Urea derivatives, methods for producing the same, and uses thereof

Abstract

The present invention aims to provide a urea derivative having excellent gelling ability, a gelling agent containing the urea derivative as an active ingredient, a cosmetic composition containing the gelling agent, and a method for efficiently producing the urea derivative. [Solution] The urea derivative according to the present invention is characterized by being represented by the following formula (I). TIFF2026112244000006.tif39105 [In the formula, R 1 is C 6-20 This represents an aliphatic hydrocarbon group, where n is an integer between 1 and 6.

Description

[Technical Field]

[0001] The present invention relates to a urea derivative having excellent gelling ability, a gelling agent containing the urea derivative as an active ingredient, a cosmetic composition containing the gelling agent, and a method for efficiently producing the urea derivative. [Background technology]

[0002] For example, liquid cosmetics such as lotions and emulsions are certainly useful in themselves, but sometimes gelling is required to prevent dripping. Similarly, with liquid pesticides, it is sometimes desirable to retain them on the target crop as much as possible after application. For liquid medicines, infants and the elderly may find it easier to ingest if the solution has a certain viscosity rather than being a simple aqueous solution or suspension.

[0003] To gel a liquid, a gelling agent is used, and there are two types of gelling agents: polymer gelling agents and low molecular weight gelling agents. Polymer gelling agents generally exhibit relatively superior gelling ability. However, polymer gelling agents can remain on the skin and cause stickiness. Furthermore, gel-type cosmetics, for example, require thixotropy, meaning they flow when applied and solidify or gel after application to prevent dripping. However, it is difficult to obtain a gel exhibiting thixotropy from polymer gelling agents. Moreover, compositions containing polymer gelling agents have difficulty penetrating nano-sized pores. Therefore, in recent years, various low molecular weight gelling agents have been investigated. Low molecular weight gelling agents are thought to self-assemble to form fibrous structures, which intertwine to form a three-dimensional network structure, and then incorporate the solvent into the voids to gel. Because this self-assembly exhibits thermal reversibility, the resulting gel also exhibits thermal reversibility.

[0004] For example, the present inventors' research group has developed a low-molecular-weight gelling agent for ionic liquids (Patent Document 1). Because ionic liquid gels are conductive, they may be usable as electrolytes that are less prone to leakage in applications such as fuel cells and secondary batteries. On the other hand, hydrogels with water as the main solvent may be applicable to cosmetics, pharmaceuticals, and culture media that come into direct contact with living organisms. In particular, for such gel-like cosmetics, it is desirable that they have low toxicity and high safety, decompose quickly after use, and have a low environmental impact and are easy to dispose of.

[0005] For example, Patent Documents 2 and 3 disclose short-chain lipid peptides that can be used as gelling agents for forming hydrogels. Patent Documents 4 to 6 disclose gelling agents in which long-chain aliphatic groups are substituted onto dipeptides, histidines, or amino acid oligomers, respectively. Peptides are considered to be highly safe and highly degradable. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] International Publication No. 2014 / 051057 Pamphlet [Patent Document 2] International Publication No. 2009 / 005151 Pamphlet [Patent Document 3] International Publication No. 2009 / 005152 Brochure [Patent Document 4] International Publication No. 2010 / 013555 Pamphlet [Patent Document 5] Japanese Patent Publication No. 2011-57620 [Patent Document 6] International Publication No. 2013 / 047458 brochure [Overview of the project] [Problems that the invention aims to solve]

[0007] As described above, various low-molecular-weight gelling agents have been studied. However, there is a need for a gelling agent that is even more excellent in gelling ability and can increase the viscosity of a composition containing water as a solvent even at a lower concentration. Therefore, an object of the present invention is to provide a urea derivative having excellent gelling ability, a gelling agent containing the urea derivative as an active ingredient, a cosmetic containing the gelling agent, and a method capable of efficiently producing the urea derivative.

Means for Solving the Problems

[0008] The present inventors have conducted intensive studies to solve the above problems. As a result, they have found that a urea derivative having a specific structure exhibits excellent gelling ability, and thus completed the present invention. Hereinafter, the present invention will be described.

