m，2H)，2.16(s，3H)，2.19(s，3H)，2.43(s，3H)，2.55(m，2H)，5.10(m，1H)，6.86(s，1H)，6.89(s，1H)，8.60(d，1H，J＝8.40Hz)，9.27(s，1H)。¹³C NMR(125MHz，DMSO-d₆)：δ10.6，19.1，19.6，20.6，25.8，29.4，46.9，115.4，126.4，129.1，132.6，134.1，135.8，136.6，158.5，159.6，159.9。MS(M+H，285)。Mp＝124-125℃。

Preparation of (R) -5, 7-dimethyl-1, 2, 3, 4-tetrahydronaphthalen-1-amine: to a solution of (S) -2- ((R) -5, 7-dimethyl-1, 2, 3, 4-tetrahydronaphthalen-1-ylamino) -2-phenylethanol (example b) (100mg, 0.339mmol) in 2.5mL MeOH at room temperature were added methylamine (1.4mL, 2M solution in MeOH) and periodic acid (200mg, 0.880mmol, in 2mL H)₂In O). The reaction mixture was stirred at room temperature for 4 hours, during which time it was extracted with diethyl ether. To the combined ether extracts 2mL of 2N HCl was added, then the biphasic mixture was stirred for 30 min, concentrated in vacuo, the remaining aqueous phase was washed with ether, basified with 6N NaOH at 0 deg.C, extracted with ether, and purified with K ₂CO₃Drying, filtration and concentration in vacuo gave 65mg of crude (R) -5, 7-dimethyl-1, 2, 3, 4-tetrahydronaphthalen-1-amine, which was used for the next reaction without further purification.

Preparation of (S) -2- ((R) -5, 7-dimethyl-1, 2, 3, 4-tetrahydronaphthalen-1-ylamino) -2-phenylethanol: to a solution of (S) -2- (5, 7-dimethyl-3, 4-dihydronaphthalenen-1 (2H) -ylideneamino) -2-phenylethanol (example c) (908mg, 3.10mmol) dissolved in 15mL anhydrous THF was added glacial acetic acid. The mixture was cooled to 0 ℃ during which time NaBH was added slowly₄. The reaction was stirred at 0 ℃ under an argon atmosphere for 2 hours, during which time 15mL of CH was added₂Cl₂Then 10mL of saturated NaHCO was added₃. The organic layer was separated and successively saturated NaHCO₃Washed (20mL, 4 times) and brine (1 time). The solution was over MgSO₄Drying, filtration, concentration in vacuo and purification by flash column chromatography (hexane: EtOAc ═ 4: 1) gave (S) -2- ((R) -5, 7-dimethyl-1, 2, 3, 4-tetrahydronaphthalen-1-ylamino) -2-phenylethanol (30% based on tetralone) as a white waxy solid.¹H NMR(500MHz，CDCl₃)：δ1.42(m，1H)，1.55(m，2H)，1.90(m，1H)，2.11(s，3H)，2.22(s，3H)，2.35(ddd，1H，J＝17.32，10.84，6.47Hz)，2.57(m，1H)，3.25(ddd，1H，J＝10.63，8.90，6.01Hz)，3.41(dt，1H，J＝10.70，4.65Hz)，3.50(bs，1H)，3.86(dd，1H，J＝8.70，4.23Hz)，4.93(t，1H，J＝5.44Hz)，6.82(s，1H)，6.85(s，1H)，7.24(td，1H，J＝7.22，1.22Hz)，7.34(t，2H，J＝7.42Hz)，7.42(dd，2H，J＝7.08，1.28Hz)。MS(M+H，296)。

Preparation of (S) -2- (5, 7-dimethyl-3, 4-dihydronaphthalen-1 (2H) -ylideneamino) -2-phenylethanol: to a 50mL round bottom flask equipped with a Dean Stark trap and reflux condenser was added 5, 7-dimethyltetralone (540mg, 3.10mmol), (S) -phenylethanolamine (468mg, 3.40mmol), toluenesulfonic acid monohydrate (30mg, 0.16mmol), and xylene (30 mL). The reaction was refluxed for 8 hours, cooled to room temperature, diluted with toluene and successively with saturated NaHCO ₃(1 time), H₂O (5 times) and brine (1 time) washes. The resulting solution was over MgSO₄Dried, filtered, concentrated in vacuo and used for the next reaction without further purification.

The compound has an EC of 0.52 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 177

(R) -3-chloro-2-hydroxy-N- (5-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) benzamide

Prepared in a similar manner to example 176 from 5-methoxy-3, 4-dihydronaphthalen-1 (2H) -one. Amide coupling was performed using 3-chlorosalicylic acid. The total yield is 27%.¹H NMR(500MHz，DMSO-d₆)：δ1.73(m，1H)，1.83(m，1H)，1.96(m，2H)，2.61(m，2H)，3.78(s，3H)，5.27(m，1H)，6.78(d，1H，J＝7.82Hz)，6.86(m，2H)，7.14(t，1H，J＝7.98Hz)，7.60(dd，1H，J＝7.88，1.30Hz)，7.94(dd，1H，J＝8.03，1.39Hz)，9.30(d，1H，J＝8.06Hz)，13.80(s，1H)。¹³C NMR(125MHz，DMSO-d₆)：δ19.5，22.7，28.9，47.4，55.3，108.6，115.8，118.7，119.8，121.1，125.9，126.2，126.4，133.8，137.3，156.7，156.8，168.7。MS(M+H，332)。Mp 175-176℃。

The compound has an EC of 0.18 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 178

3-chloro-2-hydroxy-N- (7-methyl-1, 2, 3, 4-tetrahydronaphthalen-1-yl) benzamide

To a solution of 3-chlorosalicylic acid (33mg, 0.19mmol), HOBt (28mg, 0.21mmol) and EDCI. HCl (40mg, 0.21mmol) dissolved in 1mL DMF was added a solution of 7-methyl-1, 2, 3, 4-tetrahydronaphthalen-1-amine (example a) (33mg, 0.20mmol) in 1mL DMF. The resulting mixture was stirred at room temperature for 24 hours, during which time it was concentrated in vacuo and purified by preparative LCMS to give 3-chloro-2-hydroxy-N- (7-methyl-1, 2, 3, 4-tetrahydronaphthalen-1-yl) benzamide as a white solid. ¹H NMR(500MHz，CDCl₃)：δ1.74(m，1H)，1.82(m，1H)，1.97(m，2H)，2.21(s，3H)，2.73(m，2H)，5.26(m，1H)，6.89(m，1H)，6.98(s，1H)，7.02(t，2H，J＝8.32Hz)，7.60(m，1H)，7.95(m，1H)，9.32(m，1H)，13.83(s，1H)。MS(M+H，316)。

Preparation of 7-methyl-1, 2, 3, 4-tetrahydronaphthalen-1-amine: the catalyst amount of raney nickel (slurry in water) was washed with anhydrous MeOH in a round bottom flask under an argon atmosphere. To a solution of washed Raney nickel in methanolic ammonia (15mL, 7N) was added 7-methyl-3, 4-dihydronaphthalene-1 (2H)) Ketoxime (example b) (218mg, 1.24mmol), and the mixture was dissolved in H₂Stir in a balloon for 20 hours. After completion, the reaction was filtered through celite, and the filtrate was concentrated in vacuo, diluted with EtOAc, washed with water and brine, and MgSO₄Drying, filtration and removal of the solvent under reduced pressure gave 7-methyl-1, 2, 3, 4-tetrahydronaphthalen-1-amine as a brown thick syrup which was used in the next reaction without further purification. MS (M + H, 161).

b. To a solution of 7-methyl-3, 4-dihydronaphthalen-1 (2H) -one (200mg, 1.24mmol) and hydroxylamine hydrochloride (148mg, 2.12mmol) in 1.08mL of water, 1.52mL of MeOH, and 320. mu.L of THF was added a solution of sodium acetate (274mg, 3.34mmol) dissolved in 760. mu.L of water. The mixture was stirred at 70 ℃ for 2 hours, cooled to room temperature and diluted with 2mL of water. The resulting mixture was stirred for 96 hours, water was removed from the resulting thick slurry with a pipette, toluene and residual H ₂O azeotroped to give a thick brown syrup which was used in the next reaction without further purification.

The compound has an EC of 1.48 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 179

3-chloro-2-hydroxy-N- (2-methyl-1, 2, 3, 4-tetrahydronaphthalen-1-yl) benzamide

A mixture of the two isomeric products (170mg, 49%) was prepared in a similar manner to example 178 from 2-methyl-3, 4-dihydronaphthalen-1 (2H) -one. MS (M + H, 316). M.p. of the mixture: 161-162 ℃. And (3) a product A:¹H NMR(500MHz，DMSO-d₆)：δ1.00(d，3H，J＝6.80Hz)，1.64(qd，1H，J＝11.47，5.90Hz)，2.09(m，1H)，5.39(dd，1H，J＝9.08，4.77Hz)，6.89(t，1H，J＝7.94Hz)，7.17(m，4H)，7.59(dd，1H，J＝7.88，1.38Hz)，8.00(dd，1H，J＝8.17，1.42Hz)，8.96(d，1H，J＝9.07Hz)，13.70(s，1H)。¹³C NMR(125MHz，DMSO-d₆): δ 17.0, 25.5, 28.4, 32.6, 39.0, 49.9, 115.9, 118.6, 121.1, 125.9, 126.5, 127.2, 128.8, 129.5, 133.8, 133.9, 136.3, 137.0, 156.6, 168.8. And (3) a product B:¹H NMR(500MHz，DMSO-d₆)：δ1.00(d，3H，J＝6.80Hz)，1.64(qd，1H，J＝11.47，5.90Hz)，2.09(m，1H)，5.39(dd，1H，J＝9.08，4.77Hz)，6.89(t，1H，J＝7.94Hz)，7.17(m，4H)，7.59(dd，1H，J＝7.88，1.38Hz)，8.00(dd，1H，J＝8.17，1.42Hz)，8.96(d，1H，J＝8.92Hz)，13.85(s，1H)。¹³C NMR(125MHz，DMSO-d₆)：δ19.0，28.4，29.7，34.4，54.2，115.7，118.8，121.2，125.9，126.0，126.7，127.2，128.6，133.9，136.6，137.0，156.9，169.6。

the compound has an EC of 0.38 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 180

3-chloro-2-hydroxy-N- (5-hydroxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) benzamide

Prepared in a similar manner to example 178 from 5-hydroxy-3, 4-dihydronaphthalen-1 (2H) -one and separated using chiral HPLC purification to give the pure enantiomers. MS (M + H, 318). Mp148-151 ℃.

