Method of preparation of indoleacetic acid hexyl ester, a composition and use

Abstract

The invention relates to a method of preparation of indole-3-acetic acid hexyl ester. The method of preparation is based on acid-catalyzed esterification with hexanol and removal of excess alcohol by vacuum evaporation with the addition of water. The preparation method significantly improves the stability of the product and reduces the number of by-products, which are mainly manifested by an undesirable odor. The product is suitable for cosmetic applications. The invention also relates to cosmetic compositions containing indole-3 -acetic acid hexyl ester preparedby the method according to the invention, which are, for example, in the form of a solution, emulsion, serum or gel, paste, dispersion, powder, fine powder, or nanofibers.

Description

[0001] Method of preparation of indoleacetic acid hexyl ester, a composition and use

[0002] Technical field

[0003] The invention relates to a method for preparing indoleacetic acid hexyl ester according to the structural formula I:

[0004] The method of preparation is based on acid-catalyzed esterification of indoleacetic acid with hexanol and removal of excess alcohol by vacuum evaporation with the addition of water. The method of preparation significantly improves the stability of the product and reduces the presence of undesirable by-products. These advantages allow the use of this material in cosmetic applications, for example.

[0005] State of art

[0006] Indoleacetic acid

[0007] Indoleacetic acid (IAA, structural formula II) is one of the indole products of bacterial degradation of tryptophan. This degradation occurs under the influence of the gut microbiome (Li, X. et al.: Frontiers in Pharmacology, 12, 2021) and the skin microbiome (Guenin-Mace, L. et al.: JCI Insight, 5, 20, el40598, 2020; Yu, J. et al.: Journal of Allergy and Clinical Immunology, 143, 6, 2108-2119, 2019). In microorganisms, especially bacteria and yeast, indoles function as signaling molecules that facilitate intra- and interspecific communication.

[0008] Indole-3 -acetic acid is also one of the auxins, plant hormones that promote cell proliferation and elongation, thereby significantly contributing to plant growth (Teale, W. D. et al.: Molecular Cell Biology, 7, 11, 847-859, 2006). It is present in plants both free, and bound in the form of esters or amides. Furthermore, indoles act on mammals, especially humans, where they have demonstrated the ability to modulate the barrier function of the intestinal wall and the immune system (Alexeew, E. E. et al.: The American Journal of Pathology, 188, 5, 1183-1194, 2018; Aoki, R. et al.: PLOS ONE, 9, 5, e96804, 2014; Scott, S. A. et al.: PNAS, 117, 32, 19376- 19387, 2020). The supportive effect of indoleacetic acid on tight junctions and the small intestine has been described, where it improved its barrier function (Geng, S. et al.: Journal of Crohn’s & Colitis, 12, 11, 1359-1374, 2018, Shen, J. et al: Frontiers in Immunology, 13, 762580, 2022)

[0009] Synthesis of indoleacetic acid esters using stochiometric amounts of reagents

[0010] In the publication (Mollan, R. C. et al.: Phytochemistry, 11, 1485-1488, 1972) the activation of IAA in ethyl acetate using a stoichiometric amount of dicyclohexyl carbodiimide and subsequent reaction with nitrophenol was described.

[0011] The preparation of IAA esters by activation with dicyclohexylcarbodiimide in THF has also been described (Singh, S. et al.: Synthesis, 55, 21, 3685-3692, 2023). This reagent is used stoichiometrically, the reaction is catalyzed by highly toxic DMAP and requires final purification by chromatography.

[0012] In the publication (Naik, N. et al.: European Journal of Chemistry, 2, 337-341, 2011) the activation of IAA by conversion to chloride using thionyl chloride in THF was described. This reagent is also used stoichiometrically, and when used, hydrogen chloride and sulfur dioxide are also released. The obtained products were separated by column chromatography.

[0013] The preparation of IAA ester by alkylation with a-bromopentafluorotoluene in diethyl ether in the presence of N-ethylpiperidine was also described (Epstein, E. et al.: Journal of Chromatography A, 209, 413-420, 1981). A similar procedure with 4-m ethylphenacyl bromide in THF in the presence of triethylamine was described in publication (Horky, P. et al. : European Journal of Medicinal Chemistry, 143, 843-853, 2018). These methods require the use of expensive alkyl bromides, nitrogen bases, and reaction and extraction solvents.

[0014] The main disadvantage of these methods is the use of stoichiometric amounts of alkylating agent or activator. Another disadvantage is the use of large amounts of solvents and potentially toxic additives. Catalytic synthesis ofindoleacetic acid esters

[0015] In the article (Jackson, R. W.: Journal of Biological Chemistry, 88, 659-662, 1930) the preparation of methyl and ethyl esters of indoleacetic acid was described by refluxing IAA in an excess of the appropriate alcohol with a trace of hydrogen chloride. The excess alcohol was removed by evaporation, the product was dissolved in ether, washed with sodium bicarbonate solution, and finally vacuum distilled at 180°C and 3 mBar.

[0016] In the article (Redemann, C. T. et al.: Journal of the American Chemical Society, 73, 6, 2957-58, 1951) the esterification of IAA with C1-C5 alcohols, catalyzed by hydrogen chloride, was described. The products were purified by crystallization from petroleum ether. The butyl and amyl esters were distilled at 155°C and 0.13 mBar and 0.03 mBar, respectively.

[0017] In another publication (Elderfield, R. C. et al.: Journal of Organic Chemistry, 22, 11, 1376-1380, 1957) the preparation of the IAA ethyl ester in ethanol with hydrochloric acid and the addition of anhydrous sodium sulphate as a drying agent was described. The product was again extracted with ether.

[0018] Furthermore, the article (Chu, C. K. et al: Journal of Heterocyclic Chemistry, 1777- 1779, 1986) describes the esterification of IAA with ethanol with Dowex 50 (H+) acidic resin with water removal by azeotropic distillation and 3 A molecular sieves. The excess alcohol was evaporated and the product was triturated with 30% ethanol.

[0019] The patent application (Eastwood, P. R. et al.: EP2548863A1, 2013) describes the esterification of IAA with ethanol and sulfuric acid under reflux. The reaction mixture was neutralized with sodium hydroxide and extracted with dichloromethane.

[0020] The patent (Takaahi, A. et al.: JP2015189670A, 2015) describes the preparation of indoleacetic acid methyl ester by reaction of indoleacetic acid with methanol in the presence of acetyl chloride at room temperature. The reaction was terminated by the addition of sodium bicarbonate solution. The product was extracted with ethyl acetate and purified by column chromatography.

[0021] The article (Weller, L. et al.: Journal of the American Chemical Society, 77, 4937-4938, 1955) describes the preparation of IAA esters with C6-C19 alcohols. The reactions were carried out in excess alcohol. Reactions with higher alcohols (C10-18) were heated during the reaction and the products were purified by repeated crystallization from petroleum ether. Reactions with shorter alcohols (C6-C9) were carried out at room temperature, the excess alcohol and the product were vacuum distilled. The article does not provide exact reagent ratios, reaction temperatures or reaction times. The article (Chitra, G. et al.: International Journal of Biological Macromolecules, 95, 363-375, 2016) describes the preparation of a hydrogel based on indoleacetic acid, diethylene glycol and citric acid. The reaction was carried out at 160°C for 3 hours without the presence of a catalyst. The reaction impurities were washed off with water, and no information was given about the odor of the product.

[0022] In general, esters of indole-3 -acetic acid with alcohols can be prepared in excess alcohol under acid catalysis. The acid is removed by reaction with a base and extraction into water. Excess of shorter alcohols can be removed by evaporation. The product can be purified by extraction, crystallization, column chromatography or vacuum distillation. Evaporation and vacuum distillation procedures are unsuitable for longer alcohols and their esters due to their low volatility. Vacuum distillation is also energy-intensive and poses a production risk. Crystallization requires the use of an additional solvent. Column chromatography on a production scale is very expensive. The reaction at elevated temperature in the absence of a catalyst is disadvantageous in terms of the low IAA stability.

[0023] Stability of indoleacetic acid and its derivatives

[0024] In the presence of a strong acid, such as trifluoroacetic or phosphoric acid, dimerization of indoleacetic acid occurs through the 2-position of indole (Fatum, T. M. et al.: Acta Chemica Scandinavica, 52, 784-789, 1998). This reaction also proceeds with esters of indoleacetic acid; the propyl ester was investigated in this article.

[0025] The oxidation of indoleacetic acid to form a red N-hydroxy compound using ferric salts in an acidic medium was disclosed in the article (Houff, W. H. et al.: Journal of the American Chemical Society, 76, 22, 5654-5656, 1954). Furthermore, the oxidation of indoleacetic acid using ceric nitrate in the presence of hydroxylamine to form a stable colored product was described in the article (Chrastil, J.: Analytical Biochemistry, 72, 1-2, 134-138, 1976).

[0026] The article (Yamakawa, T. et al.: Agricultural and Biological Chemistry, 1979, 43, 4, 879-880) described the limited stability of indoleacetic acid upon irradiation, where it was degraded by more than 90% upon exposure to blue light. Furthermore, the same article described the degradation of indoleacetic acid upon autoclaving at pH=2. At higher pH, indoleacetic acid should be stable. The authors of the article (Nissen, S. J. et al.: HortScience, 25, 800-802, 1990) disagree with this statement, they compared the stability of indole-3 -acetic and indole-3-butanoic acids upon autoclaving and irradiation. The degradation of indoleacetic acid occurred independently of pH (tested values 5 and 5.7). Both acids underwent degradation upon exposure to light. Indole-3 -butanoic acid showed higher stability. In an article (Hinman, R. L. et al.: Biochemistry, 4, 1, 144-158, 1965) the authors investigated the stability of indole derivatives in an oxidizing environment. Indoleacetic acid undergoes degradation by the action of peroxidase in the presence of oxygen, even in the absence of hydrogen peroxide. The ethyl ester of indoleacetic acid reacted significantly slower than indoleacetic acid alone. The oxidation reaction can be significantly accelerated by the addition of hydrogen peroxide.

[0027] Similar results were published by the authors of the article (Cohen, J. D. et al.: Planta, 139, 203-208, 1978). Indoleacetic acid was practically completely oxidized by the action of horseradish peroxidase, while its esters and amides were not oxidized. The reactions were carried out without hydrogen peroxide. According to the authors, the difference in reactivity may be due to steric reasons that prevent the binding of the substrate to the active site.

[0028] The oxidation of IAA and IAA ethyl ester by myeloperoxidase in neutrophils has been described (Escobar, J. A. et al.: Photochemistry and Photobiology, 55, 6, 895-902, 1992). Even in this case the addition of hydrogen peroxide is necessary for the reaction. The ethyl ester is metabolized even without prior hydrolysis.

[0029] In the article (Baldi, B. G. et al.: Plant Physiology, 91, 1, 9-12, 1989) the hydrolysis of IAA esters with glucose and nitrophenol under weakly basic conditions at pH=9 and higher was described.

