Pungent compounds, compositions, and uses thereof

Abstract

Disclosed herein are pungent compounds. The compounds may be used as flavor modifiers, analgesics, and threat neutralizers.

Description

Attorney Docket No. 103362-090W01PUNGENT COMPOUNDS, COMPOSITIONS, AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to, and the benefit of, U.S. Provisional Patent Application No.63 / 756,375, filed on 10 February 2025, which is incorporated herein by reference in its entirety.BACKGROUND

[0002] Chili peppers (Capsicum spp.) are valued for their distinctive chemesthetic flavor properties as food ingredients worldwide and particularly in Asian, Central, & South American cuisines.Following their introduction to Eurasia and Africa, chili peppers quickly became incorporated into diverse culinary traditions alongside other crops originating from the Americas. Various culinary applications leverage the unique characteristics of chili pepper cultivars, especially their varying levels of pungency or spiciness, to elevate flavor and enhance the sensory experience.

[0003] The Scoville Heat Unit (SHU) is a metric widely utilized to quantify the pungency intensity of chili pepper ingredients. This method involves extracting ground chili pepper with ethanol, diluting the extract in sugar water, and determining the point at which the pungency becomes barely perceptible. The number of dilutions required establishes the SHU value. However, this approach has faced substantial criticism for decades due to issues such as failure to account for sensitization or desensitization, taste fatigue, lack of statistical rigor, poor reproducibility, and the burning sensation caused by ethanol extracts.

[0004] Modern analytical methods for SHU determination address these limitations by quantifying the concentrations of pungent compounds in a sample and multiplying these values by conversion factors to calculate SHU. This analytical method remains widely used and is considered more reliable and reproducible than determination by sensory testing.

[0005] In Capsicums, the primary compounds considered responsible for pungency, as measured by SHU, are vanilloid-containing molecules known as capsaicinoids. These compounds function as agonists of the transient receptor potential vanilloid 1 (TRPV1) ion channel, which is central to the perception of pungency. Capsaicinoids are known to activate TRPV1 by binding to its vanilloid- binding pocket, resulting in the sensations of irritation, pain, or pungency commonly associated with chili peppers.

[0006] While capsaicinoid concentration is used to measure SHU in chili peppers, it is limited by the assumption that only this class of compounds, among the metabolome, influences pungency perception. Studies on TRPV1 agonism have demonstrated that numerous natural compounds can interact with this receptor. However, accurately predicting sensory perception based on TRPV1Attorney Docket No. 103362-090W01activation remains challenging, as channel activation alone does not necessarily result in the sensation of pungency. Consequently, there is a lack of research identifying secondary metabolites in chili peppers that influence pungency perception beyond the known capsaicinoids.

[0007] There remains a need for pungent compounds. There remains a need for improved compositions and methods for modulating the flavor of foods and beverages. There remains a need for improved TRPV1 agonists. There remains a need for improved compounds and methods for providing analgesia, including topical analgesia, to subjects in need thereof.BRIEF DESCRIPTION OF THE FIGURES

[0008] Figure 1 depicts group average (n = 7) time-intensity curves for capsaicin (3.125 mg / L) (dashed line) and (E)-N-(8-methylnon-6-en-1-yl)acetamide (25 mg / L) (solid line) over 10-min rating period.DETAILED DESCRIPTION

[0009] Before the present methods and systems are disclosed and described, it is to be understood that the methods and systems are not limited to specific synthetic methods, specific components, or to particular compositions. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0010] As used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from "about" one particular value, and / or to "about" another particular value. When such a range is expressed, another embodiment includes- from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

[0011] " Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0012] Throughout the description and claims of this specification, the word "comprise" and variations of the word, such as "comprising" and "comprises," means "including but not limited to," and is not intended to exclude, for example, other additives, components, integers or steps." Exemplary" means "an example of" and is not intended to convey an indication of a preferred or ideal embodiment. " Such as" is not used in a restrictive sense, but for explanatory purposes.Attorney Docket No. 103362-090W01

[0013] Disclosed are components that can be used to perform the disclosed methods and systems.These and other components are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these components are disclosed that while specific reference of each various individual and collective combinations and permutation of these may not be explicitly disclosed, each is specifically contemplated and described herein, for all methods and systems. This applies to all aspects of this application including, but not limited to, steps in disclosed methods. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the disclosed methods.

[0014] Compounds disclosed herein may be provided in the form of acceptable salts, for example physiologically acceptable salts. Examples of such salts are acid addition salts formed with inorganic acids, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids and the like; salts formed with organic acids such as acetic, oxalic, tartaric, succinic, maleic, fumaric, gluconic, citric, malic, methanesulfonic, p-toluenesulfonic, napthalenesulfonic, and polygalacturonic acids, and the like; salts formed from elemental anions such as chloride, bromide, and iodide; salts formed from metal hydroxides, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, and magnesium hydroxide; salts formed from metal carbonates, for example, sodium carbonate, potassium carbonate, calcium carbonate, and magnesium carbonate; salts formed from metal bicarbonates, for example, sodium bicarbonate and potassium bicarbonate; salts formed from metal sulfates, for example, sodium sulfate and potassium sulfate; and salts formed from metal nitrates, for example, sodium nitrate and potassium nitrate.

[0015] The term "alkyl" refers to a radical of a straight-chain or branched hydrocarbon group having a specified range of carbon atoms (e.g., a " Cue alkyl" can have from 1 to 16 carbon atoms). An alkyl group can be a saturated alkyl group or an unsaturated alkyl group, i.e., an alkyl group having one or more carbon-carbon double / triple bonds, i.e., an alkenyl or alkynyl group. Unless specified to the contrary, an "alkyl" group includes both saturated alkyl groups and unsaturated alkyl groups. The term "alkenyl" refers to straight-chain or branched hydrocarbon groups having at least one carboncarbon double bond. The term "alkynyl" refers to straight-chain or branched hydrocarbon groups having at least one carbon-carbon triple bond.

