ZA200702833B

ZA200702833B - Novel flavors, flavor modifiers, tastants, taste enhancers, umami or sweet tastants, and/or enhancers and use there-of

Info

Publication number: ZA200702833B
Application number: ZA200702833A
Authority: ZA
Inventors: Tachdjian Catherine; Sara L Adamski-Werner; Bakir Farid; Chen Qing; Darmohusodo Vincent; Hobson Stephen Terrence; Li Xiaodong; Qi Ming; Rogers Daniel Harry; Rinnova Marketa; Servant Guy; Tang Xiao-Qing; Zoller Mark; Wallace David; Xing Amy; Gubernator Klaus; Andrew P Patron
Original assignee: Senomyx Inc
Priority date: 2003-08-06
Filing date: 2004-08-06
Publication date: 2008-11-26
Also published as: ZA200601903B; UA86946C2; ZA200702832B; CN101400336A; CA2827128C; CN101400336B; UA92887C2; AR098722A2; CN101052725A; CA2827128A1

Description

i v ~ TTY

This application claims the priority of U.S. provisional patent application serial number 60/494,071 filed on August 06, 2003, and also claims the priority of

U.S. provisional patent application serial number 60/552,064, filed March 09, 2004, the entire disclosures of which are hereby incorporated herein by this reference.

FIELD OF THE INVENTION

| The present invention relates to flavour or taste modifiers, such asa flavoring or flavoring agents and flavor or taste enhancers, more particularly, savory (‘“umami’”) or sweet taste modifiers, - savory or sweet flavoring agents and savory or sweet flavor enhancers, for foods, beverages, and other comestible or orally administered medicinal products or compositions.

BACKGROUND OF THE INVENTION

For centuries, various natural and unnatural compositions and/or compounds have been added to comestible (edible) foods, beverages, and/or orally administered medicinal compositions to improve their taste. Although it has long been known that there are only a few basic types of “tastes,” the biological and biochemical basis of taste perception was poorly understood, and most taste improving or taste modifying agents have been discovered largely by simple trial and error processes.

There has been significant recent progress in identifying useful natural flavoring agents, such as for example sweeteners such as sucrose, fructose, glucose, erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, certain known natural terpenoids, flavonoids, or protein sweeteners. See for example a recent article entitled “Noncariogenic Intense Natural Sweeteners” by Kinghorn ef al. (Med Res Rev 18 (5) 347-360, 1998), which discussed recently discovered natural materials that are much more intensely sweet than common natural sweeteners such as sucrose, fructose, and the like. Similarly, there has been recent progress in identifying and commercializing new artificial sweeteners, such as aspartame, saccharin, acesulfame-K, cyclamate, sucralose, and alitame, etc., see a recent article by Ager, et al. (Angew Chem Int. Ed. 1998, 37, 1802-1817). The entire disclosure of the two references identified above are hereby incorporated herein by reference, for the purpose of describing at least in part the knowledge of those of ordinary skill in the art regarding known sweetening agents.

However, there remains in the art a need for new and improved flavoring agents. For example, one of the five known basic tastes is the “savory” or “umami” flavor of monosodium glutamate (“MSG”). MSG is known to produce adverse reactions in some people, but very little progress has been made in identifying artificial substitutes for MSG. It is known that a few naturally occurring materials can increase or enhance the effectiveness of MSG as a savory flavoring agent, so that less

MSG would be needed for a given flavoring application. For example the naturally occurring nucleotide compounds inosine monophosphate (IMP) or guanosine monophosphate (GMP) are known to have a multiplier effect on the savory taste of

MSG, but IMP and GMP are very difficult and expensive to isolate and purify from natural sources, or synthesize, and hence have only limited practical application to most commercial needs in food or medicinal compositions. Less expensive compounds that would provide the flavor of MSG itself, or enhance the effectiveness of any MSG that is present could be of very high value. Similarly, discovery of compounds that are either new “High Intensity” sweetners (i.e. they are many times sweeter than sucrose) would be of value, or any compounds that significantly increase the sweetness of known natural or artificial sweeteners, so that less of those caloric or non-caloric sweeteners would be required, would be of very high utility and value. : | In recent years substantial progress has been made in biotechnology in general, and in better understanding the underlying biological and biochemical phenomena of taste perception. For example, taste receptor proteins have been recently identified in mammals which are involved in taste perception. Particularly, two different families of G protein coupled receptors believed to be involved in taste perception, T2Rs and T1Rs, have been identified. (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) 99:4962-4966; Montmayeur, et al., Nature

Neuroscience (2001) 4(S):492-498: U.S. Patent 6,462,148; and PCT publications wo 02/06254, WO 00/63166 art, WO 02/064631, and WO 03/001876, and U.S.