[0030] Tryptophan and its metabolites, especially indoleacetic acid, are considered precursors of the aromatic compound 2-aminoacetophenone. Alkaline hydrolysis of a material with a presumed IAA content was studied (Hoenicke, K. et al.: Journal of Agriculture and Food Chemistry, 49, 11, 5494-5501, 2001).

[0031] In general, indoleacetic acid is chemically unstable and undergoes transformations under the influence of light, heat, acids or oxidizing agents. Indoleacetic acid esters are in some cases more stable, but still undergo various degradation reactions.

[0032] Use of indoleacetic acid and its derivatives

[0033] In an article (Weller, L. et al.: Journal of the American Chemical Society, 77, 4937- 4938, 1955) the effect of IAA esters with C6-C18 fatty alcohols on the parthenocarpic activity of tomatoes was investigated. Esters with Cl 4- 18 were less active than the parent acid, esters with Cl 1-12 were similarly active as the parent acid, and shorter esters were approximately 10 times more active than the parent acid.

[0034] According to the authors of the article (Qin, G. et al.: The Plant Cell, 17, 10, 2693-2704, 2005), the increased activity of esters compared to free IAA, which was observed in cell tests, may be due to the increased transport of esters due to their greater hydrophobicity. The authors studied this phenomenon on the IAA methyl ester.

[0035] According to the authors of another publication, the IAA methyl ester itself is not active and must be hydrolyzed by an appropriate enzyme (Yang, Y. et al.: Plant Physiology, 147, 3, 1034-1045, 2008).

[0036] The article (Wardman, P.: Current Pharmaceutical Design, 8, 1363-1374, 2002) describes the use of indoleacetic acid in combination with horseradish peroxidase for cancer therapy. Indoleacetic acid and its derivatives serve as a precursor of the skatole radical, which binds to DNA.

[0037] Another article describes the use of a combination of indoleacetic acid and specific red dyes for cytotoxic effects on tumor cell lines (Folkes, L. K. et al.: Cancer Research, 63, 4, 776- 779, 2003). Radicals were generated by irradiation with light of wavelength 630 nm.

[0038] Another use of the photo lability of indoleacetic acid was described in the article (Na, J-I. et al.: Lasers in Surgery and Medicine, 43, 3, 200-205, 2011). The authors used this ingredient as a photosensitizer for photodynamic therapy of acne vulgaris.

[0039] The article (Aimer, R. E. et al.: Journal of Medicinal Chemistry, 48, 20, 6174-6177, 2005) describes the preparation of 5-fluoro-2-methyl-l-sulfonylated indoleacetic acid as a CRTH2 receptor antagonist. These ingredients may be used for the treatment of inflammatory diseases.

[0040] In the patent (JP2015189670A, 2015), indoleacetic acid derivatives, substituted at positions 1 and 5 of the aromatic ring or on the methylene group, were described as inhibitors of organ fibrosis.

[0041] The patent (EP2968272B1, 2016) describes lipolytic indole derivatives for the treatment of adipose tissue disorders. Examples also include indoleacetic acid substituted with a bromine atom at position 5 of the indole ring or with an aldehyde group at position 2, 4, 5, 6 or 7 of the indole ring.

[0042] Cytotoxic and antibacterial derivatives of IAA with an attached triazolone ring have been described (Javaid, M. et al.: Frontiers in Pharmacology, 14, 1084181, 2023).

[0043] In general, it can be stated that indoleacetic acid can be used as a source of radicals or cytotoxic particles. Cases of using indoleacetic acid derivatives with a modified indole ring for the therapy of inflammatory diseases, organ fibrosis or adipose tissue disorders are described. Esterification of indoleacetic acid facilitates the transport of this ingredient in plants, thereby improving its effect. The use of indoleacetic acid esters in cosmetics has not yet been described. In general, indoleacetic acid, as one of the indole products of bacterial degradation of tryptophan, has a biological effect on microorganisms, plants and mammals. It is limitedly stable upon irradiation or heating and can be oxidized to form colored products.

[0044] It can also be stated that the preparation of indoleacetic acid esters is known. Indoleacetic acid esters can be prepared by activation with stoichiometric reagents (dicyclohexyl carbodiimide), alkylation with alkyl bromides or acid-catalyzed esterification. Most syntheses use a large excess of easily removable solvents, while other solvents (diethyl ether, dichloromethane, ethyl acetate) are used during the synthesis for extraction, chromatographic separation or crystallization. The stability of the prepared esters is usually not addressed by the authors of the articles.

[0045] The present invention addresses the preparation and use of indoleacetic acid hexyl ester with satisfactory stability and with a satisfactory number of by-products (causing undesirable odor) for use in cosmetic applications. This method is advantageous because it does not require the use of an additional solvent for dissolving reagents or for purifying the product. Furthermore, the consumption of hexanol required for synthesis is minimized and its removal is facilitated by adding water to the evaporated mixture. Furthermore, conditions were found under which a stable product is formed, which is not apparent from the prior art. Furthermore, this product is also odorless, which is a characteristic typical of indole derivatives, for example skatole, which can be formed by the degradation of indole acid (Liu, D. et al.: Nature Communications, 9, 4224, 2018). The method for preparing also affects the cytotoxic effect of the product.

[0046] The product prepared according to this invention is not cytotoxic on standard cell lines NHDF, HaCat and 3T3. Furthermore, it is not phototoxic, has anti-inflammatory effects and reduces endoplasmic reticulum stress. Thanks to these properties, it can be used, for example, in cosmetics.

[0047] Summary of the invention

[0048] The invention relates to a method for preparing indoleacetic acid hexyl ester according to the structural formula I and a method of use thereof: This derivative can be used for cosmetic purposes to improve skin properties.

[0049] The invention relates to a method for preparing an ester according to formula I, wherein indoleacetic acid is esterified with hexanol in the presence of sulfuric acid, then neutralized with sodium bicarbonate. The excess of hexanol is then removed by evaporation with water. Specifically, the method for preparing lies in preparing a suspension of indoleacetic acid in an amount of hexanol of 1.45-5 molar equivalents, preferably 3-3.5 equivalents, then sulfuric acid is added in an amount of 0.01-0.2 molar equivalents, preferably 0.05-0.10 molar equivalents, and the resulting mixture is stirred at 25-45°C, preferably at 35°C, for 18-72 hours, preferably for 24 hours. Sodium bicarbonate is added to the reaction mixture, in an amount of 2.5 - 20 molar equivalents with respect to sulfuric acid, at a temperature of 20 - 45°C, and the resulting salt is washed out with water. Then the aqueous phase is removed and water is subsequently added to the organic phase 1 - 8 times, preferably at least 3 times, in an amount of 0.5 - 2.5 volume equivalents with respect to hexanol, and the resulting mixture is evaporated on a rotary vacuum evaporator at a bath temperature of 35 - 55°C and a pressure of 10 - 30 mBar until all volatile ingredients are evaporated.

[0050] Sodium bicarbonate, which is used to neutralize sulfuric acid (and any indoleacetic acid residues), can be added to the mixture either as a 4-10 wt% aqueous solution or as a solid. If added as a solid, water is then added in an amount of 8.5-50 ml per 1 gram of sodium bicarbonate to dissolve and wash out the resulting salts.

[0051] Neutralization can be carried out at the temperature of the previous step, or generally at 20-45°C, or the mixture can be allowed to cool first, for example in air at room temperature, before neutralization. Neutralization is preferably carried out for 10 minutes to 21 hours. Stirring is not necessary, but is advantageous to accelerate neutralization.

[0052] In a preferred embodiment, the organic phase is washed with water and / or aqueous sodium bicarbonate solution after removal of the aqueous phase.

[0053] Evaporation on a vacuum evaporator is carried out by adding water to the organic mixture with the product, and the whole thing is evaporated on a vacuum evaporator. Once the mixture stops evaporating, another portion of water is added and the evaporation is repeated. This process is repeated until all volatile ingredients are removed.

[0054] The process described in this invention is more advantageous than analogous processes for esterification of indoleacetic acid in terms of lower solvent consumption for extraction, crystallization or chromatographic separation. It is also more advantageous in that the alcohol is removed at a lower temperature and higher pressure. It has also been shown that the method of preparation has a fundamental influence on the properties of the product. To prepare a suitable product, it is necessary to maintain a narrow range of preparation parameters, which is not obvious from the prior art. The method for preparing which provides a material with content of IAA hexyl ester higher than 85%, which contains more than 85% hexyl ester even after 6 months of storage, and which is odorless, is considered satisfactory.

[0055] When using a weak acid (Comparative Examples 1, 2 and 3) only a low conversion of indoleacetic acid to its hexyl ester is achieved.

[0056] The formation of undesirable odorous ingredients occurs during reaction at high temperature without the addition of an acid (Comparative Examples 4 and 5), during evaporation of alcohol at elevated temperature (Comparative Examples 6 and 7), during prolonged reaction time (Comparative Example 8) or during reaction with a longer alcohol than hexanol (Comparative Example 9).

[0057] Furthermore, the method of preparation has a fundamental influence on the stability of the product, where a decrease in the content of IAA hexyl ester over time occurs. Stability is reduced by preparation in a small amount of hexanol (Comparative Examples 10 - 14), long reaction time (Comparative Examples 13 and 14), too high reaction temperature (Comparative Examples 10, 11, 12 and 15), alkalization with an insoluble base (Comparative Examples 10, 15, 16, 17, 18, 19), omission of the evaporation step (Comparative Examples 10 and 11) or evaporation without addition of water (Comparative Examples 12, 15, 16 and 17). Unsatisfactory stability is also manifested in solutions of the materials prepared in this way in propane- 1,3 -diol (Example 29) and propylene glycol (Example 30). In addition, solutions with inadequate stability darken (Fig. 1 and 2).

[0058] Materials with unsatisfactory stability (Comparative Examples 10 and 18) further exhibit stronger cytotoxic effects (Example 32) than the material prepared according to the present invention (Example 25).

[0059] The indoleacetic acid hexyl ester prepared according to the present invention reduces the amount of misfolded or unfolded proteins in the endoplasmic reticulum, reduces the expression of pro-inflammatory cytokines and improves the expression of tight junction proteins.

[0060] The subject of the invention also includes compositions containing indoleacetic acid hexyl ester according to the structural formula I, prepared by the method according to the invention, in an amount of 0.001 - 1 wt%, which are suitable for use in cosmetics. These compositions may be in the form of a solution, emulsion (oil in water, water in oil, microemulsion or nanoemulsion), serum (aqueous, alcoholic, oily) or gel, paste, dispersion, powder or fine powder, nanofibers, microfibers, liposomes, oleosomes. The composition preferably, in addition to the IAA hexyl ester, also contains one or more ingredients selected from the group including oils, butters, waxes, emulsifiers, surfactants, thickeners, active ingredients and preservatives.