[0001] The term "heteroalkyl" refers to an alkyl group, which further includes at least one heteroatom e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. By way of example, a heteroC1-6alkyl (which may also be designated a C1-6heteroalkyl) group includes, but is not limited to, the following structures:Attorney Docket No. 103362-090W01

[0002] The term "heteroalkyl" preceded by a separate heteroatom refers to a heteroalkyl group bonded through the specified heteroatom. By way of example, a OCi.6heteroalkyl group includes, but it not limited to, the following structures:

[0003] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, " Ci.salkyl" is intended to encompass Ci, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0004] Affixing the suffix "-ene" to a group indicates the group is a polyvalent moiety, e.g., boned to two or more groups. Alkylene is the polyvalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl (each of which parent groups as defined herein).

[0005] The term "alkoxy" refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0006] The term "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 n electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (" C6-i4 aryl"). " Aryl" also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents.

[0007] " Aralkyl" is a subset of "alkyl" and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.

[0008] The term "heteroaryl" refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 n electrons shared in a cyclicAttorney Docket No. 103362-090W01array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-14 membered heteroaryl"). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. " Heteroaryl" includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. " Heteroaryl" also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0009] Exemplary heteroaryl and heterocyclyl rings include: benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3 b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3- oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-l,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1, 2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, and xanthenyl.

[0010] Unless specified to the contrary, the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups defined herein (and the "ene"Attorney Docket No. 103362-090W01 versions of said groups) may be substituted or unsubstituted. A substituted group includes a nonhydrogen substituent at a position where in the unsubstituted version a hydrogen atom would be found. Substituents include, but are not limited to, halogen, hydroxy, alkyl, alkoxy, nitro, cyano, oxo, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -NRaRb, -NRaC(=O)Rb, -NRaC(=O)NRaNRb, -NRaC(=O)ORb, - NRaSO2Rb, -C(=O)Ra, -C(=O)ORa, -C(=O)NRaRb, -OC(=O)NRaRb, -ORa, -SRa, -SORa, - S(=O)2Ra, - OS(=O)2Raand -S(=O)2ORa. Raand Rbin this context can be the same or different and independently hydrogen, halogen, hydroxyl, alkyl, alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl.

[0011] As used herein, the designation of a polyvalent moiety without specifying the specific order of attachment is intended to cover all possible arrangements. By way of example, a compound represented by the formula:A-X-B,wherein X is NHC(=O) embraces both:o o

[0012] As used herein, a chemical bond depicted: 'I represents either a single, double, or triple bond, valency permitting. By way of example,

[0013] Some compounds disclosed herein may exist as one or more tautomers. Tautomers are interconvertible structural isomers that differ in the position of one or more protons or other labile atom. By way of example:

[0014] Unless stated to the contrary, a substituent drawn without explicitly specifying the point of attachment indicates that the substituent may be attached at any possible atom. For example, in a benzofuran depicted:Attorney Docket No. 103362-090W01the substituent may be present at any one of the six possible carbon atoms.

[0015] As used herein, the term "null," when referring to a possible identity of a chemical moiety, indicates that the group is absent, and the two adjacent groups are directly bonded to one another. By way of example, for a genus of compounds having the formula CH3-X-CH3, if X is null, then the resulting compound has the formula CH3-CH3. A group having the subscript '0' is understood to represent a null group as well. By way of example, in the compound CH3-(X)Z-CH3, if X is CH2and z is 0, then the compound has the formula CH3-CH3.

[0016] A bracketed functional group with a subscripted variable should be understood to denote the number of repeated bracketed groups present. For example, a number that is selected from 0 or 1 should be interpreted as follows:

[0017] In certain instances, two or more variable groups may together form a ring. It is understood that any depicted atoms separated the identified groups will themselves form part of the ring:'3When the variable groups are substituted on an aromatic system the new ring will be a fused ring, and unless specified to the contrary may be either aromatic or non-aromatic, carbocyclic or heterocyclic:The ring may further be defined by the number of carbon atoms in the specific ring formed by the variable groups, which includes the atoms separating the variable groups:C6aryl C5heterocyclyl C5heteroarylEach of the above results when R1and R2together form a six membered (or six atom) ring. Other rings, including 3, 4, 5, 7, and 8-member rings may also be formed, and may be further limited by a specified number of carbon atoms. Although the singular "a ring" may be used to define the group,Attorney Docket No. 103362-090W01unless specified to the contrary both monocyclic and polycyclic rings are possible:

[0018] Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer, diastereomer, and meso compound, and a mixture of isomers, such as a racemic or scalemic mixture. Unless stated to the contrary, a formula depicting one or more stereochemical features does not exclude the presence of other isomers.

[0019] As used herein, the chemical group " D" refers to deuterium at an isotopic abundance greater than 25%, 35%, 50%, 60%, 70%, 80%, or 90%. In certain implementations, the chemical group " D" refers to deuterium at an isotopic abundance greater than 50%.

[0020] Disclosed herein are pungent compounds of formula (1):R1— Z R2i\rR3[formula (1)],or a physiologically acceptable salt thereof, wherein,R1is saturated C1-18alkyl, C2-18alkenyl, or C2-18alkynyl;R2is saturated C5-18alkyl, C5-18alkenyl, or C5-18alkynyl,R3is H or C1-4alkyl; andZ is C(=O), NHC(=O), OR OC(=O).

