Organic compound

Abstract

The present invention relates to a compound represented by formula (I) A compound represented by JPEG2024537344000013.jpg3568 and an edible salt thereof, wherein R1 is 2-(1H-4-imidazolyl)-ethenyl, 1H-5-indolyl, 2-(1H-5-imidazolyl)-ethenyl, 1-amino-2-(1H-4-imidazolyl)-ethyl, (1,3-thiazol-2-yl)-ethenyl, 2,3-dihydro-1H-indol-2-yl, 2-(pyrimidin-2-yl)-ethenyl, heptadecanyl, 1-hept ... R2 is selected from the group consisting of (1H-imidazol-2-yl)-ethenyl, 2-(4H-imidazol-2-yl)-ethyl, 2-phenyl-ethenyl, 2-(furan-2-yl)-ethenyl, 2-(thiophen-2-yl)-ethenyl, 2-(thiophen-3-yl)-ethenyl, 2-but-2-enoyl, 2-butyl, 2,6-dimethylhepta-1,5-dienyl, 1,3-benzothiazol-6-yl; R3 is selected from the group consisting of (1H-imidazol-2-yl)-ethenyl, 2-(4H-imidazol-2-yl)-ethyl, 2-phenyl-ethenyl, 2-(furan-2-yl)-ethenyl, 2-(thiophen-2-yl)-ethenyl, 2-(thiophen-3-yl)-ethenyl, 2-but-2-enoyl, 2-butyl, 2,6-dimethylhepta-1,5-dienyl, 1,3-benzothiazol-6-yl; -4-yl)-methyl, (1H-3-indol-3-yl)-methyl, 4-hydroxybenzyl, methylsulfanylethyl, hydroxymethyl, CH2-COOH, (pyridin-4-yl)methyl, (pyridin-2-yl)methyl, 1-(2,6-dimethylhepta-1,5-dienyl), 2-(pyrimidin-2-yl)methyl, (1H-imidazol-5-yl)-methyl, (1H-imidazol-2-yl)-methyl, (1H-pyrrol-2-yl)-methyl, phenyl, pyrimidin-5-yl, pyrazine R3 is selected from the group consisting of H, COOH, and edible salts thereof, or a compound selected from the group consisting of 3-(1H-imidazol-4-yl)prop-2-enamide, methyl 2,3-dihydro-1H-indole-2-carboxylate, and 3,6-bis[(1H-imidazol-4-yl)methyl]piperazine-2,5-dione, for use as flavor modulating compounds, as well as flavor compositions and consumer products containing said compounds.

Description

[Technical field]

[0001] The present invention generally relates to novel compounds that are useful flavor modulating compounds and their edible salts.The invention further relates to flavor compositions and consumer products, such as foodstuffs or beverages, that contain said compounds.The invention also relates to the use of said compounds and to methods of imparting, enhancing, improving, complementing or modifying flavor characteristics to flavor compositions or consumer products by using said compounds. [Background technology]

[0002] Saltiness is one of the five fundamental taste attributes, next to umami, sweetness, bitterness, and sourness. Saltiness is associated with sodium chloride and is essential for stimulating healthy mineral uptake through food. However, modern diets are rich in highly processed foods, which often contain very high amounts of sodium chloride. According to the World Health Organization (WHO), an average daily intake of 5 g / day is recommended. According to the FDA, the Personal Average Daily Intake (PADI) of sodium chloride in Americans is over 8 g, clearly exceeding the recommended value. A persistently high PADI of sodium chloride can cause negative side effects such as hypertension, cardiovascular disease, renal failure, and stroke. It is highly desirable to reduce the PADI of sodium chloride, preferably without compromising the desired saltiness. Therefore, there is a need for compounds that enhance the perception of saltiness.

[0003] Various flavor compounds as potential salt enhancers have been described in the literature, for example US 9,155,329 B2 discloses that low molecular weight amides with added hydroxyl or alkoxyl groups have salt enhancing properties. At least partial replacement of sodium chloride with other salts, such as potassium chloride, is often associated with negative taste profiles (Khetra et al, Int. Dairy J. (2019), 91, 165-171).

[0004] Another related aspect that can be confused with salt perception is umami taste, although it involves a completely different receptor mechanism. The most prominent example of a compound that confers umami taste is monosodium glutamate (MSG) (Ikeda, J. Tokyo Chem. Soc. (1909), 30, 820-836). Umami taste can be modified by the ribonucleotides inosine monophosphate (IMP) and guanosine monophosphate (GMP) (Kodama, J. Soc. of Japan. (1913), 34: 751-757; Kuninaka, J. Chem. Soc. Jpn. (1960), 34, 487-492). Other compounds that enhance umami taste include, for example, theanine (Suzuku et al. J Agric Food Chem. (2002), 50 313-318) or special oligopeptides (Yamasaki, et al, Agric. Biol. Chem. (1978), 42, 1761-1765; Tamura et al, Agric. Biol. Chem. (1989), 53, 319-325).

[0005] Glutathione has been described to affect umami and saltiness simultaneously, more precisely the duration of taste stimulation (Tazuko et al, Chem. Senses (2016), Volume 41, 623-630). A group of general taste enhancers was reported in EP1291342. A variety of other molecules are known to improve or affect salt perception, and volatile aroma compounds can help mimic increased saltiness (Batenburg et al, J. (2011), 76, 280-288). There remains a need to add new flavor modulating taste improving substances to the flavorist's palette. DISCLOSURE OF THEINVENTION

[0006] overview According to a first aspect of the present invention, there is provided a compound of formula (I): [ka] or an edible salt thereof as a flavour modifying compound. According to a second aspect of the invention there is provided a flavour composition comprising said compound.

[0007] According to a third aspect of the invention, there is provided a consumer product comprising said compound or said flavour composition. According to a fourth aspect of the present invention, there are provided novel compounds as flavour modulating compounds. According to a fifth aspect of the invention there is provided a method of imparting, enhancing, improving or modifying the flavour characteristics of a flavour composition or consumer product.

[0008] Certain embodiments of any aspect of the invention may provide one or more of the following advantages: Regulation of salty taste perception, especially positive regulation, ● Reduction of bitterness, e.g. KCl, ● Reduction of acidity, e.g. NH4Cl, Enhancement of umami taste perception, and • Enhancement of the aroma perception of foodstuffs or beverages, especially flavored foodstuffs or beverages.

[0009] The details, examples, and preferences provided in connection with one or more particular described aspects of the invention will be explained further herein and apply equally to all aspects of the invention. Every combination of the embodiments, examples, and preferences described herein, in all possible variations, is encompassed by the invention unless otherwise indicated herein or clearly contradicted by context.

[0010] Detailed Description The present invention is based on the surprising discovery that certain peptides, which are derived largely from deaminated and / or decarboxylated amino acids, have flavour modulating properties.

[0011] Thus, one or more compounds of formula (I): [ka] and edible salts thereof, wherein R1 is 2-(1H-4-imidazolyl)-ethenyl, 1H-5-indolyl, 2-(1H-5-imidazolyl)-ethenyl, 1-amino-2-(1H-4-imidazolyl)-ethyl, (1,3-thiazol-2-yl)-ethenyl, 2,3-dihydro-1H-indol-2-yl, 2-(pyrimidin-2-yl)ethenyl, heptadecanyl, 1-heptadecanyl, 1-heptadecanyl, 8,11-dienyl, or 1-heptadecanyl. ,14-trienyl, 2-(4H-imidazol-2-yl)-ethenyl, 2-(4H-imidazol-2-yl)-ethyl, 2-phenyl-ethenyl, 2-(furan-2-yl)-ethenyl, 2-(thiophen-2-yl)-ethenyl, 2-(thiophen-3-yl)-ethenyl, 2-but-2-enoyl, 2-butyl, 2,6-dimethylhepta-1,5-dienyl, 1,3-benzothiazol-6-yl;

[0012] R2 is selected from the group consisting of (1H-imidazol-4-yl)-methyl, (1H-3-indol-3-yl)-methyl, 4-hydroxybenzyl, methylsulfanylethyl, hydroxymethyl, CH2-COOH, (pyridin-4-yl)methyl, (pyridin-2-yl)methyl, 1-(2,6-dimethylhepta-1,5-dienyl), 2-(pyrimidin-2-yl)methyl, (1H-imidazol-5-yl)-methyl, (1H-imidazol-2-yl)-methyl, (1H-pyrrol-2-yl)-methyl, phenyl, pyrimidin-5-yl, pyrazin-2-yl;

[0013] R3 is selected from the group consisting of H, COOH, said compounds and edible salts thereof; Alternatively, there is provided the use of a compound selected from the group consisting of 3-(1H-imidazol-4-yl)prop-2-enamide, methyl 2,3-dihydro-1H-indole-2-carboxylate, and 3,6-bis[(1H-imidazol-4-yl)methyl]piperazine-2,5-dione as a flavour modulating compound.

[0014] As used herein, edible salts include those typically used in the food and beverage industry and include chloride, sulfate, phosphate, gluconate, sodium, citrate, carbonate, acetate and lactate. When the compounds of the present invention contain a stereocenter or a double bond, the compounds are single isomers, such as enantiomers or diastereomers or double bond isomers, or mixtures of isomers. In particular, the double bonds of the compounds of the present invention can be in the E or Z configuration, or the compounds are present as mixtures.

[0015] When the compounds of the present invention can exist in tautomeric forms, both tautomers are encompassed by the present invention. For example, the imidazole moiety of histidine and its derivatives exists in two tautomeric forms: 1H-imidazol-4-yl and 3H-imidazol-4-yl. Furthermore, the compound of the present invention may be a mixture of multiple compounds in the form of any of its isomers or mixtures thereof.

[0016] The compounds of formula (I) are amides or peptides, characterized in that they have an amide group -C(=O)N= formed by the amino nitrogen atom of one amino acid residue and the carbonyl carbon atom of another amino acid residue, alternatively the carbonyl carbon atom being provided by a fatty acid. For example, the amino acid residue (R1) bonded to the carbon atom of the amide group of the compound represented by formula (I) is a residue of an amino acid selected from the group consisting of histidine, deaminated histidine and dehydrogenated histidine.

[0017] For example, the residue R1 derived from a fatty acid has one or more CC double bonds. These double bonds can be in the E or Z configuration or can form a mixture of isomers. For example, the CC double bond configuration of one or more double bonds is Z. For example, the amino acid residue bound to the nitrogen atom of the amide group of the compound represented by formula (I) is an amino acid residue selected from the group consisting of β-alanine, histidine, tryptophan, tyrosine, and decarboxylated histidine, serine, methionine, and tyrosine.

[0018] The compounds of the invention described above have flavour modulating properties, for example some compounds can enhance the perception of saltiness and / or reduce bitterness and / or enhance umami taste. Throughout this document, the terms "taste" and "flavor" are used interchangeably to describe the sensory effects perceived through the mouth, particularly the tongue, and the olfactory epithelium in the nasal cavity.

[0019] As used herein, "flavor modulating compound" refers to a compound that does not have flavor properties of its own, but is capable of altering, complementing, or modulating the taste impact of other flavor substances contained in a flavor composition or consumer product, including the salty impact, sour impact, bitter and / or umami impact. For example, the flavor modulating compounds have no salty taste at all up to levels above 1000 ppm. Combining with a salty flavor compound, such as NaCl, can enhance the perception of saltiness.

[0020] For example, flavor modulating compounds have no discernible taste to counteract or mask bitterness at levels above 1000 ppm. When combined with a compound that may have a bitter off-taste, such as KCl, the bitterness is reduced. For example, flavor modulating compounds have no discernible taste to counter or mask the sour taste at levels above 1000 ppm. When combined with a compound that may have a sour off-taste, such as NH4Cl, the sour taste is reduced.

[0021] For example, flavor modulating compounds do not impart any umami taste at levels above 1000 ppm. When combined with a compound that can impart umami taste, such as MSG, the umami taste is enhanced. As used herein, "flavoring substance" refers to any substance capable of imparting a detectable flavor effect, particularly at a concentration of less than 0.1 wt%, more preferably less than 0.01 wt%. For example, such flavoring substances may be selected from natural flavors, artificial flavors, spices, seasonings, etc., synthetic flavor oils and flavor aromas and / or oils, oleoresins, essences, distillates, and extracts derived from plants, leaves, flowers, fruits, etc. In general, any flavor or food additive may be used as described in "Chemicals Used in Food Processing, publication 1274, pages 63-258" by the National Academy of Sciences of the United States of America. This publication is incorporated herein by reference.

[0022] The flavor modulating compounds of the present invention have been found to be extremely useful ingredients capable of imparting appreciated taste sensations to products in which they are incorporated, in the presence of other flavor substances, such as "roundness," "richness," "materiality," "clarity," "complexity," "expansive," "continuous," "long-lasting," "tingling," "numbing," "bitter," and / or "metallic." Thus, the present taste improving substances can be utilized to improve the taste (including "mouthfeel") of foodstuffs and beverages.

[0023] In a further aspect, there is provided the use of one or more compounds of formula (I) and their edible salts as flavor modulating compounds, wherein said compounds have at least one aromatic unit attached to the residue via amide bond.For example, the aromatic unit can be selected from the group consisting of phenyl, imidazole, thiazole, indole, furan, thiophene, benzothiazole, pyrimidine, pyrazine, pyrrole.The aromatic unit can be part of R1 and / or R2.In one embodiment, the aromatic unit is imidazole.

[0024] In a further aspect, there is provided the use of one or more compounds of formula (I) and their edible salts as flavor modulating compounds, wherein said compounds have two aromatic units attached to the residue via amide bond, and said aromatic units can be part of R1 and R2.For example, said aromatic units can be selected from the group consisting of phenyl, imidazole, thiazole, indole, furan, thiophene, benzothiazole, pyrimidine, pyrazine, pyrrole.In one embodiment, at least one of the two aromatic units attached to the residue via amide bond is imidazole.

[0025] In a further aspect, there is provided one or more compounds of formula (I) and their use as flavour modulating compounds in edible salts, wherein the compound is represented by formula (II) in the form of any one of its isomers or a mixture thereof: [ka] During the ceremony, [ka] represents a carbon-carbon single or double bond, X represents a heteroatom selected from the group consisting of N and S; R4 is either H or NH2; and R2 and R3 have the same meanings as defined for compounds of formula (I).

[0026] The compound of formula II has a 5-membered unsaturated heterocycle with two heteroatoms attached to the residue via amide bonds, for example, the 5-membered unsaturated heterocycle is imidazole or thiazole.

[0027] In a further aspect, there is provided one or more compounds of formula (I) and their use as flavour modulating compounds in edible salts, wherein the compound, in the form of any one of its isomers or a mixture thereof, is represented by formula (III): [ka] wherein R1 is selected from the group consisting of heptadecanyl, 1-heptadecanyl, heptadeca-8,11-dienyl, and heptadeca-8,11,14-trienyl.