[0061] Cosmetic compositions in the form of an emulsion contain the following ingredients listed below in percentages by weight: indoleacetic acid hexyl ester 0.001% to 1%

[0062] - water 1 to 97.197% waxes 0.1 to 10%

[0063] - butters 0.1 to 25% oils 1 to 97.197% emulsifiers 0.5 to 20% surfactants 0.5 to 10% thickeners 0.1 to 20% preservatives 0.5 to 5% active ingredients 0.001 to 20% other excipients 0.001 to 5%

[0064] Cosmetic compositions in the form of oil and oil serums contain the following ingredients listed in percentages by weight: indoleacetic acid hexyl ester 0.001% to 1% oils 59 to 99.389% emulsifiers 0.1 to 5% active ingredients 0.01 to 15% stabilizers 0.5 to 20%

[0065] Cosmetic compositions in the form of an aqueous gel or serum contain the following ingredients, listed in percentages by weight: indoleacetic acid hexyl ester 0.001% to 1%

[0066] - water 19 to 97.979 % surfactants 0.5 to 20 % thickeners 0.5 to 15 % preservatives 0.5 to 5 % stabilizers 0.5 to 20% active ingredients 0.01 to 15% other excipients 0.01 to 5 %

[0067] Cosmetic compositions in the form of a paste contain the following ingredients, listed in percentages by weight: indoleacetic acid hexyl ester 0.001% to 1% surfactants 1 to 50% active ingredients 0.01 to 80% oils 0.01 to 30% waxes 0.1 to 5%

[0068] - butter 0.1 to 5% preservatives 0.1 to 5% other excipients 0.001 to 5%

[0069] Oils include, for example, jojoba, almond, grapeseed, argan, avocado, hemp, macadamia, olive, castor, sunflower, coconut, sesame, apricot, marula, linseed, borage, evening primrose, cottonseed, wetland, moringa, plum, poppy seed, rice, rosehip, safflower, sea buckthorn oil, wheat germ oil, medium chain saturated triacylglyceroles, such as caprylic / capric triglyceride, squalene, silicone oil, isoamyl laurate, isopropyl myristate, heptyl undecylate, or mixtures thereof.

[0070] Butters include, for example, coconut butter, cocoa butter, avocado butter, illipe butter, kokum butter, murumuru butter, mango butter, cupuacu butter, shea butter, ucuuba butter, or mixtures thereof.

[0071] Waxes include lanolin, beeswax, carnauba wax, candelilla wax, petrolatum, berry wax (Japan wax), myrica wax, sunflower wax, laurel wax, or mixtures thereof.

[0072] Emulsifiers include the following ingredients: glyceryl stearate, glyceryl stearate SE, glyceryl caprylate, behenyl alcohol, glyceryl behenate, cetearyl glucoside, methyl glucose sesqui stearate, glyceryl stearate citrate, polyglyceryl-3 stearate, cetearyl olivate, lecithin, stearyl alcohol, sorbitan oleate, sorbitan olivate, polysorbates, polyglyceryl-2-stearate, stearic acid, palmitic acid, cetyl alcohol, cetearyl alcohol, sodium acrylate, acrylate polymers, isohexadecane or mixtures thereof.

[0073] Surfactants include, for example, cocomidopropyl betaine, decyl glucoside, coco glucoside, lauryl glucoside, sodium lauryl sulfoacetate, sodium coco sulfate, sodium dodecyl sulfate, sucrose cocoate, sodium cocoyl isethionate, sodium lauroyl glutamate, sodium lauroyl methyl isethionate, sodium laureth sulfate, or various mixtures thereof.

[0074] Thickeners include, for example, carbomer, lysolecithin, sclerotium gum, xanthan gum, pullulan, cellulose derivatives, konjac fine powder (an extract from the root of Amorphophallus konjac acrylate compounds, polysorbates, or various mixtures thereof.

[0075] Active ingredients include both water-soluble and oil-soluble ingredients. These include, for example, vitamins A, D, E, K, C and vitamins B, glycerol, coenzyme Q10, allantoin, hydrolates, bisabolol, lactic acid, amino acids, AHA and BHA acids, ceramides, glycols, zinc, sulfur, azelaic acid, peptides, proteins, hyaluronic acid and its salts or derivatives, polysaccharides, schizophyllan, panthenol, urea, extracts from plants, fungi, algae, bacteria, ferments, lysates or filtrates from bacteria, yeasts or fungi, bakuchiol, resveratrol, essential oils, kaolin, clays, activated carbon, starches, sea salt, UV filters or mixtures thereof. In the case of hyaluronic acid and / or its salts and / or its derivatives, they can be used with any molecular weight.

[0076] Preservatives include, for example, groups of ingredients containing an aromatic acid or its derivatives such as benzoic acid, salicylic acid, dehydroacetic acid; potassium sorbate, sodium benzoate, parabens, alcohols such as ethanol, isopropyl alcohol, benzyl alcohol, phenoxyethanol, phenethyl alcohol; imidazole derivatives such as hydantoin, imidazolidinyl urea or cationic surfactants such as benzalkonium chloride, or mixtures thereof.

[0077] Excipients include, for example, chelating agents, sodium hydroxide, potassium hydroxide, citric acid, lactic acid, perfumes, pigments, dyes, mica, sodium chloride, fillers, triethanolamine, or mixtures thereof.

[0078] Description of the drawings

[0079] Fig. 1 - Appearance of 1% propanediol solutions of ingredients prepared according to Examples 10, 13, 18, 19, 25 and 27 and stored at 25°C after 0, 1, 2, 3 and 6 months of storage.

[0080] Fig. 2 - Appearance of 1% propylene glycol solutions of ingredients prepared according to Examples 10, 13, 18, 19 and 25 and stored at 25°C after 0, 1, 2, 3 and 6 months of storage.

[0081] Fig. 3 - Effect of hexyl ester on the viability of mouse embryonic fibroblasts (3T3). 3T3 fibroblasts were incubated with IAA hexyl ester prepared according to Examples 10, 18 and 25 as described in Example 32 (incubation for 24 h, 37°C, 5% CO2, and cell viability was subsequently determined by MTT). Propanediol (PD) was used as a solvent control. The data represent the mean ± SEM of 3 independent replicates.

[0082] Fig. 4 - Effect of IAA hexyl ester on the expression of tight junction proteins (OCLN, TJP1) and skin barrier proteins (DSG1, FLG2). Skin explants taken from the inner part of the ear pinna of a pig (Sus scrofa) were affected as described in Example 33 (24 h, 37°C) and the expression level of individual genes in the separated epidermis was subsequently determined by qRT-PCR. The data represent the mean ± SEM of 3 independent replicates.

[0083] Fig. 5 - Effect of IAA hexyl ester on the expression of CYP1A1, HM0X1, NRF2 and SOD2. PCR Cytochrome P450 (CYP1 Al), Heme oxygenase 1 (HM0X1), Nuclear transcription factor 2 (NRF2), Superoxide dismutase 2 (SOD2). Skin explants taken from the inner part of the ear pinna of a pig (Sus scrofa) were affected as described in Example 34 (24 h, 37°C), and the expression level of individual genes in the separated epidermis was subsequently determined by qRT-PCR. The data represent the mean ± SEM of 3 independent replicates.

[0084] Fig. 6 - Effect of IAA hexyl ester on IL6, IL8, COX2 expression. Skin explants taken from the inner part of the ear pinna of a pig (Sus scrofa) were irradiated with UVA / UVB corresponding to a dose of 80 mJ / cm2UVB and subsequently affected as described in Example 35 (24 h, 37°C), and the expression level of individual genes in the separated epidermis was subsequently determined by qRT-PCR. The data represent the mean ± SEM of 3 independent replicates.

[0085] Fig. 7 - Effect of IAA hexyl ester and its individual components at corresponding concentrations on EECh-induced protein aggregation in dermal fibroblasts detected fluorescently using thioflavin T. Results are normalized to cell viability measured using resazurin. The data represent the mean ± SEM of 3 independent replicates.

[0086] Fig. 8 - Effect of emulsions prepared as described in Example 37 on the expression of OCLN and SOD2 in the epidermis. Skin explants taken from the inner part of the ear pinna of a pig (Sus scrofa) were affected as described in Example 37 (24 h, 37°C), and the expression level of individual genes in the separated epidermis was subsequently determined by qRT-PCR. The data represent the mean ± SEM of 3 independent replicates.

[0087] Fig. 9 - Effect of oil sera prepared as described in Example 38 on the expression of OCLN and SOD2 in the epidermis. Skin explants taken from the inner part of the ear pinna of a pig (Sus scrofa) were affected as described in Example 33 (24 h, 37°C), and the expression level of individual genes in the separated epidermis was subsequently determined by qRT-PCR. The data represent the mean ± SEM of 3 independent replicates.

[0088] Fig. 10 - Effect of IAA hexyl ester prepared according to Example 27 on the viability of the epidermis. Skin explants taken from the inner part of the ear pinna of a pig (Sus scrofa) were affected as described in Example 38 (18 h, 37°C), and cell viability was subsequently determined using MTT. The data represent the mean ± SEM of 3 independent replicates.

[0089] Examples of embodiments

[0090] List of abbreviations used

[0091] COX2 = cyklooxygenase 2

[0092] CYP1A1 = cytochrome P450

[0093] DSG1 = desmoglein 1 eq = equivalent; refers to the molar amount of indoleacetic acid unless otherwise stated

[0094] FLG2 = filaggrin 2

[0095] HIA = indole-3 -acetic acid hexyl ester

[0096] HM0X1 = hem oxygenase 1

[0097] HPLC-UV - high-performance liquid chromatography with ultraviolet detection

[0098] IAA = indole-3 -acetic acid

[0099] IL6 = interleukin 6 IL8 = interleukin 8

[0100] IPA = 2-propanol

[0101] LC = liquid chromatography

[0102] LCHIA = mass fraction of indoleacetic acid hexyl ester according to LC; the ratio of peak areas of the analyzed samples and the standard was used for quantification. If the data is given in parentheses, it is the time of sample collection in months during stability testing.

[0103] MTT = 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide

[0104] NMR analysis = (700 MHz, CDCh, 8 ppm) 5 8.13 (br s, 1H, N-H); 7.66 (d, J = 8.27 Hz, 1H, Ar-H); 7.37 (d, J = 7.94 Hz, 1H, Ar-H); 7.23 (t, J = 7.60 Hz, 1H, Ar-H); 7.17 (s, 1H, Ar- H); 7.16 (t, J = 7.44 Hz, 1H, Ar-H); 4.14 (t, J = 6.72 Hz, 2H, COOCH2); 3.81 (s, 2H, ArCH2); 1.65 (p, J = 7.55 Hz, 2H, COOCH2CH2), 1.38 - 1.26 (m, 6H, CH2); 0.91 (t, J = 6.88 Hz, 3H, CH3).

[0105] NRF2 = nuclear factor erythroid 2-related factor 2

[0106] OCLN = occludin

[0107] PBS = phosphate buffered saline

[0108] RPL13 A = ribosomal protein LI 3 A

[0109] SDS = sodium dodecyl sulfate

[0110] SOD2 = superoxide dismutase 2

[0111] TJP1 = tight junction protein 1

[0112] XIA = indoleacetic acid conversion; this is a calculation from the 'H NMR spectrum as the ratio of the content of indoleacetic acid ester to the sum of the content of indoleacetic acid and its ester. The percentage is calculated from the formula XIA=(IIAE) / (IIAA + IIAE)X100%, where IIAE is the integral of the singlet signal at 3.74 ppm (CH2COOR) and IIAA is the integral of the singlet signal at 3.69 ppm (CH2COOH) from 'H NMR spectrum.