[0021] In some implementations, the pungent compounds can be provided in a composition that includes the compound at a specified concentration. In some implementations, the composition can include the compound (or mixture of compounds) in an amount of an amount of at least 0.001 wt.%, at least 0.01 wt.%, at least 0.1 wt.%, at least 1 wt.%, at least 2.5 wt.%, at least 5 wt.%, at least 10 wt.%, at least 20 wt.%, at least 25 wt.%, at least 50 wt.%, at least 75 wt.%, or at least 90 wt.%.

[0022] In some implementations, the pungent compounds can be provided in a composition that does not include the compound capsaicin.

[0023] In some implementations, R2can be C5.i6alkenyl, preferably a C5.i6alkenyl having 1, 2, or 3 carbon-carbon double bond.

[0024] In some implementations, R2can be C8.i6alkenyl, preferably a C8.i6alkenyl having 1, 2, or 3 carbon-carbon double bond.

[0025] In some implementations, R2can be Cs-iealkenyl, preferably a Cs-iealkenyl having a single carbon-carbon double bond.Attorney Docket No. 103362-090W01

[0026] In some implementations, R1can be a saturated C1-16alkyl. In other implementations R1can be a C5-16alkenyl having 1, 2, or 3 carbon-carbon double bonds., preferably R1can be a C5-16alkenyl having a single carbon-carbon double bonds.

[0027] In some implementations, R1is methyl.

[0028] In some implementations, Z is C(=O).

[0029] In some implementations, R3is hydrogen.

[0030] In some implementations, R2has the formula *-R2#-R4, wherein * represents the point of attachment to N, and:R2#is C6-15alkenylene, and R4is saturated C1-10alkyl; orR2#is C2-6alkenylene, and R4is saturated C10-14alkyl

[0031] In some implementations, when R2has the formula *-R2#-R4, R2#has a single carbon-carbon double bond.

[0032] In some implementations, wherein R1and R2are the same, while in other implementations R1and R2are not the same.

[0033] In some implementations, R2has formula (2):!.R5— (CH2)n^AA / =AAP(CH2)m-(p5*K[formula (2)],wherein n is 1-12, m is 0-15, R5is H or CH3, and R5* is H or CH3.

[0034] In some implementations, R2has formula (2) and R5and R5* are each CH3.

[0035] In some implementations, R2has formula (2), n is 3, 4, 5, 6, or 7, and m is 0. In some implementations, n is 3, 4, or 6, and m is 0. In some implementations n is 5 and m is 0.

[0036] In some implementations, R2has formula (2a):H (CH2)nHr5HX(CH2)m-(p5*[formula (2a)].

[0037] In some implementations, R1has the formula:R6)— (CH2)x-~CZZZuuu’(CH2)y-|R6‘wherein - represents a single or double bond, or is absent, y is 0-12, x is 0-15, R6is H or CH3, and R6* is H or CH3.

[0038] In some implementations, — is a trans double bond.

[0039] In some implementations, — is a single bond.

[0040] In some implementations, — is absent.Attorney Docket No. 103362-090W01

[0041] In some implementations, is absent, y is 0, x is 0, and R6and R6* are each H. In some implementations, is a single or double bond, y is 3, 4, 5, 6, or 7, x is 0, and R6and R6* are each CH3. In some implementations, is a trans double bond, y is 3, 4, 5, 6, or 7, x is 0, and R6and R6* are each CH3.

[0042] In some implementations, R2has the formula:

[0043] In some implementations, R1has the formula:

[0044] In some implementations, R2has the formula:R3is H, Z is C(=O), and R1is methyl or selected fromAttorney Docket No. 103362-090W01

[0045] Also disclosed herein are pharmaceutical compositions including one or more of the disclosed compounds mixed with a pharmaceutically acceptable vehicle. The compositions may be formulated for administration to a subject in need thereof, for example enterally, parenterally, inhalationally, intranasally, or topically.

[0046] In some implementations, the composition is formulated for topical administration.Exemplary formulations include sprays, liniments, lotions, creams, ointments and / or pastes. Specific types of excipients that can be combined with the compositions include, but are not limited to, inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. Such excipients may optionally be included in the inventive formulations. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents can be present in the composition, according to the judgment of the formulator.

[0047] Exemplary diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and combinations thereof

[0048] Exemplary granulating and / or dispersing agents include, but are not limited to, potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation- exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked polyvinylpyrrolidone) (crospovidone), sodiumAttorney Docket No. 103362-090W01carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, etc., and combinations thereof.

[0049] Exemplary surface active agents and / or emulsifiers include, but are not limited to, natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate [Tween 20], polyoxy ethylene sorbitan [Tween 60], polyoxy ethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]), polyoxyethylene esters (e.g. polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. Cremophor), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and / or combinations thereof.

[0050] Exemplary binding agents include, but are not limited to, starch (e.g. cornstarch and starch paste); sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol); natural and synthetic gums (e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, polyvinylpyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan); alginates; polyethylene oxide; polyethylene glycol; inorganic calcium salts; silicic acid; polymethacrylates; waxes; water; alcohol; etc.; and combinations thereof.Attorney Docket No. 103362-090W01

[0051] Exemplary preservatives may include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. Exemplary antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and trisodium edetate. Exemplary antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal. Exemplary antifungal preservatives include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid. Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol. Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. Other preservatives include, but are not limited to, tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, NeoIone, Kathon, and Euxyl. In certain embodiments, the preservative is an anti-oxidant. In other embodiments, the preservative is a chelating agent.

[0052] The disclosed compounds may be present in the composition in an amount from 1-500 mg, from 1-250 mg, from 1-100 mg, from 1-10 mg, from 10-50 mg, from 10-100 mg, from 50-100 mg, from 100-250 mg, or from 250-500 mg.