[0009] [1] A urea derivative or a salt thereof, characterized by being represented by the following formula (I).

Chemical formula

[0010] [3] A gelling agent, characterized by containing the urea derivative according to [1] or [2] above as an active ingredient. [4] A cosmetic, characterized by containing the gelling agent according to [3] above. [5] An aqueous electrolyte, characterized by containing the gelling agent according to [3] above and water. [6] An aqueous metal ion battery, characterized by containing the aqueous electrolyte according to [5] above.

[0011] [7] A method for producing a urea derivative or a salt thereof, comprising The urea derivative is represented by the following formula (I), A method characterized by including a step of reacting an isocyanate compound represented by the following formula (II) with a dipeptide compound represented by the following formula (III).

Chemical formula

[0012] C 6-20 Examples of the aliphatic hydrocarbon group include a C 6-20 alkyl group, a C 6-20 alkenyl group, and a C 6-20 alkynyl group, and a C 6-20 alkyl group is preferred. Also, a C 8-16 aliphatic hydrocarbon group is preferred, a C 10-14 aliphatic hydrocarbon group is more preferred, and a C 11-13 aliphatic hydrocarbon group is even more preferred. Generally, it can be said that the higher the number of carbon atoms in the aliphatic hydrocarbon group, the better the gelability of the urea derivative (I), and the lower the toxicity when the number is smaller.

[0013] In the present disclosure, the C 6-20 alkyl group refers to a linear or branched monovalent saturated aliphatic hydrocarbon group having 6 or more and 20 or less carbon atoms. For example, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, etc. may be mentioned. Preferably it is a C 8-16 alkyl group, more preferably a C 10-14 alkyl group, and even more preferably a C 11-13 alkyl group.

[0014] C 6-20 An alkenyl group is a linear or branched monounsaturated aliphatic hydrocarbon group having 6 to 20 carbon atoms and at least one carbon-carbon double bond. Examples include hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, and icocenyl. Preferably C 8-16 It is an alkenyl group, more preferably C 10-14 It is an alkenyl group, and more preferably C 11-13 It is an alkenyl group.

[0015] C 6-20 An alkynyl group is a linear or branched monounsaturated aliphatic hydrocarbon group having 6 to 20 carbon atoms and at least one carbon-carbon triple bond. Examples include hexynyl, heptynyl, octinyl, noninyl, desinyl, undecynyl, dodecynyl, tridecynyl, tetradecynyl, pentadecynyl, hexadesinyl, heptadecynyl, octadecynyl, nonadesinyl, icosinyl, etc. Preferably C 8-16 It is an alkynyl group, more preferably C 10-14 It is an alkynyl group, and more preferably C 11-13 It is an alkynyl group.

[0016] The number of methylene groups (-CH2-) in the urea derivative (I), n, is preferably 4 or less, more preferably 3 or less, and even more preferably 1 or 2. When n=1, the C-terminal amino acid is alanine; when n=2, it is β-alanine; and when n=3, it is 4-aminobutyric acid. Furthermore, the dipeptide composed of β-alanine and histidine is called carnosine, and L-carnosine is known as a radical scavenger in living organisms. [Effects of the Invention]

[0017] The urea derivative according to the present invention has excellent gelling ability, and can gel liquids with water as the main solvent even at low concentrations. Furthermore, because it is highly safe, it can be used as a component of compositions that are applied directly to living organisms, such as cosmetics and pharmaceuticals. Moreover, because it is a short-chain peptide, it is easily decomposed by enzymes exhibiting peptidase activity after use, making it safe in this respect as well. On top of that, the urea derivative according to the present invention can be easily synthesized. Therefore, the gelling agent according to the present invention is extremely useful as a hydrogel component for cosmetics, pharmaceuticals, pesticides, contact lenses, diapers, culture media, fragrances, soil substitutes for plant growth, drying inhibitors, carriers for chromatography, electrolytes, and carriers for the synthesis of compounds such as proteins. [Brief explanation of the drawing]

[0018] [Figure 1] Figure 1 is a graph showing the results of cytotoxicity tests of the urea derivative according to the present invention and a conventional gelling agent, an amide derivative. [Figure 2] Figure 2 is a graph showing the results of cytotoxicity tests of the urea derivative according to the present invention and a conventional gelling agent, an amide derivative. [Modes for carrying out the invention]

[0019] The present invention will be described below with specific examples, but the present invention is not limited to the following examples. In this disclosure, "compound represented by formula (x)" may be abbreviated as "compound (x)".