The compound has an EC of 1.17 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line ₅₀。

Example 181

3-chloro-N- (5-ethoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) -2-hydroxybenzamide

Prepared in analogy to example 178 from 5-ethoxy-3, 4-dihydronaphthalen-1 (2H) -one (example a). Amide coupling was performed using 3-methylisoxazole-4-carboxylic acid.¹H NMR(500MHz，DMSO-d₆)：δ1.33(t，3H，J＝6.98Hz)，1.73(m，2H)，1.89(m，2H)，2.42(s，3H)，2.60(m，2H)，4.01(m，2H)，5.12(m，1H)，6.81(t，2H，J＝8.65Hz)，7.11(t，1H，J＝7.94Hz)，8.62(d，1H，J＝8.51Hz)，9.26(s，1H)。MS(M+H，301)。

Preparation of 5-ethoxy-3, 4-dihydronaphthalen-1 (2H) -one: to 5-hydroxy-3, 4-dihydronaphthalen-1 (2H) -one (600mg, 3.70mmol) and K₂CO₃(2.56g, 18.5mmol) to a solution in 18mL DMF was added ethyl iodide (1.48mL, 18.5 mmol). In a microwave reactor, the reaction was heated at 180 ℃ for 20 minutes. After completion, the reaction was diluted with EtOAc, washed with 1N HCl (2X), brine, and MgSO₄Dried, filtered and concentrated in vacuo. The resulting red crystals were purified by flash column chromatography (hexanes: EtOAc ═ 2: 1) to give 5-ethoxy-3, 4-dihydronaphthalen-1 (2H) -one (490mg, 70%) as a light yellow solid.¹H NMR(500MHz，DMSO-d₆): δ 1.36(t, 3H, J ═ 6.95Hz), 2.01 (quintuple, 2H, J ═ 6.48Hz), 2.54(m, 2H), 2.81(t, 2H, J ═ 6.12Hz), 4.07(q, 2H, J ═ 7.00Hz), 7.19(dd, 1H, J ═ 8.02, 0.80Hz), 7.28(t, 1H, J ═ 8.02Hz), 7.46(dd, 1H, J ═ 7.72, 0.96 Hz).

The compound has an EC of 4.5 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line ₅₀。

Example 182

(R) -3-methyl-N- (5-methyl-1, 2, 3, 4-tetrahydronaphthalen-1-yl) isoxazole-4-carboxamide

From 5-methyl-3, 4-dihydronaphthalen-1 (2H) -one in a similar manner to example 178¹And (4) preparing. Amide coupling was performed using 3-methylisoxazole-4-carboxylic acid. The pure enantiomers were isolated using chiral HPLC purification.¹H NMR(500MHz，DMSO-d₆)：δ1.75(m，2H)，1.91(m，

¹Zhang，X.；De Los Angeles，J.E.；He，M.-Y.；Dalton，J.T.；Shams，G.；Lei，L.；Patil，P.N.；Feller，D.R.；Miller，D.D.；Hsu，F.-L.J.Med.Chem.1997，40，3014-3024.

2H)，2.19(s，3H)，2.42(s，3H)，2.61(m，2H)，5.13(m，1H)，7.06(m，3H)，8.62(d，1H，J＝8.51Hz)，9.25(s，1H)。MS(M+H，271)。

The compound has an EC of 2.80 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 183

(R) -3-chloro-2-hydroxy-N- (6-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) benzamide

Prepared in analogy to example 178 from 6-methoxy-3, 4-dihydronaphthalen-1 (2H) -one. The pure enantiomers were isolated using chiral HPLC purification.¹HNMR(500MHz，DMSO-d₆)：δ1.74(m，1H)，1.83(m，1H)，1.97(m，2H)，2.77(m，2H)，3.72(s，3H)，5.23(m，1H)，6.70(d，1H，J＝2.60Hz)，6.74(dd，1H，J＝8.60，2.78Hz)，6.87(t，1H，J＝8.03Hz)，7.08(d，1H，J＝8.52Hz)，7.60(dd，1H，J＝7.88，1.38Hz)，7.94(dd，1H，J＝8.13，1.43Hz)，9.25(d，1H，J＝8.34Hz)，13.83(s，1H)。¹³C NMR(125MHz，DMSO-d₆)：δ20.1，29.1，29.6，46.9，55.0，112.5，113.1，115.8，118.6，121.1，126.2，128.4，129.2，133.8，138.7，156.8，158.2，168.7。MS(M+H，332)。Mp 111-113℃。

The compound has an EC of 0.85 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 184

(R) -3-chloro-2-hydroxy-N- (7-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) benzamide

Prepared in a similar manner to example 178 from 7-methoxy-3, 4-dihydronaphthalen-1 (2H) -one. The pure enantiomers were isolated using chiral HPLC purification.¹H NMR(500MHz，DMSO-d₆)：δ1.74(m，1H)，1.82(m，1H)，1.97(m，2H)，2.71(m，2H)，3.66(s，3H)，5.24(m，1H)，6.70(d，1H，J＝2.69Hz)，6.79(dd，1H，J＝8.44，2.78Hz)，6.87(t，1H，J＝7.96Hz)，7.06(d，1H，J＝8.46Hz)，7.60(dd，1H，J＝7.88，1.28Hz)，7.95(dd，1H，J＝8.01，2.60Hz)，9.33(m，1H)，13.75(s，1H)。MS(M+H，332)。

The compound has an EC of 0.26 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 185

(R) -3-chloro-N- (3, 4-dihydro-2H-benzopyran-4-yl) -2-hydroxybenzamide

Prepared in a similar manner to example 178 from 2, 3-dihydrobenzopyran-4-one. The pure enantiomers were isolated using chiral HPLC purification.¹H NMR(500MHz，DMSO-d₆)：δ2.12(m，2H)，4.27(m，2H)，5.33(m，1H)，6.81(d，1H，J＝8.27Hz)，6.89(td，2H，J＝7.49，0.72Hz)，7.17(d，2H，J＝7.40Hz)，7.60(d，1H，J＝7.32Hz)，7.93(d，1H，J＝8.03Hz)，9.40(br.s，1H)，13.65(s，1H)。MS(M+H，304)。

The compound has an EC of 1.03 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 186

3-chloro-2-hydroxy-N- (5-methoxy-2-methyl-1, 2, 3, 4-tetrahydronaphthalen-1-yl) benzamide

A mixture of the two sets of enantiomers was obtained in a similar manner to example 178 from 5-methoxy-2-methyl-3, 4-dihydronaphthalen-1 (2H) -one (example a). Enantiomer pair a:¹H NMR(500MHz，DMSO-d₆): δ 0.92(d, 3H, J ═ 6.78Hz), 1.67(m, 1H), 1.76(m, 1H), 2.02(m, 2H), 2.80(m, 1H), 3.79(s, 3H), 5.34(m, 1H), 6.79(d, 1H, J ═ 7.69), 6.84(d, 1H, J ═ 7.82Hz), 7.13(t, 1H, J ═ 7.90Hz), 7.56(m, 1H), 7.93(m, 1H), 8.90(br.s, 1H). MS (M + H, 346). Enantiomer pair B:¹HNMR(500MHz，DMSO-d₆)：δ0.99(d，3H，J＝6.47Hz)，1.55(m，1H)，1.67(m，1H)，1.76(m，1H)，2.02(m，2H)，2.80(m，1H)，3.78(s，3H)，4.92(m，1H)，6.72(d，1H，J＝7.85Hz)，6.84(m，1H)，7.13(m，1H)，7.56(m，1H)，7.93(m，1H)，9.25(br.S，1H)。MS(M+H，346)。

preparation of 5-methoxy-2-methyl-3, 4-dihydronaphthalen-1 (2H) -one: to a solution of LDA (2.85mL, 2.0M solution in heptane/THF/ethylbenzene) in 2mL THF at-78 deg.C was added a solution of 5-methoxy-3, 4-dihydronaphthalen-1 (2H) -one (1.00g, 5.70mmol) in 2mL THF. The mixture was stirred at-78 ℃ for 20 minutes, during which MeI was added dropwise. The reaction was warmed to room temperature over 17 hours using saturated NH ₄The reaction was stopped with Cl. Suspension through Et₂O extraction with MgSO₄Dried, filtered, concentrated in vacuo, and flash column chromatographed (hexane: EtOAc ═ 9: 1) to give 5-methoxy-2-methyl-3, 4-dihydronaphthalen-1 (2H) -one (374mg, 35%) as a clear oil.¹HNMR(500MHz，CDCl₃)：δ1.24(d，3H，J＝6.72Hz)，1.83(m，1H)，2.20(dq，1H，J＝13.32，4.50Hz)，2.58(m，1H)，2.74(ddd，1H，J＝16.66，11.35，4.92Hz)，3.08(dt，1H，J＝17.80，4.32Hz)，3.86(s，3H)，7.00(dd，1H，J＝7.90，0.70Hz)，7.26(t，1H，J＝7.82Hz)，7.64(dd，1H，J＝7.86，0.72Hz)。

The compound has an EC of 0.50 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 187

(R) -3-ethyl-N- (5-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) isoxazole-4-carboxamide