[0028] The compounds represented by formula (II) are derived from histidine and fatty acid. The fatty acid may be saturated or have one or more double bonds. The compounds represented by formula (III) are taste modulating compounds, and in particular they can enhance salty taste.

[0029] In a further aspect of the present invention, there is provided the use of a compound according to formula (I) as defined above or an additional compound, wherein the compound is selected from the group consisting of: 3-(1H-imidazol-4-yl)-N-[2-(1H-imidazol-4-yl)ethyl]prop-2-enamide, N-[2-(1H-imidazol-4-yl)ethyl]-1H-indole-5-carboxamide, histidyl tyrosine, N-[3-(1H-imidazo N-[2-(1H-imidazol-4-yl)ethyl]-3-(1,3-thiazol-2-yl)prop-2-enamide, N-[Octadeca-9,12,15- trienoyl]histidine, N-[octadec-9-enoyl]histidine, N-octadecanoylhistidine, 3-(1H-imidazol-4-yl)prop-2-enamide, 3-(1H-imidazol-4-yl)-N-[2-(pyridin-4-yl)ethyl]prop-2-enamide, 2,3-dihydro-1H-indole-2-carboxylate methyl, 3-(1H-imidazol-4-yl)-N-[2-(pyridin-2-yl)ethyl]prop- 2-enamide, N-[3,7-dimethylocta-2,6-dien-1-yl]-3-(1H-imidazol-4-yl)prop-2-enamide, N-[2-(1H-imidazol-4-yl)ethyl]-2,3-dihydro-1H-indole-2-carboxamide, 3-(pyrimidin-2-yl)-N-[2-(pyrimidin-2-yl)ethyl]prop-2-enamide, 3,6-bis[(1H-imidazol-4-yl)methyl]piperazine-2,5-dione, 3-(4H-imidazol-2-yl)-N-[2-(1H-imidazol-5-yl)ethyl]prop-2-enamide, 3-(1H-imidazol-4-yl)-N-[2-(1H-imidazol-2-yl)ethyl]prop-2-enamide, N-(2-hydroxyethyl)-3-(1H-imidazol-4-yl)propanamide, 3-(1H-imidazol-4-yl)-N-[2-(1H-pyrrol-2-yl)ethyl]prop-2-enamide, 3-[2-amino-3-(1H-imidazol-4-yl)propanamide] Propanoic acid, N-[2-(1H-imidazol-4-yl)ethyl]-3-phenylprop-2-enamide, N-benzyl-3-(1H-imidazol-4-yl)prop-2-enamide, 3-(1H-imidazol-4-yl)-N-[(pyrimidin-5-yl)methyl]prop-2-enamide, 3-(1H-imidazol-4-yl)-N-[(pyrazin-2-yl)methyl]prop-2-enamide, 3-(furan-2-yl)-N-[2-(1H-imidazol-4-yl)ethyl]prop-2-enamide, N-[2-(1H-imidazo N-[2-(1H-imidazol-4-yl)ethyl]-3-(thiophen-2-yl)prop-2-enamide, N-[2-(1H-imidazol-4-yl)ethyl]-3-(thiophen-3-yl)prop-2-enamide, 3-(1H-imidazol-4-yl)-2-{[(2E)-3-phenylprop-2-enoyl]amino}propanoic acid, 3-(1H-imidazol-4-yl)-2-{[(2E)-2-methylbut-2-enoyl]amino}propanoic acid, N-[2-(1H-imidazol-4-yl)ethyl]-2-methylbutanamide, N-[2-(1H-imidazol-4-yl)ethyl]-3-(thiophen-3-yl)prop-2-enamide, 2-{[3-(furan-2-yl)prop-2-enoyl]amino}-3-(1H-imidazol-4-yl)propanoic acid, 3-(1H-imidazol-5-yl)-2-{[3-(1H-imidazol-4-yl)prop-2-enoyl]amino}propanoic acid, N-[2-(1H-imidazol-5-yl)ethyl]-1,3-benzothiazole-6-carboxamide, 3-(1H-imidazol-4-yl)-N-(2-phenylethyl)prop-2-enamide.

[0030] In particular, there is provided the use of a compound according to formula (I) as defined above or an additional compound, wherein the compound is selected from the group consisting of: (2Z)- or (2E)-3-(1H-imidazol-4-yl)-N-[2-(1H-imidazol-4-yl)ethyl]prop-2-enamide, N-[2-(1H-imidazol-4-yl)ethyl]-1H-indole-5-carboxamide, Histidyltyrosine, N-[3-(1H-imidazol-5-yl)prop-2-enoyl]-tryptophan, histidylhistidine, N-[3-(methylsulfanyl)propyl]histidineamide, N-(2-hydroxyethyl)histidineamide, histidyl-β-alanine, N-[2-(1H-imidazol-4-yl)ethyl]-3-(1,3-thiazol-2-yl)prop-2-eneamide , 3-(1H-imidazol-4-yl)prop-2-enamide, 3-(1H-imidazol-4-yl)-N-[2-(pyridin-4-yl)ethyl]prop-2-enamide, 2,3-dihydro-1H-indole-2-carboxylate methyl, 3-(1H-imidazol-4-yl)-N-[2-(pyridin-2-yl)ethyl]prop-2-enamide, N-[3,7-dimethyloct-2,6- dien-1-yl]-3-(1H-imidazol-4-yl)prop-2-enamide, N-[2-(1H-imidazol-4-yl)ethyl]-2,3-dihydro-1H-indole-2-carboxamide, 3-(pyrimidin-2-yl)-N-[2-(pyrimidin-2-yl)ethyl]prop-2-enamide, 3,6-bis[(1H-imidazol-4-yl)methyl]piperazine-2,5-dione.

[0031] In a further aspect of the invention there is provided the use of a mixture of compounds according to formula (I) as defined above as flavour modulating compound. In a further aspect, the flavor modulating compounds according to the present invention are particularly useful in a wide variety of flavor compositions and consumer products, including savory foods, non-flavored foods such as dairy products, beverages, confectioneries, and the like.

[0032] For example, the flavour composition comprises at least 0.01 wt%, or at least 0.1 wt%, or at least 0.5 wt% of flavour substance based on the total weight of the composition and 0.001 to 80 wt% of a flavour modulating compound according to the present invention, preferably 0.01 to 50 wt%, more preferably 0.01 to 20 wt% of a flavour modulating compound based on the total weight of the composition. In a typical flavour composition the flavour modulating compound and the flavour substance are used in a weight ratio of from 10:1 to 1:150, preferably from 5:1 to 1:100.

[0033] The flavour composition comprising the flavour modulating compound may suitably be prepared in the form of a liquid, a paste or a powder, for example the flavour composition is a free-flowing powder. Typical examples of flavor compositions include savory flavors, sour / acid flavors, and the like.

[0034] The flavor modulating compound of the present invention can be used in a flavor composition in addition to a flavor substance together with one or more ingredients or excipients that are conventionally used in flavor compositions, such as carrier materials and other auxiliaries that are commonly used in the art. Suitable excipients for flavor compositions are well known in the art, and include, but are not limited to, solvents (including water, alcohol, ethanol, oils, fats, vegetable oils, and miglyol), binders, diluents, disintegrants, lubricants, flavoring agents, coloring agents, preservatives, antioxidants, emulsifiers, stabilizers, flavor enhancers, anti-caking agents, etc.

[0035] Examples of such carriers or diluents for flavor compositions can be found, for example, in "Perfume and Flavour Materials of Natural Origin", S. Arctander, Ed., Elizabeth, NJ, 1960; "Perfume and Flavour Chemicals", S. Arctander, Ed., Vol. I & II, Allured Publishing Corporation, Carol Stream, USA, 1994; "Flavourings", E. Ziegler and H. Ziegler (ed.), Wiley-VCH Weinheim, 1998, and "CTFA Cosmetic Ingredient Handbook", J. Nikitakis (ed.), 1st ed., The Cosmetic, Toiletry and Fragrance Association, Inc., Washington, 1988.

[0036] Other suitable and desirable ingredients of the flavour composition are described in standard texts, such as "Handbook of Industrial Chemical Additives", ed. M. and I. Ash, 2nd Ed., (Synapse 2000). In another aspect of the present invention, there is further provided a consumer product comprising at least one compound of formula (I), or a flavour composition comprising one or more compounds of formula (I), and a product base.

[0037] "Product base" means the combination of all conventional, art-recognized ingredients required for a particular consumable composition. In another aspect of the present invention, there is provided a consumer product selected from the group consisting of foodstuffs and beverages, said consumer product comprising at least 1 ppm, preferably at least 20 ppm, more preferably at least 50 ppm or 70 ppm ppb of one or more flavour modulating compounds according to formula (I) and / or an edible salt thereof.

[0038] For example, the product contains at least 0.0001 wt%, more preferably at least 0.0003 wt%, even more preferably at least 0.001 wt%, and most preferably at least 0.003 wt% of at least one flavor modulating compound. Typically, the product contains the flavor modulating compound at a concentration of 1 wt% or less, preferably 0.5 wt% or less.

[0039] Typical examples of foodstuffs according to the present invention include soups, sauces, stocks, bouillons, broths, cheese products such as cheese sauces, vegan cheese substitutes, dressings, mayonnaise, condiments, margarines, noodles, chips, curls, meat products, vegan meat substitutes and beverages etc. For example, the aforementioned foodstuffs can be low sodium products.

[0040] The flavour modulating compounds according to the invention can be advantageously applied to impart desired taste attributes to the aforementioned products, in addition, the present taste improving substances are able to modulate the taste impact of other flavour ingredients contained in these same products, thus improving the overall flavour quality of these products.

[0041] In another aspect of the invention there is provided the use of a compound of formula (I) as a flavour modulating compound. The compounds may be used in pure or diluted form and may be provided in liquid or solid form.

[0042] In another aspect of the present invention, there is provided a method for imparting, enhancing, improving or modifying the flavor properties of a flavor composition or consumer product, comprising adding to said composition or consumer product a flavor modulating compound, which is at least one compound of formula (I) or an edible salt thereof. For example, the flavor modulating compound is added in an amount of at least 0.0003 wt%, preferably at least 0.001 wt%.

[0043] Some of the compounds of formula (I) are known from different uses, but most of the compounds are novel. For example, 3-(1H-imidazol-4-yl)-N-[2-(1H-imidazol-4-yl)ethyl]prop-2-enamide was described as a natural histamine derivative by Baures et al. (Molecules (2002), 7(11), 813-816). The organoleptic properties of said compound were not disclosed.

[0044] Thus, the present invention provides a compound of formula (I): [ka] and an edible salt thereof, wherein R1 is 2-(1H-4-imidazolyl)-ethenyl, 1H-5-indolyl, 2-(1H-5-imidazolyl)-ethenyl, 1-amino-2-(1H-4-imidazolyl)-ethyl, (1,3-thiazol-2-yl)-ethenyl, 2,3-dihydro-1H-indol-2-yl, 2-(pyrimidin-2-yl)ethenyl, heptadecanyl, 1-heptadecanyl, 1-heptadecanyl, 8,11-dienyl, or 1-heptadecanyl. ,14-trienyl, 2-(4H-imidazol-2-yl)-ethenyl, 2-(4H-imidazol-2-yl)-ethyl, 2-phenyl-ethenyl, 2-(furan-2-yl)-ethenyl, 2-(thiophen-2-yl)-ethenyl, 2-(thiophen-3-yl)-ethenyl, 2-but-2-enoyl, 2-butyl, 2,6-dimethylhepta-1,5-dienyl, 1,3-benzothiazol-6-yl;

[0045] R2 is selected from the group consisting of (1H-imidazol-4-yl)-methyl, (1H-3-indol-3-yl)-methyl, 4-hydroxybenzyl, methylsulfanylethyl, hydroxymethyl, CH2-COOH, (pyridin-4-yl)methyl, (pyridin-2-yl)methyl, 1-(2,6-dimethylhepta-1,5-dienyl), 2-(pyrimidin-2-yl)methyl, (1H-imidazol-5-yl)-methyl, (1H-imidazol-2-yl)-methyl, (1H-pyrrol-2-yl)-methyl, phenyl, pyrimidin-5-yl, pyrazin-2-yl;

[0046] R3 is selected from the group consisting of H, COOH; However, the compound is not 3-(1H-imidazol-4-yl)-N-[2-(1H-imidazol-4-yl)ethyl]prop-2-enamide, histidyltyrosine, histidylhistidine, N-(2-hydroxyethyl)histidineamide, histidyl-β-alanine, N-octadecanoylhistidine, or N-[(9Z)-octadec-9-enoyl]histidine.

[0047] In a further aspect, there is provided a compound of formula (I) and its edible salts as flavor modulating compound as defined above, wherein said compound has at least one aromatic unit attached to the residue via amide bond.For example, aromatic unit can be selected from the group consisting of phenyl, imidazole, thiazole, indole, furan, thiophene, benzothiazole, pyrimidine, pyrazine, pyrrole.Aromatic unit can be part of R1 and / or R2. In one embodiment, the aromatic unit is imidazole.

[0048] In a further aspect, there is provided a compound of formula (I) and its edible salts as flavor modulating compound as defined above, wherein the compound has two aromatic units attached to the residue via amide bond, and wherein the aromatic units can be part of R1 and R2.For example, the aromatic units can be selected from the group consisting of phenyl, imidazole, thiazole, indole, furan, thiophene, benzothiazole, pyrimidine, pyrazine, pyrrole. In one embodiment, at least one of the two aromatic units attached to the residue via an amide bond is an imidazole.

[0049] In a further aspect, there is provided a compound of formula (I) and edible salts thereof as flavour modulating compounds, said compound being represented by formula (II) in the form of any one of its isomers or mixtures thereof: [ka] During the ceremony, [ka] represents a carbon-carbon single or double bond, X represents a heteroatom selected from the group consisting of N and S; R4 is either H or NH2; and R2 and R3 have the same meanings as defined for compounds of formula (I).

[0050] The compound represented by formula II has a 5-membered unsaturated heterocycle with two heteroatoms attached to the residue via amide bonds.For example, the 5-membered unsaturated heterocycle is imidazole or thiazole.In a further aspect, there is provided a compound represented by formula (I) and its edible salts as flavor modulating compounds, wherein the compound is represented by formula (III) in the form of any one of its isomers or mixtures thereof: [ka] wherein R1 is selected from the group consisting of heptadecanyl, 1-heptadecanyl, heptadeca-8,11-dienyl, and heptadeca-8,11,14-trienyl.