[0113] Example 1 - Comparative Example

[0114] Esterification of indoleacetic acid with hexanol in the presence of H3PO4

[0115] Phosphoric acid (0.003 mL, 0.06 mmol, 0.01 eq) was added to a suspension of indoleacetic acid (1.00 g, 6 mmol) and hexanol (2.15 mL, 17 mmol, 2.8 eq) with stirring at 35°C. The reaction mixture was stirred for 24 hours. The reaction mixture was then concentrated on a vacuum evaporator (35°C, 10 mBar). The product was analyzed using 'H NMR and LC.

[0116] XIA = 10 %

[0117] LCHIA = 13.1 % Example 2 - Comparative Example

[0118] Esterification of indoleacetic acid with hexanol in the presence of H3PO4

[0119] Phosphoric acid (0.015 mL, 0.29 mmol, 0.05 eq) was added to a suspension of indoleacetic acid (1.00 g, 6 mmol) and hexanol (2.15 mL, 17 mmol, 2.8 eq) with stirring at 35°C. The reaction mixture was stirred for 24 hours. The reaction mixture was then concentrated on a vacuum evaporator (35°C, 10 mBar). The product was analyzed using NMR and LC.

[0120] XIA = 37 %

[0121] LCHIA = 44.3 %

[0122] Example 3 - Comparative Example

[0123] Esterification of indoleacetic acid with hexanol in the presence of KHSO4

[0124] Potassium hydrogen sulfate (0.016 g, 0.12 mmol, 0.02 eq.) was added to a suspension of indoleacetic acid (1.00 g, 6 mmol) and hexanol (2.15 mL, 17 mmol, 2.8 eq) with stirring at 35°C. The reaction mixture was stirred for 24 hours. The reaction mixture was then concentrated on a vacuum evaporator (35°C, 10 mBar). The product was analyzed using NMR and LC.

[0125] XIA = 2 %

[0126] LCHIA = 1.8 %

[0127] Example 4 - Comparative Example

[0128] Esterification of indoleacetic acid with hexanol without addition of acid

[0129] A mixture of indoleacetic acid (0.10 g, 0.57 mmol) and hexanol (0.077 mL, 0.63 mmol, 1.1 eq) was heated to 140°C for 9 h under a nitrogen atmosphere. The reaction mixture was then concentrated on a vacuum evaporator (60°C, 15 mBar). The product and the reaction mixture have a strong odor. The product was analyzed using NMR and LC. IA=H %

[0130] LCHIA = 14.2 %

[0131] Example 5 - Comparative Example

[0132] Esterification of indoleacetic acid with hexanol without addition of acid

[0133] A mixture of indoleacetic acid (2.204 g, 13 mmol) and hexanol (3.09 mL, 25 mmol, 1.9 eq.) was heated to 140°C for 13 h under a nitrogen atmosphere. The reaction mixture was then concentrated on a vacuum evaporator (60°C, 15 mBar). The product and the reaction mixture have a strong odor. The product was analyzed using NMR and LC. XIA = 93 %

[0134] LCHIA = 93.7 %

[0135] Example 6 - Comparative Example

[0136] Esterification of indoleacetic acid with hexanol in the presence of H2SO4

[0137] Sulfuric acid (0.075 mL, 1.4 mmol, 0.05 eq.) was added to a suspension of indoleacetic acid (5 g, 29 mmol) in hexanol (10.75 mL, 86 mmol, 3.0 eq.) with stirring at 35°C. The reaction mixture was stirred for 24 hours at 35°C. Then the reaction mixture was cooled to room temperature and solid calcium carbonate (0.5 g, 5 mmol, 0.17 eq.) was added. The suspension was stirred for 30 minutes and then filtered through a frit. The filtrate was evaporated on a rotary vacuum evaporator (65°C, 10 mBar, 33 hours). The product has a strong odor. The product was analyzed using

[0138] XIA = 95 %

[0139] LCHIA = 95.7 %

[0140] Example 7 - Comparative Example

[0141] Esterification of indoleacetic acid with hexanol in the presence of H2SO4

[0142] Sulfuric acid (0.153 mL, 2.8 mmol, 0.1 eq.) was added to a suspension of indoleacetic acid (5 g, 29 mmol) in hexanol (10.75 mL, 86 mmol, 3 eq.) with stirring at 35°C. The reaction mixture was stirred for 24 hours at 35°C. Then the reaction mixture was cooled to room temperature and solid calcium carbonate (0.5 g, 5 mmol, 0.172 eq.) was added. The suspension was stirred for 30 minutes and then filtered through a frit. The filtrate was evaporated on a rotary vacuum evaporator (55°C, 10 mBar) with the addition of water (1 x 15 mL). The product has a strong odor. The product was analyzed using NMR and LC.

[0143] XIA= 97 %

[0144] LCHIA = 97.5 %

[0145] Example 8 - Comparative Example

[0146] Esterification of indoleacetic acid with hexanol in the presence of H2SO4

[0147] Sulfuric acid (0.075 mL, 1.4 mmol, 0.05 eq.) was added to a suspension of indoleacetic acid (5 g, 29 mmol) in hexanol (3.6 mL, 29 mmol, 1 eq.) with stirring at 35°C. The reaction mixture was stirred for 120 hours at 35°C. Then the reaction mixture was cooled to room temperature and solid calcium carbonate (0.5 g, 5 mmol, 0.172 eq.) was added. The suspension was stirred for 30 minutes and then filtered through a frit. The product and the reaction mixture have a pungent odor. The product was analyzed using NMR and LC.

[0148] XIA= 95 %

[0149] LCHIA = 90.7 %

[0150] Example 9 - Comparative Example

[0151] Esterification of indoleacetic acid with dodecanol in the presence of H2SO4

[0152] Sulfuric acid (0.075 mL, 1.4 mmol, 0.05 eq) was added to dodecanol (7.04 mL, 31 mmol, 1.1 eq) with stirring at 25°C. Indoleacetic acid (5 g, 29 mmol) was then added and the resulting reaction mixture was heated to 65°C and stirred for 24 hours. During this time, the mixture was homogenized. Then the reaction mixture was cooled to room temperature. The reaction mixture solidified. The product and the reaction mixture have a strong odor. The product was analyzed using

[0153] XIA = 96 %

[0154] Example 10 - Comparative Example

[0155] Esterification of indoleacetic acid with hexanol in the presence of H2SO4

[0156] Sulfuric acid (1.5 mL, 28 mmol, 0.05 eq.) was added to hexanol (79 mL, 630 mmol, 1.1 eq.) with stirring at 25°C. Indoleacetic acid (100 g, 570 mmol) was then added and the resulting reaction mixture was heated to 65°C and stirred for 24 hours. During this time, the mixture was homogenized. Then the reaction mixture was cooled to room temperature and solid calcium carbonate (10 g, 100 mmol, 0.175 eq.) was added. The suspension was stirred for 10 minutes and then filtered through a frit. The product was analyzed using NMR and LC.

[0157] XIA= 94 %

[0158] LCHIA = 90.8 % (0M); 85.9 % (IM); 82.5 % (2M); 77.9 % (3M); 70.2 % (6M).

[0159] Solution in propane- 1,3 -diol: LCHIA = 0.826 % (0M); 0.820 % (IM); 0.709 % (2M), 0.726 % (3M); 0.564 % (6M).

[0160] Solution in propylene glycol: LCHIA = 0.839 % (0M); 0.767 % (IM); 0.728 % (2M), 0.716 % (3M); 0.576 % (6M).

[0161] Example 11 - Comparative Example

[0162] Esterification of indoleacetic acid with hexanol in the presence of H2SO4

[0163] Sulfuric acid (0.075 mL, 1.4 mol, 0.05 eq.) was added to a suspension of indoleacetic acid (5 g, 29 mmol) in hexanol (3.94 mL, 31 mmol, 1.1 eq.) with stirring at 65°C. The reaction mixture was stirred for 25 hours at 65°C. Then the reaction mixture was cooled to room temperature, solid sodium bicarbonate (0.42 g, 5 mmol, 0.172 eq.) was added and, after dissolution, water (10 ml) was added. The mixture was stirred for 30 minutes and then the aqueous phase was removed. The organic phase was washed with water (3 ^ 15mL). The product was analyzed using

[0164] %IA=98 %

[0165] LCHIA = 92.3 % (0M); 86.5 % (IM); 83.2 % (2M); 80.5 % (3M); 77.1 % (6M).

[0166] Example 12 - Comparative Example

[0167] Esterification of indoleacetic acid with hexanol in the presence of H2SO4

[0168] Sulfuric acid (0.075 mL, 1.4 mol, 0.05 eq.) was added to a suspension of indoleacetic acid (5 g, 29 mmol) in hexanol (3.94 mL, 31 mmol, 1.1 eq.) with stirring at 60°C. The reaction mixture was stirred for 27 hours at 65°C. Then the reaction mixture was cooled to room temperature, solid sodium bicarbonate (0.42 g, 5 mmol, 0.172 eq.) was added and, after dissolution, water (10 ml) was added. The mixture was stirred for 30 minutes and then the aqueous phase was removed. The organic phase was washed with water (3 x 15mL) and then evaporated on a rotary vacuum evaporator (35°C, 10 mBar). The product was analyzed using and LC. %IA=98 %

[0169] LCHIA = 94.3 % (0M); 87.7 % (IM); 83.2 % (2M); 80.5 % (3M); 78.0 % (6M).

[0170] Example 13 - Comparative Example

[0171] Esterification of indoleacetic acid with hexanol in the presence of H2SO4

[0172] Sulfuric acid (0.075 mL, 1.4 mol, 0.05 eq.) was added to a suspension of indoleacetic acid (5 g, 29 mmol) in hexanol (3.94 mL, 31 mmol, 1.1 eq.) with stirring at 35°C. The reaction mixture was stirred for 144 hours at 35°C. Then the reaction mixture was cooled to room temperature, solid sodium bicarbonate (0.42 g, 5 mmol, 0.172 eq.) was added and, after dissolution, water (10 ml) was added. The mixture was stirred for 30 minutes and then the aqueous phase was removed. The organic phase was washed with water (3 x 15mL) and then evaporated on a rotary vacuum evaporator (45°C, 10 mBar). The product was analyzed using and LC. %IA=95 %

[0173] LCHIA = 88.5 % (0M); 83.7 % (IM); 82.2 % (2M); 80.5 % (3M); 79.0 % (6M). Solution in propane-1, 3-diol: LCHIA = 1.215 % (0M); 1.063 % (IM); 1.001 % (2M), 0.939 % (3M); 0.887 % (6M).