Patent publication US 2003-0232407 Al). The entire disclosures of the articles, patent applications, and issued patents cited immediately above are hereby incorporated herein by reference, for all purposes, including their disclosures of the identities and structures of T2Rs and T1Rs mammalian taste receptor proteins and s

2° 20y7/G2833 : methods for artificially expressing those receptors in cell lines and using the resulting cell lines for screening compounds as potential “savory” or “sweet” flavoring agents.

Whereas the T2R family includes a family of over 25 genes that are involved in bitter taste perception, the T1Rs only includes three members, T1R1, TIR2 and

TIR3. (see Li, et al, Proc. Natl. Acad. Sci. USA (2002) 99:4962-4966.) Recently it was disclosed in WO 02/064631 and/or WO 03/001876 that certain T1R members, when co-expressed in suitable mammalian cell lines, assemble to form functional taste receptors. Particularly it was found that co-expression of TIR1 and TI1R3 in a suitable host cell results in a functional TIR1/T1R3 savory (“umami’”) taste receptor that responds to savory taste stimuli, including monosodium glutamate. Similarly, it was found that co-expression of TIR2 and T1R3 in a suitable host cell results in a functional T1R2/T1R3 “sweet” taste receptor that responds to different taste stimuli including naturally occurring and artificial sweeteners. (See Li, et al. (Id.). The references cited above also disclosed assays and/or high throughput screens that measure TIR1/T1R3 or TIR2/T1R3 receptor activity by fluorometric imaging in the presence of the target compounds. We employed the above-described assays and/or high throughput screening methods to identify initial “lead” compounds that modulate the activity of TIR1/T1R3 “savory” taste receptors, or TIR2/T1R3 “sweet” taste receptors, then embarked on a long, complex and iterative process of investigation, evaluation, and optimization, so as to arrive at the various inventions described below.

SUMMARY OF THE INVENTION

The invention has many aspects, all of which relate in some fashion to certain non-naturally occurring amide compounds and/or amide derivative compounds having the generic structure shown below in Formula (I): 0

A © ko ty wherein R', R? and R® can be and are independently further defined in various ways, as is further detailed below. In all the embodiments of the amide compounds of

Formula (I) the R! group is an organic residue comprising at least three carbon atoms, with a variety of alternative limits on the size and/or chemical characteristics of the R! group, as will be further described below. In many but not all embodiments, the amide compounds of Formula (I) are “primary” amides, i.e. one of R* and R® is an organic group comprising at least three carbon atoms, while the other of R? and R® is hydrogen.

The amide compounds of Formula (I) also comprise certain sub-classes of amide derivatives or classes of derivatives related to amides, such as for example ureas, urethanes, oxalamides, acrylamides, and the like, as will be further described © below.

Many of the subgenuses and species of the “amide” compounds of Formula (I) are shown below to bind to and/or activate one or both of the TIR1/T1R3 “savory” (“umami”)or TIR2/T1R3 sweet receptors in-vitro, at relatively low concentrations on the order of micromolar or lower concentrations. The amide compounds are also believed to similarly interact with savory or sweet flavor receptors of animals or humans in vivo, as has been confirmed by actual human taste tests of some of compounds of Formula (I).

Accordingly, many of the subgenuses and species of the “amide” compounds of Formula (I) further described hereinbelow can, at surprisingly low concentrations be used as savory or sweet flavoring agents, or savory or sweet agent enhancers.

Accordingly, in some embodiments, the invention relates to methods for modulating - the savory taste of a comestible or medicinal product comprising: a) providing at least one comestible or medicinal product, or a precursor thereof, and b) combining the comestible or medicinal product or precursor thereof with at least a savory flavor modulating amount, or a sweet flavor modulating amount, of at least one non-naturally occurring amide compound, or a comestibly acceptable salt thereof, so as to form a modified comestible or medicinal product; wherein the amide compound has the formula: 0]

R! A vd R®

L wherein R! comprises an organic or hydrocarbon residue having at least three carbon atoms and optionally one or more heteroatoms

A independently selected from oxygen, nitrogen, sulfur, halogens, or phosphorus; and wherein optionally one of R? and R® is H, and wherein at least one of the other of R? and R® comprises an organic or hydrocarbon residue having at least three carbon atoms and optionally one or more heteroatoms independently selected from oxygen, nitrogen, sulfur, halogens, or phosphorus.