[0051] In a further aspect, the present invention provides a compound of formula (I) as defined above, wherein the compound is selected from the group consisting of N-[2-(1H-imidazol-4-yl)ethyl]-1H-indole-5-carboxamide, N-[3-(1H-imidazol-5-yl)prop-2-enoyl]tryptophan, N-[3-(methylsulfanyl)propyl]histidineamide, N-[octadeca-9,12-dienoyl]histidine, N-[2-(1H-imidazol-4-yl)ethyl]-3-(1,3-thiaz ... 3-(1H-imidazol-4-yl)-N-[2-(pyridin-4-yl)ethyl]prop-2-enamide, N-[3,7-dimethylocta-2,6-dien-1-yl]-3-(1H-imidazol-4-yl)prop-2-enamide, N-[2-(1H-imidazol-4-yl)ethyl]-2,3-Dihydro-1H-indole-2-carboxamide, 3-(pyrimidin-2-yl)-N-[2-(pyrimidin-2-yl)ethyl]prop-2-enamide, 3-(4H-imidazol-2-yl)-N-[2-(1H-imidazol-5-yl)ethyl]prop-2-enamide, 3-(1H-imidazol-4-yl)-N-[2-(1H-imidazol-2-yl)ethyl]prop-2-enamide, N-(2-hydroxyethyl)-3-(1H-imidazol-4-yl)propanamide, 3-( 1H-imidazol-4-yl)-N-[2-(1H-pyrrol-2-yl)ethyl]prop-2-enamide, N-benzyl-3-(1H-imidazol-4-yl)prop-2-enamide, 3-(1H-imidazol-4-yl)-N-[(pyrimidin-5-yl)methyl]prop-2-enamide, 3-(1H-imidazol-4-yl)-N-[(pyrazin-2-yl)methyl]prop-2-enamide, 3-(furan-2-yl)-N-[2-(1H-imidazol-4-yl)ethyl]prop-2-enamide N-[2-(1H-imidazol-4-yl)ethyl]-3-(thiophen-2-yl)prop-2-enamide, N-[2-(1H-imidazol-4-yl)ethyl]-3-(thiophen-3-yl)prop-2-enamide, 3-(1H-imidazol-4-yl)-2-{[(2E)-2-methylbut-2-enoyl]amino}propanoic acid, N-[2-(1H-imidazol-4-yl)ethyl]-2-methylbutanamide, N-[2-(1H-imidazol-4-yl)ethyl]-3,7 -Dimethylocta-2,6-dienamide, 2-{[3-(furan-2-yl)prop-2-enoyl]amino}-3-(1H-imidazol-4-yl)propanoic acid, 3-(1H-imidazol-5-yl)-2-{[3-(1H-imidazol-4-yl)prop-2-enoyl]amino}propanoic acid, N-[2-(1H-imidazol-5-yl)ethyl]-1,3-benzothiazole-6-carboxamide, 3-(1H-imidazol-4-yl)-N-(2-phenylethyl)prop-2-enamide.

[0052] The compounds of the invention can be prepared from amino acids or modified amino acids, such as decarboxylated or deamidated amino acids, and from fatty acids. For example, the compounds of the invention can be prepared from amino acids selected from the group consisting of β-alanine, histidine, tryptophan, and tyrosine, modified amino acids selected from the group consisting of decarboxylated histidine, serine, methionine, tyrosine, or deaminated and dehydrogenated histidine.

[0053] The compounds of the invention may be prepared by peptide synthesis from two amino acids. They are suitably generated by reacting the amine of the first amino acid with the carboxyl group of the second amino acid. Other compounds of the invention may be prepared from one amino acid or a derivative thereof and a fatty acid.

[0054] The preparation of the compounds of the invention can be carried out by methods known in the art, for example the compounds can be obtained by chemical or enzymatic reactions. The present invention will now be described in further detail with reference to the following non-limiting examples, which are for illustrative purposes only and it will be understood that variations and modifications may be made by those skilled in the art. EXAMPLES

[0055] Example 1: (2E)-3-(1H-imidazol-4-yl)-N-[2-(1H-imidazol-4-yl)ethyl]prop-2-enamide (E)-3-(1H-imidazol-4-yl)acrylic acid (13.8 g, 100 mmol) was dissolved in DMF (800 ml). 1-Hydroxypyrrolidine-2,5-dione (12.66 g, 110 mmol) and dicyclohexylmethandiimine (22.70 g, 110 mmol) were added with stirring at room temperature. Stirring was continued for 24 hours and the solvent was evaporated to a volume of about 200 mL. The solid (dicyclohexylurea) was filtered to give 220 g of filtrate. To the filtrate (a solution of 2,5-dioxopyrrolidin-1-yl (E)-3-(1H-imidazol-4-yl)acrylate in DMF) was added an aqueous solution of histamine.2HCl (18.4 g, 100 mmol) and sodium bicarbonate (16.8 g, 200 mmol) and the mixture was stirred at 50° C. for 3 h. The solvent was evaporated and methanol (200 mL) was added to the residue. The remaining solid (NaCl) was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography. The isolated product was stirred with acetone for 3 h to remove the impurity NHS. The product was filtered and dried in a vacuum oven at 50° C. / 15 mbar. 15 g of (2E)-3-(1H-imidazol-4-yl)-N-[2-(1H-imidazol-4-yl)ethyl]prop-2-enamide was obtained as a white powder with a purity of 95%. Yield: 62%. 1 H NMR (D2O, 600 MHz) δ = 8.35 (1H, s), 7.83 (1H, s), 7.44 (1H, s), 7.42 (1H, d, J = 15.1 Hz), 7.19 (1H, s), 6.49 (1H, d, J = 15.8 Hz), 3.61 (2H, J = 6.5 Hz), 2.96 (2H, J = 6.5 Hz). 13 C NMR (D2O, 151 MHz) δ = 171.9, 140.9, 137.7, 136.7, 134.8, 124.4, 120.0, 119.3, 41.4, 27.6.

[0056] Example 2: N-[2-(1H-imidazol-4-yl)ethyl]-1H-indole-5-carboxamide 1H-Indole-5-carboxylic acid (5 g, 31.0 mmol) was dissolved in DMF (350 ml) and 1-hydroxypyrrolidine-2,5-dione (3.93 g, 34.1 mmol) and dicyclohexylmethandiimine (7.04 g, 34.1 mmol) were added with stirring at room temperature. Stirring was continued for 24 hours. The solids were filtered and the filtrate was evaporated to about 100 mL. To a solution of 2,5-dioxopyrrolidin-1-yl-1H-indole-5-carboxylate (8.01 g, 31 mmol) in DMF was added a solution of sodium bicarbonate (5.21 g, 62.0 mmol) and histamine 2HCl in water (50 ml). The mixture was stirred at 50° C. for 4 h. The volatiles were evaporated and the residue was taken up in methanol. The remaining solid (NaCl) was filtered and the filtrate was evaporated. The residue was purified by flash column chromatography with eluent DCM / methanol. The isolated product was further purified using an acidic Dowex cation exchanger to remove residual NHS, finally giving 200 mg of 90% pure product. 1 H NMR (DMSO-d6, 600 MHz) δ = 8.45 (1H, t, J = 5.5 Hz), 8.11 (1H, s), 7.69 - 7.79 (1H, m), 7.62 (1H, d, J = 8.0 Hz), 7.40 - 7.49 (2H, m), 6.93 (1H, s), 6.52 (1H, br s), 3.38 - 3.63 (2H, m), 2.80 (2H, t, J = 7.6 Hz). 13 C NMR (DMSO-d6, 151 MHz) δ = 167.0, 137.1, 134.3, 133.9, 126.8, 126.4, 125.4, 120.2, 119.6, 116.5, 110.6, 101.9, 59.6, 39.1, 26.5.

[0057] Example 3: L-Histidyl-L-Tyrosine The compounds were obtained from Bachem. 1H NMR (D2O, 600 MHz) δ = 7.99 (1H, s), 7.11 - 7.17 (2H, m, J = 8.3 Hz), 7.08 (1H, s), 6.81 - 6.87 (2H, m), 4.40 (1H, dd, J = 8.6 Hz, J = 5.2 Hz), 3.99 - 4.05 (1H, m), 3.08 - 3.17 (3H, m), 2.91 (1H, dd, J = 14.1 Hz, J= 8.6 Hz). 13 C NMR (D2O, 151 MHz) δ = 180.7, 173.2, 157.0, 138.5, 133.4, 132.5, 132.3, 120.6, 118.2, 59.6, 56.0, 39.3, 31.6.

[0058] Example 4: N-[(2E)-3-(1H-imidazol-5-yl)prop-2-enoyl]-L-tryptophan 4 g of methyl L-tryptophanate was dissolved in DMF and 1.54 g of NaHCO3 was added with stirring. Then 175 ml of a freshly prepared solution of 0.125 mol / l 2,5-dioxopyrrolidin-1-yl 3-(1H-imidazol-4-yl)acrylate in DMF was added. The resulting mixture was warmed to 40° C. and stirring was continued for 6 hours. The reaction mixture was concentrated by evaporating the DMF. 250 ml of ethyl acetate was added to the residue and washed with 100 ml of water. The ethyl acetate extract was washed again with 100 ml of water and concentrated by evaporation. Purification was carried out by flash chromatography with dichloromethane:methanol. 3.5 g of intermediate (E)-(4-(1H-imidazol-5-yl)but-2-enoyl)-methyl L-tryptophanate was obtained.

[0059] The resulting methyl ester was then hydrolyzed as follows: 1 g of methyl (E)-(4-(1H-imidazol-5-yl)but-2-enoyl)-L-tryptophanate was dissolved in methanol. 12 ml of 1 M NaOH solution was added to the solution. After completion of hydrolysis, the mixture was cooled to 0° C. and acidified to pH 1.8 with 1 M HCl solution. The mixture was concentrated by evaporation and ethyl acetate was added to the residue. After filtration, the mixture was concentrated again by evaporation and purified by flash chromatography with dichloromethane and methanol. 0.5 grams of the desired product was obtained. 1 H NMR (DMSO-d6, 600 MHz) δ = 10.92 (1H, s), 9.13 (1H, s), 8.70 (1H, d, J = 7.6 Hz), 7.93 (1H, s), 7.55 (1H, d, J = 8.3 Hz), 7.33 (2H, br d, J = 8.3 Hz), 7.31 (2H, br d, J = 15.8 Hz), 7.16 (1H, d, J = 2.1 Hz), 7.05 (1H, t, J = 7.6 Hz), 6.98 (1H, t, J 5,6 = 7.2 Hz), 6.72 (1H, d, J = 15.8 Hz, 4.54 - 4.63 (1H, m), 3.20 - 3.28 (1H, m), 3.09 (1H, dd, J = 14.8 Hz, J = 9.3 Hz). 13 C NMR (DMSO-d6, 151 MHz) δ = 173.4, 164.1, 136.1, 135.9, 129.4, 127.1, 123.6, 121.0, 119.9, 118.4, 118.2, 111.5, 110.0 48.6, 40.0, 26.9

[0060] Example 5: L-histidyl-L-histidine The compounds were obtained from Bachem. 1 H NMR (DMSO-d6, 600 MHz) δ = 9.15 (1H, br d, J = 7.6 Hz), 8.96 (1H, s), 8.79 (1H, br s,), 7.44 (1H, s), 7.37 (1H, s), 4.54 - 4.61 (1H, m), 4.24 (1H, t, J = 6.5 Hz), 3.14 - 3.26 (3H, m), 3.07 (1H, dd, J = 15.1 Hz, J = 9.0 Hz).13 C NMR (DMSO-d6, 151 MHz) δ = 171.5, 167.6, 134.5, 133.9, 129.3, 127.7, 118.1, 117.6, 117.1, 116.2, 60.4, 52.0, 51.3, 26.7, 26.1.

[0061] Example 6: N-[3-(methylsulfanyl)propyl]histidine amide a) N in DMF (100 ml) α To a mixture of 1-Boc-histidine (3.0g, 11.75mmol) and 1-hydroxypyrrolidine-2,5-dione (1.62g, 14.10mmol), dicyclohexylmethandiimine (2.91g, 14.10mmol) was added and stirred at room temperature overnight. The formed dicyclohexylurea was filtered off. 3-(methylthio)propan-1-amine (1.5g, 14.10mmol) was added to the filtrate and stirred at 50°C for 3 hours. After removing DMF by evaporation under reduced pressure, the residue was taken up in 100ml water and then extracted twice with ethyl acetate (2x100ml). The organics were washed once with brine (100ml), dried over magnesium sulfate, filtered and evaporated. The crude product was purified by silica gel column chromatography with DCM / methanol to give the intermediate 3-(methylthio)propanyl-N α -Boc-histidine amide was obtained as an off-white solid.

[0062] b) Intermediate 3-(methylthio)propanyl-N α -Boc-histidineamide (0.36 g, 1.051 mmol) was dissolved in 100 ml of methanol and cooled to 4° C. in an ice bath. Then, 15 ml of 3 M HCl in methanol was added and stirred for 2 h. The solvent was evaporated and the residue was purified on a silica gel column with DCM / methanol to give 0.15 g (48.6%) of the desired N-[3-(methylsulfanyl)propyl]histidineamide hydrochloride as a pink solid. The purity is >95% by NMR analysis. 1H NMR (DMSO-d6, 600 MHz) δ = 9.08 (1H, s), 8.82 (1H, t, J = 5.5 Hz), 8.55 (3H, br s), 7.51 (1H, s), 4.22 (1H, br t, J = 6.2 Hz), 3.31 - 3.37 (1H, m), 3.11 - 3.26 (4H, m), 2.42 (2H, td, J = 7.2 Hz, J = 3.4 Hz), 2.02 (3H, s), 1.57 - 1.68 (2H, m). 13 C NMR (DMSO-d6, 151 MHz) δ = 167.0, 134.0, 127.0, 117.7, 65.0, 51.3, 37.7, 30.4, 28.1, 26.4, 14.6.

[0063] Example 7: N-(2-hydroxyethyl)histidine amide N-(2-hydroxyethyl)histidine amide was prepared by the procedure of Example 6. Boc-His-OH (3.0 g, 11.75 mmol) was coupled with ethanolamine (0.86 g, 14.10 mmol) using dicyclohexylmethane diimine (2.91 g, 14.10 mmol) and 1-hydroxypyrrolidine-2,5-dione (1.62 g, 14.10 mmol). The desired N-(2-hydroxyethyl)histidine amide hydrochloride was obtained as a white precipitate by adding ether to the reaction mixture of step 2. Yield: 0.7 g (22.5%), purity >95% by NMR analysis. 1 H NMR (DMSO-d6, 600 MHz) δ = 9.04 (1H, s), 8.67 (1H, br d, J = 4.8 Hz), 7.46 (1H, s), 4.14 (1H, br t, J = 6.5 Hz), 3.30 - 3.48 (2H, m), 3.17 - 3.26 (2H, m), 3.11 - 3.17 (2H, m, H-1), 3.06 - 3.11 (2H, m). 13C NMR (DMSO-d6, 151 MHz) δ = 167.3, 134.2, 126.9, 118.2, 59.5, 51.5, 42.0, 26.4.