[0020] In the urea derivative (I) according to the present invention, the carboxyl group (-CO2H) is -CO2 - It is also acceptable for the imino groups in the imidazole group (=NH and =N- respectively) to be in the same state as =NH2 + and =NH + -The state may be such that salts are formed. Furthermore, salts may be formed intramolecularly or between molecules, and salts may be formed with acids.

[0021] The salts of the urea derivative (I) according to the present invention are not particularly limited, but examples include inorganic acid salts such as hydrogen chloride, hydrobromide, hydroiodide, sulfate, nitrate, perchlorate, and phosphate; organic acid salts such as oxalate, malonate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, and trifluoromethanesulfonate; acidic amino acids such as glutamate and aspartate; alkali metal salts such as lithium salt, sodium salt, and potassium salt; group 2 metal salts such as calcium salt and magnesium salt; and organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt, and benzalkonium salt.

[0022] The urea derivative (I) according to the present invention is useful as an active ingredient in a gelling agent that increases the viscosity of a liquid. In this disclosure, gelation includes not only gelation in the narrow sense, which makes a liquid insoluble, but also gelation in the broad sense, which increases the viscosity of a liquid while maintaining its solubility and compatibility. The definition of gelation is not particularly limited, but for example, gelation can be defined as the liquid not flowing even after dissolving a gelling agent in a liquid in a test tube and letting it stand at room temperature for 24 hours, and then inverting the test tube.

[0023] Examples of solvents for the liquid to be gelled include water and mixed solvents of a water-miscible organic solvent and water. A water-miscible organic solvent refers to an organic solvent that is miscible with water without limitation, and examples include water-miscible alcohol solvents such as methanol, ethanol, and 2-propanol; water-miscible ketone solvents such as acetone; water-miscible amide solvents such as dimethylformamide and dimethylacetamide; and water-miscible sulfoxide solvents such as dimethyl sulfoxide. The proportion of water in the mixed solvent is preferably 50% by volume or more, more preferably 60% by volume or more or 80% by volume or more, and even more preferably 90% by volume or more, 95% by volume or more or 98% by volume or more. In this disclosure, the proportion of water refers to the ratio of the volume of water to the total volume of water and the volume of the water-miscible organic solvent before mixing.

[0024] The gelling agent according to the present invention may contain, in addition to the urea derivative (I), other components preferred as gelling agents. The other components are not particularly limited, but examples include surfactants, swelling agents, antifreeze agents, viscosity modifiers, pH adjusters, and ionic strength adjusters.

[0025] If the gelling agent according to the present invention contains components other than the urea derivative (I), the proportion of these components is not particularly limited and can be adjusted as appropriate. For example, the proportion of these components can be 0.1% by mass or more and 50% by mass or less relative to the total amount of the urea derivative (I) and the other components. The proportion is preferably 0.5% by mass or more, more preferably 1% by mass or more, preferably 10% by mass or less, and more preferably 5% by mass or less. Of course, the above-mentioned other components do not need to be included.

[0026] Furthermore, the gelling agent according to the present invention may contain a solvent. Examples of solvents include water, a mixed solvent of water and a water-miscible organic solvent, and an oil-in-water emulsion. Examples of mixed solvents are the same as those mentioned above. Examples of oil phases in an oil-in-water emulsion include edible oil, mineral oil, gasoline, kerosene, ether-based solvents, aromatic hydrocarbon solvents such as toluene, ionic liquids, and fluorinated solvents.

[0027] Conventional hydrogelling agents can gel when mixed at a concentration of approximately 3% by mass or more relative to the total aqueous solution. In contrast, the gelling agent according to the present invention can gel when the ratio of urea derivative (I) to the liquid to be gelled is 0.06% by mass or more.