Additional optional limitations on the chemical and physical characteristics of the R!, R?, and R® groups will be described below. Some of the amide compounds of

Formula (I) have been synthesized by methods known in the prior art for various purposes, but to the knowledge of the inventors it has not been previously reco gnized that such amides can be utilized at very low concentrations as savory or sweet flavoring agents, or savory or sweet taste enhancers. Moreover many of the amide compounds of Formula (I) disclosed herein are novel compounds that have not been previously synthesized at all, and are effective savory or sweet taste flavoring agents or taste enhancers.

The invention also relates to the comestible or medicinal products produced by - the processes mentioned above, and to comestible or medicinal products or compositions, or their precursors that contain the amide compounds of Formula (I), which include but are not necessarily limited to food, drink, medicinal products and compositions intended for oral administration, and the precursors thereof.

In many embodiments, one or more of the amide compounds of Formula (I) further identified, described, and/or claimed herein, or a comestibly acceptable salt thereof, can be used in mixtures or in combination with other known savory or sweet compounds, or used as flavor enhancers in comestible food, beverage and medicinal compositions, for human or animal consumption.

In some embodiments, the amide compounds of Formula (I), while having little or perhaps even no sweet or savory flavor when tasted in isolation, can be employed at very low concentrations in order to very significantly enhance the effectiveness of other savory or sweet flavor agents in a comestible or medicinal composition, or a precursor thereof. The inventions described herein also relate to the flavor-modified comestible or medicinal products that contain flavor modulating amounts of one or more of the amide compounds disclosed herein.

Many of the amide compounds of Formula (I) and/or its various subgenuses of amide compounds, when used together with MSG or alone, increase or modulate a response in vitro, and savory taste perception in humans at surprisingly low concentrations. In some.embodiments, the amide compounds of the invention are

TIRI/TIR3 receptor agonists and accordingly can induce or enhance savory taste perception in humans. These compounds can enhance, potentiate, modulate or induce other natural and synthetic savory flavoring agents.

In related embodiments, many of the amide compounds within the scope of

Formula (I) are TIR2/T1R3 receptor agonists and accordingly can induce sweet taste perception in humans at surprisingly low concentrations. These compounds can enhance, potentiate, modulate or induce other natural, semi-synthetic, or synthetic . . sweet flavoring agents, such as for example sucrose, fructose, glucose, erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, certain known natural terpenoids, ‘flavonoids, or protein sweeteners, aspartame, saccharin, acesulfame-K, cyclamate, sucralose, and alitame, and the like, or a mixture thereof.

Unexpectedly, it has also been determined that in many embodiments of the compounds of Formula (I) there are significant structural similarities and/or overlaps between the amide compounds that can produce or enhance the sweet and savory tastes of comestible or medicinal compositions, even though it is believed that the relevant biological taste receptor proteins are significantly different. Even more unexpectedly, it has been deiermined that at least some of the amide compounds of

Formula (I) disclosed herein can induce or enhance both the sweet and savory tastes of the comestible or medicinal products. Therefore in some aspects the invention is related to compounds of Formula (I) or its various subgenuses and species compounds that modulate (e.g., induce, enhance or potentiate) the flavor of known natural or synthetic sweetener agents.

In some embodiments, the invention relates to novel compounds, flavoring agents, flavor enhancers, flavor modifying compounds, and/or compositions containing the compounds of Formula (I), and its various subgenuses and species compounds. . In other embodiments, the invention is directed to compounds of Formula (I) or its various subgenuses and species compounds that modulate (e.g., induce, enhance or potentiate) the flavor of monosodium glutamate (MSG), or synthetic savory flavoring agents.

In some embodiments, the invention relates to comestible or medicinal compositions suitable for human or animal consumption, OF precursors thereof, containing at least one compound of Formula (I), ara comestibly or pharmaceutically acceptable salt thereof. These compositions will preferably include comestible products such as foods or beverages, medicinal products or compositions intended for oral administration, and oral hygiene products, and additives which when added to these products modulate the flavor or taste thereof, particularly by enhancing (increasing) the savory and/or sweet taste thereof.