[0064] Example 8: Histidyl-β-alanine Histidyl-β-alanine hydrochloride was prepared by the procedure described in Example 6. Boc-His-OH (3.0 g, 11.75 mmol) was coupled with β-alanine (1.25 g, 14.10 mmol) using coupling reagents dicyclohexylmethanediimine (2.91 g, 14.10 mmol) and 1-hydroxypyrrolidine-2,5-dione (1.62 g, 14.10 mmol). 0.84 g of the desired compound was obtained as a white solid. The purity is >95% by NMR analysis. 1 H NMR (D2O, 600 MHz) δ = 8.56 (1H, s), 7.38 (1H), 4.22 (1H, t, J = 6.5 Hz), 3.46 - 3.55 (1H, m), 3.31 - 3.37 (1H, m), 3.29 - 3.40 (3H, m), 2.36 (2H, td, J = 6.5 Hz, J = 2.1 Hz). 13 C NMR (D2O, 151 MHz) δ = 182.7, 170.9, 137.6, 129.6, 121.1, 55.3, 51.8, 39.6, 39.0, 29.5.

[0065] Example 9: N-[(9Z,12Z)-Octadeca-9,12-dienoyl]-L-histidine L-histidine hydrochloride (4.13 g, 21.54 mmol) was dissolved in 60 ml of aqueous NaOH (2.37 g, 59.2 mmol). The solution was diluted with 60 ml of THF and cooled in an ice bath. A solution of (9Z,12Z)-octadeca-9,12-dienoyl chloride (5.33 g, 17.95 mmol) in 40 ml of THF was then added dropwise. After stirring at room temperature for 2 hours, the reaction mixture was acidified with dilute HCl solution and then extracted with 200 ml of ethyl acetate. The precipitate formed in the ethyl acetate was filtered, washed with hot heptane and then dried in a vacuum oven at 40° C. 2.96 g of ((9Z,12Z)-octadeca-9,12-dienoyl)-L-histidine was obtained as an orange solid. The purity is >95% by NMR analysis. 1 H NMR (DMSO-d6, 600 MHz) δ = 8.54 (1H, s), 8.22 (1H, d, J = 8.3 Hz), 7.18 (1H, s), 5.24 - 5.40 (3H, m), 4.48 (1H, td, J = 8.8 Hz, J = 5.2 Hz), 3.06 (1H, dd, J = 15.1 Hz, J = 4.8 Hz), 2.93 (1H, dd, J = 14.8 Hz, J = 9.3 Hz), 2.73 (1H, br t, J = 6.9 Hz), 2.06 (2H, br t, J = 7.2 Hz), 1.92 - 2.03 (4H, m, H-8), 1.44 - 1.52 (1H, m), 1.41 (2H, quin, J = 7.4 Hz), 1.09 - 1.35 (16H, m), 0.85 (3H, br t, J = 6.9 Hz). 13 C NMR (DMSO-d6, 151 MHz) δ = 172.6, 172.3, 133.9, 130.8, 129.8, 127.8, 116.8, 51.4, 40.0, 35.1, 31.3, 30.9, 29.1, 29.1, 28.9, 28.8, 28.7, 28.6, 28.5, 27.0, 26.7, 26.6, 25.2, 25.2, 22.1, 22.0, 14.0.

[0066] Example 10: (2E)-N-[2-(1H-imidazol-4-yl)ethyl]-3-(1,3-thiazol-2-yl)prop-2-enamide (E)-3-(thiazol-2-yl)acrylic acid (1 g, 6.44 mmol) was dissolved in DMF (25 ml) under heating. Di(1H-imidazol-1-yl)methanone (1.254 g, 7.73 mmol) was added with stirring and the reaction mixture was stirred at RT for 1 day. TEA (0.898 ml, 6.44 mmol) and 2-(1H-imidazol-4-yl)ethan-1-amine (0.716 g, 6.44 mmol) were added and stirring was continued at RT for 1 day. The mixture was then stirred at 50° C. for 3 h. The solvent was evaporated. The solid residue was taken up in acetone and filtered. The solid was further purified by flash column chromatography. 0.3 g of light brown product was obtained. The purity is >95% by NMR analysis. 1 H NMR (D2O, 600 MHz) δ = 8.62 (1H, s), 8.23 ​​(1H, d, J = 3.3 Hz), 8.12 (1H, d, J = 4.1 Hz, H-5), 7.70 (1H, d, J = 15.8 Hz), 7.30 (1H, s), 7.13 (1H, d, J 3,2(E) = 15.8 Hz), 3.67 (2H, t, J = 6.5 Hz), 3.04 (2H, t, J 2,1 = 6.5 Hz). 13 C NMR (D2O, 151 MHz) δ = 169.1, 168.2, 138.3, 136.1, 135.3, 133.5, 128.0, 127.9, 119.3, 41.5, 26.9.

[0067] Example 11: N-[(9Z,12Z,15Z)-Octadeca-9,12,15-trienoyl]-L-histidine N-[(9Z,12Z,15Z)-octadeca-9,12,15-trienoyl]-L-histidine was prepared according to the procedure of Example 9. L-histidine hydrochloride (4.13 g, 21.54 mmol) was reacted with (9Z,12Z,15Z)-octadeca-9,12,15-trienoyl chloride (5.33 g, 17.95 mmol) to give 2.33 g of N-[(9Z,12Z,15Z)-octadeca-9,12,15-trienoyl]-L-histidine as an orange solid. 1 H NMR (DMSO-d6, 600 MHz) δ = 7.97 (1H, br d, J = 7.6 Hz), 5.26 - 5.41 (5H, m), 4.41 - 4.53 (1H, m), 3.01 (1H, dd, J = 14.8 Hz, J = 5.2 Hz), 2.89 (1H, dd, J = 14.8 Hz, J = 8.6 Hz), 2.72 - 2.81 (3H, m, H-11), 1.99 - 2.11 (5H, m), 1.38 - 1.51 (2H, m), 1.17 - 1.34 (10H, m), 0.93 (2H, t, J = 7.6 Hz), 0.82 - 0.89 (1H, m). 13 C NMR (DMSO-d6, 151 MHz) δ = 172.5, 171.9, 134.1, 131.3, 129.8, 129.6, 127.8, 127.6, 127.3, 126.8, 116.6, 51.6, 40.0, 35.0, 30.7, 28.8, 28.5, 28.4, 28.3, 27.9, 26.5, 26.4, 25.0, 24.9, 24.3, 21.7, 19.8, 13.8, 13.6.

[0068] Example 12: N-[(9Z)-Octadec-9-enoyl]-L-histidine A solution of (Z)-docos-13-enoyl chloride (11.69 g; 32.7 mmol) in 30 ml of DCM was added dropwise to a mixture of ethyl L-histidine (5 g; 27.3 mmol) and triethylamine (11.05 g; 109 mmol) in 300 ml of DCM. After stirring at room temperature for 2 h, the reaction mixture was washed with water (2×150 ml). The DCM layer was dried over MgSO4 and then evaporated under reduced pressure to give the intermediate ethyl oleoyl-L-histidine.

[0069] Hydrolysis of this intermediate was carried out by adding a solution of sodium hydroxide (1.56 g; 39.0 mmol) in 50 ml of water to a cold solution of ethyl oleoyl-L-histidine (8.74 g; 19.52 mmol) in 50 ml of methanol (50 ml). After stirring at room temperature for 2 h, the reaction mixture was acidified with dilute HCl. The solid formed was filtered off, washed with heptane and n-pentane, and then dried in a vacuum oven at 40 °C. 0.3 g (3%) of oleoyl-L-histidine was obtained as a white solid. The purity is >95% by NMR analysis. 1 H NMR (DMSO-d6, 600 MHz) δ = 8.03 (1H, br d, J = 7.6 Hz), 7.55 (1H, s), 6.78 (1H, s), 5.27 - 5.36 (2H, m), 4.32 - 4.44 (1H, m), 2.91 (1H, br dd, J > = 15.1 Hz, J = 4.8 Hz), 2.81 (1H, br dd, J = 14.8 Hz, J = 8.6 Hz), 2.01 - 2.09 (2H, m), 1.95 - 2.00 (3H), 1.42 (3H, dt, J = 14.1 Hz, J = 7.4 Hz), 1.10 - 1.34 (21H, m), 0.84 (3H, br t, J = 6.9 Hz, H-18). 13C NMR (DMSO-d6, 151 MHz) δ = 172.8, 171.8, 134.3, 129.4, 129.4, 52.0, 40.0, 35.0, 31.0, 28.9, 28.9, 28.8, 28.7, 28.6, 28.4, 28.4, 28.4, 28.3, 26.4, 26.4, 24.9, 21.8, 13.6.

[0070] Example 13: N-Octadecanoylhistidine N-Octadecanoylhistidine was prepared according to the procedure of Example 9. L-Histidine hydrochloride (3.77 g, 19.69 mmol) was reacted with stearoyl chloride (4.97 g; 16.41 mmol) to give 1.9 g (26%) of the desired compound as a white solid with a purity of >95% by NMR analysis. 1 H NMR (DMSO-d6, 600 MHz) δ = 8.11 (1H, d, J = 7.6 Hz), 8.04 (1H, br s), 7.93 (1H, s), 7.06 (1H, s), 6.98 (1H, s), 4.44 (1H, td, J = 8.3 Hz, J = 5.5 Hz), 3.86 - 3.91 (2H, m), 3.02 - 3.09 (2H, m), 2.97 (3H, td, J = 14.8 Hz, J = 6.2 Hz), 2.86 (2H, br dd, J = 15.1 Hz, J = 9.0 Hz), 2.18 (1H, t, J = 7.6 Hz), 2.05 (2H, t, J = 7.6 Hz), 1.44 - 1.50 (1H, m), 1.41 (2H, quin, J = 7.4 Hz), 1.24 - 1.28 (4H, m), 1.23 (28H, s), 1.15 - 1.18 (2H, m), 0.85 (4H, t, J = 6.9 Hz). 13C NMR (DMSO-d6, 151 MHz) δ = 174.6, 172.9, 172.2, 170.0, 134.8, 134.4, 52.8, 51.7, 40.0, 35.1, 33.7, 31.3, 29.1, 29.1, 29.0, 28.8, 28.8, 28.6, 28.7, 27.2, 25.2, 24.5, 22.1, 14.0.

[0071] Example 14: (2E)-3-(1H-imidazol-4-yl)prop-2-enamide Compounds were obtained from Aldrich. 1 H NMR (DMSO-d6, 600 MHz) δ = 11.89 - 12.77 (1H), 7.71 (1H, s), 7.37 - 7.52 (1H), 7.36 (1H, s), 7.28 (1H, d, J = 15.8 Hz), 6.90 (1H, br s), 6.47 (1H, br d, J = 15.8 Hz). 13 C NMR (DMSO-d6, 151 MHz) δ = 167.4, 137.1, 131.3, 118.5.

[0072] Example 15: (2E)-3-(1H-imidazol-4-yl)-N-[2-(pyridin-4-yl)ethyl]prop-2-enamide A mixture of (E)-3-(1H-imidazol-4-yl)acrylic acid (2.1 g, 15.20 mmol), 1-hydroxypyrrolidine-2,5-dione (1.925 g, 16.72 mmol) and DCC (3.45 g, 16.72 mmol) in DMF (150 ml) was stirred for 24 h. The formed dicyclohexylurea was then filtered off. The filtrate was added with 2-(pyridin-4-yl)ethan-1-amine (2 g, 16.37 mmol) and stirred at 50° C. for 4 h. After removing the DMF by evaporation under reduced pressure, the remaining crude product was added to a silica gel column and eluted with DCM / methanol. 0.9 g (24.4%) of (2E)-3-(1H-imidazol-4-yl)-N-[2-(pyridin-4-yl)ethyl]prop-2-enamide was obtained as a white solid with a purity of >95% by NMR. 1H NMR (DMSO-d6, 600 MHz) δ = 8.28 - 8.64 (2H, m), 8.12 (1H, br s), 7.69 (1H, br s), 7.39 (1H, br s), 7.28 (1H, d, J = 15.1 Hz), 7.24 (2H, d, J = 5.5 Hz), 6.50 (1H, br d, J = 16.5 Hz), 3.42 (2H, q, J = 6.9 Hz), 2.78 (2H, t, J = 6.9 Hz). 13 C NMR (DMSO-d6, 151 MHz) δ = 165.8, 149.5, 148.5, 137.2, 136.9, 131.7, 124.3, 118.9, 118.2, 40.0, 34.4.

[0073] Example 16: 2,3-Dihydro-1H-indole-2-carboxylate methyl Indoline-2-carboxylic acid (5 g, 30.6 mmol) was dissolved in 100 ml of methanol and cooled in an ice bath. Acetyl chloride (16.5 g, 210 mmol) was added dropwise with stirring. After stirring in the ice bath for 1 h, the solution was left at room temperature overnight. The solvent was then removed by evaporation under reduced pressure at 30° C. The remaining residual solid was recrystallized from methanol to give 6.3 g (96%) of methyl indoline-2-carboxylate, HCl as a white solid. Purity is >95% by NMR. 1 H NMR (DMSO-d6, 600 MHz) δ = 7.11 (1H, d, J = 7.6 Hz), 7.04 (1H, t, J = 7.6 Hz), 6.73 - 6.80 (2H, m), 4.54 (1H, dd, J = 10.0 Hz, J = 6.5 Hz), 3.65 - 3.71 (3H, m), 3.35 (1H, dd, J = 16.5 Hz, J = 10.3 Hz), 3.15 (1H, dd, J = 15.8 Hz, J = 6.2 Hz). 13C NMR (DMSO-d6, 151 MHz) δ = 172.7, 147.4, 127.9, 127.4, 124.4, 120.1, 111.0, 59.0, 52.1, 32.9.

[0074] Example 17: (2E)-3-(1H-imidazol-4-yl)-N-[2-(pyridin-2-yl)ethyl]prop-2-enamide (2E)-3-(1H-imidazol-4-yl)-N-[2-(pyridin-2-yl)ethyl]prop-2-enamide was prepared according to the procedure of Example 15. (E)-3-(1H-imidazol-4-yl)acrylic acid (2g, 14.48mmol) was coupled with 2-(pyridin-2-yl)ethan-1-amine (2g, 16.37mmol) using 1-hydroxypyrrolidine-2,5-dione (1.833g, 15.93mmol) and DCC (3.29g, 15.93mmol). 0.9g (25.7%) of (2E)-3-(1H-imidazol-4-yl)-N-[2-(pyridin-2-yl)ethyl]prop-2-enamide was obtained as a white solid. The purity is >95% by NMR. 1 H NMR (DMSO-d6, 600 MHz) δ = 9.19 (1H, br s), 8.78 - 8.83 (1H, m), 8.75 - 8.78 (1H, m), 8.50 (1H, t, J = 7.8 Hz), 7.96 (1H, br d, J = 8.3 Hz), 7.94 (1H, s), 7.92 (1H, t, J = 6.9 Hz), 7.26 (1H, dt, J = 15.8 Hz, J = 1.4 Hz), 6.71 (1H, d, J = 15.8 Hz), 5.35 (7H, br s), 3.63 (2H, br t, J = 6.2 Hz), 3.26 (2H, br t, J = 6.2 Hz). 13 C NMR (DMSO-d6, 151 MHz) δ = 164.6, 154.5, 146.6, 141.3, 135.8, 129.1, 128.0, 125.5, 124.6, 124.4, 120.1, 38.2, 33.0.