[0174] Solution in propylene glycol: LCHIA= 1.215 % (0M); 1.129 (IM); 0.997 % (2M), 0.928 % (3M); 0.794 (6M). Example 14 - Comparative Example

[0175] Esterification of indoleacetic acid with hexanol in the presence of H2SO4

[0176] Sulfuric acid (0.075 mL, 1.4 mol, 0.05 eq.) was added to a suspension of indoleacetic acid (5 g, 29 mmol) in hexanol (4.3 mL, 34 mmol, 1.2 eq.) with stirring at 35°C. The reaction mixture was stirred for 100 hours at 35°C. Then the reaction mixture was cooled to room temperature, solid sodium bicarbonate (0.42 g, 5 mmol, 0.172 eq.) was added and, after dissolution, water (10 ml) was added. The mixture was stirred for 30 minutes and then the aqueous phase was removed. The organic phase was washed with water (3 x 15 mL) and then evaporated on a rotary vacuum evaporator (45°C, 10 mBar) with repeated additions of water (5 x 25 mL). The product was analyzed using NMR and LC.

[0177] %IA=97 %

[0178] LCHIA = 96.5 % (0M); 92.7 % (IM); 89.5 % (2M); 86.2 % (3M); 84.5 % (6M).

[0179] Example 15 - Comparative Example

[0180] Esterification of indoleacetic acid with hexanol in the presence of H2SO4

[0181] Sulfuric acid (0.075 mL, 1.4 mmol, 0.05 eq.) was added to a suspension of indoleacetic acid (5 g, 29 mmol) in hexanol (10.7 mL, 86 mmol, 3 eq.) with stirring at 65°C. The reaction mixture was stirred for 22 hours at 65°C. Then the reaction mixture was cooled to room temperature and solid calcium carbonate (0.5 g, 5 mmol, 0.175 eq.) was added. The suspension was stirred for 30 minutes and then filtered through a frit. The filtrate was evaporated on a rotary vacuum evaporator (45°C, 10 mBar, 30 hours). The product was analyzed using LC.

[0182] %IA=98 %

[0183] LCHIA = 97.6 % (0M); 93.1 % (IM); 89.8 % (2M); 86.3 % (3M); 81.9 % (6M).

[0184] Example 16 - Comparative Example

[0185] Esterification of indoleacetic acid with hexanol in the presence of H2SO4

[0186] Sulfuric acid (0.075 mL, 1.4 mmol, 0.05 eq.) was added to a suspension of indoleacetic acid (5 g, 29 mmol) in hexanol (10.7 mL, 86 mmol, 3 eq.) with stirring at 35°C. The reaction mixture was stirred for 22 hours at 35°C. Then the reaction mixture was cooled to room temperature and solid calcium carbonate (0.5 g, 5 mmol, 0.175 eq.) was added. The suspension was stirred for 30 minutes and then filtered through a frit. The filtrate was evaporated on a rotary vacuum evaporator (45°C, 10 mBar, 30 hours). The product was analyzed using NMR and LC.

[0187] %IA=95 %

[0188] LCHIA = 95.5 % (0M); 91.1 % (IM); 86.8 % (2M); 85.5 % (3M); 82.0 % (6M). Example 17 - Comparative Example

[0189] Esterification of indoleacetic acid with hexanol in the presence of H2SO4

[0190] Sulfuric acid (0.075 mL, 1.4 mmol, 0.05 eq.) was added to a suspension of indoleacetic acid (5 g, 29 mmol) in hexanol (10.7 mL, 86 mmol, 3 eq.) with stirring at 35°C. The reaction mixture was stirred for 22 hours at 35°C. Then the reaction mixture was cooled to room temperature and solid calcium carbonate (0.29 g, 2.9 mmol, 0.1 eq.) was added. The suspension was stirred for 30 minutes and then filtered through a frit. The filtrate was evaporated on a rotary vacuum evaporator (45°C, 10 mBar, 21 hours). The product was analyzed using NMR and LC.

[0191] %IA=95 %

[0192] LCHIA = 93.5 % (0M); 93.1 % (IM); 88.9 % (2M); 86.5 % (3M); 81.8 % (6M).

[0193] Example 18 - Comparative Example

[0194] Esterification of indoleacetic acid with hexanol in the presence of H2SO4

[0195] Sulfuric acid (1.5 mL, 28 mmol, 0.05 eq.) was added to a suspension of indoleacetic acid (100 g, 570 mmol) in hexanol (215 mL, 1 710 mmol, 3 eq.) with stirring at 35°C. The reaction mixture was stirred for 24 hours at 35°C. Then the reaction mixture was cooled to room temperature and solid calcium carbonate (10 g, 100 mmol, 0.175 eq.) was added. The suspension was stirred for 10 minutes and then filtered through a frit. The filtrate was evaporated on a rotary vacuum evaporator (45°C, 20 mBar) with repeated additions of water (1 x 250 mL, 3 x 100 mL). The product was analyzed using LC.

[0196] %IA=98 %

[0197] LCHIA = 98.0 % (0M); 90.9 % (IM); 87.5 % (2M); 83.9 % (3M); 81.9 % (6M).

[0198] Solution in propane- 1,3 -diol: LCHIA = 0.890 % (0M); 0.890 % (IM); 0.860 % (2M), 0.845 % (3M); 0.805 (6M).

[0199] Solution in propylene glycol: LCHIA = 0.893 % (0M); 0.868 % (IM); 0.844 % (2M), 0.857 % (3M); 0.846 % (6M).

[0200] Example 19 - Comparative Example

[0201] Esterification of indoleacetic acid with hexanol in the presence of H2SO4

[0202] Sulfuric acid (1.5 mL, 28 mmol, 0.05 eq.) was added to a suspension of indoleacetic acid (100 g, 570 mmol) in hexanol (215 mL, 1 710 mmol, 3 eq.) with stirring at 35°C. The reaction mixture was stirred for 24 hours at 35°C. Then the reaction mixture was cooled to room temperature and solid calcium carbonate (10 g, 100 mmol, 0.175 eq.) was added. The suspension was stirred for 15 minutes and then filtered through a frit. The filtrate was evaporated on a rotary vacuum evaporator (40°C, 30 mBar) with repeated additions of water (1 x 250 mL, 11 x 100 mL). The product was analyzed using NMR and LC.

[0203] %IA=93 %

[0204] LCHIA = 88.5 % (0M); 82.5 % (IM); 81.3 % (2M); 80.7 % (3M); 80.5 % (6M).

[0205] Solution in propane- 1,3 -diol: LCHIA = 1.200 % (0M); 1.085 % (IM); 1.035 % (2M), 1.000 % (3M); 0.969 % (6M).

[0206] Solution in propylene glycol: LCHIA = 1.250 % (0M); 1.104 % (IM); 1.066 % (2M), 1.018 % (3M); 0.960 % (6M).

[0207] Example 20

[0208] Esterification of indoleacetic acid with hexanol in the presence of H2SO4

[0209] Sulfuric acid (0.003 mL, 0.06 mmol, 0.01 eq.) was added to a suspension of indoleacetic acid (1.00 g, 6 mmol) and hexanol (2.15 mL, 17 mmol, 2.8 eq.) with stirring at 35°C. The reaction mixture was stirred for 52 hours. Then the reaction mixture was cooled to room temperature, solid sodium bicarbonate (0.1 g, 1.2 mmol, 0.2 eq.) was added and after dissolving water (5 mL) was added. The mixture was stirred for 5 minutes and then the aqueous phase was removed. The organic phase was washed with water (2 x 5 mL) and then evaporated on a rotary vacuum evaporator (35°C, 10 mBar) with repeated additions of water (2 x 5 mL). The product was analyzed using LC.

[0210] %IA=88 %

[0211] LCHIA = 87.9 % (0M); 87.2 % (IM); 86.8 % (2M); 86.4 % (3M); 86.1 % (6M).

[0212] Example 21

[0213] Esterification of indoleacetic acid with hexanol in the presence of H2SO4

[0214] Sulfuric acid (0.015 mL, 0.28 mmol, 0.05 eq.) was added to a suspension of indoleacetic acid (1.00 g, 6 mmol) and hexanol (2.15 mL, 17 mmol, 2.8 eq.) with stirring at 35°C. The reaction mixture was stirred for 24 hours. Then the reaction mixture was cooled to room temperature, solid sodium bicarbonate (0.1 g, 1.2 mmol, 0.2 eq.) was added and after dissolving water (5 mL) was added. The mixture was stirred for 5 minutes and then the aqueous phase was removed. The organic phase was washed with water (2 x 5 mL) and then evaporated on a rotary vacuum evaporator (35°C, 10 mBar) with repeated additions of water (3 x 5 mL). The product was analyzed using LC.

[0215] XIA = 97 %

[0216] LCHIA = 97.4 % (0M); 95.8 % (IM); 95.2 % (2M); 94.9 % (3M); 92.9 % (6M). Example 22

[0217] Esterification of indoleacetic acid with hexanol in the presence of H2SO4

[0218] Sulfuric acid (0.075 mL, 1.4 mmol, 0.05 eq.) was added to a suspension of indoleacetic acid (5 g, 29 mmol) in hexanol (5.4 mL, 42 mmol, 1.45 eq.) with stirring at 25°C. The reaction mixture was stirred for 66 hours at 45°C. Then solution of sodium bicarbonate (0.48 g, 5.8 mmol, 0.2 eq.) in water (12 mL) was added. The mixture was stirred for 45 minutes at 45°C and then the aqueous phase was removed. The organic phase was washed with water (2 ^ 10 mL) and then evaporated on a rotary vacuum evaporator (55°C, 10 mBar) with addition of 15 mL of water. The product was analyzed using and LC.

[0219] %IA=96 %

[0220] LCHIA = 95.8 % (0M); 95.3 % (IM); 94.6 % (2M); 94.3 % (3M); 92.7 % (6M).

[0221] Example 23

[0222] Esterification of indoleacetic acid with hexanol in the presence of H2SO4

[0223] Sulfuric acid (0.075 mL, 1.4 mmol, 0.05 eq.) was added to a suspension of indoleacetic acid (5 g, 29 mmol) in hexanol (17.9 mL, 143 mmol, 5 eq.) with stirring at 25°C. The reaction mixture was stirred for 18 hours at 35°C. Then the reaction mixture was cooled to room temperature and then solution of sodium bicarbonate (1.2 g, 14.5 mmol, 0.5 eq.) in water (12 mL) was added. The mixture was stirred for 25 minutes and then the aqueous phase was removed. The organic phase was washed with water (2 x 10 mL) and then evaporated on a rotary vacuum evaporator (55°C, 10 mBar) with repeated additions of water (3 x 15 mL). The product was analyzed using

[0224] %IA=94 %

[0225] LCHIA = 93.4 % (0M); 92.9 % (IM); 92.2 % (2M); 90.8 % (3M); 89.9 % (6M).