The present invention also relates to novel genuses and species of amide compounds within the scope of the compounds of Formula (I), and derivatives, flavoring agents, comestible or medicinal products or compositions, including savory or sweet flavoring agents and flavor enhancers containing the same. : The foregoing discussion merely summarizes certain aspects of the inventions and is not intended, nor should it be construed, as limiting the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

The present invention can 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 drawings and Tables and their previous and following description. Before the present compounds, compositions, and/or methods are disclosed and described, it is to be understood that unless otherwise specifically indicated by the claims, the invention is not limited to specific ‘ foods or food preparation methods, specific comestibles or pharmaceutical carriers or

J formulations, or to particular modes of formulating the compounds of the invention Co into comestible or medicinal products or compositions intended for oral - administration, because as one of ordinary skill in relevant arts is well aware, such . things can of course, 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.

DEFINITIONS

As used herein, the term “medicinal product” includes both solids and Liquid compositions which are ingestible non-toxic materials which have medicinal value or comprise medicinally active agents such as cough syrups, cough drops, aspirin and chewable medicinal tablets. : 7 oo o

An oral hygiene product includes solids and liquids such as toothpaste or mouthwash.

A “comestibly, biologically or medicinally acceptable carrier or excipient” is a solid or liquid medium and/or composition that is used to prepare a desired dosage form of the inventive compound, in order to administer the inventive compound in a dispersed/diluted form, so that the biological effectiveness of the inventive compound is maximized. A comestibly, biologically or medicinally acceptable carrier includes many common food ingredients, such as water at neutral, acidic, or basic pH, fruit or vegetable juices, vinegar, marinades, beer, wine, natural water/fat emulsions such as milk or condensed milk, edible oils and shortenings, fatty acids, low molecular weight oligomers of propylene glycol, glyceryl esters of fatty acids, and dispersions or emulsions of such hydrophobic substances in aqueous media, salts such as sodium chloride, wheat flours, solvents such as ethanol, solid edible diluents such as vegetable powders or flours, or other liquid vehicles; dispersion or suspension aids; surface active agents; isotonic agents; thickening or emulsifying agents, preservatives; solid binders; lubricants and the like.

A “flavor” herein refers to the perception of taste and/or smell in a subject, which include sweet, sour, salty, bitter, umami, and others. The subject may be a human or an animal.

A “flavoring agent” herein refers to a compound or a biologically acceptable salt thereof that induces a flavor or taste in a animal or a human.

A “flavor modifier” herein refers to a compound or biologically acceptable + salt thereof that modulates, including enhancing or potentiating, and inducing, the tastes and/or smell of a natural or synthetic flavoring agent in a animal or a human.

A “flavor enhancer” herein refers to a compound or biologically acceptable salt thereof that enhances the tastes or smell of a natural or synthetic flavoring agent. “Savory flavor” herein refers to the savory “umami” taste typically induced by

MSG (mono sodium glutamate) in a animal or a human. “Savory flavoring agent,” “savory compound” or “savory receptor activating compound” herein refers to a compound or biolo gically acceptable salt thereof that elicits a detectable savory flavor in a subject, e.g., MSG (mono sodium glutamate) or a compound that activates a TIR1/T1R3 receptor in vitro. The subject may be a human or an animal.

“Sweet flavoring agent,” “sweet compound” or “sweet receptor activating compound” herein refers to a compound or biologically acceptable salt thereof that elicits a detectable sweet flavor in a subject, e.g, sucrose, fructose, glucose, and other known natural saccharide-based sweeteners, or known artificial sweeteners such as saccharine, cyclamate, aspartame, and the like as is further discussed herein, or a compound that activates a TIR2/T1R3 receptor in vitro. The subject may be a human or an animal.

A “savory flavor modifier” herein refers to a compound or biologically acceptable salt thereof that modulates, including enhancing or potentiating, inducing, and blocking, the savory taste of a natural or synthetic savory flavoring agents, e.g., monosodium glutamate (MSG) in a animal or a human.

A “sweet flavor modifier” herein 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 sweet flavoring agents, e.g., sucrose, fructose, glucose, and other known natural saccharide-based sweeteners, or known artificial sweeteners such as saccharine, cyclamate, aspartame, and the like, in a animal or a human. : A “savory flavor enhancer” herein refers to a compound or biologically acceptable salt thereof that enhances or potentiates the savory taste of a natural or synthetic savory flavoring agents, e.g., monosodium glutamate (MSG) in a animal or a human.

A “sweet flavor enhancer” herein refers to a compound or biologically acceptable salt thereof that enhances or potentiates the sweet taste of a natural or * synthetic sweet flavoring agents, e.g., sucrose, fructose, glucose, and other known natural saccharide-based sweeteners, or known artificial sweeteners such as. saccharine, cyclamate, aspartame, and the like as is further discussed herein in an animal or a human.