[0053] The compositions may include one or more additional active agents, for example an analgesic or anti-inflammatory. In some implementations the composition may include an additional analgesic such as capsaicin, diclofenac, lidocaine, benzocaine, methyl salicylate, trolamine, prilocaine, pramoxine, dibucaine, phenol, tetracaine, camphor, dyclonine, menthol, and combinations thereof. In some implementations the compositions may include an antiinflammatory such as alclofenac, alclometasone dipropionate, algestone acetonide, alpha amylase,Attorney Docket No. 103362-090W01amcinafal, amcinafide, amfenac sodium, amiprilose hydrochloride, anakinra, anirolac, anitrazafen, apazone, balsalazide disodium, bendazac, benoxaprofen, benzydamine hydrochloride, bromelains, broperamole, budesonide, carprofen, cicloprofen, cintazone, cliprofen, clobetasol propionate, clobetasone butyrate, clopirac, cloticasone propionate, cormethasone acetate, cortodoxone, deflazacort, desonide, desoximetasone, dexamethasone dipropionate, diclofenac potassium, diclofenac sodium, diflorasone diacetate, diflumidone sodium, dif lunisal, difluprednate, diftalone, dimethyl sulfoxide, drocinonide, endrysone, enlimomab, enolicam sodium, epirizole, etodolac, etofenamate, felbinac, fenamole, fenbufen, fenclofenac, fenclorac, fendosal, fenpipalone, fentiazac, flazalone, fluazacort, flufenamic acid, flumizole, flunisolide acetate, flunixin, flunixin meglumine, fluocortin butyl, fluorometholone acetate, fluquazone, flurbiprofen, fluretofen, fluticasone propionate, furaprofen, furobufen, halcinonide, halobetasol propionate, halopredone acetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol, ilonidap, indomethacin, indomethacin sodium, indoprofen, indoxole, intrazole, isoflupredone acetate, isoxepac, isoxicam, ketoprofen, lofemizole hydrochloride, lornoxicam, loteprednol etabonate, meclofenamate sodium, meclofenamic acid, meclorisone dibutyrate, mefenamic acid, mesalamine, meseclazone, methylprednisolone suleptanate, morniflumate, nabumetone, naproxen, naproxen sodium, naproxol, nimazone, olsalazine sodium, orgotein, orpanoxin, oxaprozin, oxyphenbutazone, paranyline hydrochloride, pentosan polysulfate sodium, phenbutazone sodium glycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicam olamine, pirprofen, prednazate, prifelone, prodolic acid, proquazone, proxazole, proxazole citrate, rimexolone, romazarit, salcolex, salnacedin, salsalate, sanguinarium chloride, seclazone, sermetacin, sudoxicam, sulindac, suprofen, talmetacin, talniflumate, talosalate, tebufelone, tenidap, tenidap sodium, tenoxicam, tesicam, tesimide, tetrydamine, tiopinac, tixocortol pivalate, tolmetin, tolmetin sodium, triclonide, triflumidate, zidometacin, zomepirac sodium, and combinations thereof.

[0054] Also disclosed herein are methods of providing analgesia to a subject in need thereof by administering to the subject an effective amount of one or more of the disclosed compounds. The compounds may be topically administered to provide analgesic, for instance at or adjacent to the site of the subject's discomfort. The compounds may also be parenterally administered, for instance subcutaneously, intramuscularly, or intraarticularly.

[0055] In some implementations, the compounds are administered to a subject experiencing neuralgia, for example postherpetic neuralgia, trigeminal neuralgia, peripheral neuropathy, and alcoholic neuropathy. In some implementations the compounds may be administered to treat a subject experiencing muscle aches and pains, included strained and torn muscles. In some implementations the compounds may be administered to a subject experiencing joint paint. InAttorney Docket No. 103362-090W01some implementations the compounds may be administered to a patient experiencing rheumatoid arthritis pain. In some implementations the compounds may be administered to a patient experiencing idiopathic pain.

[0056] Also disclosed herein are methods of modulating the flavor of an article by adding one or more of the disclosed compounds. In some implementations the compound may be added to a food, a beverage, or a pharmaceutical dosage form, for example a liquid dosage form. In some implementations the compound may be added at a concentration, relative to the article, from 0.001- 10 wt.%, from 0.001-1 wt.%, from 0.001-0.5 wt.%, from 0.001-0.1 wt.%, from 0.001-0.01 wt.%, from 0.01-0.1 wt.%, or from 0.1-1 wt.%. In some implementations the compounds may be added at a concentration from 0.1-100 mg / kg, from 0.01-10 mg / kg, from 0.01-1 mg / kg, or from 0.01-0.1 mg / kg.

[0057] In some implementations the compounds may be added to a non-alcoholic beverage, for example a milk product (including both diary milk and plant / nut milk products), a tea product, a coffee product, a fruit juice product, a vegetable juice product, an energy drink product, a soda product, or a horchata product.

[0058] In some implementations, the compounds may be added to an alcoholic beverage, for example a distilled spirit drink such as a Bloody Mary, Moscow Mule, Margarita, whiskey and whiskey cocktails, a hard seltzer product, a beer or a wine.

[0059] Also disclosed herein are defensive compositions including one or more of the disclosed compounds. The defensive compositions may be used to neutralize a threatening subject such as a human, bear, or canine. In addition to the disclosed compound(s), the defensive compositions can include a solvent such as water, an alcohol like ethanol, isopropanol, 2-(2-butoxyethoxy)ethanol, dipropylene glycol monomethyl ether. The defensive compositions can include an emulsifier like propylene glycol. In some implementations the defensive composition can be provided in an aerosol canister including a gas such as nitrogen, carbon dioxide, or a fluorocarbon like HFC. In some implementations the defensive composition is a liquid composition provided under pressure. The compounds may be present in the defensive composition at a concentration from 0.1-25 wt.%, from 0.1-10 wt.%, from 0.1-5 wt.%, from 0.1-1 w.%, from 1-5 wt.%, from 1-10 wt.%, from 5-10 wt.%, or from 10-25 wt.%.EXAMPLES

[0060] The following examples are for the purpose of illustration of the invention only and are not intended to limit the scope of the present invention in any manner whatsoever.