To a solution of 3-ethylisoxazole-4-carboxylic acid (example a) (30mg, 0.21mmol), HOBt (41mg, 0.30mmol) and EDCI. HCl (58mg, 0.30mmol) dissolved in 2mL DMF was added (R) -5-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-amine (example c) (53mg, 0.30 mmol). The reaction was stirred at room temperature for 24 hours, during which time it was concentrated in vacuo and purified by preparative TLC to give (R) -3-ethyl-N- (5-methoxy-1, 2, 3, 4-tetrahydro-l-ethyl) as a white solidNaphthalen-1-yl) isoxazole-4-carboxamides.¹H NMR(400MHz，CD₃OD)：δ1.30(t，3H，J＝7.20Hz)，1.84(m，2H)，1.97(m，2H)，2.68(m，2H)，2.96(q，2H，J＝7.60Hz)，3.81(s，3H)，5.21(m，1H)，6.80(d，1H，J＝7.60Hz)，6.85(d，1H，J＝7.60Hz)，7.14(d，1H，J＝8.00Hz)，8.98(s，1H)。MS(M+H，301)。

Preparation of 3-ethylisoxazole-4-carboxylic acid: to a solution of ethyl 3-ethylisoxazole-4-carboxylate (example b) (422mg, 2.49mmol) in 2mL EtOH: H₂To a solution in O (1: 1), NaOH (110mg, 2.74mmol) was added. The reaction was stirred at room temperature for 24 h, during which time it was neutralized with 1N HCl, extracted with EtOAc and over MgSO ₄Drying, filtration and concentration in vacuo gave a white solid which was used for the next reaction without further purification.

b, preparation of ethyl 3-ethylisoxazole-4-carboxylate: at 0 ℃, to a strain according to McMurry, j.e.; syn. Coll. Vol.6, 781 method of 2.0g, 11.8mmol of ethyl 3- (pyrrolidin-1-yl) acrylate and Et₃N (4.7mL) and nitropropane (1.38mL, 15.4mmol) in 12mL CHCl₃To the solution in (1), POCl was added through a dropping funnel over a period of 3 hours₃(1.21mL, 13.00mmol) in 2.5mL CHCl₃The solution of (1). After the addition of POCl₃After the mixture was allowed to warm to room temperature, it was stirred for 20 hours and then washed with H₂And O stops the reaction. The organic layer was separated and washed sequentially with 1N HCl, 5% NaOH and brine. The resulting solution was over MgSO₄Drying, filtration, concentration in vacuo and purification by flash column chromatography (hexane: EtOAc ═ 4: 1) gave ethyl 3-ethylisoxazole-4-carboxylate (1.43g, 72%) as a white solid.¹H NMR(500MHz，DMSO-d₆)：δ1.21(t，3H，J＝7.62Hz)，1.28(t，3H，J＝7.30Hz)，2.85(q，2H，J＝7.47Hz)，4.26(q，2H，J＝6.98Hz)，9.51(s，1H)。¹³C NMR(125MHz，DMSO-d₆)：δ11.9，14.0，18.5，60.5，79.1，160.8，162.7，164.7，164.8。

Preparation of (R) -5-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-amine: at 0 deg.C to (S) -2- (C)To a solution of R) -5-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-ylamino) -2-phenylethanol (example d) (3.22g, 10.83mmol) in 70mL MeOH was added methylamine (7.5mL, 40% aq.) and periodic acid (6.4g, 28.15mmol, in 50mL water). The reaction mixture was stirred at room temperature for 4 hours, during which time it was extracted with diethyl ether. To the combined ether extracts was added 30mL of 2N HCl, the biphasic mixture was stirred for 30 minutes, concentrated in vacuo, the remaining aqueous phase was washed with ether, basified with 6N NaOH solution at 0 deg.C, extracted with ether, and extracted with K ₂CO₃Drying, filtration and concentration in vacuo gave 1.72g of crude (R) -5-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-amine (90%) which was used for the next reaction without further purification.

Preparation of (S)2- ((R) -5-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-ylamino) -2-phenylethanol: to NaBH at 0 ℃ under an argon atmosphere₄(781mg, 20.63mmol) was dissolved in 40mL of anhydrous THF, and glacial acetic acid (3.48mL, 60.10mmol) was added dropwise. The mixture was stirred at 0 ℃ for 15 minutes or until the evolution of bubbles ceased. A solution of (S) -2- (5-methoxy-3, 4-dihydronaphthalen-1 (2H) -ylideneamino) -2-phenylethanol (example e) (5.3g, 17.94mmol) dissolved in 25mL anhydrous THF was added to NaBH (OAc)₃In the mixture, the reaction was stirred at 0 ℃ for 3 hours. After completion, by addition of saturated K₂CO₃The reaction was terminated, diluted with EtOAc and the organic layer was MgSO₄Drying, filtration, concentration in vacuo and purification by flash column chromatography (15-25% EtOAc in hexanes) afforded (S) -2- ((R) -5, 7-dimethyl-1, 2, 3, 4-tetrahydronaphthalen-1-ylamino) -2-phenylethanol (3.22g, 60% as tetralone) as a white waxy solid.¹H NMR(500MHz，CDCl₃)：δ1.70(m，3H)，1.84(m，1H)，2.51(m，1H)，2.74(m，1H)，3.50(dd，1H，J＝10.73，7.95Hz)，3.71(dd，1H，J＝10.76，4.67Hz)，3.77(m，1H)，3.81(s，3H)，3.99(dd，1H，J＝7.95，4.60Hz)，6.72(d，1H，J＝7.98Hz)，6.96(d，1H，J＝7.70Hz)，7.15(t，1H，J＝7.90Hz)，7.29(m，1H)，7.36(m，4H)。MS(M+H，298)。

(S) -2- (5-methoxy-3, 4-diylidenePreparation of Hydronaphthalen-1 (2H) -ylideneamino) -2-phenylethanol to a 50mL round-bottomed flask equipped with a dean-Stark trap and reflux condenser were added 5-methoxytetralone (3.7g, 21.0mmol), (S) -phenylethanolamine (3.17g, 23.1mmol), toluenesulfonic acid monohydrate (200mg, 1.05mmol), and xylene (40 mL). The reaction was refluxed overnight, cooled to room temperature, diluted with toluene and sequentially with saturated NaHCO ₃(1 time), H₂O (5 times) and brine (1 time) washes. The resulting solution was over MgSO₄Dried, filtered, concentrated in vacuo and used for the next reaction without further purification.

The compound has an EC of 0.40 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 188

(R) -3-propyl-N- (5-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) isoxazole-4-carboxamide

Prepared in a similar manner to example 187 using 3-propylisoxazole-4-carboxylic acid.¹HNMR(400MHz，CD₃OD)：δ1.01(t，3H，J＝7.60Hz)，1.74(sext，2H，J＝8.00Hz)，1.83(m，2H)，1.96(m，2H)，2.67(m，2H)，2.90(t，2H，J＝7.20Hz)，3.80(s，3H)，5.20(m，1H)，6.80(d，1H，J＝7.60Hz)，6.85(d，1H，J＝7.60Hz)，7.14(d，1H，J＝8.00Hz)，8.98(s，1H)。MS(M+H，315)。

The compound has an EC of 0.24 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 189

(R) -3-butyl-N- (5-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) isoxazole-4-carboxamide

Prepared in a similar manner to example 187 using 3-butylisoxazole-4-carboxylic acid.¹HNMR(400MHz，CD₃OD)：δ0.96(t，3H，J＝7.20Hz)，1.40(sext，2H，J＝6.80Hz)，1.69(quint，2H，J＝7.60Hz)，1.84(m，2H)，1.97(m，2H)，2.67(m，2H)，2.92(t，2H，J＝7.20Hz)，3.80(s，3H)，5.20(m，1H)，6.80(d，1H，J＝7.60Hz)，6.85(d，1H，J＝7.60Hz)，7.14(d，1H，J＝8.00Hz)，8.98(s，1H)。MS(M+H，329)。

The compound has an EC of 0.36 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 190

(R) -3-methyl-N- (5-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) isoxazole-4-carboxamide

Prepared in a similar manner to example 187 using 3-methylisoxazole-4-carboxylic acid.¹HNMR(400MHz，CD₃OD)：δ1.84(m，3H)，1.97(m，3H)，2.48(s，3H)，3.80(s，3H)，5.21(m，1H)，6.80(d，1H，J＝7.60Hz)，6.85(d，1H，J＝7.60Hz)，7.14(d，1H，J＝8.00Hz)，8.98(s，1H)。MS(M+H，287)。

The compound has an EC of 0.95 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 191

(S) -4-allyl-2, 3, 5, 6-tetrafluoro-N- (3-methylbutyl-2-yl) benzamide

To a Smith flask were added 2, 3, 5, 6-tetrafluoro-4-allylbenzoic acid (238mg, 1.02mmol), HOBt (260mg, 2.13mmol), EDCI (225mg, 1.18mmol), triethylamine (0.160mL, 1.15mmol), ACN (2.5mL) and DMF (0.5 mL). To the solution was added (S) -3-methylbutyl-2-amine (163.3uL, 1.24mmol), the solution was sealed and transferred to a microwave oven. After heating in a microwave oven (150 ℃, 5 min fixed retention time), the reaction mixture was diluted with DCM, 1N HCl, water, NaHCO₃The solution, water and brine were washed over MgSO₄Drying, filtration and removal of the solvent in vacuo gave the crude product as a pale yellow solid. From EtOH/H₂Recrystallization from O gave the title compound as white needles (105mg, 34%).¹H NMR(DMSO-d6)δ0.88(d，J＝6.8Hz，6H)，1.07(d，J＝6.8Hz，3H)，1.70(m，1H)，3.50(d，J＝6Hz，2H)，3.83(m，1H)，5.02(d，J＝17Hz，1H)，5.10(dd，J＝1.3，10.1Hz，1H)，5.94(m，1H)，8.64(d，J＝8.6Hz，1H)。MS(304.1，M+H)。

The compound has an EC of 0.14 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 192