[0075] Example 18: (2E)-N-[(2E)-3,7-dimethylocta-2,6-dien-1-yl]-3-(1H-imidazol-4-yl)prop-2-enamide (2E)-N-[(2E)-3,7-dimethylocta-2,6-dien-1-yl]-3-(1H-imidazol-4-yl)prop-2-enamide was prepared according to the procedure of Example 15. (E)-3-(1H-imidazol-4-yl)acrylic acid (2 g, 14.48 mmol) was coupled with geranylamine (2.441 g, 15.93 mmol) using 1-hydroxypyrrolidine-2,5-dione (1.833 g, 15.93 mmol) and DCC (3.29 g, 15.93 mmol). There was obtained 1.1 g (27.8%) of (2E)-N-[(2E)-3,7-dimethylocta-2,6-dien-1-yl]-3-(1H-imidazol-4-yl)prop-2-enamide as an off-white solid, >90% pure by NMR. 1 H NMR (CDCl3, 600 MHz) δ = 9.46 (1H, br s), 7.82 (1H, s), 7.42 (1H, d, J = 15.1 Hz), 7.15 (1H, s), 6.88 (1H, br s), 6.60 (1H, d, J = 15.1 Hz, 5.17 - 5.25 (1H, m), 4.97 - 5.13 (1H, m), 3.92 (2H, br t, J = 6.2 Hz), 2.00 - 2.07 (2H, m), 1.94 - 2.00 (2H, m), 1.65 (3H, br s), 1.64 (3H, br s), 1.56 (3H, s). 13 C NMR (CDCl3, 151 MHz) δ = 166.3, 139.8, 136.5, 133.8, 131.7, 129.5, 123.8, 121.4, 119.8, 119.6, 39.5, 39.4, 37.8, 25., 16.3.

[0076] Example 19: N-[2-(1H-imidazol-4-yl)ethyl]-2,3-dihydro-1H-indole-2-carboxamide A solution of methyl indoline-2-carboxylate (1.34 g, 7.56 mmol) and histamine (0.6 g, 5.40 mmol) in 20 ml of THF and 20 ml of methanol was stirred under reflux for 4 h. After removal of the solvent, the crude product was purified by silica gel column chromatography with DCM and methanol. 0.3 g (20.6%) of N-[2-(1H-imidazol-4-yl)ethyl]-2,3-dihydro-1H-indole-2-carboxamide was obtained as a white solid. The purity is >95% by NMR. 1 H NMR (DMSO-d6, 600 MHz) δ = 7.97 (1H, t, J = 5.5 Hz), 7.60 (1H, s), 6.99 (1H, d, J = 7.6 Hz), 6.94 (1H, t, J 6,4 = 7.6 Hz), 6.81 (1H, s), 6.55 - 6.60 (2H, m), 5.93 (1H, br s), 4.18 (1H, dd, J = 10.3 Hz, J = 8.3 Hz), 3.29 - 3.37 (2H, m), 3.27 (1H, dd, J = 15.8 Hz, J = 9.6 Hz), 2.86 (1H, dd, J = 15.8 Hz, J = 8.3 Hz), 2.65 (2H, t, J = 7.2 Hz). 13 C NMR (DMSO-d6, 151 MHz) δ = 173.3, 151.2, 134.6, 127.3, 127.2, 124.2, 117.9, 116.5, 109.1, 60.9, 40.0, 38.5, 34.6, 26.8.

[0077] Example 20: (2E)-3-(pyrimidin-2-yl)-N-[2-(pyrimidin-2-yl)ethyl]prop-2-enamide (E)-3-(pyrimidin-2-yl)acrylic acid (919 mg, 1.2 Eq, 6.12 mmol) was dissolved in DMF (25 ml). CDI (992 mg, 1.2 Eq, 6.12 mmol) was added under stirring and stirring was continued for 24 h. The next day, TEA (1.03 g, 1.42 mL, 2 Eq, 10.2 mmol) and 2-pyrimidin-2-yl-ethylamine dihydrochloride (1.00 g, 1 Eq, 5.10 mmol) were added and the mixture was stirred at 50° C. for 3 h. The solvent was evaporated and the residue was purified by flash column chromatography with eluent DCM / methanol. 0.3 g of the desired compound was obtained. 1 H NMR (DMSO-d6, 600 MHz) δ = 8.80 (2H, d, J = 4.8 Hz), 8.71 (2H, d, J = 4.8 Hz), 8.52 (1H, br t, J = 5.5 Hz), 7.40 (1H, t, J = 4.8 Hz), 7.33 (1H, t, J = 4.8 Hz), 7.27 (1H, d, J = 15.1 Hz), 7.21 (1H, d, J = 15.8 Hz), 3.62 (2H, q, J = 6.9 Hz), 3.05 (2H, t, J = 7.2 Hz). 13 C NMR (DMSO-d6, 151 MHz) δ = 168.0, 164.1, 162.5, 157.7, 157.3, 137.5, 130.9, 120.6, 119.3, 38.5, 37.7.

[0078] Example 21: 3,6-bis[(1H-imidazol-4-yl)methyl]piperazine-2,5-dione A 30 ml vial was charged with methyl histidate, 2HCl (5.00 g, 1 Eq, 20.7 mmol), TEA (4.18 g, 5.76 ml, 2 Eq, 41.3 mmol) and ethanol (7 ml). The vial was placed in a microwave oven and heated at 140° C. for 3 hours. The maximum pressure was 4 bar. The solid was filtered and washed with cold ethanol. After drying, 0.4 g of a yellow solid was obtained. 1H NMR (D2O, 600 MHz) δ = 8.67 (1H, s), 7.33 (1H, s), 4.93 - 4.94 (1H, m), 4.24 (1H, t, J = 4.5 Hz), 3.36 (1H, dd, J = 15.1 Hz, J = 4.8 Hz), 3.19 (1H, dd, J = 15.8 Hz, J= 4.8 H). 13 C NMR (D2O, 151 MHz) δ = 171.1, 136.8, 130.0, 120.8, 56.5, 31.1.

[0079] Example 22: Taste The compound of Example 1 ((2E)-3-(1H-imidazol-4-yl)-N-[2-(1H-imidazol-4-yl)ethyl]prop-2-enamide) was tasted by a sensory panel at various concentrations in water. No effect was seen up to 40 ppm, but a slight mouth drying effect was seen above 50 ppm. This effect was significant up to 1000 ppm, while the taste itself was not detected, especially no saltiness was detected at all. Solubility problems arose above 1000 ppm.

[0080] Example 23: Increasing saltiness Two aqueous solutions were prepared. A) 0.5% NaCl, and B) 0.5% NaCl with 50 ppm of (2E)-3-(1H-imidazol-4-yl)-N-[2-(1H-imidazol-4-yl)ethyl]prop-2-enamide (compound of Example 1). The solutions were tasted by a sensory panel. Solution A was described as "salty". Solution B was described as having a saltier, mineral note.

[0081] Example 24: Salt Intensification The compound of Example 1 ((2E)-3-(1H-imidazol-4-yl)-N-[2-(1H-imidazol-4-yl)ethyl]prop-2-enamide) was tasted by a sensory panel at various concentrations in 0.3% NaCl solution. Below 1 ppm, the compound of Example 1 did not produce a perceived salt enhancement. At levels of 1 ppm and above, a salt enhancement effect was observed, providing a longer lasting, mineral, and richer salty taste. Overall, the effect was perceived up to 200 ppm, with the preferred range of the compound being 50-70 ppm.

[0082] Example 25: Enhancing umami flavor Two aqueous solutions were prepared. A) 0.5% NaCl, 0.03% MSG, 0.007% ribotide, and B) 0.5% NaCl, 0.03% MSG, 0.007% ribotide and 50 ppm (2E)-3-(1H-imidazol-4-yl)-N-[2-(1H-imidazol-4-yl)ethyl]prop-2-enamide (compound of Example 1). The solutions were tasted by a sensory panel. Solution A was a model solution for savory taste and contained MSG (monosodium glutamate) and ribotide (IMP / GMP, 50 / 50 mixture) as savory taste enhancers. Solution B was described as having a strong boost in saltiness and umami compared to solution A.

[0083] Example 26: Masking bitterness Two aqueous solutions were prepared. A) 0.3% KCl, and B) (2E)-3-(1H-imidazol-4-yl)-N-[2-(1H-imidazol-4-yl)ethyl]prop-2-enamide (compound of Example 1) with 50 ppm of 0.3% KCl. The solutions were tasted by a sensory panel. Solution B was described as less bitter, saltier and more minerally than solution A.

[0084] Example 27: Effect on broth A model broth base containing 0.3% NaCl was compared to a sample further containing 50 ppm of the compound of Example 1. The solutions were tasted by a sensory panel. The sample containing the compound of Example 1 was described as more mineral and salty compared to the model broth base. The sharp sourness of the broth base was reduced.

[0085] Example 28: Effect on cheese sauce The effect of the compound of Example 1 on a cheese sauce was investigated. Thus, a sensory panel compared the cheese sauce with a sauce sample that further contained 50 ppm of the compound of Example 1. The sauce containing the compound of Example 1 was described as being more mineral and salty, with residual minerality and natural aged cheese characteristics compared to the plain sauce.

[0086] Example 29: Combination with other taste modulating compounds The combination of taste modulating compounds was tasted in a 0.3% NaCl solution in water. A) 50 ppm of the compound of Example 1 and 50 ppm of N-lactoylethanolamine; B) 50 ppm of the compound of Example 1 and 0.04 ppm of N-oleoylmethionine; C) 50 ppm of the compound of Example 1, 50 ppm of N-lactoylethanolamine, and 0.04 ppm of N-oleoylmethionine. The solutions were tasted by a sensory panel. Sample A was described as exhibiting a distinct combination of two taste modulating compounds, providing stronger salty and mineral flavors and body. Sample B was perceived as saltier with a clear boost in the initial salinity peak. Sample C had rounder salinity peaks and boosted salt bodies. The combination of three taste modulating compounds was preferred by a sensory panel.

[0087] Example 30: Effect on potato chips Potato chips with 1.5% salt were tasted by a sensory panel with and without the additional compound of Example 1. Potato chips further containing 70 ppm of the compound of Example 1 had a greater salt impact and a longer lasting effect compared to potato chips without the compound of Example 1.

[0088] Example 31: Effect on mayonnaise Commercially available mayonnaise with and without the addition of the compound of Example 1 was compared by a sensory panel. Compared to pure mayonnaise, the sample further containing 70 ppm of the compound of Example 1 was described as having an instant tangy salty taste with a mineral lingering and enhanced sourness.

[0089] Example 32: Effect on cone curl Cheese flavored corn curls with and without the addition of the compound of Example 1 were compared by a sensory panel. The taste of the corn curls spiked with 70 ppm of the compound of Example 1 was described as saltier, longer lasting and minerally compared to curls without the addition of the compound of Example 1.

[0090] Example 33: Effects on vegan cheese Samples of vegan cheese containing 0.2% Cheese Parmesan Natural Flavor were compared by a sensory panel with and without the compound of Example 1. The addition of 70 ppm of the compound of Example 1 is described as making the sample saltier and more minerally, enhancing the overall flavor.

[0091] Example 34: Effects on vegan burgers The soy-based vegan burger was tasted by a sensory panel with and without the compound of Example 1. The burger containing 70 ppm of the compound of Example 1 tastes saltier and has a mineral taste when compared to the sample without the compound of Example 1, which contributes positively to the perception of the burger.

[0092] Example 35: Effects on processed meat Samples of the processed meats, full salt and reduced salt flavours, with and without the compound of Example 1, were tasted by a sensory panel. Sample 1 contained the full salt flavor base. Sample 2 contained the full salt flavor base and 70 ppm of the compound of Example 1. Sample 3 contained a reduced salt (33.3%) flavor base and a salty flavor modulator containing KCl. Sample 4 contained reduced salt (33.3%) flavor base, a salty flavor modulator containing KCl, and 70 ppm of the compound of Example 1.

[0093] Sample 2, containing 70 ppm of the compound of Example 1, is perceived as saltier and more minerally compared to Sample 1 without the compound of the invention. Compared to sample 1, sample 3 had less saltiness, more astringency and dryness, and exhibited a slight bitterness. Compared to sample 1, sample 4 had an improved salt peak, increased salinity, longer lasting saltiness, significantly reduced bitterness and astringency, and increased salivation.

[0094] Example 36: Taste The compounds of Examples 2-21 were tasted in water by a sensory panel. Solutions containing 50 ppm of each of the compounds were tasteless.

[0095] Example 37: Increasing saltiness Aqueous solutions containing 0.5% NaCl and 50 ppm of each of the compounds of Examples 2 to 21 were prepared, tasted by a sensory panel, and compared with an aqueous solution containing 0.5% NaCl. All solutions containing the compounds of Examples 2-21 are described as saltier than 0.5% NaCl in water.

[0096] Example 38: (2E)-3-(4H-imidazol-2-yl)-N-[2-(1H-imidazol-5-yl)ethyl]prop-2-enamide 1-Hydroxypyrrolidine-2,5-dione (689 mg, 1.1 Eq, 5.99 mmol) was added to a yellow solution of (E)-3-(1H-imidazol-2-yl)acrylic acid hydrochloride (0.950 g, 1 Eq, 5.44 mmol) and TEA (1.10 g, 1.52 ml, 2 Eq, 10.9 mmol) in DMF (100 ml) and stirred for 5 min. Dicyclohexylmethandiimine (1.23 g, 1.1 Eq, 5.99 mmol) was then added and stirred at RT for 24 h. The next day the formed dicyclohexylurea was filtered and the filtrate was placed in the refrigerator overnight. The precipitated dicyclohexylurea was filtered off. To the filtrate was added a solution of 2-(1H-imidazol-5-yl)ethan-1-amine (605 mg, 1 Eq, 5.44 mmol) in DMF (50 ml). The resulting mixture was stirred at RT for 2 h and at 55° C. for 2 h. After removal of the solvent, the crude product was purified by silica gel column chromatography using eluent DCM / methanol. 0.8 g of the desired (E)-N-(2-(1H-imidazol-5-yl)ethyl)-3-(1H-imidazol-2-yl)acrylamide was obtained as a white solid. The purity is >95% by NMR analysis. 1 H NMR (DMSO-d6, 600 MHz) δ =1.06 - 1.12 (1 H, m) 1.73 - 1.79 (1 H, m) 2.67 (2 H, t, J=7.23 Hz 2 H) 3.37 - 3.38 (2 H, m) 6.37 (1 H, d, J=15.84 Hz) 6.81 (1 H, s) 7.10 (1 H, dd, J=4.82, 3.44 Hz) 7.36 (1 H, d, J=3.44 Hz,) 7.54 (1 H, s) 7.56 (1 H, d, J=15.15 Hz) 7.59 (1 H, d, J=5.51 Hz) 8.16 (1 H, br t, J=5.85 Hz). 13 C NMR (DMSO-d6,151 MHz,) δ = 25.98, 38.49, 40.05, 116.57, 122.16, 127.27, 133.01, 134.28, 143.38, 164.89.