[0061] Powdered Fatalii chili pepper (500 g) was extracted in 1 L 80% methanol in water (v / v). After sonicating for 30 minutes, the mixture was decanted to collect the supernatant. This process was repeated three times to finally collect about 3 L of extract that was vacuum filtered through 90 mmAttorney Docket No. 103362-090W01 filter paper (Whatman, Maidstone, UK). The eluent was concentrated using a Rotovapor R-210 ( Büchi AG, Flawil, Switzerland), diluted with water, and freeze-dried using a FreeZone 4.5 L -50 C benchtop freeze dryer (Labconco, Kansas City, MO, USA). The freeze-dried sample was reconstituted in 20% methanol and cleaned with solid-phase extract (SPE) using Oasis HLB 6 g bed cartridges (Waters, Milford, MA, USA). The cartridges were conditioned with 20 mL each of 100% methanol and water. Reconstituted chili pepper extract (20 mL) was loaded onto each cartridge followed by a washing phase using 120 mL 60% methanol. The SPE cartridge was then eluted in two steps using 120 mL 70% methanol and 60 mL 90% methanol. The solvent was removed under vacuum from each eluent prior to further freeze-drying. The two 70% and 90% methanol SPE eluents were then reconstituted in 30 mL of 50% and 70% methanol, respectively.

[0062] The sample was injected on a Preparative LC / MS-Micromass ZQ coupled with a 2545 binary gradient manager and fraction collector 2767 (Waters, Milford, MA) using an XSelect 10 mm x 250 mm HSS T3 OBD 5 μm particle size Prep column (Waters, Milford, MA). The reconstituted 50% methanol SPE isolate was separated with a binary mobile phase of (A) 0.1% formic acid in water and (B) 0.1% formic acid in methanol at a flow rate of 5 ml / min using 300 μL injection volumes. The gradient was 0-30 minutes holding at 65% B; 30-30.1 minutes, 65%-95% B; 30.1-40 minutes holding at 95% B; 40-40.1 minutes, 95%-65% B; 40.1-45 minutes holding at 65% B. The mass-based collection of 198.18 m / z yielded compound 3. All the fractions containing compound 1 were pooled and freed of solvent prior to freeze drying. The final purity of compound 1 was determined to be > 90% by total ion chromatogram peak area using UPLC / MS-QToF in negative and positive ESI modes and confirmed by1H NMR analysis. Subsequently, the reconstituted 70% SPE methanol isolate was separated with a binary mobile phase of (A) 0.1% formic acid in water and (B) 0.1% formic acid in methanol at a flow rate of 5 ml / min using 100 μL injection volumes. The gradient was 0-30 minutes holding at 85% B; 30-30.1 minutes, 85%-95% B; 30.1-40 minutes holding at 95% B; 40-40.1 minutes, 95%-85% B; 40.1-45 minutes holding at 85% B. This gradient yielded three separate fractions containing compounds 2, 3, and 4. The respective fractions were pooled and proceeded onto a second LC dimension of fractionation to achieve higher purity.ID Structure1 0NH 12 O1H1Attorney Docket No. 103362-090W01

[0063] The pungency activity for compounds 1-4 was evaluated using the half-tongue 2-AFC methodology. Compounds 1-4 were tested at 50 mg / L, which was comparable to the total concentration of CAP and DHC used for sensory evaluation of the 10 chili pepper samples.Compound 1 was identified as eliciting a pungent sensation for a significant number of panelists (25 / 28, p-score < 0.001) (Table 3). At 50 mg / L, panelists gave an average pungency rating of 2.5 on the 15-point line scale. This closely corresponded to an anchor of " Barely Noticeable". Because of this low rating, a higher concentration was selected at 400 mg / L for an additional half-tongue 2-AFC test. This concentration was selected because it was approximately the concentration of compound 1 in the dried Fatalii powder prior to any normalization or dilution. At this higher concentration, all panelists (26 / 26, p-score < 0.001) selected compound 1 as producing a pungent sensation with an average pungency rating was 9.1, or between " Moderately Intense" and " Intense" on the line scale.2-AFC TestSample Selected Average Pungency Concentration P-valueCompound, as More Intensity Difference (mg / L) (1-tailed)Pungent ± Standard Error 50 25 / 28 < 0.001* 2.5 ± 0.051400 26 / 26 < 0.001* 9.1 ± 0.062 50 12 / 30 0.9 n.s.3 50 13 / 30 0.82 n.s.450 12 / 30 0.9 n.s.

[0064] To further characterize the pungency profile of compound 1, a time-intensity analysis was conducted at 25 mg / L for compound 1 in water. For comparison, a 3.125 mg / L aqueous solution of CAP was also evaluated. A review of the time-intensity analysis data revealed differences in the pungency profiles between the samples.Attorney Docket No. 103362-090W01

[0065] The mean maximum intensity for CAP and compound 1 were 12 ± 2.2 and 11.1 ± 1.3 and were not significantly different (P = 0.19). Thus, CAP was approximately 8-fold more pungent than compound 1 based on the perceived maximum intensity. However, a review of the time ofmax intensity data indicated CAP and compound 1 were significantly different (P = 0.003) at 258.6 and 97.0 seconds, respectively. Similarly, the rate of decrease before intensity between CAP and compound 1 was significantly different (P = 0.04) at 0.034 and 0.10. Consequently compound 1 reported approximately a 3-fold faster decrease in pungency perception compared to CAP.Average Sample Parameter Score(± Standard Deviation)Capsaicin (E)-N-(8- P-value (3.125 mg / L) methylnon-6-en-l- Time-Intensity Parametersyl)acetamide(25 mg / L)Maximum Intensity 12 ± 2.2 11.1 ± 1.3 0.19 Time of Yz maximum intensity 258.6 ± 120.6 97.0 ± 42.4 0.003* (sec)Time of Extinction > 600 480 ± 73.5 N / A (sec)Rate of decrease to maximum intensity _. „ _ _ „ „„ _ _ _y0.034 ± 0.02 0.10 ± 0.09 0.040* (intensity / sec)