An “umami receptor activating compound” herein refers to a compound that activates an umami receptor, such as a TIR1/T1R3 receptor.

A “sweet receptor activating compound” herein refers to a compound that activates a sweet receptor, such as a TIR2/T1R3 receptor.

An “umami receptor modulating compound” herein refers to a compound that modulates (activates, enhances or blocks) an umami receptor.

A “sweet receptor modulating compound” herein refers to a compound that modulates (activates, enhances or blocks) a sweet receptor.

An “umami receptor enhancing compound” herein refers to a compound that enhances or potentiates the effect of a natural or synthetic umami receptor activating compound, e.g., monosodium glutamate (MSG).

A “sweet receptor enhancing compound” herein refers to a compound that enhances or potentiates the effect of a natural or synthetic sweet receptor activating . compound, e.g., sucrose, fructose, glucose, and other known natural saccharide-based sweeteners, or known artificial sweeteners such as saccharine, cyclamate, aspartame, and the like as is further discussed herein.

A “savory flavoring agent amount” herein refers to an amount of a compound that is sufficient to induce savory taste in a comestible or medicinal product or composition, or a precursor thereof. A fairly broad range of a savory flavoring agent amount can be from about 0.001 ppm to 100 ppm, or a narrow range from about 0.1 ppmto about 10 ppm. Alternative ranges of savory flavoring agent amounts can be from about 0.01 ppm to about 30 ppm, from about 0.05 ppm to about 15 ppm, from about 0.1 ppm to about 5 ppm, or from about 0.1 ppm to about 3 ppm. .

A “sweet flavoring agent amount” herein refers to an amount of a compound that is sufficient to induce sweet taste in a comestible or medicinal product or composition, or a precursor thereof. A fairly broad range of a sweet flavoring agent amount can be from about 0.001 ppm to 100 ppm, or a narrow range from about 0.1 ppm to about 10 ppm. Alternative ranges of sweet flavoring agent amounts can be . from about 0.01 ppm to about 30 ppm, from about 0.05 ppm to about 15 ppm, from about 0.1 ppm to about 5 ppm, or from about 0.1 ppm to about 3 ppm.

A “savory flavor modulating amount” herein refers to an amount of a compound of Formula (J) that is sufficient to alter (either increase or decrease) savory taste in a comestible or medicinal product or composition, or a precursor thereof, sufficiently to be perceived by a human subject. A fairly broad range of a savory flavor modulating amount can be from about 0.001 ppm to 100 ppm, or a narrow range from about 0.1 ppm to about 10 ppm. Alternative ranges of savory flavor modulating amounts can be from about 0.01 ppm to about 30 ppm, from about 0.05 ppm to about 15 ppm, from about 0.1 ppm to about 5 ppm, or from about 0.1 ppmto about 3 ppm.

A “sweet flavor modulating amount” herein refers to an amount of a compound of Formula (I) that is sufficient to alter (either increase or decrease) sweet taste in a comestible or medicinal product or composition, or a precursor thereof, sufficiently to be perceived by a human subject. A fairly broad range of a sweet flavor modulating amount can be from about 0.001 ppm to 100 ppm, or a narrow range from about 0.1 ppm to about 10 ppm. Alternative ranges of sweet flavor modulating amounts can be from about 0.01 ppm to about 30 ppm, from about 0.05 . ppm to about 15 ppm, from about 0.1 ppm to about 5 ppm, or from about 0.1 ppm to about3 ppm.

A “savory flavor enhancing amount” herein refers to an amount of a compound that is sufficient to enhance the taste of a natural or synthetic flavoring agents, e.g., monosodium glutamate (MSG) in a comestible or medicinal product or composition. A fairly broad range of a savory flavor enhancing amount can be from about 0.001 ppm to 100 ppm , or a narrow range from about 0.1 ppm to about 10 ppm.

Alternative ranges of savory flavor enhancing amounts can be from about 0.01 ppm to about 30 ppm, from about 0.05 ppm to about 15 ppm, from about 0.1 ppm to about 5 ppm, or from about 0.1 ppm to about 3 ppm.