[0226] Example 24

[0227] Esterification of indoleacetic acid with hexanol in the presence of H2SO4

[0228] Sulfuric acid (0.3 mL, 5.7 mmol, 0.2 eq.) was added to a suspension of indoleacetic acid (5 g, 29 mmol) in hexanol (10.7 mL, 86 mmol, 3 eq.) with stirring at 25°C. The reaction mixture was stirred for 19 hours at 25°C. Then solid sodium bicarbonate (1.2 g, 14.5 mmol, 0.5 eq.) was added and, after dissolution, water (10 ml) was added. The mixture was stirred for 45 minutes at 25°C and then the aqueous phase was removed. The organic phase was washed with water (2 x 10 mL) and then evaporated on a rotary vacuum evaporator (45°C, 10 mBar) with repeated additions of water (2 x 15 mL). The product was analyzed using NMR and LC. %IA=94 %

[0229] LCHIA = 88.2 % (0M); 87.5 % (IM); 87.1 % (2M); 86.4 % (3M); 85.9 % (6M).

[0230] Example 25

[0231] Esterification of indoleacetic acid with hexanol in the presence of H2SO4

[0232] Sulfuric acid (0.075 mL, 1.4 mmol, 0.05 eq.) was added to a suspension of indoleacetic acid (5 g, 29 mmol) in hexanol (10.75 mL, 86 mmol, 3 eq.) with stirring at 35°C. The reaction mixture was stirred for 24 hours at 35°C. Then the reaction mixture was cooled to room temperature, solid sodium bicarbonate (0.42 g, 5 mmol, 0.172 eq.) was added and, after dissolution, water (10 ml) was added. The reaction mixture was evaporated on a rotary vacuum evaporator (40°C, 30 mBar) with repeated additions of water (3 x 10 mL). The residue after evaporation was washed with water (3 x 10 mL). The product was analyzed using and LC.

[0233] XIA= 100 %

[0234] LCHIA = 100.0 % (0M); 98.4 % (IM); 97.4 % (2M); 95.9 % (3M); 95.6 % (6M).

[0235] Solution in propane- 1,3 -diol: LCHIA = 1.255 % (0M); 1.210 % (IM); 1.180 % (2M), 1.149 % (3M); 1.182 (6M).

[0236] Solution in propylene glycol: LCHIA = 1.225 % (0M); 1.207 % (IM); 1.153 % (2M), 1.131 % (3M); 1.135 (6M).

[0237] Example 26

[0238] Esterification of indoleacetic acid with hexanol in the presence of H2SO4

[0239] Sulfuric acid (0.075 mL, 1.4 mmol, 0.05 eq.) was added to a suspension of indoleacetic acid (5 g, 29 mmol) in hexanol (10.7 mL, 86 mmol, 3 eq.) with stirring at 35°C. The reaction mixture was stirred for 72 hours at 35°C. Then the reaction mixture was cooled to 20°C, solid sodium bicarbonate (0.42 g, 5 mmol, 0.172 eq.) was added and, after dissolution, water (10 ml) was added. The mixture was stirred for 1260 minutes and then the aqueous phase was removed. The organic phase was washed with sodium bicarbonate solution (0.42 g, 5 mmol, 0.172 eq.) in water (10 mL) and with water (2 x 10 mL) and then evaporated on a rotary vacuum evaporator (45°C, 30 mBar) with repeated additions of water (5 x 10 mL). The product was analyzed using 'H NMR and LC.

[0240] XIA= 100 %

[0241] LCHIA = 100.0 % (0M); 97.6 % (IM); 96.9 % (2M); 96.2 % (3M); 95.4 % (6M). Example 27

[0242] Esterification of indoleacetic acid with hexanol in the presence of H2SO4

[0243] Sulfuric acid (1.5 mL, 28 mmol, 0.05 eq.) was added to a suspension of indoleacetic acid (100 g, 570 mmol) in hexanol (215 mL, 1 710 mmol, 3 eq.) with stirring at 35°C. The reaction mixture was stirred for 24 hours at 35°C Then the reaction mixture was cooled to room temperature, solid sodium bicarbonate (8.4 g, 100 mmol, 0.175 eq.) was added and, after dissolving, water (100 mL) was added. The mixture was stirred for 5 minutes and then the aqueous phase was removed. The organic phase was washed with sodium carbonate solution (8.4 g, 100 mmol, 0.175 eq.) in water (100 mL) and with water (2 x 100 mL) and then evaporated on a rotary vacuum evaporator (45°C, 20 mBar) with repeated additions of water (2 x 250 mL, 6 x 100 mL). The product was analyzed using NMR and LC.

[0244] XIA= 100 %

[0245] LCHIA = 93.8 % (0M); 92.7 % (IM); 92.5 % (2M); 91.3 % (3M); 90.6 % (6M).

[0246] Solution in propane- 1,3 -diol: LCHIA = 0.94 % (0M); 0.926 % (IM); 0.929 % (2M), 0.929 % (3M); 0.899 % (6M).

[0247] Example 28

[0248] Stability of IAA hexyl ester samples

[0249] Ingredients prepared according to Examples 10 - 27 were stored in the dark at 25°C and after 1, 2, 3 and 6 months samples were taken and the content of indoleacetic acid hexyl ester LCHIA was measured. LCHIA values are given for individual examples.

[0250] Example 29

[0251] Stability of IAA hexyl ester solutions in propanediol

[0252] Ingredients prepared according to Examples 10, 13, 18, 19, 25 a 27 were diluted with propane- 1 ,3 -diol to a 1% concentration. The resulting solutions were stored in the dark at 25°C and after 1, 2, 3, and 6 months, samples were taken, an image recording was made and the content of indoleacetic acid hexyl ester LCHIA was measured. The image records are shown in Fig. 1. LCHIA values are given for individual examples.

[0253] Example 30

[0254] Stability of IAA hexyl ester solutions in propylene glycol

[0255] Ingredients prepared according to Examples 10, 13, 18, 19 a 25 were diluted with propylene glycol to a 1% concentration. The resulting solutions were stored in the dark at 25°C and after 1, 2, 3, and 6 months, samples were taken, an image recording was made and the content of indoleacetic acid ester LCHIA was measured. The image records are shown in Fig. 2. LCHIA values are given for individual examples.

[0256] Example 31

[0257] Effect of IAA hexyl ester on the viability of 3T3 fibroblasts depending on the method of its preparation

[0258] NIH-3T3 mouse embryonic fibroblasts (ATCC collection, USA) were incubated for 24 h (37°C, 5% CO2) with tested materials prepared according to Examples 10, 18 and 25 dissolved in propylene glycol, and subsequently diluted into culture medium (Dubelcco’s modified Eagle’s medium with fetal bovine serum (10%), 20 pM L glutamine and Peniciline / Streptomycine (100 U ml'VlOO pg ml'1) to the final concentration of propylene glycol 0.1%. Cell viability was then determined using MTT (Cole, S. P. C.: Cancer Chemotherapy and Pharmacology, 17, 259 - 263, 1986). Cells were cultured with MTT in culture medium (0.5 mg / mL, 37°C, 2,5 h). After removal of MTT, the cell monolayer was lysed and the resulting formazan dissolved by adding a solubilizing solution (45 % isopropanol, 45 % DMSO and 10 % Tritonu-X-100) and incubating for 30 minutes on a shaker. The absorbance of the resulting solutions was detected at 570 and 690 nm with a spectrophotometer (EnVision® 2105 Multimode Plate Reader, Perkin, Elmer, USA).

[0259] The results (Fig. 3) showed that the materials prepared according to Examples 10 and 18 significantly reduced cell viability even at a concentration of 30 pg / mL, while the material prepared according to Example 25 had a slight negative effect on cell viability at a concentration of 50 pg / mL according to EN ISO 10993-5.

[0260] Example 32

[0261] Effect of IAA hexyl ester on gene expression of occludin, tight junction protein 1, Filaggrin 2 and Desmoglein 1 in the epidermis

[0262] Pig (Sus scrofa) ears for this experiment were obtained from a local slaughterhouse as a byproduct. Skin explants were excised from the cleaned and shaved inner part of the ear pinna and incubated (2 h, 4-8°C) in culture medium (see Example 31) with Penicillin / Streptomycin (500 U ml_1 / 500 pg ml'1). They were then incubated on agar plates (1% agar in phosphate- buffered saline (PBS) and culture medium 1 : 1) with 0.001% or 0.01% IAA hexyl ester or 0.0007% or 0.007% IAA or 0.004% hexanol in a humid chamber (18 h, 37°C). In addition to the test ingredients, an unaffected control and caprylic / capric triglyceride used as a solvent for IAA hexyl ester, IAA and hexanol were also included in the experiment.

[0263] After incubation, a disc of epidermis (0 8 mm) was detached from the dermis using heat shock by immersing the skin explant in deionized water (60°C, 90 seconds). Total RNA was isolated from the epidermis sample by the guanidine thiocyanate-phenol acidic extraction method using TRI Reagent (Sigma Aldrich, USA) according to the instructions provided by the supplier. Reverse transcription was performed using the High Capacity cDNA Reverse Transcription Kit (Thermo Fisher Scientific, MA, USA) in a GenePro thermal cycler (Bioer Technology, China) according to the manufacturer's instructions. Subsequent qPCR was performed using a specific TaqMan gene expression assay for OCLN (Ss03377507_ul), for TJP1 (Ss03373514_m both Thermo Fisher Scientific, MA, USA), for FLG2 (qSscCEP0043559, BioRad, CA, USA), DSG1 (qSscCEP0030156, BioRad, CA, USA) and RPL13A (qSscCEP0037198, BioRad, CA, USA) as reference gene; and TaqMan Fast Advanced Master mix (Thermo Fisher Scientific, MA, USA) according to the supplier's recommendations in a one-step real-time PCR cycler (Thermo Fisher Scientific, MA, USA). Data were analyzed using the 2-AACt method. Data were normalized to negative controls. T-test was used for statistical data evaluation.

[0264] Filaggrin is a structural protein essential for the development and maintenance of the skin barrier. Desmoglein is a desmosomal carherin that enables intercellular junctions. Occludin and tight junction protein 1 are proteins of the tight junctions between epithelial cells, which further support the formation of the skin barrier. IAA hexyl ester significantly increased the expression of all monitored genes not only compared to the unaffected control, but also compared to IAA at lower and higher concentrations (10; 100 ug / mL) (Fig. 4).

[0265] Example 33

[0266] Effect of IAA hexyl ester on gene expression of Cytochrome P450, Hem oxygenase, Nuclear transcription factor 2 and Superoxide dismutase

[0267] Skin explants were treated and RNA isolated from the epidermis as described in Example 32. Subsequent qPCR was performed using a specific TaqMan gene expression assay for CYP1 Al (qSscCIP0026937, BioRad, CA, USA), for HMOX (Ss03378516_ul Thermo Fisher Scientific, MA, USA), for NRF2 (qSscCEP0028399, BioRad, CA, USA), SOD2 (qSscCEP0043531, BioRad, CA, USA) and RPL13A (qSscCEP0037198, BioRad, CA, USA) as a reference gene; and TaqMan Fast Advanced Master mix (Thermo Fisher Scientific, MA, USA) according to the supplier's recommendations in a one-step real-time PCR cycler (Thermo Fisher Scientific, MA, USA). Data were analyzed using the 2-AACt method. Data were normalized to negative controls. T-test was used for statistical data evaluation. The results are summarized in Fig. 5. IAA hexyl ester increases CYP1 Al expression, as does IAA, indicating activation of the Aryl hydrocarbon receptor. This receptor is critical not only for skin barrier development, but activation of its non-canonical signaling pathway also leads to NRF2 expression, which in turn leads to the expression of the antioxidant enzymes HM0X1 and SOD2. IAA hexyl ester increased the expression of NRF2, HM0X1 and SOD2 at both concentrations studied.