[0066] The compositions and methods of the appended claims are not limited in scope by the specific compositions and methods described herein, which are intended as illustrations of a few aspects of the claims and any compositions and methods that are functionally equivalent are intended to fall within the scope of the claims. Various modifications of the compositions and methods in addition to those shown and described herein are intended to fall within the scope of the appended claims. Further, while only certain representative compositions and method steps disclosed herein are specifically described, other combinations of the compositions and method steps also are intended to fall within the scope of the appended claims, even if not specifically recited. Thus, a combination of steps, elements, components, or constituents may be explicitly mentioned herein or less, however, other combinations of steps, elements, components, and constituents are included, even though not explicitly stated. The term "comprising" and variations thereof as used herein is used synonymously with the term "including" and variations thereof and are open, non-limiting terms. Although the terms "comprising" and "including" have been used herein to describe various embodiments, the terms "consisting essentially of" and "consisting of" can be used in place of "comprising" and "including" to provide for more specific embodiments ofAttorney Docket No. 103362-090W01the invention and are also disclosed. Other than in the examples, or where otherwise noted, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood at the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, to be construed in light of the number of significant digits and ordinary rounding approaches

Claims

Attorney Docket No. 103362-090W01CLAIMSWhat is claimed is:

1. A composition comprising a compound having the formula:R1— Z R2N'R3or a physiologically acceptable salt thereof, wherein,R1is saturated C1-18alkyl, C2-18alkenyl, or C2-18alkynyl;R2is saturated C5-18alkyl, C5-18alkenyl, or C5-18alkynyl,R3is H or C1-4alkyl; andZ is C(=O), NHC(=O), or OC(=O)wherein the composition comprises the compound in an amount of at least 0.001 wt.%, at least 0.01 wt.%, at least 0.1 wt.%, at least 1 wt.%, at least 2.5 wt.%, at least 5 wt.%, at least 10 wt.%, at least 20 wt.%, at least 25 wt.%, at least 50 wt.%, at least 75 wt.%, or at least 90 wt.%; preferably greater than 0.05 wt.%;orwherein the composition does not comprise capsaicin.

2. The composition of any preceding claim, wherein R2is C5.i6alkenyl, preferably a C5.i6alkenyl having 1, 2, or 3 carbon-carbon double bonds.

3. The composition of any preceding claim, wherein R2is Cg.i6alkenyl, preferably a Cg.i6alkenyl having 1, 2, or 3 carbon-carbon double bonds.

4. The composition of any preceding claim, wherein R2is Cg.i6alkenyl having 1 carbon-carbon double bonds.

5. The composition of any preceding claim, wherein R1is saturated C1-16alkyl or C2-16alkenyl.

6. The composition of any preceding claim, wherein R1is saturated Cn2alkyl or C5-i2alkenyl.

7. The composition of any preceding claim, wherein R3is H.

8. The composition of any preceding claim, where Z is C(=O).

9. The composition of any preceding claim, wherein R2has the formula *-R2#-R4, wherein * represents the point of attachment to N, and:R2#is Cg-isalkenylene, and R4is saturated Cuoalkyl; orR2#is C2-6alkenylene, and R4is saturated Cio-i4alkyl.

10. The composition of any preceding claim, wherein R2#has 1 carbon-carbon double bond.

11. The composition of any preceding claim, wherein R2has the formula:Attorney Docket No. 103362-090W0112. The composition of any preceding claim, wherein R1and R2are the same, or wherein R1and R2are not the same.

13. The composition of any preceding claim, wherein R2has the formula:(CH2)n (CH2)mwherein n is 1-12, m is 0-15, R5is H or CH3, and R5* is H or CH3.

14. The composition of any preceding claim, wherein R5and R5* are each CH3.

15. The composition of any preceding claim, wherein n is 3, 4, 5, 6, or 7, and m is 0.

16. The composition of any preceding claim, wherein n is 4, 5, or 6, and m is 0.

17. The composition of any preceding claim, wherein n is 5, and m is 0.

18. The composition of the preceding claim, wherein R2has the formula:(CH2)n^ _ZHHX(CH2)m19. The composition of any preceding claim, wherein R1has the formula:R6)— (CH2)x-~^— (CH2)y-|R6‘ / wherein represents a single or double bond, or is absent, y is 0-12, x is 0-15, R6is H or CH3, and R6* is H or CH3.

20. The composition of any preceding claim, wherein is absent, y is 0, x is 0, and R6and R6* are each H.

21. The composition of any preceding claim, wherein is a single or double bond, y is 3, 4, 5, 6, or 7, x is 0, and R6and R6* are each CH3.

22. The composition of any preceding claim, wherein, wherein - is a single bond.

23. The composition of any preceding claim, wherein R2has the formula:

24. The composition of any preceding claim, wherein R1has the formula:Attorney Docket No. 103362-090W01, or 25. The composition of any preceding claim, wherein R2isR3is H, Z is C(=O), and R1is methyl or selected from:Attorney Docket No. 103362-090W0126. The composition of any preceding claim, further comprising a pharmaceutically acceptable vehicle.