(S) -2, 3, 5, 6-tetrafluoro-N- (3-methylbutyl-2-yl) -4-propylbenzamide

(S) -4-allyl-2, 3, 5, 6-tetrafluoro-N- (3-methylbutyl-2-yl) benzamide (see example 191) (80.3mg, 0.26mmol), ammonium formate (86mg, 5 equiv.), Pd/C (10%, 9.2mg), and EtOH (2.5mL) were added to a Smith-processing flask. The solution was sealed and transferred to a microwave oven. Heating in a microwave oven (140 ℃, 6 min) Bell fixed retention time), the reaction mixture was diluted with acetonitrile (2mL), filtered through celite, and the volatile solvents were removed in vacuo to give the crude product as a pale yellow solid (93 mg). Recrystallization from EtOH/water afforded the title compound as white whisker (45mg, 56%).¹H NMR(DMSO-d6)δ0.88(s，9H)，0.90(m，9H)，1.05(d，J＝6.8Hz，3H)，1.60(m，2H)，1.70(m，1H)，2.71(t，J＝7.5Hz，2H)，3.80(m，1H)，8.64(d，J＝8.8Hz，1H)。MS(306.3，M+H)。

The compound has an EC of 0.14 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 193

N- (4-bromo-2, 6-difluorophenyl) -4-methylisoindoline-2-carboxamide

Prepared in a similar manner to example 172 using 2, 6-difluoro-4-bromophenyl isocyanate and 4-methylisoindoline (example 193 a).¹H NMR(500MHz，DMSO-d₆)：δ2.25(s，3H)，4.65(s，2H)，4.71(s，2H)，7.10(d，J＝7.4Hz，1H)，7.16(d，J＝7.4Hz，1H)，7.22(t，J＝7.4Hz，1H)，7.52(d，J＝7.1Hz，2H)，8.29(s，1H)。MS(MH⁺，369，367)。

The compound has an EC of 0.02 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 193 a: 4-methylisoindoline: a solution of 3-methylphthalimide (1.61g, 10.0 mmol; example 193b) and borane-dimethylsulfide complex (2.0M in THF, 20mL, 40.0mmol) in dry THF (20mL) was refluxed under an argon atmosphere for 48 h. After it was cooled to 0 ℃, the reaction was carefully quenched with MeOH (10mL) followed by 3N HCl (10 mL). The solution was then refluxed for a further 2 hours and used in an ice bathCooled again to 0 ℃ and neutralized with 3N NaOH. With Et ₂The mixture was O (3 times) extracted and the combined organic layers were washed with brine and dried with solid NaOH. The solvent was evaporated to give crude 4-methylisoindoline as a brown oil which was used directly in the synthesis of urea without further purification. MS (MH)⁺，134)。

Example 193 b: 3-methylphthalimide: stirred powder of 3-methylphthalic anhydride (3.24g, 20.0mmol) was treated with concentrated ammonia solution (ca. 28%, 10 mL). The solution was gradually heated to 250 ℃ until the mixture was in a static molten state. It took about one hour until all the water was removed, and about one hour until the temperature of the reaction mixture reached 250 c and the mixture became a homogeneous melt. The hot reaction mixture was cooled and solidified to give 3-methylphthalimide as a beige solid, which was almost pure without further treatment. The analytical sample was purified by sublimation to give 3-methylphthalimide as a white solid.¹H NMR(500MHz，DMSO-d₆)：δ2.59(s，3H)，7.59(d，J＝7.4Hz，1H)，7.61(d，J＝7.4Hz，1H)，7.67(t，J＝7.4Hz，1H)，10.35(b，1H)。MS(MH⁺，162)。

Example 194

N- (2, 6-difluoro-4-methylphenyl) -4-methylisoindoline-2-carboxamide

Methylmagnesium chloride (3.0M in THF, 0.1mL, 0.3mmol) was slowly added to anhydrous ZnCl in anhydrous THF (1mL) under an argon atmosphere ₂(68mg, 0.3 mmol). The resulting white slurry was stirred at 50 ℃ for 3 hours. In a separate flask, a solution of N- (4-bromo-2, 6-difluorophenyl) -4-methylisoindoline-2-carboxamide (example 192) (37mg, 0.1mmol) in anhydrous THF (2mL) under an argon atmosphere was treated sequentially with PdCl₂(dppf) (8mg, 0.01mmol) and CuI (9mg, 0.05 mmol). The zinc alkyl slurry, which had been stirred at 50 ℃ for 3 hours, was slowly added to the above solution. The reaction mixture was then stirred at 65 ℃ overnight. After cooling to room temperature, with NH₄The reaction was quenched with aqueous Cl and extracted with dichloromethane (2 times). The combined organic layers were washed with brine, washed with Na₂SO₄And (5) drying. After evaporation of the solvent, the residue was purified by silica chromatography (EtOAc/hexane: 2: 8) to give the title compound (24mg, 79%) as a white solid.¹H NMR(400MHz，DMSO-d₆)：δ2.23(s，3H)，2.30(s，3H)，4.66(s，2H)，4.70(s，2H)，6.95(d，J＝8.6Hz，2H)，7.08(d，J＝7.4Hz，1H)，7.13(d，J＝7.4Hz，1H)，7.19(t，J＝7.4Hz，1H)，8.09(s，1H)。MS(MH⁺，303)。

This compound has an EC of.060. mu.M for activation of the hT1R2/hT1R3 sweet taste receptor expressed in the HEK293 cell line₅₀。

Example 195

N- (2, 6-difluoro-4-methoxyphenyl) -4-methylisoindoline-2-carboxamide

A solution of N- (4-bromo-2, 6-difluorophenyl) -4-methylisoindoline-2-carboxamide (example 192) (22mg, 0.06mmol) in anhydrous DMF (2mL) was treated sequentially with CuBr (6mg, 0.04mmol) and MeONa (25% in MeOH, 5.0 equiv.) under an argon atmosphere. The reaction mixture was then stirred at 110 ℃ for 1 hour under an argon atmosphere. After cooling to room temperature, the reaction mixture was neutralized with 1N HCl and extracted with EtOAc (2 times). The combined organic layers were washed with brine, washed with Na ₂SO₄And (5) drying. After evaporation of the solvent, the residue was purified by silica chromatography, first eluting with 20% EtOAc in hexanes to give the title compound as a white solid (7mg, 37%):¹H NMR(400MHz，DMSO-d₆)：δ2.23(s，3H)，3.76(s，3H)，4.65(s，2H)，4.70(s，2H)，6.76(d，J＝9.4Hz，2H)，7.08(d，J＝7.4Hz，1H)，7.13(d，J＝7.4Hz，1H)，7.19(t，J＝7.4Hz，1H)，7.98(s，1H)。MS(MH⁺，319)。

the compound has an EC of 067 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 196

N- (4-bromo-2, 6-difluorophenyl) -4-nitroisoindoline-2-carboxylic acid amide

Prepared in a similar manner to example 172 using 2, 6-difluoro-4-bromophenyl isocyanate and 4-nitroisoindoline (example 196 a). MS (MH)⁺，398，400)。

Example 196 a: 4-nitroisoindoline: a solution of 3-nitrophthalimide (1.95g, 10.0mmol) and borane dimethylsulfide complex (2.0M in THF, 20mL, 20.0mmol) in dry THF (20mL) was refluxed for 48 hours under an argon atmosphere. After it was cooled to 0 ℃, the reaction was carefully quenched with MeOH (10mL) followed by 3N HCl (10 mL). The solution was then refluxed for a further 3 hours and cooled again to 0 ℃ with an ice bath and neutralized with concentrated ammonia solution. With Et₂The mixture was O (3X) extracted and the combined organic layers were washed with brine and solid Na₂SO₄And (5) drying. The solvent was evaporated to give crude 4-nitroisoindoline as a brown oil which was used directly in the synthesis of urea without further treatment. MS (MH) ⁺，165)。

This compound has an EC of 1.07 μ M for activation of hT1R2/hT1R3 sweet taste receptor expressed in HEK293 cell line₅₀。

Example 197

N- (4-bromo-2, 6-difluorophenyl) -5-methylisoindoline-2-carboxamide

Prepared in a similar manner to example 172 using 2, 6-difluoro-4-bromophenyl isocyanate and 5-methylisoindoline (example 197 a).¹H NMR(500MHz，DMSO-d₆)：δ2.32(s，3H)，4.69(b，4H)，7.12(d，J＝7.8Hz，1H)，7.16(s，1H)，7.23(d，J＝7.8Hz，1H)，7.52(d，J＝7.1Hz，2H)，8.25(s，1H)。MS(MH⁺，369，367)。

Example 197 a: 5-methylisoindoline: a solution of 4-methylphthalimide (1.61g, 10.0mmol) and borane dimethylsulfide complex (2.0M in THF, 15mL, 30.0mmol) in dry THF (10mL) was refluxed under an argon atmosphere for 3 days. After it was cooled to 0 ℃, the reaction was carefully quenched with MeOH (5mL) followed by 3N HCl (10 mL). The solution was then refluxed for a further 2 hours and cooled again to 0 ℃ with an ice bath and finally neutralized with 3N NaOH. With Et₂The reaction mixture was extracted O (3 times) and the combined organic layers were washed with brine and dried with solid NaOH. The solvent was evaporated to give crude 5-methylisoindoline as a brown oil which was used directly in the synthesis of urea without further purification. MS (MH)⁺，134)。

The compound has an EC of 0.52 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 198

5-bromo-N- (4-bromo-2, 6-difluorophenyl) isoindoline-2-carboxylic acid amide

To and withPrepared in a similar manner to example 172 using 2, 6-difluoro-4-bromophenyl isocyanate and 5-bromoisoindoline (example 198 a).¹H NMR(500MHz，DMSO-d₆)：δ4.69(bs，2H)，4.73(bs，2H)，7.33(d，J＝8.2Hz，1H)，7.50(dd，J＝8.2Hz，1.7Hz，1H)，7.52(d，J＝7.2Hz，2H)，7.59(s，1H)，8.31(s，1H)。MS(MH+，433，431，435)。

Example 198 a: 5-bromoisoindoline: prepared in a similar manner to example 192a using 4-bromophthalimide. MS (MH)⁺，198，200)。

The compound has an EC of 0.42 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 199

N- (3, 4- (methylenedioxy) phenyl) -4-methylisoindoline-2-carboxamide

Prepared in a similar manner to example 172 using 3, 4- (methylenedioxy) phenyl isocyanate and 4-methylisoindoline (example 197 a).¹H NMR(500MHz，DMSO-d₆)：δ2.26(s，3H)，4.68(s，2H)，4.73(s，2H)，5.95(s，2H)，6.81(d，J＝8.4Hz，1H)，6.82(d，J＝8.4Hz，1H)，7.09-7.22(m，3H)，7.25(d，J＝2.1Hz，1H)，8.25(s，1H)。MS(MH⁺，297)。