A “sweet flavor enhancing amount” herein refers to an amount of a compound that is sufficient to enhance the taste of a natural or synthetic flavoring agents, e.g., sucrose, fructose, glucose, and other known natural saccharide-based sweeteners, or known artificial sweeteners such as saccharine, cyclamate, aspertame, and the like as is further discussed herein) in a comestible or medicinal product or composition. A fairly broad range of a sweet flavor enhancing amount can be from about 0.001 ppm to 100 ppm , or a narrow range from about 0.1 ppm to about 10 ppm. Altemative ranges of sweet flavor enhancing amounts can be from about 0.01 ppm to about 30 : ppm, from about 0.05 ppm to about 15 ppm, from about 0.1 ppm to about 5 ppm, or from about 0.1 ppm to about 3 ppm.

An “umami receptor modulating amount” herein refers to an amount of a compound that is sufficient to modulate (activate, enhance or block) an umami receptor. A preferable range of an umami receptor modulating amount is 1 pM to 100 mM and most preferably 1 nM to 100 pM and most preferably 1nM to 30 uM. A fairly broad range of a umami flavor enhancing amount can be from about 0.001 ppm to 100 ppm , or a narrow range from about 0.1 ppm to about 10 ppm. Alternative ranges of umami flavor enhancing amounts can be from about 0.01 ppm to about 30 ppm, from about 0.05 ppm to about 15 ppm, from about 0.1 ppm to about 5 ppm, or from about 0.1 ppm to about 3 ppm. :

A “T1R1/T1R3 receptor modulating or activating amount” is an amount of compound that is sufficient to modulate or activate a TIR1/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 a savory compound. Preferably an umami receptor is a G protein coupled receptor, and more preferably the umami receptor is a TIR1/T1R3 receptor. :

Compounds of the invention modulate an umami receptor and preferably are agonists of the TIR1/T1R3 receptor. An agonist of this receptor has the effect of activating the G protein signaling cascade. In many cases, this agonist effect of the compound on the receptor also produces a perceived savory flavor in a taste test. It 1s desirable, therefore, that such inventive compounds serve as a replacement for MSG, which is not tolerated by some in, for example, comestible products.

In addition, this agonist effect also is responsible for the synergistic savory taste effect, which occurs when a compound of the invention is combined with another savory flavoring agent such as MSG. The nucleotides, IMP or GMP, are conventionally added to MSG, to intensify the savory flavor of MSG, so that relatively less MSG is needed to provide the same savory flavor in comparison to

MSGalone. Therefore, it is desirable that combining compounds of the invention with another savory flavoring agent such as MSG advantageously eliminates the need to add expensive nucleotides, such as IMP, as a flavor enhancer, while concomitantly reducing or eliminating the amount of a savory compound such as MSG needed to provide the same savory flavor in comparison to the savory compound or MSG alone.

A “sweet receptor modulating amount” herein refers to an amount of a compound that is sufficient to modulate (activate, enhance or block) a sweet receptor.

A preferable range of an sweet receptor modulating amount is 1 pM to 100 mM and most preferably 1 nM to 100 pM and most preferably 1nM to 30 uM.

A “T1R2/T1R3 receptor modulating or activating amount” is an amount of compound that is sufficient to modulate or activate a TIR2/T1R3 receptor. These amounts are preferably the same as the sweet receptor modulating amounts.

A “sweet receptor” is a taste receptor that can be modulated by a sweet compound. Preferably an sweet receptor is a G protein coupled receptor, and more preferably the umami receptor is a TIR2/T1R3 receptor.

Many compounds of Formula (I) can modulate a sweet receptor and preferably are agonists of the TIR2/T1R3 receptor. An agonist of this receptor has the effect of activating the G protein signaling cascade. In many cases, this agonist effect of the compound on the receptor also produces a perceived sweet flavor in a taste test. Itis desirable, therefore, that such inventive compounds serve as a replacement for sucrose, fructose, glucose, and other known natural saccharide-based sweeteners, or known artificial sweeteners such as saccharine, cyclamate, aspartame, and the like, or mixtures thereof as is further discussed herein. .

A “synergistic effect” relates to the enhanced savory and/or sweet flavor of a combination of savory and/or or sweet compounds or receptor activating compounds, in comparison to the sum of the taste effects or flavor associated effects associated : with each individual compound. In the case of savory enhancer compounds, a synergistic effect on the effectiveness of MSG may be indicated for a compound of

Formula (T) having an EC50 ratio (defined hereinbelow) of 2.0 or more, or preferably 5.0 or more, or 10.0 or more, or 15.0 or more. An ECS50 assay for sweet enhancement has not yet been developed, but in the case of both savory and sweet enhancer compounds, a synergistic effect can be confirmed by human taste tests, as described : elsewhere herein.