27. The composition of any preceding claim, wherein the composition is for topical administration.

28. The composition of any preceding claim, wherein the composition is a cream, lotion, or spray.

29. The composition of any preceding claim, further comprising an additional analgesic agent.

30. The composition of any preceding claim, further comprising an additional analgesic agent is selected from capsaicin, diclofenac, lidocaine, benzocaine, methyl salicylate, trolamine, prilocaine, pramoxine, dibucaine, phenol, tetracaine, camphor, dyclonine, menthol, and combinations thereof.

31. The composition of any preceding claim, further comprising an anti-inflammatory agent.

32. The composition of any preceding claim, further comprising an anti-inflammatory agent selected from alclofenac, alclometasone dipropionate, algestone acetonide, alpha amylase, amcinafal, amcinafide, amfenac sodium, amiprilose hydrochloride, anakinra, anirolac, anitrazafen, apazone, balsalazide disodium, bendazac, benoxaprofen, benzydamine hydrochloride, bromelains, broperamole, budesonide, carprofen, cicloprofen, cintazone, cliprofen, clobetasol propionate, clobetasone butyrate, clopirac, cloticasone propionate, cormethasone acetate, cortodoxone, deflazacort, desonide, desoximetasone, dexamethasone dipropionate, diclofenac potassium, diclofenac sodium, diflorasone diacetate, diflumidone sodium, diflu nisal, difluprednate, diftalone, dimethyl sulfoxide, drocinonide, endrysone, enlimomab, enolicam sodium, epirizole, etodolac, etofenamate, felbinac, fenamole, fenbufen, fenclofenac, fenclorac, fendosal, fenpipalone, fentiazac, flazalone, fluazacort, flufenamic acid, flumizole, flunisolide acetate, flunixin, flunixin meglumine, fluocortin butyl, fluorometholone acetate, fluquazone, flurbiprofen, fluretofen, fluticasone propionate, furaprofen, furobufen, halcinonide, halobetasol propionate, halopredone acetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol, ilonidap, indomethacin, indomethacin sodium, indoprofen, indoxole, intrazole, isoflupredone acetate, isoxepac, isoxicam, ketoprofen, lofemizole hydrochloride, lornoxicam, loteprednol etabonate, meclofenamate sodium, meclofenamic acid, meclorisone dibutyrate, mefenamic acid, mesalamine, meseclazone, methylprednisolone suleptanate, morniflumate, nabumetone, naproxen, naproxen sodium, naproxol, nimazone, olsalazine sodium, orgotein, orpanoxin, oxaprozin, oxyphenbutazone, paranyline hydrochloride, pentosan polysulfate sodium, phenbutazone sodium glycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicam olamine, pirprofen, prednazate, prifelone, prodolic acid, proquazone, proxazole, proxazole citrate, rimexolone, romazarit, salcolex, salnacedin, salsalate, sanguinarium chloride, seclazone, sermetacin, sudoxicam, sulindac, suprofen,Attorney Docket No. 103362-090W01talmetacin, talniflumate, talosalate, tebufelone, tenidap, tenidap sodium, tenoxicam, tesicam, tesimide, tetrydamine, tiopinac, tixocortol pivalate, tolmetin, tolmetin sodium, triclonide, triflumidate, zidometacin, zomepirac sodium, and combinations thereof.

33. A method of modulating the flavor of an article, comprising adding to the article the composition according to any preceding claim.

34. The method of any preceding claim, wherein the article comprises a food, a beverage, a pharmaceutical, or an adhesive.

35. The method of any preceding claim, wherein the article comprises an alcoholic beverage or a non-alcoholic beverage.

36. A method of providing analgesia to a subject in need thereof, comprising administering to the subject a compound having the formula:R1— Z R2i\rR3or a physiologically acceptable salt thereof, wherein,R1is saturated C1-18alkyl, C2-18alkenyl, or C2-18alkynyl;R2is saturated C5-18alkyl, C5-18alkenyl, or C5-18alkynyl,R3is H or C1-4alkyl; andZ is C(=O), NHC(=O), or OC(=O)wherein the composition comprises the compound of any preceding claim in an amount of at least 0.001 wt.%, at least 0.01 wt.%, at least 0.1 wt.%, at least 1 wt.%, at least 2.5 wt.%, at least 5 wt.%, at least 10 wt.%, at least 20 wt.%, at least 25 wt.%, at least 50 wt.%, at least 75 wt.%, or at least 90 wt.%;orwherein the composition does not comprise capsaicin.

37. The method of claim 36, wherein R2is C5-16alkenyl, preferably a C5-16alkenyl having 1, 2, or 3 carbon-carbon double bonds.

38. The method of claim 36 or 37, wherein R2is C8-16alkenyl, preferably a C8-16alkenyl having 1, 2, or 3 carbon-carbon double bonds.

39. The method of any of claims 36-38, wherein R2is C8-16alkenyl having 1 carbon-carbon double bonds.

40. The method of any of claims 36-39, wherein R1is saturated C1-16alkyl or C2-16alkenyl.

41. The method of any of claims 36-40, wherein R1is saturated C1-12alkyl or C5-12alkenyl.

42. The method of any of claims 36-41, wherein R3is H.

43. The method of any of claims 36-42, where Z is C(=O).Attorney Docket No. 103362-090W0144. The method of any of claims 36-43, wherein R2has the formula *-R2#-R4, wherein * represents the point of attachment to N, and:R2#is C6-15alkenylene, and R4is saturated C1-10alkyl; orR2#is C2-6alkenylene, and R4is saturated C10-14alkyl.

45. The method of any of claims 36-44, wherein R2#has 1 carbon-carbon double bond.

46. The method of any of claims 36-45, wherein R2has the formula:

47. The method of any of claims 36-46, wherein R1and R2are the same, or wherein R1and R2are not the same.

48. The method of any of claims 36-47, wherein R2has the formula:wherein n is 1-12, m is 0-15, R5is H or CH3, and R5* is H or CH3.