The compound has an EC of 0.95 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 200

(R) -N- (3, 3-dimethylbutyl-2-yl) -2, 6-dimethyl-4- (methylthio) benzamide

Prepared in a similar manner to example 13 using (R) -3, 3-dimethylbutyl-2-amine and 2, 6-dimethyl-4- (methylthio) benzoic acid (example 200 a). The yield was 23%.¹H NMR(500MHz，CDCl₃)：δ0.90(s，9H)，1.03-1.05(s，3H)，2.19(s，6H)，2.45(s，3H)，3.87-3.90(m，1H)，6.93(s，1H)，7.99-8.00(d，1H)。MS(M+H，280)。

Example 200 a: 2, 6-dimethyl-4- (methylthio) benzoic acid: 3, 5-Dimethylphenylthiomethane (6.6mmol) in 100ml of anhydrous acetonitrile was mixed with N-bromosuccinimide (6.6mmol) and stirred at room temperature overnight. The solvent was removed by vacuum and the residual solid was treated with hexane. The solid was filtered, washed with hexane, the hexane fractions combined and concentrated under reduced pressure to give a yellow oil (99%). The crude bromide was dried under vacuum and then diluted with 75ml of anhydrous THF. The solution was cooled to-78 ℃ under an argon atmosphere and a 2.5M solution (6.7mmol) of n-butyllithium in hexane was added dropwise over a period of 30 minutes. The mixture was then stirred for an additional 30 minutes and the pieces were immersed in the solution in dry ice. After 30 minutes the cooling bath was removed and the mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was poured onto 100ml crushed ice and acidified to pH 1 with 6N HCl. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine and water, MgSO ₄Drying and concentration in vacuo gave a white solid (98%).¹H NMR(500MHz，dMSO)：δ2.23(s，6H)，2.46(s，3H)，6.96(s，2H)，13.0(bs，1H)。

The compound has an EC of 1.02 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 201

2, 6-dimethyl-N- (2-methylcyclohexyl) -4-propoxybenzamide

4-hydroxy-2, 6-dimethyl-N- (2-methylcyclohexyl) benzamide (example 201a) (0.38mmol) was dissolved in 2ml of pure EtOH and 50mg of KOH. The mixture was stirred at 80 ℃ for 1 hour, then propyl iodide (1.5mmol) was added dropwise to the hot mixture. The mixture was stirred at 80 ℃ overnight. The solvent was evaporated and the material was purified on silica gel. The yield was 57%.¹H NMR(500MHz，CDCl₃)：δ0.91-0.97(m，6H)，1.03-1.04(m，1H)，1.14-1.18(m，2H)，1.24-1.26(m，1H)，1.35-1.36(m，1H)，1.55-1.6(m，1H)，1.67-1.73(m，4H)，1.84-1.86(m，1H)，2.18(s，6H)，3.32(s，3H)，3.36-3.42(m，1H)，3.88-3.90(t，2H)，6.58(s，2H)，7.98-8.00(d，1H)。MS(M+H，304)。

Example 201 a: 4-hydroxy-2, 6-dimethyl-N- (2-methylcyclohexyl) benzamide: 4-methoxy-2, 6-dimethyl-N- (2-methylcyclohexyl) benzamide (example 69) (3mmol) was dissolved in 30ml of anhydrous DCM under an argon atmosphere and cooled to-78 ℃. Dropwise add 1M BBr₃Solution in DCM (3.3mmol) and remove the cooling bath. The mixture was stirred at room temperature for 34 hours, then concentrated in vacuo. The residue was dissolved in ethyl acetate and taken up with saturated NaHCO₃Water and brine wash. The organic phase is over MgSO₄Drying and concentration under vacuum gave the product as a white foam (95%). ¹H NMR(500MHz，CDCl₃)：δ0.90-0.91(s，3H)，1.03-1.05(s，3H)，1.00-1.03(m，1H)，1.13-1.17(m，2H)，1.25-1.27(m，1H)，1.35-1.37(m，1H)，1.60-1.62(d，1H)，1.62-1.72(m，2H)，1.83-1.85(m，1H)，2.13(s，6H)，3.36-3.42(m，1H)，6.40(s，2H)，7.93-7.95(d，2H)。MS(M+H，262)。

This compound has an EC of 0.69 μ M for activation of hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

Example 202

4- (furan-2-yl) -2, 6-dimethyl-N- (2-methylcyclohexyl) benzamide

3, 5-dimethyl-4- (2-methylcyclohexylcarbamoyl) phenyltrifluoromethanesulfonate (example 202a) (0.25mmol) was dissolved in 10ml of toluene, 2ml of EtOH and 1.5ml of water. Furan-2-ylboronic acid (0.25mmol) and K were added₂CO₃(0.5mmol) and the mixture was degassed with a stream of argon (20 min). Then the catalyst Pd (PPh) is added₃)₄The mixture was refluxed at 80 ℃ overnight. The solvent was evaporated off, the residue was dissolved in ethyl acetate and washed with water. The organic extracts were combined and extracted with MgSO₄Dried and evaporated under reduced pressure. The crude material was purified on preparative TLC plates to give the product as a white solid. (40%).¹H NMR(500MHz，CDCl₃)：δ1.04-1.06(s，3H)，1.13-1.80(m，8H)，2.15-2.23(m，1H)，2.36(s，6H)，3.70-3.73(m，1H)，5.43-5.45(d，1H)，6.46-6.47(m，1H)，6.62-6.63(d，1H)，7.32(s，2H)，7.45-7.46(d，1H)。MS(M+H，312)。

Example 202 a: 3, 5-dimethyl-4- (2-methylcyclohexylcarbamoyl) phenyltrifluoromethanesulfonate: to a solution of 4-hydroxy-2, 6-dimethyl-N- (2-methylcyclohexyl) benzamide (example 200a) (7.65mmol) in DCM (50ml) was added pyridine (9.18 mmol). The solution was cooled to 0 ℃ and trifluoromethanesulfonic anhydride (9.18mmol) was added dropwise. The reaction mixture was then slowly warmed to room temperature and stirred overnight. The mixture was diluted with DCM and saturated aqueous NaHCO with 1N HCl ₃Washed with brine and the organic phase over MgSO₄And (5) drying. Removal of the solvent under reduced pressure gave the product as a white solid (20%).

The compound has an EC of 1.02 μ M for activating hT1R2/hT1R3 sweet taste receptors expressed in HEK293 cell line₅₀。

A number of amide compounds of formula (I) were also synthesized and tested experimentally for their efficacy as activators of the hT1R2/hT1R3 "sweet" receptor expressed in the HEK293 cell line.

The test results are shown in table E below.

Measurement of sweetness and sweetness enhancement by human panelists

The purpose is as follows: the test compounds were investigated for their different tastes and aftertaste intensity. The maximum concentration of test compound that does not cause an undesirable characteristic or aftertaste is determined.

Summary: test compounds were tasted separately by trained subjects at different concentrations (typically aqueous solutions containing test compounds at concentrations of 1, 3, 10 and 30 μ M, and optionally at concentrations of 50 μ M and/or 100 μ M) and the intensity of multiple taste attributes were rated. The test compound can also be tasted while dissolved in a "key tastant" solution.

The procedure is as follows: an appropriate amount of the test compound is dissolved in water, which typically also contains 0.1% ethanol, which is used to aid in the initial dispersion of the compound in the aqueous stock solution. Where appropriate, the test compounds may also be dissolved in an aqueous solution of a "primary flavor" (e.g., 4% sucrose, 6% fructose/glucose or 7% fructose/glucose at pH 7.1 or 2.8).

Five subjects were used for preliminary taste testing. These subjects had a proven ability to taste the desired taste attributes and were trained to use a labeled scale of magnitude (LMS) from 0 (barely noticeable sweetness) to 100 (the most intense sweetness that is conceivable). The subjects were prohibited from eating (except for water) for at least one hour prior to the test. Prior to taste testing, subjects consumed the wafer and rinsed their mouth with water four times to clean the mouth.

The aqueous solution was dispensed in 10ml volumes into 1 ounce sample cups and provided to human subjects at room temperature. Test compound samples with varying concentrations of test compound dissolved in a suitable primary flavor (e.g., 4% sucrose, 6% fructose, or 6% fructose/glucose, typically at a pH of 7.1) can also be provided to a human subject. The human subjects also received reference samples of different concentrations of the primary flavor (e.g., sucrose, fructose, or fructose/glucose, typically at a pH of 7.1) for comparison.

The test person tasted the solution starting from the lowest concentration and rated the intensity of the following attributes on the marked scale (LMS): sweet, salty, sour, bitter, salty, fresh (fresh) and others (aftertaste). In the tasting gap, the test person rinsed with water three times. If a particular concentration causes an undesirable characteristic or aftertaste, the latter tasting at a higher concentration can be omitted. After rest, the test subjects tasted a solution of the main flavor (e.g., typically 4% sucrose, 6% fructose, or 6% fructose/glucose at pH 7.1) without the test compound. The test compound-added solutions of the primary flavor were then tasted in increasing order of concentration. The master flavour solution can be tasted again if necessary for comparison with the "master flavour + test compound" solution. Allowing for discussion between panelists.

The maximum concentration of test compound that does not cause an undesirable characteristic or aftertaste is the highest concentration of the particular compound that is to be tested in the subsequent sensory test. To confirm the results of the preliminary test, the test can be repeated by another panel of panelists.

For new test compounds, the primary analytical test is always the first test to be performed. Depending on the results of the preliminary analytical test, additional more quantitative measurements may be made to further characterize the test compound.

"reference difference method" human taste test procedure

The purpose is as follows: it was determined how the intensity of the test sample of the test compound differs in sweetness from that of the reference sample. To obtain statistically significant data, this type of study requires a larger panel of panelists (typically 15-20 subjects).