When the compounds described here include one or more chiral centers, the stereochemistry of such chiral centers can independently be in the R or S x configuration, or a mixture of the two. The chiral centers can be further designated as

RorSorR,Sord,D, LL ord], D,L. Correspondingly, the amide compounds of the invention, if they can be present in optically active form, can actually be present in the form of a racemic mixture of enantiomers, or in the form of either of the separate enantiomers in substantially isolated and purified form, or as a mixture comprising any relative proportions of the enantiomers. :

Regarding the compounds described herein, the suffix “ene” added to any of - the described terms means that the substituent is connected to two other parts in the compound. For example, “alkylene ” is (CHa)n, “alkenylene” is such a moiety that contains a double bond and “alkynylene” is such a moiety that contains a triple bond.

As used herein, “hydrocarbon residue” refers to a chemical sub-group within a larger chemical compound which has only carbon and hydrogen atoms. The hydrocarbon residue may be aliphatic or aromatic, straight-chain, cyclic, branched, saturated or unsaturated. The hydrocarbon residue, when so stated however, may

Claims

SE BEE a 222007702833 «CG CLAIMS

1. A comestible or medicinal composition comprising: a) at least one comestible or medicinal product, or a precursor thereof; and b) at least a sweet flavor modulating amount of at least one non-naturally occurring amide compound, or a comestibly acceptable salt thereof, wherein the amide compound has the formula: : 0

2 . Ae Ls wherein R' is selected from the group consisting of an arylalkyl, heteroarylalkyl, alkyl, cycloalkyl, -R*OH, -R*0 R’ -R*CN, -R*CO,H, -R*CO,R’, -R*COR’, -R*SR®, and -R*SO,R’, and optionally substituted derivative thereof comprising 1, 2, 3, or 4 carbonyl, amino groups, hydroxyl, or halogen groups: and wherein R* and R® are C,-C¢ hydrocarbon residues wherein one of R? and R? is H-the other of R* and R® comprises a hydrocarbon residue having at least three carbon atoms and optionally one to ten heteroatoms independently selected from oxygen, nitrogen, sulfur, halogens, or phosphorous; and wherein the amide compound has a molecular weight of 500 grams per mole or less.

2. The composition of claim 1 wherein the amide compound has a molecular weight from 175 to 500 grams per mole.

3. The composition of claim 1 wherein the amide compound has a molecular weight from 200 to 450 grams per mole.

NREL c+ 2007702833

4. The composition of claim 1 wherein the amide compound has a molecular weight from 225 to 400 grams per mole.

5. The composition of claim 1 wherein the amide compound has a molecular weight from 250 to 350 grams per mole.

6. The composition of claim 1 wherein R? is hydrogen.

7. The composition of claim 6 wherein R' is arylalkyl, heteroarylalkyl, or substituted derivatives thereof.

8. The compositions of claim 6 wherein R' is heteroarylalkyl, or substituted derivatives thereof. :

9. The composition of claim 6 wherein R! has between 3 and 16 carbon atoms and 0,1,2,3, 4, or 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, fluorine, or : chlorine.

10. The composition of claim 8 wherein said substituted derivatives thereof comprise 1, 2, 3, or 4 substituent groups, independently selected from hydrogen, hydroxy, fluoro, chloro, NH,, NHCHj3, N(CH3),, CO,CH3, SEt, SCH3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.

11. The composition of claim 6 wherein R? is alkyl, cycloalkyl, -R*OH, -R*O R®, -R*CN, -R*CO,H, -R*CO,R, -R*COR’, -R*SR’, and -R*SO,R’.

12. The composition of claim 6 wherein R? is C;-C;o branched alkyl.

13. The composition of claim 1 wherein the comestible or medicinal product is a food for animal consumption.

~-2007// 02833

14. The composition of claim 1 wherein the comestible or medicinal product is a food for human consumption.

15. The composition of claims 1-14 wherein the comestible or medicinal product is selected from the group consisting confectioneries, bakery products, ice creams, dairy products, sweet or savory snacks, snack bars, meal replacement products, ready meals, soups, pastas, noodles, canned foods, frozen foods, dried foods, chilled foods, oils and fats, baby foods, and spreads.

16. The composition of claim 1 wherein the comestible or medicinal product comprises one or more meats, poultry, fish, vegetables, grains, or fruits.

17. The composition of claim 1 wherein the comestible or medicinal product is a frozen food, an uncooked food, or a fully or partially cooked food.

18. The composition of claim 1 wherein the comestible or medicinal product is a soup, a dehydrated or concentrated soup, or a dry soup.