[0268] Example 34

[0269] Effect of IAA hexyl ester on gene expression of pro-inflammatory cytokines Interleukin 6, Interleukin 8 and Cyclooxygenase 2 in the epidermis

[0270] Skin explants were prepared as described in Example 32 and irradiated with UVA / UVB (80 mJ / cm2UVB) using a 300 W xenon arc lamp (Oriel Arc Lamp Housing, Newport, CA, USA) and 280-400 nm optical filters (Newport, CA, USA). They were then treated with 0.001% IAA hexyl ester or 0.0007% IAA or 0.004% hexanol in a humid chamber (18 h, 37°C). In addition to the test ingredients, an unaffected control and caprylic / capric triglyceride used as a solvent for IAA hexyl ester, IAA and hexanol were also included in the experiment. After incubation, an epidermis disc (08 mm) was separated from the dermis and RNA was isolated from it as described in Example 33. Subsequent qPCR was performed using a specific TaqMan gene expression assay for IL6 (Ss073083 l 6_g l Fisher Scientific, MA, USA), IL8 (Ss03392437_mlFisher Scientific, MA, USA) and COX2 (SsO3394694 ml Thermo Fisher Scientific, MA, USA), and RPL13A (qSscCEP0037198, BioRad, CA, USA) as a reference gene; and TaqMan Fast Advanced Master mix (Thermo Fisher Scientific, MA, USA) according to the supplier's recommendations in a one-step real-time PCR cycler (Thermo Fisher Scientific, MA, USA). Data were analyzed using the 2-AACt method. Data were normalized to negative controls. T-test was used for statistical data evaluation. The results are summarized in Fig. 6.

[0271] IAA hexyl ester effectively suppressed UV-induced increased expression of both pro- inflammatory cytokines IL6 and IL8, as well as the pro-inflammatory enzyme COX2. The effect of IAA hexyl ester was more pronounced than the effect of IAA and hexanol alone.

[0272] Example 35

[0273] Effect of IAA hexyl ester on the amount of misfolded or unfolded proteins in the endoplasmic reticulum

[0274] Normal human dermal fibroblasts isolated from the eyelid region (tissue obtained during plastic surgery, informed consent was obtained from all donors) were cultured in culture medium as described in Example 31. Cells were plated at appropriate density on a suitable panel and were cultured with H2O2 solution (500 pM) in culture medium (2 h, 37°C, 5% CO2), then rinsed with PBS and cultured with 0.001% IAA hexyl ester or 0.0007% IAA or 0.0004% hexanol (72 h, 37°C, 5% CO2). Cells were then rinsed with PBS and unfolded or misfolded proteins were detected according to the article Correia da Silva, D. et al.: Frontiers in Pharmacology, 13, 956154, 2022. Briefly: cells were incubated with culture medium with 5 pM Thioflavin T (1 h, 37°C, 5% CO2). Subsequently, fluorescence (excitation wavelength 450 nm, emission wavelength 482 nm) was detected with a spectrophotometer (EnVision® 2105 Multimode Plate Reader, Perkin, Elmer, USA). To determine cell viability, the thioflavin T medium was removed, the cells were rinsed with PBS and incubated with fresh culture medium containing 10 pg / mL resazurin (1 h, 37°C, 5% CO2). Fluorescence was detected (excitation wavelength 570 nm, emission wavelength 600 nm) with a spectrophotometer (EnVision® 2105 Multimode Plate Reader, Perkin, Elmer, USA). Data were normalized to the viability values of the unaffected control. The results are summarized in Fig. 7.

[0275] IAA hexyl ester reduces the formation of protein aggregates not only compared to the H2O2 control, but also to its individual components. Thus, it is able to reduce endoplasmic reticulum stress.

[0276] Example 36

[0277] Emulsions containing IAA hexyl ester prepared according to the Example 21

[0278] Table 1 : Emulsions used in the Example 36

[0279] First, the tested emulsions were prepared. The composition of the tested emulsions is given in Table 1. Phase A and phase B were prepared separately. These prepared phases were placed in water baths and heated to 75°C while stirring continuously, all ingredients had to be properly dissolved. Then phase A was added to phase B at higher speeds (290 rpm) to form an emulsion. The resulting emulsion was slowly cooled to max. 40°C while stirring continuously and then the water-soluble active ingredients were added. Slow cooling means removing from the water bath and cooling in air. Everything was mixed thoroughly and then the oil-soluble active ingredients were added and everything was mixed thoroughly again. The cooled emulsion was then preserved by adding phase E. The pH of the emulsion was then measured and adjusted using phase F.

[0280] Skin explants were prepared as described in Example 32, and then treated with the emulsions in Table 1 in a humid chamber (18 h, 37°C). In addition to the test ingredients, an unaffected control was also included in the experiment. After incubation, a disc of epidermis (08 mm) was separated from the dermis and RNA was isolated from it as described in Example 32. Subsequent qPCR was performed using a specific TaqMan gene expression assay for OCLN (Ss03377507_ul Thermo Fisher Scientific, MA, USA), pro SOD2 (qSscCEP0043531, BioRad, CA, USA) a RPL13A (qSscCEP0037198, BioRad, CA, USA) as reference gene; a TaqMan Fast Advanced Master mix (Thermo Fisher Scientific, MA, USA) according to the supplier’s recommendations in a one-step real-time PCR cycler (Thermo Fisher Scientific, MA, USA). Data were analyzed using the 2-AACt method. Data were normalized to negative controls. T- test was used for statistical data evaluation. The results are summarized in Fig. 8.

[0281] Hexyl ester incorporated into the emulsion (o / w) increased the expression of OCLN and SOD2 in the epidermis (Fig. 8). This phenomenon was observed both in the case of comparing the emulsion with hexyl ester versus the unaffected control or placebo emulsion, and in the case of comparing the emulsion with active ingredients and hexyl ester versus the unaffected control or emulsion with active ingredients.

[0282] Example 37

[0283] Oil serum containing IAA hexyl ester prepared according to the Example 27

[0284] Table 2 Oil serums used in the Example 37

[0285] First, oil serums were prepared and tested. The composition of these serums is given in Table 2. All ingredients were weighed together in a beaker and a stirrer was inserted. The mixture was stirred on an electromagnetic stirrer until all ingredients were dissolved.

[0286] Skin explants were prepared as described in Example 32, and then treated with the oil serums described in Table 2 in a humid chamber (18 h, 37°C). In addition to the test ingredients, an unaffected control was also included in the experiment. After incubation, a disc of epidermis (08 mm) was separated from the dermis and RNA was isolated from it as described in Example 32. Subsequent qPCR was performed using a specific TaqMan gene expression assay for OCLN (Ss03377507_ul Thermo Fisher Scientific, MA, USA), for SOD2 (qSscCEP0043531, BioRad, CA, USA) and RPL13A (qSscCEP0037198, BioRad, CA, USA) as reference gene; and TaqMan Fast Advanced Master mix (Thermo Fisher Scientific, MA, USA) according to the supplier’s recommendations in a one-step real-time PCR cycler (Thermo Fisher Scientific, MA, USA). Data were analyzed using the 2-AACt method. Data were normalized to negative controls. T-test was used for statistical data evaluation. The results are summarized in Fig. 9. Hexyl ester incorporated into oil serum increased the expression of OCLN and SOD2 in the epidermis (Fig. 9). This phenomenon was observed both in the case of comparing oil serum with hexyl ester versus unaffected control or placebo oil serum, and in the case of comparing oil serum with active ingredients and hexyl ester versus unaffected control or oil serum with active ingredients.

[0287] Example 38

[0288] Effect of hexyl ester prepared according to the Example 27 on the viability of the epidermis

[0289] Skin explants were prepared as described in Example 32 with the exception that 2 x 2 cm square explants were cut from the skin. These explants were placed in Franz cells with 320 pl of culture medium (Example 31) in the acceptor compartment. 100 pl of 0.5% or 1% IAA hexyl ester in caprylic / capric triglyceride was applied to the donor compartment. Caprylic / capric triglyceride was included in the experiment as a solvent control, 1% sodium dodecyl sulfate (500 pl) was included as a positive control and demineralized water as a solvent control for sodium dodecyl sulfate. Explants in Franz cells were incubated in a humid chamber (37°C, 18 h). The explants were then removed from the Franz cells and an epidermis sample was taken in the area defined by the donor cell space, as described in Example 32. The viability of the epidermis was determined using the MTT assay, as described in Example 31, with the following adjustment of conditions: MTT concentration 1 mg / mL, 3 h incubation with MTT.

[0290] IAA hexyl ester does not show a negative effect on epidermis viability at any of the tested concentrations (0.5%, 1%) (Fig. 10).

[0291] Example 39

[0292] Cosmetic compositions containing IAA hexyl ester prepared according to the Example 21

[0293] Table 3: Composition of an oil-in-water cosmetic emulsion containing IAA hexyl ester prepared according to the Example 27

[0294] Aqueous and oil phases are prepared and heated in a water bath to 75 °C and all ingredients are dissolved. Then the aqueous phase is added to the oil phase and they are emulsified at higher speeds (290 rpm). The resulting emulsion is slowly cooled to a maximum of 40°C while stirring continuously and water-soluble active ingredients are added. Everything is mixed thoroughly, and then the oil-soluble active ingredients are added and everything is mixed thoroughly again. The cooled emulsion is then preserved. If the pH is not between 5 and 6, it is adjusted with a 50% citric acid solution or a 30% potassium or sodium hydroxide solution.

[0295] Table 4: Composition of a water-in-oil cosmetic emulsion containing IAA hexyl ester prepared according to the Example 27

[0296] Aqueous and oil phases are prepared and heated in a water bath to 75 °C and all ingredients are dissolved. Then the aqueous phase (A) is added to the oil phase (B) and they are emulsified at higher speeds (290 rpm). The resulting emulsion is slowly cooled to a maximum of 40°C while stirring continuously and water-soluble active ingredients are added. Everything is mixed thoroughly, and then the oil-soluble active ingredients are added and everything is mixed thoroughly again. The cooled emulsion is then preserved. If the pH is not between 5 and 6, it is adjusted with a 50% citric acid solution or a 30% potassium or sodium hydroxide solution.

[0297] Table 5 Composition of a water-in-oil cosmetic emulsion containing IAA hexyl ester prepared according to the Example 27

[0298] Aqueous and oil phases are prepared and heated in a water bath to 75 °C and all ingredients are dissolved. Then the aqueous phase is added to the oil phase and they are emulsified at higher speeds (290 rpm). The resulting emulsion is slowly cooled to a maximum of 40°C while stirring continuously and water-soluble active ingredients are added. Everything is mixed thoroughly, and then the oil-soluble active ingredients are added and everything is mixed thoroughly again. The cooled emulsion is then preserved. If the pH is not between 5 and 6, it is adjusted with a 50% citric acid solution or a 30% potassium or sodium hydroxide solution.