Summary: a group of 10 or more panelists taste a pair of solutions, with one sample being a "reference sample" (which typically does not contain a test compound and is an approved substance or a Generally Recognized As Safe (GRAS) substance, i.e., a sweetener) and the other sample being a "test sample" (which may or may not contain a test compound). The human subjects rate the difference in intensity of the main attribute between the test and reference samples by a range of values from-5 (sweetness much less than the reference) to +5 (sweetness much more than the reference). A score of 0 indicates that the test sample is as sweet as the reference sample.

The procedure is as follows: ten or more human subjects were used to perform the "reference difference" test. Previously, subjects were well known for the taste of the primary attribute and trained to use the-5- +5 scale. The subjects were not allowed to eat (except for water) at least one hour prior to the test. The human subjects ate the wafer and rinse four times with water to clean the mouth.

The test solutions may include the test compound, test compound + primary flavor (e.g., 4% sucrose, 6% fructose/glucose, or 7% fructose/glucose at pH 7.1 or 2.8) in water and a series of solutions containing only the primary flavor as reference samples.

The master flavour sample without test compound is used to determine whether the panelist is able to rate accurately, i.e. the reference sample itself is tested (blind test) to determine how accurately the panelist rates on a given test day. The solution was dispensed in 10ml volumes into 1 ounce sample cups at room temperature and provided to human subjects.

The test subjects tasted the reference sample first, then immediately the test sample, and rated the intensity difference of the main attribute on the reference difference scale (-5- + 5). All samples were spit out. The test person can taste the sample again, but only with a given sample volume. Between tasting each pair of samples, the human subject must rinse with water at least twice. Depending on the sample being tasted, it may be desirable to consume a cracker between tasting pairs of samples.

The scores for each test were averaged over the number of human subjects and the standard error was calculated. Scores of blind reference tests can be used to determine taste assessment accuracy. Assuming that the reference sample is identical in all tests, differences between pairs of samples can be determined using ANOVA and multiple comparative tests, such as Tukey's honeyly signed Difference test. If the same test sample pair is tested in another series, a Student's t-test (paired, two-tailed; α ═ 0.05) can be used to determine if there are any differences between the ratings of the series.

A variety of different reference sweeteners have been used to measure sweetness enhancement. For example, to test (R) -3-methyl-N- (1, 2, 3, 4-tetrahydronaphthalen-1-yl) isoxazole-4-carboxamide, a reference sample consisting of 4% sucrose was used that had a sweetness greater than a threshold level (i.e., 2% sucrose) and that was the sweetness in the sweet taste region where the human subject was most sensitive to subtle changes in the sweet taste sensation. To test 2, 3, 5, 6-tetrafluoro-4-methyl-N- (2-methylcyclohexyl) benzamide, a 50: 50 fructose: glucose mixture was used to better simulate the high fructose corn syrup solution commonly used in the beverage industry. It has been demonstrated that 6% fructose/glucose mixture is roughly equivalent in sweet taste to 6% sucrose, 6% sucrose being in a range where evaluators are sensitive to subtle changes in sweet taste. After an initial study with 6% fructose/glucose at pH 7.1, the study was directed to evaluate the performance of this compound in a prototype product that was more similar to a cola beverage (i.e., higher sweetener concentration and lower pH).

The results of some human taste tests conducted on the sweet amide compounds of the present invention in an aqueous composition intended to mimic a carbonated beverage composition are listed in table F below.

Table f sweet taste test results

Compound numbering	Content of solution	pH	Sensory equivalent sweet taste solution
				175	50 μ M Compound 175+ 4% sucrose	*	6% sucrose
171	30 μ M Compound 171+ 6% fructose/glucose	*	Greater than 6% but less than 8% fructose/glucose
				170	30 μ M Compound 170+ 6% fructose/glucose	pH 7.1	Greater than 6% but less than 8% fructose/glucose
162	10 μ M Compound 162+ 6% fructose/glucose	pH 7.1	Greater than or equal to 8% fructose/glucose
				162	10 μ M Compound 162+ 7% fructose/glucose	pH 2.8	Greater than or equal to 9% fructose/glucose
168	30 μ M Compound 168+ 6% fructose/glucose	pH 7.1	Fructose/glucose equal to 8%
				163	10 μ M Compound 163+ 6%Fructose/glucose	pH 7.1	Greater than 6% but less than 8% fructose/glucose

191	5 μ M Compound 191+ 6% fructose/glucose	pH 7.1	Greater than 6% but less than 8% fructose/glucose
				192	3 μ M Compound 192+ 6% fructose/glucose	pH 7.1	Greater than 6% but less than 8% fructose/glucose
176	10 μ M Compound 176+ 7% fructose/glucose	pH 2.8	Equal to 10.5% fructose/glucose
				176	10 μ M Compound 176+ 7% fructose/glucose	pH 7.1	Equal to 10% fructose/grapeCandy
177	3 μ M Compound 177+ 6% fructose/glucose	pH 7.1	Fructose/glucose equal to 10%

^*The pH of these aqueous solutions was not determined or controlled

Example 203

Soup product using ethanol stock solution

The compounds of the invention were diluted 1000 times the desired concentration in the soup using 200 proof ethanol. The compound may be sonicated and heated (if stable) to ensure complete dissolution in ethanol. A soup from gravy base is made by adding 6g of vegetable gravy base to 500mL of hot water in a glass or porcelain bowl. The water was heated to 80 ℃. The concentration of MSG in the dissolved gravy was 2.2g/L and no IMP was added. After the gravy base is dissolved, the ethanol stock solution is added to the soup base. For 500mL of soup, 0.5mL of 1000-fold stock ethanol was added to give a final ethanol concentration of 0.1%. If ethanol affects the taste of the soup, a higher concentration of the ethanol stock can be prepared as long as the compound is soluble.

Example 204

Potato chip product

The salt mixture of the compounds of the present invention was prepared by mixing the compounds of the present invention with salt such that the addition of the salt mixture to the potato chips at a weight ratio of 1.4% resulted in the desired concentration of the compound. For the case of 1ppm final compound on the chip, 7mg of compound was mixed with 10g of salt. The compound and salt were ground using a mortar and pestle and mixed well. The chips are broken into uniformly sized pieces using a crutcher. For every 98.6g of potato chips, 1.4g of the salt mixture was weighed. The shredded potato chips are first microwaved for 50 seconds or until warmed. The chips were spread on a large piece of aluminum foil. The salt mixture was spread evenly over the potato chips. The chips were then placed in a plastic bag to ensure that all the salt was also placed in the bag. The salt mixture and the chips were then shaken to ensure that the salt spread evenly across the chips.

Example 205

Biscuit product

The compounds of the invention were diluted 1000 times the desired concentration in the final product with 200 proof ethanol. The compound may be sonicated and heated (if stable) to ensure complete dissolution in ethanol. The solution containing the compound of the present invention is then mixed with the other liquid components (i.e., water, de-shelled eggs, and spices) until fully blended. The mixture is mixed with a dry emulsifier such as lecithin and further mixed with shortening. The shortening is mixed with the already thoroughly mixed dry ingredients (i.e., flour, sugar, salt, cocoa powder). The dough is divided into portions and placed on a baking sheet and baked at the desired temperature until complete.

Example 206

Fruit juice product

The compounds of the present invention were diluted 1000 times the desired concentration in the juice with 200 proof ethanol. The compounds are further mixed with an alcohol component of natural and/or artificial flavors to prepare "key". The main flavor is mixed with a portion of the juice concentrate to ensure homogeneity. The remaining portion of the juice concentrate is diluted with water and mixed. Mixing with sweetener such as HFCS (High Fructose Corn Syrup), aspartame or sucralose, and blending. As a final step, the flavor/compound portion was added and blended.

Example 207

Flavored tomato juice or hemomary (blood Mary) mixture

The compounds of the invention are added as dry ingredients to a perfume mixture, optionally containing monosodium glutamate, and mixed thoroughly. The perfume mixture is dispersed in a portion of the paste, mixed, and the mixed paste is further mixed into the remaining paste. The tomato paste is then diluted with water to obtain a flavoured tomato juice or hemomary mixture, which is optionally processed at elevated temperatures for a short period of time.

Example 208

Human taste testing of low sodium tomato juice

To evaluate the ability of the compounds of the present invention to enhance the savory flavor of low-sodium tomato juice (naturally containing some monosodium glutamate), a human taste test was performed.

Sample preparation procedure

The final tomato juice sample for taste testing was formulated to contain 90 vol% of a pre-made stock solution of low-sodium tomato juice (pH 4.2, 80-100 mg Na/8 oz, 16mM naturally occurring MSG), 5 vol% of a stock solution formulated to produce the selected final sodium level of the final juice, and 5 vol% of a compound of the present invention. The selected oxalamide compounds of the invention were dissolved in LSB (low sodium phosphate buffer) to provide a stock solution at a concentration of 20 times the desired final concentration in the final tomato juice. The desired final sodium concentration for most of the final tomato juices tested was 73.6mM (400 mg sodium in 8 ounces of juice), so the stock solution of NaCl made up to 1.48M NaCl. The stock solution was adjusted to pH 4.2 using 1M citric acid solution, and then sonicated to ensure complete dissolution of the added compound. 50mL of the test compound stock solution and 50mL of sodium chloride were added to 900mL of pre-made low sodium tomato raw juice to prepare a final sample of 1,000mL of tomato juice sample for taste testing.

Taste test for human

Sixteen subjects were tested for taste. The subjects were not allowed to eat (except for water) for at least one hour prior to testing. Before the test began, the subjects ate the wafer and rinsed with water to clean the mouth. A 15mL sample was provided in a 2 oz sample cup at room temperature. Panelists were rinsed in the gaps between tasting each sample and were encouraged to eat crackers to remove all aftertaste before starting to taste the next sample. Samples were provided in a randomly equalized order in each series (using different blinding codes). Within two repeated series, the panelists were asked to rate umami (savoury taste level) and the samples were rated on an unscrambled line scale (rating 0-10). There was a rest time of 5 minutes between tasting series, for a total of 4 series over a period of two days. The samples tasted were as follows:

tasted sample
	400mg Na/8 oz tomato juice
400mg Na +3 μ M Compound 123/8 ounce tomato juice
	400mg Na +3 μ M Compound 157/8 ounce tomato juice

Scores for each panelist and series were averaged and scores were evaluated using a two-way ANOVA (factor: panelist and sample) and Duncan's multiple comparison test (α ═ 0.05) to determine significant differences in intensity ratings. The results are summarized below.