19. The composition of claim 1 wherein the comestible or medicinal product is a snack food.

20. The composition of claim 1 wherein the comestible or medicinal product is a cooking aid product, a meal solution product, a meal enhancement product, a seasoning, or a seasoning blend.

21. The composition of claim 1 wherein the comestible or medicinal product is a cake, cookie, pie, candy, chewing gum, gelatin, ice cream, sorbet, pudding, jam, jelly, salad dressing, condiment, cereal, canned fruit, or fruit sauce.

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22. The composition of claim 1 wherein the comestible or medicinal product is a beverage, a beverage mix, or a beverage concentrate.

23. The composition of claim 1 wherein the amide compound is present in the comestible or medicinal product at a concentration from about 0.01 ppm to about 30 ppm.

24. A comestible, or a precursor thereof comprising at least one compound of claim 1 further. comprising a sweetener selected from aspartame, saccharin, acesulfame-K, cyclamate, sucralose, alitame, or a mixture thereof. :

25. A comestible, or a precursor thereof comprising at least one compound of claim 1 further comprising a sweetener selected from sucrose, fructose, glucose, erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, terpenoids, or flavonoids.

26. A method for modulating the taste of a comestible or medicinal product comprising: a) providing at least one comestible or medicinal product, and b) combining the comestible or medicinal product with at least a savory flavor modulating amount of an oxalamide compound, or a salt thereof, so as to form a modified comestible or medicinal product; wherein the oxalamide compound has the formula of N1-(2,4-dimethoxybenzyl)-N2-(2- (pyridin-2-yl)ethyl)oxalamide.

27. The method of claim 26 wherein the modified comestible or medicinal product is a composition for human or animal consumption.

28. The method of claim 26 wherein the modified comestible or medicinal product is a food, beverage, or oral hygiene product.

29. The method of claim 28 wherein the food or beverage product is selected from the group consisting of confectioneries, bakery products, dairy products, meal replacement products, 209 AMENDED SHEET 2008 -1- 20

J soup products, dehydrated and culinary food, frozen food, canned food, snack food, baby food product, oils and fats, and seasonings or seasoning blends.

30. The method of claim 26 wherein the modified comestible or medicinal product is a pharmaceutical composition for oral administration.

31. The method of claim 26 wherein the oxalamide compound is present in the modified : comestible or medicinal product at a concentration from about 0.01 ppm to about 30 ppm.

32. The method of claim 26 wherein the oxalamide compound is present in the modified comestible or medicinal product in a concentration from about 0.05 ppm to about 15 ppm.

33. The method of claim 26 wherein the oxalamide compound is present in the modified comestible or medicinal product in a concentration from about 0.1 ppm to about 5 ppm.

34. The method of claim 26 wherein the oxalamide compound is present in the modified comestible or medicinal product in a concentration from about 0.1 ppm to about 3 ppm.

35. A comestible or medicinal product, comprising atleast a savory flavor modulating amount of at least one oxalamide compound, or a salt thereof, wherein the oxalamide compound has the formula of N1-(2,4-dimethoxybenzyl)-N2-(2-(pyridin-2-yl)ethyl)oxalamide.

36. An oxalamide compound having the formula N1-(2,4-dimethoxybenzyl)-N2-(2-(pyridin-2- yDethyl)oxalamide or a salt thereof. no

37. The comestible or medicinal product of claim 35, which is a composition for human or animal consumption.

38. The comestible or medicinal product of claim 35, which is a food, beverage, or oral hygiene product.

39. The comestible or medicinal product of claim 38, wherein the food or beverage product is selected from the group consisting of confectioneries, bakery products, dairy products, meal replacement products, soup products, dehydrated and culinary food, frozen food, canned food, snack food, baby food product, oils and fats, and seasonings or seasoning blends.

40. The comestible or medicinal product of claim 35, which is a pharmaceutical composition for oral administration.

41. The comestible or medicinal product of claim 35, wherein the oxalamide compound is present in a concentration from about 0.01 ppm to about 30 ppm.

42. The comestible or medicinal product of claim 35, wherein the oxalamide compound is present in a concentration from about 0.05 ppm to about 15 ppm.

43. The comestible or medicinal product of claim 35, wherein the oxalamide compound is present in a concentration from about 0.1 ppm to about 5 ppm.

44. The comestible or medicinal product of claim 35, wherein the oxalamide compound is present in a concentration from about 0.1 ppm to about 3 ppm. 211 : 2008 -1- 20 AMENDED SHEET