[0097] Example 39: (2E)-3-(1H-imidazol-4-yl)-N-[2-(1H-imidazol-2-yl)ethyl]prop-2-enamide (E)-N-(2-(1H-imidazol-2-yl)ethyl)-3-(1H-imidazol-4-yl)acrylamide was synthesized using the same procedure as described in Example 38. (E)-3-(1H-imidazol-4-yl)acrylic acid (825 mg, 1.1 Eq, 5.98 mmol) was coupled with 2-(1H-imidazol-2-yl)ethan-1-amine, 2HCl (1.00 g, 1 Eq, 5.43 mmol) to give 0.8 g of the desired compound as a pale yellow solid. The purity is >90% by NMR analysis. 1 H NMR (DMSO-d6, 600 MHz) δ = 8.36 (1H, br t, J = 5.9 Hz), 7.75 (1H, s), 7.49 (2H, s, H-11), 7.39 (1H, s), 7.29 (1H, d, J = 15.8 Hz), 6.46 (1H, d, J = 15.8 Hz), 3.56 (2H, q, J = 6.2 Hz), 3.22 - 3.28 (1H, m), 3.08 (2H, t, J = 6.5 Hz). 13 C NMR (DMSO-d6, 151 MHz) δ, 145.3, 137.1, 135.3 (C-16), 130.9 (C-4), 121.3 (C-17), 119.1 (C-11, 12), 118.0 (C-3), 36.9 (C-6), 26.3 (C-7).

[0098] Example 40: N-(2-hydroxyethyl)-3-(1H-imidazol-4-yl)propanamide (E)-N-(2-hydroxyethyl)-3-(1H-imidazol-4-yl)acrylamide (0.5 g, 2.76 mmol) was dissolved in methanol (40 ml) to give a pale yellow solution. The solution was purged with nitrogen for 5 min, then Pd-C 10% (60 mg, 0.564 mmol) was added to the solution. The reaction mixture was stirred at RT under 1 atm of hydrogen until no more hydrogen was consumed. The catalyst was filtered and the filtrate was evaporated. The residual solid was washed with ether and dried in a vacuum oven at 50° C. 0.5 g of the desired N-(2-hydroxyethyl)-3-(1H-imidazol-4-yl)propanamide was obtained as a white solid. The purity is >90% by NMR analysis. 1 H NMR (DMSO-d6, 600 MHz) δ = 8.78 (1H, s), 7.27 (1H, s), 3.35 (2H, t, J = 5.9 Hz), 3.08 (2H, t, J = 6.2 Hz), 2.84 (2H, t, J = 7.6 Hz), 2.46 (2H, t, J = 7.6 Hz) 13 C NMR (DMSO-d6, 151 MHz) δ = 172.0, 133.4, 133.0, 115.8, 60.0, 41.8, 34.0, 20.4.

[0099] Example 41: (2E)-3-(1H-imidazol-4-yl)-N-[2-(1H-pyrrol-2-yl)ethyl]prop-2-enamide (E)-3-(1H-imidazol-4-yl)acrylic acid (1.00 g, 1 Eq, 7.24 mmol) was dissolved in DMF (25 ml). CDI (carbonyldiimidazole) (1.41 g, 1.2 Eq, 8.69 mmol) was added with stirring at RT and stirring was continued at RT for 24 h. 2-(1H-pyrrol-2-yl)ethan-1-amine (798 mg, 1 Eq, 7.24 mmol) was added and the reaction mixture was stirred at 50° C. for 3 h. The solvent was evaporated and the residue was purified by flash column chromatography to give 0.3 g of a light brown solid. The purity is >95% by NMR analysis. 1H NMR (DO, 600 MHz) δ = 8.60 (1H, s), 7.55 (1H, m), 7.20 (1H, d, J = 15.8 Hz), 6.44 (1H, d, J = 15.8 Hz), 3.39 (2H, t, J = 6.5 Hz), 2.71 (2H, t, J = 6.9 Hz), other protons were exchanged by deuterium by the solvent ( 13 (See C NMR multiplets.) 13 C NMR (D2O, 151 MHz) δ = 166.9, 134.9, 133.3, 129.5, 129.0, 124.7, 123.5, 119.6, 118.9, 117.4 (1C, t, J = 25.43 Hz), 107.2 (1C, t, J = 24.98 Hz) 104.9 (1C, t, J = 25.88 Hz) 39.7, 26.5.

[0100] Example 42: 3-[2-amino-3-(1H-imidazol-4-yl)propanamide]propanoic acid The synthesis of the target product was carried out by saponification of methyl 3-(2-amino-3-(1H-imidazol-4-yl)propanamido)propanoate (0.91 g; 3.79 mmol) with sodium hydroxide (0.30 g; 7.58 mmol) in water (100 ml). After acidification with dilute hydrochloric acid, the precipitated solid was filtered, washed with methanol and dried in a vacuum oven. 0.84 g of the target compound was obtained as a white solid. The purity is >90% by NMR analysis. 1 H NMR (D2O, 600 MHz) δ = 8.56 (1H, s), 7.38 (1H, s), 4.22 (1H, t, J = 6.5 Hz), 3.46 - 3.55 (1H, m), 3.31 - 3.37 (1H, m), 3.29 - 3.40 (3H, m), 2.36 (2H, td, J = 6.5 Hz, J = 2.1 Hz), 1.41 (1H, s), 1.37 (1H, s). 13C NMR (D2O, 151 MHz) δ = 182.7, 170.9, 137.6, 129.6, 121.1, 55.3, 51.8, 39.6, 39.0, 29.5.

[0101] Example 43: (2Z)-3-(1H-imidazol-4-yl)-N-[2-(1H-imidazol-4-yl)ethyl]prop-2-enamide 2.00 g of trans urocanic acid was dissolved in 1000 ml of demineralized water. The pH was adjusted to pH 9.00 using 1 M NaOH solution. The resulting mixture was placed in a UV reactor and cooled to 0° C. A constant slow stream of nitrogen bubbles was passed through the solution. Initiation of isomerization was performed by UV illumination using a UV lamp N1 from Heraeus Noblelight at 0° C. for 7 hours. The solution was then brought up to pH 3.8 by adding 1 M HCl solution. The resulting solution was then freeze-dried at 0.5 mbar for 120 hours. 2.00 grams of an off-white colored mixture was obtained. NMR of the mixture showed a cis:trans ratio of 0.85:1.

[0102] 2.00 g of a mixture of cis-trans-urocanic acid in a ratio of 0.85:1 was dissolved in 90 ml of anhydrous DMF. 1.83 g of N-hydroxysuccinimide was added and the mixture was stirred for 10 min. A solution of 3.29 g of DCC in 30 ml of anhydrous DMF was added dropwise to the mixture over 10 min. Stirring was then continued at RT for another 24 h. The resulting mixture was filtered and the residue was washed with 2 * 5 ml of anhydrous DMF. The filtrate was kept overnight at -18 °C under N2 atmosphere and filtered again. The residue was washed with 2 * 5 ml of anhydrous DMF. To the resulting filtrate, a solution of 2.43 g of sodium bicarbonate and 2.67 g of histamine dihydrochloride in 22 ml of water was added dropwise with stirring. The reaction mixture was then warmed to 45 °C and stirring was continued for 5 h. The reaction mixture was left at RT overnight. The resulting mixture was evaporated to dryness using a rotavapor. The resulting residue was stirred with 25 ml of methanol for 1 h. A white precipitate was formed and filtered. The filtrate was evaporated again to dryness. To the resulting residue, an amount of 25 ml of absolute ethanol was added. The mixture was stirred again for 1 h and then filtered. The ethanol was removed by evaporation. Purification was then performed using flash chromatography with DCM:MeOH as eluent. 0.25 g of (Z)-N-(2-(1H-imidazol-4-yl)ethyl)-3-(1H-imidazol-4-yl)acrylamide was obtained. 1 H NMR (DMSO-d6, 600 MHz) δ = 7.77 (1H, s), 7.56 (1H, s), 7.27 - 7.36 (1H, m), 6.82 (1H, s, 6.70 (1H, d, J = 12.4 Hz), 5.68 (1H, d, J = 12.4 Hz3), 3.28 - 3.46 (2H, m), 2.71 (2H, t, J = 7.2 Hz). 13 C NMR (DMSO-d6, 151 MHz) δ = 167.1, 137.7, 135.2, 127.5, 116.6, 39.6, 27.3.

[0103] Example 44: (2E)-N-[2-(1H-imidazol-4-yl)ethyl]-3-phenylprop-2-enamide A solution of cinnamoyl chloride (7.2 g, 43.2 mmol) in dichloromethane (50.0 ml) was added dropwise to a solution of 2-(1H-imidazol-4-yl)ethan-1-amine (5.2 g, 46.8 mmol) and TEA (13.77 ml, 99 mmol) in ethanol (50 ml) cooled in an ice bath. After addition, the cooling bath was removed and stirring was continued for 1 h, then the reaction mixture was left at room temperature overnight. DCM and ethanol were then removed by evaporation under reduced pressure. Purification of the crude product was achieved by washing with DCM, ether, and pentane, followed by recrystallization from ethanol. 8.0 g of the desired N-(2-(1H-imidazol-4-yl)ethyl)cinnamamide was obtained as a white powder. The purity is >95% by NMR analysis. 1 H NMR (DMSO-d6, 600 MHz) δ = 8.21 (1H, t, J = 5.5 Hz), 7.53 - 7.58 (3H, m), 7.42 (1H, d, J = 15.8), 7.40 (2H, t, J = 7.5 Hz), 7.6 (1H, t, J = 7.5 Hz), 6.82 (1H, s), 6.64 (1H, d, J = 15.8 Hz), 3.41 (2H, m) 2.69 (2H, t, J = 7.4 Hz). 13 C NMR (DMSO-d6, 151 MHz) δ = 164.9, 138.5, 135.0, 134.7, 129.4, 129.0, 127.5, 122.3, 38.9, 27.1.

[0104] Example 45: (2E)-N-benzyl-3-(1H-imidazol-4-yl)prop-2-enamide (E)-3-(1H-imidazol-4-yl)acrylic acid (2.00 g, 1 Eq, 14.5 mmol) was dissolved in DMF (75 ml). 1-Hydroxypyrrolidine-2,5-dione (1.83 g, 1.1 Eq, 15.9 mmol) was added. Dicyclohexylmethandiimine (3.29 g, 1.1 Eq, 15.9 mmol) was added and stirring was continued at RT for 24 h. The solid formed (dicyclohexylurea) was filtered and phenylmethanamine (1.71 g, 1.1 Eq, 15.9 mmol) was added to the filtrate. The reaction mixture was stirred at 50° C. for 3 h. The solvent was evaporated and the residue was taken up in methanol. Silica (15 g) was added and the solvent was evaporated. The product was purified by flash column chromatography to give 1.8 g of solid sample material. The spectrum is consistent with the desired structure with purity >95%. 1 H NMR (METHANOL-d4, 600 MHz) δ = 7.75 (1H, s), 7.48 (1H, d, J = 15.1 Hz), 7.32 - 7.36 (2H, m), 7.31 (2H, br s), 7.22 - 7.29 (1H, m), 6.54 (1H, br d, J = 15.1 Hz), 4.48 (2H, s). 13 C NMR (METHANOL-d4, 151 MHz) δ = 169.1 (C-1), 140.1 (C-1), 138.6 (C-2), 129.7 (C-3, 5), 128.8 (C-2, 6), 128.4 (C-4), 119.3 (C-2(E)), 44.5.

[0105] Example 46: (2E)-3-(1H-imidazol-4-yl)-N-[(pyrimidin-5-yl)methyl]prop-2-enamide (E)-3-(1H-imidazol-4-yl)acrylic acid (1.00 g, 1 Eq, 7.24 mmol) was dissolved in DMF (25 ml). CDI (1.41 g, 1.2 Eq, 8.69 mmol) was added with stirring at RT and stirring was continued at RT for 24 h. 5-Aminomethylpyrimidine (790 mg, 1.00 Eq, 7.24 mmol) was added and the reaction mixture was stirred at 50° C. for 3 h. The solvent was evaporated and the residue was purified by flash column chromatography to give 0.1 g of a white solid. The structure is confirmed by NMR with a high purity of >95%. 1 H NMR (D2O, 600 MHz) δ = 9.07 (1H, s), 8.77 - 8.81 (2H, m), 8.76 - 8.79 (1H, m), 7.75 (1H, s), 7.46 (1H, d, J = 16.5 Hz), 6.72 (1H, d, J = 15.8 Hz), 4.60 (2H, s). 13 C NMR (D2O, 151 MHz) δ = 170.5, 159.3, 159.2, 138.1, 135.3, 132.0, 128.7, 125.9, 122.9, 41.7.

[0106] Example 47: (2E)-3-(1H-imidazol-4-yl)-N-[(pyrazin-2-yl)methyl]prop-2-enamide (E)-3-(1H-imidazol-4-yl)acrylic acid (5.00 g, 1 Eq, 36.2 mmol) was dissolved in DMF (125 ml). N,N'-carbonyldiimidazole (7.04 g, 1.2 Eq, 43.4 mmol) was added with stirring at RT and stirring was continued at RT for 24 h. Pyrazin-2-ylmethanamine (3.95 g, 1 Eq, 36.2 mmol) was added and the reaction mixture was stirred at 50° C. for 3 h. The solvent was evaporated and the residue was purified by flash column chromatography to give 3 g of product with purity >95%. 1H NMR (D2O, 600 MHz) δ = 8.64 (2H, s,), 8.59 (1H, s), 8.50 (1H, d, J = 2.7 Hz), 7.61 (1H, s,), 7.30 (1H, d, J = 15.9 Hz), 6.61 (1H, d, J = 15.8 Hz), 4.61 (2H, s). 13 C NMR (D2O, 151 MHz) δ = 170.6, 157.3, 148.1, 143.8, 143.7, 138.1, 131.9, 128.7, 125.8, 123.0, 45.6.