Table G tomato juice taste test results

Compound (I)	Name of Compound	Test data
			123	N1- (2, 4-Dimethoxybenzyl) -N2- (2- (pyridin-2-yl) ethyl) ethanediamide	The 3 μ M compound enhances the savory taste of 16mM glutamate (naturally occurring) in low sodium tomato juice by 1.4-1.5 times
157	N1- (2-methoxy-4-methylbenzyl) -N2- (2- (5-methylpyridin-2-yl) ethyl) ethanediamide	The 3 μ M compound enhances the savory taste of 16mM glutamate (naturally occurring) in low sodium tomato juice by 1.8-1.9 times

Various modifications and alterations of this invention will become apparent to those skilled in the art without departing from the spirit and scope of this invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims (76)

1. A method for increasing the sweetness of a comestible or medicinal product, comprising:

a) providing at least one food or pharmaceutical product, or one or more precursors thereof, and

b) combining the food or pharmaceutical product or one or more precursors thereof with at least one aromatic or heteroaromatic amide compound or an edible salt of such an amide compound to form an improved food or pharmaceutical product comprising at least about 0.001ppm of the amide compound;

wherein the amide compound has the following structure:

wherein A is a five or six membered aryl or heteroaryl ring;

m is 1, 2 or 3;

R¹' each is independently selected from hydroxyl, NH₂SH, halogen, C₁-C₈An organic group;

R²is a group having the structure

Wherein R is²Comprising an enantiomeric excess of a given optical configuration, n is 1, 2 or 3, R²' each with R²Is bonded to an aromatic or non-aromatic ring of (A), and each R²' independently selected from hydroxyl, NH₂SH, halogen, C₁-C₄An organic radical, and

wherein the improved edible or pharmaceutical product further comprises at least a sweet flavoring amount of one or more natural, semi-synthetic or synthetic sweet flavoring agents, or a mixture of said sweet flavoring agents.

2. The method of claim 1, wherein R is₂Groups contain the specified optical configuration of at least 90% enantiomeric excess.

3. The method of claim 1, wherein each R is¹' and each R²' is independently selected from hydroxyl, fluorine, chlorine, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃、S(O)CH₃、S(O)₂CH₃SEt, methyl, ethyl, isopropyl, n-propyl,N-butyl, 1-methyl-propyl, isobutyl, tert-butyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy.

4. The method of claim 1, wherein a is a benzene ring.

5. The method of claim 1, wherein the a group is one of the groups of the formula:

6. the method of claim 5, wherein m is 1 or 2 and R is¹' are each independently selected from hydrogen, hydroxy, fluorine, chlorine, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃、S(O)CH₃、S(O)₂CH₃SEt, methyl, ethyl, isopropyl, n-propyl, n-butyl, 1-methyl-propyl, isobutyl, tert-butyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy.

7. The method of claim 1, wherein the a group has the structure:

wherein R is¹' is hydrogen, hydroxy, NH₂SH, halogen, C₁-C₈Alkyl radical, C₁-C₈Haloalkyl, C ₁-C₈Haloalkoxy, C₁-C₈Alkoxy radical, C₁-C₈Alkoxy-alkyl, C₁-C₈Hydroxy-alkyl, OH, NH₂、NHR⁶、NR⁶ ₂、CN、CO₂H、CO₂R⁶、CHO、COR⁶、SH、SR⁶、S(O)R⁶、S(O)₂R⁶And halogen, wherein R⁶Is C₁-C₄An alkyl group.

8. The method of claim 7, wherein R¹Is' a C₁-C₈An alkyl group.

9. The method of claim 7, wherein R¹' is hydroxy, fluoro, chloro, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃、S(O)CH₃、S(O)₂CH₃SEt, methyl, ethyl, isopropyl, n-propyl, n-butyl, 1-methyl-propyl, isobutyl, tert-butyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, CH₂OCH₃、CH₂OH、CH₂NH₂、CH₂NHCH₃Or CH₂N(CH₃)₂A group.

10. The method of claim 1, wherein the amide compound is one of the following:

(R) -N- (5-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) -3-propylisoxazole-4-carboxamide;

(R) -3-butyl-N- (5-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) isoxazole-4-carboxamide;

(R) -3-ethyl-N- (5-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) isoxazole-4-carboxamide;

(R) -N- (5, 7-dimethyl-1, 2, 3, 4-tetrahydronaphthalen-1-yl) -3-methylisoxazole-4-carboxamide;

(R) -3-chloro-2-hydroxy-N- (5-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) benzamide; or

(R) -3-chloro-2-hydroxy-N- (7-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) benzamide.

11. The method of any one of claims 1 to 10, wherein the natural, semi-synthetic or synthetic sweet flavouring is selected from sucrose, fructose, glucose, erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, aspartame, saccharin, acesulfame k, cyclamate, sucralose and alitame or mixtures thereof.

12. The method of any one of claims 1 to 10, wherein the modified comestible or medicinal product has a sweeter taste as determined by a majority of at least 8 people in a taste tester panel compared to a control comestible or medicinal product that does not contain the amide compound.

13. The method of any one of claims 1 to 10, wherein the prepared edible or pharmaceutical product is selected from the group consisting of a confectionery product, a bakery product, an ice cream, a dairy product, a sweet or savoury snack, a snack bar, a meal replacement, a ready meal, a soup, an edible batter, a noodle, a canned food, a frozen food, a dried food, a frozen food, a fat, an infant food and a spread.

14. The method of any one of claims 1 to 10, wherein the improved food or pharmaceutical product comprises one or more meats, poultry, fish, vegetables, grains, or fruits.

15. A method according to any one of claims 1 to 10 wherein the modified food or pharmaceutical product is a frozen food, an uncooked food or a fully or partially cooked food.

16. The method of any one of claims 1 to 10, wherein the modified food or pharmaceutical product is a soup, a dehydrated or concentrated soup, or a dry soup.

17. The method of any one of claims 1 to 10, wherein the modified edible or pharmaceutical product is a snack food.

18. The method of any one of claims 1 to 10, wherein the improved food or pharmaceutical product is a cooking aid, a dietary solution product, a dietary supplement, a condiment, or a mixture of condiments.

19. The method of any one of claims 1 to 10, wherein the modified comestible or medicinal product is a cake, biscuit, pie, candy, chewing gum, jelly, ice cream, sorbet, pudding, jam, fudge, salad dressing, condiment, cereal, canned fruit, or fruit sauce.

20. The method of any one of claims 1 to 10, wherein the improved food or pharmaceutical product is a beverage, a beverage mix or a beverage concentrate.

21. The method of any one of claims 1 to 10, wherein the improved food or pharmaceutical product is soda or fruit juice.

22. The method of any one of claims 1 to 10, wherein the modified food or pharmaceutical product is an alcoholic beverage.

23. The method of any one of claims 1 to 10, wherein the improved edible or pharmaceutical product is an oral hygiene product.

24. The method of any one of claims 1 to 10, wherein the amide compound is present in the modified comestible or medicinal product in a concentration of from about 0.01ppm to about 30 ppm.

25. The method of any one of claims 1 to 10, wherein the modified comestible or medicinal product has a sweeter taste as determined by a majority of at least 8 people in a taste tester panel compared to a control comestible or medicinal product that does not contain the compound.

26. The method of any of claims 1-10, wherein the amide compound has an EC of less than about 2 μ Μ for binding to the hT1R2/hT1R3 receptor expressed in a HEK 293-ga 15 cell line₅₀。

27. A food or pharmaceutical product made by the method of any one of claims 1 to 26.

28. A method for enhancing the sweetness of a comestible or medicinal product, comprising:

a) providing at least one food or pharmaceutical product, or one or more precursors thereof, and

b) combining the food or pharmaceutical product or one or more precursors thereof with at least one urea compound or an edible salt of the urea compound to form an improved food or pharmaceutical product comprising at least about 0.001ppm of the urea compound;

c) wherein the improved food or pharmaceutical product further comprises a known natural or artificial sweetener,

wherein the urea compound has the formula:

wherein m is 1, 2 or 3, and each R¹' and R²' is independently selected from fluorine, chlorine, bromine, NH₂、NHCH₃、N(CH₃)₂、SEt、SCH₃、S(O)CH₃、S(O)₂CH₃Methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy, or two R¹' the groups together form a methylene dioxy ring.

29. The method of claim 28, wherein the urea compound has the formula:

30. the method of claim 29, wherein R²' is methyl or methoxy.

31. The method of claim 28, wherein the aniline group has the formula:

wherein R is ¹′、R¹"and R¹"' is independently selected from hydrogen, fluoro, chloro, bromo, methyl, and methoxy.

32. The method of claim 28, wherein the aniline group has the formula:

wherein R is¹' and R¹"is independently selected from the group consisting of fluoro, chloro, bromo, methyl and methoxy.

33. The method of claim 28, wherein R is¹' the groups together form a methylenedioxy ring group having the formula:

34. the method of claim 28, wherein the urea compound comprises from about 0.1ppm to about 100ppm of the modified comestible or medicinal product, and wherein the modified comestible or medicinal product has a sweeter taste, as determined by a majority of a taste tester panel of at least 8 people, compared to a control comestible or medicinal product that does not contain the urea compound.

35. The method of any one of claims 28 to 34, wherein the natural, semi-synthetic or synthetic sweet flavouring is selected from sucrose, fructose, glucose, erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, aspartame, saccharin, acesulfame k, cyclamate, sucralose and alitame or mixtures thereof.

36. The method of any one of claims 28 to 34, wherein the modified comestible or medicinal product has a sweeter taste as determined by a majority of at least 8 people in a taste tester panel compared to a control comestible or medicinal product that does not contain the amide compound.