[0299] Table 6 Composition of aqueous gel containing IAA hexyl ester prepared according to the Example 27

[0300] Phase A is prepared and all ingredients are dissolved. Separately phase B is prepared and again all ingredients are dissolved while stirring continuously. Then phase B is added to phase A and everything is mixed thoroughly. To the resulting solution (phase A+B), 30% NaOH (phase C) is added while stirring continuously. Phase D is added. If the pH is not between 5 and 6, it is adjusted with a 50% citric acid solution or a 30% potassium or sodium hydroxide solution.

[0301] Table 7 Composition of whipped butter containing IAA hexyl ester prepared according to the Example 21

[0302] Phase A is prepared, all ingredients are dissolved while stirring continuously in a water bath. After dissolution, the phase is cooled to room temperature and phase B is added while stirring continuously. The resulting mixture is placed in the refrigerator for about 1 hour to cool. Phase C is then whiped up into the cooled mixture. Table 8 Composition of aqueous serum containing IAA hexyl ester prepared according to the Example 27

[0303] Phase A is prepared, all ingredients are dissolved while stirring continuously. Then phase B is added to phase A and all ingredients are dissolved while stirring continuously. Phase C is added to phases AB while stirring continuously and everything is mixed thoroughly, then phase D is added and everything is mixed thoroughly again. If the pH is not between 5 and 6, it is adjusted with a 50% citric acid solution or a 30% potassium or sodium hydroxide solution. Table 9 Composition of oil serum containing IAA hexyl ester prepared according to the

[0304] Example 27 Phases A and B are prepared separately. Phase A is placed on the mixer and stirring begins, phase B is added gradually to phase A. Then phase C is added while stirring continuously and everything is mixed thoroughly. Table 10 Composition of a face paste for problematic skin containing IAA hexyl ester prepared according to the Example 27

[0305] Phase A is prepared and everything is mixed. Phase B is added gradually to phase A while stirring (one component at a time, which is mixed into the mixture, and then the next). Then phase D is added while stirring. Finally, phase C is added while stirring.

Claims

CLAIMS1. Method of preparation of indoleacetic acid hexyl ester according to the structural formula (I),characterized in that a suspension of indoleacetic acid and 1.45 - 5 molar equivalents of hexanol is prepared, the suspension is acidified with 0.01 - 0.20 molar equivalents of sulfuric acid, the resulting mixture is stirred at a temperature of 25 to 45°C for 18 to 72 hours, then neutralized with 2.5 - 20 molar equivalents of sodium bicarbonate with respect to sulfuric acid, where sodium bicarbonate is in the form of a 4-10 wt% aqueous solution or in the form of a solid ingredient followed by the addition of water in an amount of 8.5- 50 ml per gram of sodium bicarbonate, then the aqueous phase is removed, subsequently the excess hexanol is removed by vacuum evaporation at a temperature of 35 to 55 °C and a pressure of 1 to 3 kPa with 1 - 8 additions of water in an amount of 0.5 - 2.5 volume equivalents with respect to hexanol, resulting in the indoleacetic acid hexyl ester according to the structural formula (I) or a mixture of the indoleacetic acid hexyl ester according to the structural formula (I) and indoleacetic acid, wherein the weight ratio LCHIA of the indoleacetic acid hexyl ester in the mixture is higher than 85% and wherein the weight ratio LCHIA of the indoleacetic acid hexyl ester in the mixture after storage in darkness at 25°C for 0 to 6 months is higher than 85%.

2. The method of preparation of indoleacetic acid hexyl ester according to claim 1, characterized in that the amount of hexanol is 3 to 3.5 molar equivalents relative to indoleacetic acid and / or that the amount of sulfuric acid is 0.05 to 0.10 molar equivalents relative to indoleacetic acid.

3. The method of preparation of indoleacetic acid hexyl ester according to claim 1 or 2, characterized in that during neutralization, the mixture is stirred at a temperature of 20 to 45 °C for 10 minutes to 21 hours.

4. The method of preparation of indoleacetic acid hexyl ester according to any one of the preceding claims, characterized in that after removal of the aqueous phase, the organic phase is washed with an aqueous solution of sodium bicarbonate and / or water.

5. Use of indoleacetic acid hexyl ester, where the weight ratio LCHIA of the indoleacetic acid hexyl ester in the mixture of the indoleacetic acid hexyl ester according to the structural formula (I) and indoleacetic acid is higher than 85% and wherein the weight ratio LCHIA of the indoleacetic acid hexyl ester in the mixture after storage in darkness at 25°C for 0 to 6 months is higher than 85%, for the preparation of a cosmetic composition.

6. A cosmetic composition, characterized in that it comprises indoleacetic acid hexyl ester, having the weight ratio LCHIA of the indoleacetic acid hexyl ester in the mixture of the indoleacetic acid hexyl ester according to the structural formula (I) and indoleacetic acid higher than 85% and the weight ratio LCHIA of the indoleacetic acid hexyl ester in the mixture after storage in darkness at 25°C for 0 to 6 months higher than 85%, in an amount of 0.001% to l%wt.

7. The cosmetic composition according to claim 6, characterized in that it further comprises one or more ingredients selected from: oils, butters, waxes, emulsifiers, surfactants, thickeners, active ingredients and preservatives.

8. The cosmetic composition according to claim 7, wherein the oils are selected from the group comprising jojoba, almond, grape, argan, avocado, hemp, macadamia, olive, castor, sunflower, coconut, sesame, apricot, marula, linseed, borage, evening primrose, cottonseed, wetland, moringa, plum, poppy seed, rice, rosehip, safflower, sea buckthorn oil, wheat germ oil, medium-chain saturated triacylglycerols, such as caprylic / capric triglyceride, squalene, silicone oil, isoamyl laurate, isopropyl myristate, heptyl undecylate or mixtures thereof; the butters are selected from the group comprising coconut butter, cocoa butter, avocado butter, illipe butter, kokum butter, murumuru butter, mango butter, cupuacu butter, shea butter, ucuuba butter or mixtures thereof; the waxes are selected from the group comprising lanolin, beeswax, carnauba wax, candelilla wax, petrolatum, berry wax (Japan wax), myrica wax, sunflower wax, laurel wax or mixtures thereof; emulsifiers are selected from the group comprising glyceryl stearate, glyceryl stearate SE, glyceryl caprylate, behenyl alcohol, glyceryl behenate, cetearyl glucoside, methyl glucose sesqui stearate, glyceryl stearate citrate, polyglyceryl- 3 stearate, cetearyl olivate, lecithin, stearyl alcohol, sorbitan oleate, sorbitan olivate, polysorbates, polyglyceryl -2-stearate, stearic acid, palmitic acid, cetyl alcohol, cetearyl alcohol, sodium acrylate, acrylate polymers, isohexadecane or mixtures thereof; surfactants are selected from the group comprising cocomidopropyl betaine, decyl glucoside, coco glucoside, lauryl glucoside, sodium lauryl sulfoacetate, sodium cocosulfate, sodium dodecyl sulfate, sucrose cocoate, sodium cocoyl isethionate, sodium lauroyl glutamate, sodium lauroyl methyl isethionate, sodium laureth sulfate or various mixtures thereof; thickeners are selected from the group comprising carbomer, lysolecithin, sclerotium gum, xanthan gum, pullulan, cellulose derivatives, konjac fine powder (extract from the root of Amorphophallus konjac), acrylate compounds, polysorbates or mixtures thereof; the active ingredients are selected from the group including vitamins A, D, E, K, C and vitamins B, glycerol, coenzyme Q10, allantoin, hydrolates, bisabolol, lactic acid, amino acids, alpha-hydroxy acids and beta-hydroxy acids, ceramides, glycols, zinc, sulfur, azelaic acid, peptides, proteins, hyaluronic acid and its salts or derivatives, polysaccharides, schizophyllan, panthenol, urea, extracts from plants, fungi, algae, bacteria, ferments, lysates or filtrates from bacteria, yeasts or fungi, bakuchiol, resveratrol, essential oils, kaolin, clays, activated carbon, starches, sea salt, UV filters or mixtures thereof; preservatives are selected from the group comprising benzoic acid, salicylic acid, dehydroacetic acid; potassium sorbate, sodium benzoate, parabens, ethanol, isopropyl alcohol, benzyl alcohol, phenoxyethanol, phenethyl alcohol, hydantoin, imidazolidinyl urea, benzalkonium chloride or mixtures thereof; excipients are selected from the group comprising chelating agents, sodium hydroxide, potassium hydroxide, citric acid, lactic acid, perfumes, pigments, dyes, mica, sodium chloride, fillers, triethanolamine or mixtures thereof.

9. The cosmetic composition according to claim 7 or 8, characterized in that it is in the form of a solution, emulsion, serum or gel, paste, dispersion, powder, fine powder or nanofibers.

10. The cosmetic composition according to claim 9, characterized in that it is in the form of emulsion and comprises: indoleacetic acid hexyl ester in an amount of 0.001% to 1% by weight- water in an amount of 1 to 97.197% by weight- waxes in an amount of 0.1 to 10% by weight- butters in an amount of 0.1 to 25% by weight oils in an amount of 1 to 97.197% by weight emulsifiers in an amount of 0.5 to 20% by weight surfactants in an amount of 0.5 to 10% by weight- thickeners in an amount of 0.1 to 20% by weight preservatives in an amount of 0.5 to 5% by weight active ingredients in an amount of 0.001 to 20% by weightother excipients in an amount of 0.001 to 5% by weight11. The cosmetic composition according to claim 9, characterized in that it is in the form of an oil or oil serum and comprises: indoleacetic acid hexyl ester in an amount of 0.001% to 1% by weight oils in an amount of 59 to 99,389% by weight emulsifiers in an amount of 0.1 to 5% by weight active ingredients in an amount of 0.01 to 15% by weight stabilizers in an amount of 0.5 to 20% by weight12. The cosmetic composition according to claim 9 characterized in that it is in the form of an aqueous gel or serum and contains: indoleacetic acid hexyl ester in an amount of 0.001% to 1% by weight- water in an amount of 1 to 97.979% by weight surfactants in an amount of 0.5 to 20% by weight- thickeners in an amount of 0.5 to 15% by weight preservatives in an amount of 0.5 to 5% by weight stabilizers in an amount of 0.5 to 20% by weight active ingredients in an amount of 0.01 to 15% by weight other excipients 0.01 to 5% by weight13. The cosmetic composition according to claim 9, characterized in that it is in form of paste and contains: indoleacetic acid hexyl ester in an amount of 0.001% to 1% by weight- water in an amount of 1 to 50% by weight active ingredients in an amount of 0.01 to 80% by weight oils in an amount of 0.01 to 30% by weight- waxes in an amount of 0.1 to 5% by weight- butter in an amount of 0.1 to 5% by weight preservatives in an amount of 0.1 to 5% by weight other excipients 0.001 to 5% by weight

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