[0107] Example 48: (2E)-3-(furan-2-yl)-N-[2-(1H-imidazol-4-yl)ethyl]prop-2-enamide (E)-N-(2-(1H-imidazol-4-yl)ethyl)-3-(furan-2-yl)acrylamide was synthesized by the same procedure as described for N-(2-(1H-imidazol-4-yl)ethyl)cinnamamide (Example 44). 2-(1H-imidazol-4-yl)ethan-1-amine (2.00 g, 1 Eq, 18.0 mmol) was reacted with (E)-3-(furan-2-yl)acryloyl chloride (3.10 g, 1.10 Eq, 19.8 mmol) to give 1.6 g of the desired (E)-N-(2-(1H-imidazol-4-yl)ethyl)-3-(furan-2-yl)acrylamide as a beige powder. The purity is >95% by NMR analysis. 1 H NMR (DMSO-d6, 600 MHz) δ = 8.94 (1H, s), 8.47 (1H, br t, J = 5.5 Hz), 7.76 (1H, s), 7.41 (1H, s), 7.21 (1H, d, J = 15.8 Hz), 6.76 (1H, d, J = 2.8 Hz), 6.57 (1H, br s), 6.41 (1H, d, J = 15.8 Hz,), 3.47 (2H, q, J = 6.2 Hz), 2.83 (2H, br t, J = 6.5 Hz) 13C NMR (DMSO-d6, 151 MHz) δ = 165.0, 150.9, 144.8, 133.6, 131.2, 126.1, 119.3, 116.2, 113.9, 112.4, 55.0, 37.8, 24.6.

[0108] Example 49: (2E)-N-[2-(1H-imidazol-4-yl)ethyl]-3-(thiophen-2-yl)prop-2-enamide 2-(1H-imidazol-4-yl)ethan-1-amine (1.00 g, 1 Eq, 9.00 mmol) was dissolved in methanol (20 ml) and diluted with DCM (50 ml). Triethylamine (2.73 g, 3 Eq, 27.0 mmol) was added, followed by the dropwise addition of a solution of (E)-3-(thiophen-2-yl)acryloyl chloride (1.86 g, 1.2 Eq, 10.8 mmol) in DCM (50 ml) at RT. After stirring for 2 h at RT, the solution was evaporated. The residual solid was washed with DCM, then with ethyl acetate and ether. The solid was taken up in THF (150 ml) and stirred at 50° C. for 15 min. The insoluble solid was filtered. The THF solution was cooled to RT and then diluted with ether until precipitation occurred. The white precipitate was filtered, washed with ether and then dried in a vacuum oven at 40° C. 0.7 g of (E)-N-(2-(1H-imidazol-4-yl)ethyl)-3-(thiophen-2-yl)acrylamide was obtained as a white powder with a purity of >95% by NMR analysis. 1 H NMR (DMSO-d6, 600 MHz) δ = 8.16 (1H, br t, J = 5.9 Hz), 7.59 (1H, d, J = 5.5 Hz), 7.56 (1H, d, J = 15.1 Hz), 7.54 (1H, s), 7.36 (1H, d, J 17,20 = 3.4 H), 7.10 (1H, dd, J = 4.8 Hz, J = 3.4 Hz), 6.81 (1H, s), 6.37 (1H, d, J = 15.8 Hz), 3.37 - 3.38 (2H, m), 2.67 (2H, t, J = 7.2 Hz). 13C NMR (DMSO-d6, 151 MHz) δ = 164.6, 139.9, 134.7, 131.6, 130.6, 128.3, 127.8, 121.0, 38.9, 25.1.

[0109] Example 50: (2E)-N-[2-(1H-imidazol-4-yl)ethyl]-3-(thiophen-3-yl)prop-2-enamide Histamine (1.1 g, 1 Eq, 9.9 mmol) was dissolved in methanol (10 ml) and diluted with DCM (50 ml). TEA (3.0 g, 4.1 ml, 3 Eq, 30 mmol) was added followed by dropwise addition of a solution of (E)-3-(thiophen-3-yl)acryloyl chloride (2.0 g, 1.2 Eq, 12 mmol) in DCM (50 ml) at RT. After stirring for 2 h at RT, the solution was evaporated. The remaining residual solid was transferred to a silica gel column chromatography and then eluted with DCM / methanol to give 1.1 g of the desired (E)-N-(2-(1H-imidazol-4-yl)ethyl)-3-(thiophen-3-yl)acrylamide as an off-white powder. Purity is >95% by NMR. 1 H NMR (DIMETHYLFORMAMIDE-d7, 600 MHz) δ = 7.82 (1H, d, J = 2.1 Hz), 7.63 - 7.66 (1H, m), 7.61 - 7.66 (1H, m), 7.54 (1H, d, J = 15.1 Hz), 7.41 (1H, d, J = 4.8 Hz), 6.92 (1H, s), 6.60 (1H, d, J = 15.8 Hz), 3.53 - 3.58 (2H, m), 2.81 (2H, t, J = 7.6 Hz). 13 C NMR (DIMETHYLFORMAMIDE-d7, 151 MHz) δ = 165.8, 138.8, 135.2, 133.0, 127.6, 127.3, 125.5, 122.5, 39.7, 27.7.

[0110] Example 51: 3-(1H-imidazol-4-yl)-2-{[(2E)-3-phenylprop-2-enoyl]amino}propanoic acid Synthesis: L-histidine (3.00g, 1Eq, 19.3mmol) was dissolved in an aqueous solution of sodium hydroxide (1.8g, 2.3Eq, 44.5mmol) in water (50ml) and diluted with THF (50ml). A solution of cinnamoyl chloride (4.19g, 1.3Eq, 25.1mmol) in THF (50ml) was then added dropwise at RT. The reaction mixture was stirred at RT for 3h, neutralized with 1M HCl and evaporated under reduced pressure at 30°C. The remaining solid was purified by silica gel column chromatography using DCM / methanol. 0.5g of the desired compound cinnamoyl-L-histidine was obtained as a white solid. The purity is >95% by NMR. 1H NMR (METHANOL-d4, 600 MHz) δ = 7.95 (1H, s), 7.55 (2H, br d, J = 6.2 Hz), 7.48 (1H, d, J = 15.8 Hz, ), 7.35 - 7.39 (2H, m), 7.33 - 7.39 (1H, m), 7.00 (1H, s), 6.70 (1H, d, J = 15.8 Hz), 4.66 (1H, dd, J = 6.9 Hz, J α,β<''> = 4.8 Hz), 3.25 (1H, dd, J β<''>,β<'> = 15.1 Hz, J β<''>,α = 4.8 Hz), 3.10 (1H, dd, J β<'>,β<''> = 15.1 Hz, J = 7.6 Hz. 13 C NMR (METHANOL-d4, 151 MHz) δ = 177.3, 168.0, 141.8, 136.5, 135.4, 133.1, 130.9, 130.1, 129.0, 122.3, 119.9, 55.9, 30.4.

[0111] Example 52: 3-(1H-imidazol-4-yl)-2-{[(2E)-2-methylbut-2-enoyl]amino}propanoic acid (E)-(2-Methylbut-2-enoyl)-L-histidine was synthesized using the same procedure as described for cinnamoyl-L-histidine (Example 51). L-histidine (2.50 g, 1 Eq, 16.1 mmol) was reacted with (E)-2-methylbut-2-enoyl chloride (2.00 g, 1.05 Eq, 16.9 mmol). 0.8 g of the desired compound was obtained as a white solid. The purity is >98% by NMR. 1 H NMR (DMSO-d6, 600 MHz) δ = 7.95 (1H, d, J = 7.6 Hz), 7.60 (1H, s), 6.81 (1H, s), 6.34 (1H, qd, J = 6.9 Hz, J = 1.4 Hz), 4.38 (1H, d, J = 6.9 Hz), 2.96 (2H, d, J = 6.2 Hz, H-9), 1.72 (3H, s), 1.69 (3H, d, J = 7.6 Hz). 13 C NMR (DMSO-d6, 151 MHz) δ = 173.4, 168.0, 134.7, 133.7, 131.5, 129.9, 116.8, 52.8, 28.4, 13.7, 12.3.

[0112] Example 53: N-[2-(1H-imidazol-4-yl)ethyl]-2-methylbutanamide N-(2-(1H-imidazol-4-yl)ethyl)-2-methylbutanamide was synthesized using the same procedure as described for (E)-N-(2-(1H-imidazol-4-yl)ethyl)-3-(thiophen-3-yl)acrylamide (Example 50). Histamine (1.5 g, 1 Eq, 13 mmol) was reacted with 2-methylbutanoyl chloride (1.6 g, 1 Eq, 13 mmol). 0.4 g of the desired N-(2-(1H-imidazol-4-yl)ethyl)-2-methylbutanamide was obtained as a pale yellow solid. The purity is >95% by NMR. 1 H NMR (DMSO-d6, 600 MHz) δ = 7.80 - 7.92 (1H, m), 7.57 (1H, s), 6.79 (1H, s), 3.20 - 3.32 (2H m), 2.62 (2H, t, J = 7.2 Hz), 2.07 - 2.13 (1H, m), 1.42 - 1.50 (1H, m), 1.22 - 1.31 (1H, m), 0.95 (3H, d, J = 6.9 Hz), 0.76 (3H, t, J = 7.6 Hz). 13 C NMR (DMSO-d6, 151 MHz) δ = 175.4, 134.6, 134.2), 116.9, 41.4, 38.5, 27.0, 26.9, 17.7, 11.8.

[0113] Example 54: (2E)-N-[2-(1H-imidazol-4-yl)ethyl]-3,7-dimethylocta-2,6-dienamide (E)-N-(2-(1H-imidazol-4-yl)ethyl)-3,7-dimethylocta-2,6-dienamide was synthesized using the same procedure as described for (E)-N-(2-(1H-imidazol-4-yl)ethyl)-3-(thiophen-3-yl)acrylamide (Example 50). Histamine (1.00 g, 1 Eq, 9.00 mmol) was reacted with (E)-3,7-dimethylocta-2,6-dienoyl chloride (2.50 g, 1.49 Eq, 13.4 mmol). 0.5 g of the desired N-(2-(1H-imidazol-4-yl)ethyl)-2-methylbutanamide was obtained as a white solid. The purity is >95% by NMR. 1 H NMR (DMSO-d6, 600 MHz) δ = 7.82 (1H, br t, J = 5.2 Hz), 7.52 (1H, s), 6.77 (1H, br s), 5.62 (1H, br s), 5.05 - 5.11 (1H, m), 3.25 - 3.30 (3H, m), 2.62 (2H, br t, J = 7.2 Hz), 2.06 - 2.12 (1H, m), 2.05 - 2.09 (1H, m), 2.01 - 2.06 (1H, m), 2.01 - 2.06 (3H, m), 1.63 - 1.66 (3H, m), 1.53 - 1.61 (4H, m). 13 C NMR (DMSO-d6, 151 MHz) δ = 166.0, 151.4, 134.6, 131.4, 123.5, 118.8, 40.2, 38.5, 25.7, 25.5, 17.6.

[0114] Example 55: 2-{[(2E)-3-(furan-2-yl)prop-2-enoyl]amino}-3-(1H-imidazol-4-yl)propanoic acid L-histidine (3.00 g, 1 Eq, 19.3 mmol) was dissolved in an aqueous solution of sodium bicarbonate (4.06 g, 2.5 Eq, 48.3 mmol) in water (50 ml) and diluted with THF (30 ml). A solution of (E)-3-(furan-2-yl)acryloyl chloride (3.94 g, 1.3 Eq, 25.1 mmol) in THF (30 ml) was then added dropwise at RT. The reaction mixture was stirred overnight at RT and then neutralized with 1 M HCl. The reaction mixture was extracted with ethyl acetate (2x 150 ml) to remove unreacted (E)-3-(furan-2-yl)acrylic acid. The aqueous layer was evaporated under reduced pressure at 30° C. The remaining solid was suspended in methanol (200 ml), stirred for 15 min and then filtered. The filtrate was evaporated. The remaining solid was resuspended in methanol (200 ml), stirred and then filtered. The filtrate was evaporated. The remaining residual solid was transferred to a silica gel column chromatography and then eluted with DCM / methanol to give 1.3 g of the desired compound as an off-white solid. The purity is >95% by NMR. 1H NMR (D2O, 600 MHz) δ = 7.73 (1H, s), 7.58 (1H, d, J = 1.4 Hz), 7.25 (1H, d, J = 15.1 Hz), 6.96 (1H, s), 6.72 (1H, d, J 17,18 = 3.4 Hz), 6.55 (1H, dd, J 18,17 = 3.4 Hz, J = 2.1 Hz), 6.44 (1H, d, J = 15.8 Hz), 4.57 (1H, dd, J 12,11 = 9.0 Hz, J 12,11 = 4.8 Hz), 3.19 (1H, dd, J 11,11 = 14.8 Hz, J 11,12 = 4.5 Hz), 3.02 (1H, dd, J 11,11 = 15.1 Hz, J 11,12 = 9.0 Hz). 13 C NMR (D2O, 151 MHz) δ = 180.9, 170.8, 153.6, 147.9, 138.4, 135.8, 131.1, 120.4, 120.0, 117.7, 115.3, 58.2, 32.1.

[0115] Example 56: 3-(1H-imidazol-5-yl)-2-{[(2E)-3-(1H-imidazol-4-yl)prop-2-enoyl]amino}propanoic acid The reaction was carried out under dry conditions with a slow nitrogen flow. The activated ester of urocanic acid and N-hydroxysuccinimide was first prepared by dissolving (E)-3-(1H-imidazol-4-yl)acrylic acid (1.727 g, 1 Eq, 12.50 mmol) in 80 ml of anhydrous DMF with stirring. To this solution, 1-hydroxypyrrolidine-2,5-dione (1.582 g, 1.1 Eq, 13.75 mmol) was added and stirring was continued for about 10 min at RT. To the mixture was then added dropwise a solution of dicyclohexylmethandiimine (2.837 g, 1.1 Eq, 13.75 mmol) in 25 ml of anhydrous DMF over a period of 10 min. The resulting mixture was stirred at RT for 24 h. The reaction mixture was then filtered to remove the dicyclohexylurea formed. The residue was washed with 2*5ml of anhydrous DMF and the obtained clear filtrate was stored overnight under nitrogen at -18°C and filtered again. The residue was washed with 2*5ml of anhydrous DMF. The result is a solution of 12.5mmol of the active ester of urocanic acid in about 100ml of anhydrous DMF. A 250ml reaction flask was charged with 12.5mmol of the obtained solution of the active ester of urocanic acid in DMF. L-histidine dihydrochloride (2.851g, 1Eq, 12.50mmol) and sodium bicarbonate (2.993g, 2.85Eq, 35.63mmol) in 20ml of water were added dropwise at RT for 15 minutes. During the addition, the pH of the reaction mixture was maintained at pH 9 using 1M NaOH solution. After the addition, the temperature was kept at 40°C for 4 hours. The reaction mixture was cooled to RT. Then 37% HCl was carefully added to adjust the pH to 2.5. 100 ml water was added to the mixture and washed with 3 * 20 ml ethyl acetate. The aqueous phase was then evaporated to dryness using a rotavapor. 50 ml absolute ethanol was added to the resulting residue and stirred overnight at RT. The mixture was filtered. The resulting filtrate was evaporated and the resulting residue was washed with 30 ml acetonitrile, filtered and evaporated to dryness. LC-MS analysis of the resulting residue confirmed the desired molar amount present in the product. Purification was performed using a RPC18-prep HPLC. 100 mg of the desired product was isolated. 1H NMR (600 MHz, D2O) δ = 8.70 (1 H, s), 8.60 (1 H, d, J=1.4 Hz), 7.71 (1 H, br s), 7.38 (1 H, d, J=15.8 Hz), 7.28 (1 H, br s), 6.67 (1 H, d, J=15.8 Hz), 4.66 (1 H, dd, J=8.3, 4.8 Hz), 3.32 - 3.36 (1 H, m), 3.17 (1 H, dd, J=15.5, 8.6 Hz). 13 C NMR (151 MHz, D2O) δ = 178.9, 169.4, 138.1, 136.0, 132.4, 132.3, 128.9, 125.3, 122.9, 119.6, 57.2, 30.2.