49. The method of any of claims 36-48, wherein R5and R5* are each CH3.

50. The method of any of claims 36-49, wherein n is 3, 4, 5, 6, or 7, and m is 0.

51. The method of any of claims 36-50, wherein n is 4, 5, or 6, and m is 0.

52. The method of any of claims 36-51, wherein n is 5, and m is 0.

53. The method of any of claims 36-52, wherein R2has the formula:|— (CH2)nHr5H / XCH2)m- (54. The method of any of claims 36-53, wherein R1has the formula:R6- (CH2)x' / uuCZZZvuv'(CH2)y- 1wherein - represents a single or double bond, or is absent, y is 0-12, x is 0-15, R6is H or CH3, and R6* is H orCH3.

55. The method of any of claims 36-54, wherein is absent, y is 0, x is 0, and R6and R6* are each H.

56. The method of any of claims 36-54, wherein — is a single or double bond, y is 3, 4, 5, 6, or 7, x is 0, and R6and R6* are each CH3.

57. The method of any of claims 36-54, wherein, wherein is a single bond.

58. The method of any of claims 36-57, wherein R2has the formula:Attorney Docket No. 103362-090W0159. The method of any of claims 36-58, wherein R1has the formula:

60. The method of any of claims 36-59, wherein R2isR3is H, Z is C(=O), and R1is methyl or selected from:Attorney Docket No. 103362-090W0161. The method of any preceding claim, wherein the compound is administered topically or parenterally.

62. The method of any preceding claim, wherein the subject is experiencing neuralgia (including postherpetic neuralgia, trigeminal neuralgia, peripheral neuropathy, and alcoholic neuropathy), muscle pain, joint pain, rheumatoid arthritis pain.

63. A method of neutralizing a threatening subject, comprising contacting the threatening subject with a compound having the formula:R1— Z R2i\rR3or a physiologically acceptable salt thereof, wherein,R1is saturated C1-18alkyl, C2-18alkenyl, or C2-18alkynyl;R2is saturated C5-18alkyl, C5-18alkenyl, or C5-18alkynyl,R3is H or C1-4alkyl; andZ is C(=O), NHC(=O), or OC(=O)wherein the composition comprises the compound of any preceding claim in an amount of at least 0.001 wt.%, at least 0.01 wt.%, at least 0.1 wt.%, at least 1 wt.%, at least 2.5 wt.%, at least 5 wt.%, at least 10 wt.%, at least 20 wt.%, at least 25 wt.%, at least 50 wt.%, at least 75 wt.%, or at least 90 wt.%;orwherein the composition does not comprise capsaicin.

64. The method of claim 63, wherein R2is Cs-iealkenyl, preferably a Cs-iealkenyl having 1, 2, or 3 carbon-carbon double bonds.

65. The method of claim 63 or 64, wherein R2is Cs-iealkenyl, preferably a Cs-iealkenyl having 1, 2, or 3 carbon-carbon double bonds.

66. The method of any of claims 63-65, wherein R2is Cs-iealkenyl having 1 carbon-carbon double bonds.Attorney Docket No. 103362-090W0167. The method of any of claims 63-66, wherein R1is saturated C1-16alkyl or C2-16alkenyl.

68. The method of any of claims 63-67, wherein R1is saturated C1-12alkyl or C5-12alkenyl.

69. The method of any of claims 63-68, wherein R3is H.

70. The method of any of claims 63-69, where Z is C(=O).

71. The method of any of claims 63-70, wherein R2has the formula *-R2#-R4, wherein * represents the point of attachment to N, and:R2#is C6-15alkenylene, and R4is saturated C1-10alkyl; orR2#is C2-6alkenylene, and R4is saturated C10-14alkyl.

72. The method of any of claims 63-71, wherein R2#has 1 carbon-carbon double bond.

73. The method of any of claims 63-72, wherein R2has the formula:

74. The method of any of claims 63-73, wherein R1and R2are the same, or wherein R1and R2are not the same.

75. The method of any of claims 63-74, wherein R2has the formula:wherein n is 1-12, m is 0-15, R5is H or CH3, and R5* is H or CH3.

76. The method of any of claims 63-75, wherein R5and R5* are each CH3.

77. The method of any of claims 63-76, wherein n is 3, 4, 5, 6, or 7, and m is 0.

78. The method of any of claims 63-77, wherein n is 4, 5, or 6, and m is 0.

79. The method of any of claims 63-78, wherein n is 5, and m is 0.

80. The method of any of claims 63-79, wherein R2has the formula:H (CH2)n _HR5H (CH2)m-81. The method of any of claims 63-80, wherein R1has the formula:R6)— (CH2)x-~vCZZZvvu'(CH2)y-|R6*wherein — represents a single or double bond, or is absent, y is 0-12, x is 0-15, R6is H or CH3, and R6* is H or CH3.

82. The method of any of claims 63-80, wherein is absent, y is 0, x is 0, and R6and R6* are each H.Attorney Docket No. 103362-090W01 83. The method of any of claims 63-80, wherein is a single or double bond, y is 3, 4, 5, 6, or 7, x is 0, and R6and R6* are each CH3.

84. The method of any of claims 63-80, wherein is a single bond.

85. The method of any of claims 63-84, wherein R2has the formula:

86. The method of any of claims 63-85, wherein R1has the formula:

87. The method of any of claims 63-86, wherein R2isR3is H, Z is C(=O), and R1is methyl or selected from:Attorney Docket No. 103362-090W0188. The method of any preceding claim, wherein the threatening subject is contacted with the composition in the face and head.

89. The method of any preceding claim, wherein the composition is delivered to the threatening subject via a spray.

90. The method of any preceding claim, wherein the threatening subject is a human, canine, or bear.

91. The composition of any of claims 1-25, wherein the composition comprises a solvent and optionally an emulsifier.

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