37. The method of any one of claims 28 to 34, wherein the modified comestible or medicinal product is selected from the group consisting of a confectionery product, a bakery product, an ice cream, a dairy product, a sweet or savory snack, a snack bar, a meal replacement, a ready meal, a soup, a pasta, a noodle, a canned food, a frozen food, a dried food, a frozen food, a fat, an infant food and a spread.

38. The method of any one of claims 28 to 34, wherein the improved food or pharmaceutical product comprises one or more meats, poultry, fish, vegetables, grains, or fruits.

39. A method according to any one of claims 28 to 34 wherein the modified food or pharmaceutical product is a frozen food product, an uncooked food product or a fully or partially cooked food product.

40. The method of any one of claims 28 to 34, wherein the modified food or pharmaceutical product is a soup, a dehydrated or concentrated soup, or a dry soup.

41. The method of any one of claims 28 to 34, wherein the modified edible or pharmaceutical product is a snack food.

42. The method of any one of claims 28 to 34, wherein the improved food or pharmaceutical product is a cooking aid, a dietary solution product, a food enhancement, a condiment, or a condiment mixture.

43. The method of any one of claims 28 to 34, wherein the modified comestible or medicinal product is a cake, biscuit, pie, candy, chewing gum, jelly, ice cream, sorbet, pudding, jam, fudge, salad dressing, condiment, cereal, canned fruit, or fruit sauce.

44. The method of any one of claims 28 to 34, wherein the improved food or pharmaceutical product is a beverage, a beverage mix or a beverage concentrate.

45. The method of any one of claims 28 to 34, wherein the improved food or pharmaceutical product is soda or fruit juice.

46. The method of any one of claims 28 to 34, wherein the modified food or pharmaceutical product is an alcoholic beverage.

47. A method according to any one of claims 28 to 34 wherein the improved food or pharmaceutical product is an oral hygiene product.

48. A food or pharmaceutical product made by the method of any one of claims 28 to 47.

49. An edible composition comprising greater than about 0.001ppm of one or more of the following compounds:

3-ethyl-N- (hept-4-yl) benzamide;

5-ethyl-N- (hept-4-yl) -4- (methoxymethyl) furan-2-carboxamide;

3, 4-dimethyl-N- (2-methylcyclohexyl) benzamide;

2-amino-3-methoxy-N- (2-methylcyclohexyl) benzamide;

n- (hept-4-yl) -3- (methylthio) benzamide; or

1, 2, 3, 4-tetrahydroquinoline-7-carboxamide, N- (hept-4-yl) -benzamide;

or an edible salt of said compound, or mixtures thereof.

50. An edible composition comprising greater than about 0.001ppm of one or more of the following compounds:

(S) -N- (2, 3-dihydro-1H-inden-1-yl) -4-methoxy-3-methylbenzamide;

4-methoxy-N- (5-methoxy-2, 3-dihydro-1H-inden-1-yl) -3-methylbenzamide;

(S) -4-methoxy-N- (5-methoxy-2, 3-dihydro-1H-inden-1-yl) -3-methylbenzamide;

2-amino-3-methoxy-N- (5-methoxy-2, 3-dihydro-1H-inden-1-yl) benzamide

2-amino-3-methoxy-N- (6-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) benzamide;

(S) -2-amino-3-methoxy-N- (6-methoxy-1, 2, 3, 4-tetrahydronaphthalen-1-yl) benzamide;

(S) -2-amino-3-methoxy-N- (1, 2, 3, 4-tetrahydronaphthalen-1-yl) benzamide;

or an edible salt of said compound, or mixtures thereof.

51. A comestible or medicinal composition comprising a comestible or medicinal product, or one or more precursors thereof, and at least about 0.0001ppm of an amide compound having the structure:

wherein A is a five or six membered aryl or heteroaryl ring;

m is 1, 2 or 3;

R¹' each is independently selected from hydroxyl, NH₂SH, halogen and C₁-C₈An organic group;

R²is a group having the structure

Wherein R is²Comprising an enantiomeric excess of a given optical configuration, n is 1, 2 or 3, R²' each with R²Is bonded to an aromatic or non-aromatic ring, and R²' each is independently selected from hydroxyl, NH₂SH, halogen or C₁-C₄An organic group;

wherein the improved edible or pharmaceutical product further comprises at least a sweet flavouring amount of one or more natural, semi-synthetic or synthetic sweet flavourings or mixtures of said sweet flavourings.

52. An improved food or pharmaceutical product comprising at least one food or pharmaceutical product or one or more precursors thereof, and at least about 0.001ppm of at least one urea compound having the formula:

Wherein m is 1, 2 or 3, and each R¹' and R²' is independently selected from fluorine, chlorine, bromine, NH₂、NHCH₃、N(CH₃)₂、SEt、SCH₃、S(O)CH₃、S(O)₂CH₃Methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy, or two R¹' the groups together form a methylene dioxy ring.

53. An improved food or pharmaceutical product comprising at least one food or pharmaceutical product or one or more precursors thereof, and at least about 0.001ppm of at least one compound having the structure:

wherein A is a five or six membered aryl or heteroaryl ring;

m is 0, 1, 2, 3 or 4;

R¹' each is independently selected from hydroxyl, NH₂SH, halogen and C₁-C₈An organic group;

R²comprising a tetrahydronaphthalene ring or an indane ring modified to contain one or more heteroatoms or groups of heteroatoms independently selected from oxygen, nitrogen or sulfur.

54. The improved comestible or medicinal product of claim 53, wherein R²Has the following structure:

wherein n is 1, 2 or 3, R²' each with R²Is bonded to an aromatic or non-aromatic ring, and R²' each is independently selected from hydroxyl, NH₂SH, halogen or C₁-C₄An organic group.

55. The improved comestible or medicinal product of claim 53, wherein R²Has one of the following structures:

wherein n is 1, 2 or 3, R²' each with R²Is bonded to an aromatic or non-aromatic ring, and R²' each is independently selected from hydroxyl, NH₂SH, halogen or C₁-C₄An organic group.

56. The improved comestible or medicinal product of claim 53, wherein R²Has the following structure:

wherein n is 0, 1, 2 or 3; x_hIs O, S, SO₂NH or NR_hWherein R is_hIs C₁-C₄An organic group; r²' each with R²Is bonded to an aromatic or non-aromatic ring, and R²' each is independently selected from hydroxyl, NH₂SH, halogen or C₁-C₄An organic group.

57. The improved comestible or medicinal product of claim 53, wherein R²Has the following structure:

wherein n is 0, 1, 2 or 3; wherein R is_hIs C₁-C₄An organic group; r²' each is independently selected from hydroxyl, NH₂SH, halogen or C₁-C₄An organic group.

58. The improved comestible or medicinal product of claim 53, wherein R²Has the following structure:

wherein n is 1, 2 or 3; r²' each with R²Is bonded to an aromatic or non-aromatic ring, and R²' each is independently selected from hydroxyl, NH₂SH, halogen or C ₁-C₄An organic group.

59. The improved comestible or medicinal product of claim 53, wherein R²Has the following structure:

wherein n is 1, 2 or 3; r²' each with R²Is bonded to an aromatic or non-aromatic ring, and R²' each is independently selected from hydroxyl, NH₂SH, halogen or C₁-C₄An organic group.

60. The improved comestible or medicinal product of any of claims 54-59, wherein C₁-C₄The organic groups are independently selected from hydrogen, hydroxy, fluorine, chlorine, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃、S(O)CH₃、S(O)₂CH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.

61. The improved comestible or medicinal product of any of claims 53-60 wherein A is a benzene ring.

62. The improved comestible or medicinal product of claim 53, wherein C₁-C₈The organic groups are independently selected from hydrogen, hydroxy, fluorine, chlorine, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃、S(O)CH₃、S(O)₂CH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.

63. The improved comestible or medicinal product of any of claims 53-60 wherein the A group has one of the following formulas:

64. The improved comestible or medicinal product of claim 63, wherein C₁-C₈The organic groups are independently selected from hydrogen, hydroxy, fluorine, chlorine, NH₂、NHCH₃、N(CH₃)₂、COOCH₃、SCH₃、S(O)CH₃、S(O)₂CH₃SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.

65. The improved comestible or medicinal product of any of claims 53-64, further comprising at least a sweet flavoring amount of one or more natural, semi-synthetic, or synthetic sweet flavors or mixtures thereof.

66. The improved comestible or medicinal product of any one of claims 53-64, wherein the natural, semi-synthetic, or synthetic sweet flavoring comprises sucrose, fructose, glucose, erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, aspartame, saccharin, acesulfame potassium, cyclamate, sucralose, and alitame, or mixtures thereof.

67. The improved comestible or medicinal product of any of claims 53-64, wherein the improved comestible or medicinal product comprises one or more meats, birds, fish, vegetables, grains, or fruits.

68. The modified comestible or medicinal product of any of claims 53-64, wherein the modified comestible or medicinal product is a frozen food, an uncooked food, or a fully or partially cooked food.

69. The modified comestible or medicinal product of any one of claims 53-64, wherein the modified comestible or medicinal product is a soup, a dehydrated or concentrated soup, or a dry soup.

70. The modified comestible or medicinal product of any of claims 53-64 wherein the modified comestible or medicinal product is a snack food.

71. The modified comestible or medicinal product of any of claims 53-64 wherein the modified comestible or medicinal product is a cooking aid, a meal solution product, a meal enhancement product, a flavoring, or a flavoring blend.

72. The modified comestible or medicinal product of any one of claims 53-64 wherein the modified comestible or medicinal product is a cake, biscuit, pie, candy, chewing gum, pectin, ice cream, sorbet, pudding, jam, fudge, salad dressing, condiment, cereal, canned fruit, or fruit sauce.

73. The improved comestible or medicinal product of any of claims 53-64 wherein the improved comestible or medicinal product is a beverage, a beverage mix, or a beverage concentrate.

74. The improved comestible or medicinal product of any of claims 53-64, wherein the improved comestible or medicinal product is soda or fruit juice.

75. The improved comestible or medicinal product of any of claims 53-64, wherein the improved comestible or medicinal product is an alcoholic beverage.

76. The improved comestible or medicinal product of any of claims 53-64, wherein the improved comestible or medicinal product is an oral hygiene product.