[0116] Example 57: N-[2-(1H-imidazol-5-yl)ethyl]-1,3-benzothiazole-6-carboxamide A suspension of 2-(1H-imidazol-4-yl)ethan-1-amine,2HCl (1.473 g, 8.00 mmol) in pyridine (25 ml) was stirred in an ice / water bath. Benzo[d]thiazole-6-carbonyl chloride (1.976 g, 10 mmol) was added. The reaction mixture was stirred in the ice / water bath for 30 min and at RT for 24 h. Pyridine was evaporated, the residue was taken up in water and sodium hydroxide solution was added to the suspension to pH=11. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried and evaporated. The small amount of residue was mainly the desired product, but not pure. The aqueous layer was also evaporated and the residue was taken up in methanol. The remaining solid (NaCl) was filtered and the filtrate was evaporated. The residue was also mostly the desired product. Purification was performed on a portion of the crude product by flash column chromatography to give 0.2 g of a white solid with a purity of >95% by NMR. 1H NMR (600 MHz, DMSO-d6) δ = 9.53 (1 H, s), 8.74 (1 H, t, J=5.2 Hz), 8.64 (1 H, s), 8.15 (1 H, d, J=9.0 Hz), 7.99 (1 H, d, J=8.5 Hz), 7.55 (1 H, s), 6.84 (1 H, s), 3.52 (2 H, q, J=6.9 Hz), 2.78 (2 H, t, J=7.6 Hz). 13 C NMR (151 MHz, DMSO-d6) δ = 165.6, 158.8, 154.6, 134.7, 133.7, 131.9, 125.3, 122.7, 122.0, 40.0, 33.4, 27.0.

[0117] Example 58: (2E)-3-(1H-imidazol-4-yl)-N-(2-phenylethyl)prop-2-enamide (E)-3-(1H-imidazol-4-yl)acrylic acid (15 g, 109 mmol) was dissolved in dioxane (250 ml). To this emulsion, 1-hydroxypyrrolidine-2,5-dione (13.75 g, 119 mmol) and DCC (24.65 g, 119 mmol) were added. The mixture was stirred at room temperature for 24 h. The solids were filtered off. A portion (1 / 3) of the filtrate was used in the next reaction step. To a solution of the filtrate in 92 g of dioxane, 2-phenylethan-1-amine (4.40 g, 36.3 mmol) was added. The solution was stirred at 50° C. for 3 h. The dioxane was evaporated and the residue was taken up in DCM. The solids were removed by filtration and the filtrate was washed with sodium bicarbonate solution. The organic layer was separated, dried and evaporated. The residue was purified by flash column chromatography to give 1 g of a light yellow solid. This solid was further purified by preparative HPLC to give 80 mg of product with purity >98% by NMR. 1H NMR (600 MHz, DMSO-d6) δ = 12.22 (1 H, br s), 8.10 (1 H, br t, J=5.5 Hz), 7.69 (1 H, s), 7.39 (1 H, s), 7.26 - 7.31 (4 H, m), 7.18 - 7.24 (4 H, m), 6.51 (1 H, d, J=15.1 Hz), 3.37 - 3.40 (2 H, m), 2.75 (2 H, t, J=7.2 Hz). 13 C NMR (151 MHz, DMSO-d6) δ = 165.7, 139.6, 137.3, 136.8, 131.6, 128.7, 128.3, 126.1, 118.8, 118.4, 40.3, 35.3.

[0118] Example 59: Increasing saltiness Aqueous solutions containing 0.5% NaCl and 50 ppm of each of the compounds of Examples 38 to 58 were prepared, tasted by a sensory panel, and compared with an aqueous solution containing 0.5% NaCl. All solutions containing the compounds of Examples 38-58 were described as saltier than the 0.5% NaCl solution in water, and several were described as having more metallic, rich, umami, mineral, clean salty, and slightly sour flavors.

[0119] Example 60: Enhancing umami flavor Two aqueous solutions were prepared. A) 0.5% NaCl, 0.03% MSG, 0.007% ribotide, and B) 0.5% NaCl, 0.03% MSG, 0.007% ribotide, and 50 ppm of each of the compounds in Examples 38-58. The solutions were tasted by a sensory panel. Solution A was a model solution for savory tastes and contained MSG (monosodium glutamate) and ribotide (IMP / GMP, 50 / 50 mixture) as savory taste enhancers. Solution B, containing compounds of Examples 38-58, was described as having a strong boost in saltiness and umami taste, respectively, compared to solution A. Additionally, some examples were described as richer, more minerally, and with a slight acidity.

Claims

1. One or more compounds of formula (I): 【Chemical 1】 and edible salts thereof, wherein: R 1 are 2-(1H-4-imidazolyl)-ethenyl, 1H-5-indolyl, 2-(1H-5-imidazolyl)-ethenyl, 1-amino-2-(1H-4-imidazolyl)-ethyl, (1,3-thiazol-2-yl)-ethenyl, 2,3-dihydro-1H-indol-2-yl, 2-(pyrimidin-2-yl)ethenyl, heptadecanyl, 1-heptadecanyl, 1-heptadecanyl, heptadecan-8,11-dienyl, heptadecan-8,11, selected from the group consisting of 14-trienyl, 2-(4H-imidazol-2-yl)-ethenyl, 2-(4H-imidazol-2-yl)-ethyl, 2-phenyl-ethenyl, 2-(furan-2-yl)-ethenyl, 2-(thiophen-2-yl)-ethenyl, 2-(thiophen-3-yl)-ethenyl, 2-but-2-enoyl, 2-butyl, 2,6-dimethylhepta-1,5-dienyl, 1,3-benzothiazol-6-yl; R 2 are (1H-imidazol-4-yl)-methyl, (1H-3-indol-3-yl)-methyl, 4-hydroxybenzyl, methylsulfanylethyl, hydroxymethyl, CH 2 -COOH, (pyridin-4-yl)methyl, (pyridin-2-yl)methyl, 1-(2,6-dimethylhepta-1,5-dienyl), 2-(pyrimidin-2-yl)methyl, (1H-imidazol-5-yl)-methyl, (1H-imidazol-2-yl)-methyl, (1H-pyrrol-2-yl)-methyl, phenyl, pyrimidin-5-yl, pyrazin-2-yl; R 3 is selected from the group consisting of H, COOH, and edible salts thereof; or a compound selected from the group consisting of 3-(1H-imidazol-4-yl)prop-2-enamide, methyl 2,3-dihydro-1H-indole-2-carboxylate, and 3,6-bis[(1H-imidazol-4-yl)methyl]piperazine-2,5-dione, Use as a flavor modifying compound.

2. 2. The use according to claim 1, wherein the compound is selected from the group consisting of 3-(1H-imidazol-4-yl)-N-[2-(1H-imidazol-4-yl)ethyl]prop-2-enamide, N-[2-(1H-imidazol-4-yl)ethyl]-1H-indole-5-carboxamide, histidyltyrosine, N-[3-(1H-imidazol-5-yl)prop-2-enoyl]-tryptophan, histidylhistidine. , N-[3-(methylsulfanyl)propyl]histidine amide, N-(2-hydroxyethyl)histidine amide, histidyl-β-alanine, N-[octadeca-9,12-dienoyl]histidine, N-[2-(1H-imidazol-4-yl)ethyl]-3-(1,3-thiazol-2-yl)prop-2-enamide, N-[octadeca-9,12,15-trienoyl]histidine, N-[octadec-9-enoyl 1H-imidazol-4-yl]histidine, N-octadecanoylhistidine, 3-(1H-imidazol-4-yl)prop-2-enamide, 3-(1H-imidazol-4-yl)-N-[2-(pyridin-4-yl)ethyl]prop-2-enamide, 2,3-dihydro-1H-indole-2-carboxylic acid methyl ester, 3-(1H-imidazol-4-yl)-N-[2-(pyridin-2-yl)ethyl]prop-2-enamide, N-[3,7-di Methylocta-2,6-dien-1-yl]-3-(1H-imidazol-4-yl)prop-2-enamide, N-[2-(1H-imidazol-4-yl)ethyl]-2,3-dihydro-1H-indole-2-carboxamide, 3-(pyrimidin-2-yl)-N-[2-(pyrimidin-2-yl)ethyl]prop-2-enamide, 3,6-bis[(1H-imidazol-4-yl)methyl]piperazine-2,5-dione.

3. A flavor composition comprising a compound as defined in claim 1 or claim 2.

4. The flavor composition according to claim 3, wherein the compound is contained in an amount of 0.001 to 80 wt% based on the total weight of the composition.

5. A consumer product comprising a compound as defined in claim 1 or claim 2 and a consumer product base.

6. 6. A consumer product according to claim 5, comprising at least 1 ppm, preferably at least 20 ppm, more preferably at least 50 ppm or 70 ppm ppb of one or more flavour modulating compounds according to formula (I) and / or edible salts thereof.

7. 6. The consumer product of claim 5, wherein the consumer product is selected from foodstuffs and beverages.

8. Compounds of formula (I): 【Chemistry 2】 and edible salts thereof, wherein: R 1 are 2-(1H-4-imidazolyl)-ethenyl, 1H-5-indolyl, 2-(1H-5-imidazolyl)-ethenyl, 1-amino-2-(1H-4-imidazolyl)-ethyl, (1,3-thiazol-2-yl)-ethenyl, 2,3-dihydro-1H-indol-2-yl, 2-(pyrimidin-2-yl)ethenyl, heptadecanyl, 1-heptadecanyl, 1-heptadecanyl, heptadecan-8,11-dienyl, heptadecan-8,11, selected from the group consisting of 14-trienyl, 2-(4H-imidazol-2-yl)-ethenyl, 2-(4H-imidazol-2-yl)-ethyl, 2-phenyl-ethenyl, 2-(furan-2-yl)-ethenyl, 2-(thiophen-2-yl)-ethenyl, 2-(thiophen-3-yl)-ethenyl, 2-but-2-enoyl, 2-butyl, 2,6-dimethylhepta-1,5-dienyl, 1,3-benzothiazol-6-yl; R 2 are (1H-imidazol-4-yl)-methyl, (1H-3-indol-3-yl)-methyl, 4-hydroxybenzyl, methylsulfanylethyl, hydroxymethyl, CH 2 -COOH, (pyridin-4-yl)methyl, (pyridin-2-yl)methyl, 1-(2,6-dimethylhepta-1,5-dienyl), 2-(pyrimidin-2-yl)methyl, (1H-imidazol-5-yl)-methyl, (1H-imidazol-2-yl)-methyl, (1H-pyrrol-2-yl)-methyl, phenyl, pyrimidin-5-yl, pyrazin-2-yl; R 3 is selected from the group consisting of H, COOH, and edible salts thereof; However, the compound is not 3-(1H-imidazol-4-yl)-N-[2-(1H-imidazol-4-yl)ethyl]prop-2-enamide, histidyltyrosine, histidylhistidine, N-(2-hydroxyethyl)histidinamide, histidyl-β-alanine, N-octadecanoylhistidine, or N-[(9Z)-octadec-9-enoyl]histidine.

9. 9. The compound of claim 8, selected from the group consisting of N-[2-(1H-imidazol-4-yl)ethyl]-1H-indole-5-carboxamide, N-[2-(1H-imidazol-4-yl)ethyl]-1H-indole-5-carboxamide, N-[3-(1H-imidazol-5-yl)prop-2-enoyl]tryptophan, N-[3-(methylsulfanyl)propyl]histidineamide, N-[octadeca-9,12-dienoyl]histidine, N-[2-(1H-imidazol-4-yl)ethyl]-3-(1, 3-thiazol-2-yl)prop-2-enamide, N-[octadeca-9,12,15-trienoyl]histidine, 3-(1H-imidazol-4-yl)-N-[2-(pyridin-4-yl)ethyl]prop-2-enamide, 3-(1H-imidazol-4-yl)-N-[2-(pyridin-2-yl)ethyl]prop-2-enamide, N-[3,7-dimethylocta-2,6-dien-1-yl]-3-(1H-imidazol-4-yl)prop-2-enamide, N-[2-(1H-imidazol-4-yl)ethyl]-2,3-Dihydro-1H-indole-2-carboxamide, 3-(pyrimidin-2-yl)-N-[2-(pyrimidin-2-yl)ethyl]prop-2-enamide, 3-(4H-imidazol-2-yl)-N-[2-(1H-imidazol-5-yl)ethyl]prop-2-enamide, 3-(1H-imidazol-4-yl)-N-[2-(1H-imidazol-2-yl)ethyl]prop-2-enamide, N-(2-hydroxyethyl)-3-(1H-imidazol-4-yl)propanamide, 3-( 1H-imidazol-4-yl)-N-[2-(1H-pyrrol-2-yl)ethyl]prop-2-enamide, N-benzyl-3-(1H-imidazol-4-yl)prop-2-enamide, 3-(1H-imidazol-4-yl)-N-[(pyrimidin-5-yl)methyl]prop-2-enamide, 3-(1H-imidazol-4-yl)-N-[(pyrazin-2-yl)methyl]prop-2-enamide, 3-(furan-2-yl)-N-[2-(1H-imidazol-4-yl)ethyl]prop-2-enamide 3-(1H-imidazol-4-yl)-2-{[(2E)-2-methylbut-2-enoyl]amino}propanoic acid, N-[2-(1H-imidazol-4-yl)ethyl]-2-methylbutanamide, N-[2-(1H-imidazol-4-yl)ethyl]-3,7-dimethyl ... -dimethylocta-2,6-dienamide, 2-{[3-(furan-2-yl)prop-2-enoyl]amino}-3-(1H-imidazol-4-yl)propanoic acid, 3-(1H-imidazol-5-yl)-2-{[3-(1H-imidazol-4-yl)prop-2-enoyl]amino}propanoic acid, N-[2-(1H-imidazol-5-yl)ethyl]-1,3-benzothiazole-6-carboxamide, 3-(1H-imidazol-4-yl)-N-(2-phenylethyl)prop-2-enamide.

10. 1. A method for imparting, enhancing, improving or modifying flavor characteristics to a flavor composition or consumer product, the method comprising adding to said composition or consumer product at least one compound as defined in claim 1 or claim 2 or an edible salt thereof.

Images