[0028] The liquid to be gelled by the gelling agent according to the present invention may be water or the mixed solvent alone, a solution with water or the mixed solvent as the main solvent, or a dispersion with water or the mixed solvent as the main solvent. Such a solution may be a buffer solution, or it may contain a surfactant, a swelling agent, an antifreeze, a viscosity modifier, a pH adjuster, an ionic strength adjuster, a fragrance, etc. However, the pH of such an aqueous solution is preferably 3.0 or higher and 9.0 or lower, and more preferably 6.0 or higher and 8.0 or lower.

[0029] The liquid to be gelled may contain water-miscible organic solvents other than water, or an oil phase that forms oil droplets in an oil-in-water emulsion. However, since such water-miscible organic solvents and oil phases may inhibit gelation, the ratio of water-miscible organic solvents and oil phases to the liquid to be gelled is preferably 30% by mass or less, more preferably 15% by mass or less, or 10% by mass or less, and even more preferably 1% by mass or less.

[0030] The amount of gelling agent used according to the present invention may be adjusted as appropriate. For example, the urea derivative (I) may be added and mixed so that its ratio to the liquid to be gelled is 0.05% by mass or more, and the amount may be increased as appropriate while observing the gelling process. The amount is preferably 2.0% by mass or less, more preferably 1.5% by mass or less, and even more preferably 1.0% by mass or less or 0.5% by mass or less, within the range in which gelling is possible.

[0031] A liquid to which the gelling agent according to the present invention has been added may have thixotropic properties. Specifically, the storage modulus (G') of the gel is 3 times or more relative to the loss modulus (G”). That is, the gel formed by adding the gelling agent according to the present invention has high viscosity when stationary, suppressing dripping, while being easily spreadable, and may have particularly desirable properties as a gel-like cosmetic. The above ratio is more preferably 4 times or more, and even more preferably 5 times or more.

[0032] The urea derivative (I) according to the present invention can be easily synthesized by simply reacting an isocyanate compound (II) with a dipeptide compound (III).

[0033] Specifically, for example, isocyanate compound (II) can be added to a solution of dipeptide compound (III) under basic conditions.

[0034] The solvent for the solution of dipeptide compound (III) is not particularly limited as long as it can adequately dissolve dipeptide compound (III) and does not inhibit the reaction with isocyanate compound (II). Examples include water; alcohol solvents such as methanol, ethanol, and 2-propanol; nitrile solvents such as acetonitrile; halogenated aliphatic hydrocarbon solvents such as dichloromethane and chloroform; ketone solvents such as acetone; ether solvents such as diethyl ether and tetrahydrofuran; and mixed solvents of two or more of these. The concentration of dipeptide compound (III) in the solution can be adjusted as appropriate, but for example, it can be between 5 mg / mL and 50 mg / mL.

[0035] Examples of bases used to make the solution of dipeptide compound (III) basic include alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal carbonates such as sodium carbonate and potassium carbonate; trialkylamines such as triethylamine and diisopropylethylamine; and aromatic organic bases such as pyridine and bis(dimethylamino)naphthalene. The base should be added until the pH of the solution of dipeptide compound (III) is between 7.5 and 9.

[0036] Under basic conditions, isocyanate compound (II) can be added to a solution of dipeptide compound (III). Isocyanate compound (II) may be added directly or as a solution. The solvent for the solution of isocyanate compound (II) can be the same as the solvent for the solution of dipeptide compound (III).

[0037] After adding the isocyanate compound (II), the reaction mixture can be stirred or shaken while the reaction proceeds. The reaction conditions can be adjusted as appropriate depending on the solvent, etc., but for example, they can be set to a temperature between room temperature and 80°C. The reaction may also be carried out under heated reflux conditions. The reaction time can be determined by preliminary experiments or until the consumption of the isocyanate compound (II) or dipeptide compound (III) is confirmed by thin-layer chromatography, etc., but for example, it can be between 1 hour and 50 hours.

[0038] After the reaction is complete, standard workup procedures can be carried out. For example, some or all of the solvent can be removed by vacuum distillation after the reaction. Then, the target compound, urea derivative (I), can be purified by repeating precipitation and washing using a poor solvent.

[0039] The urea derivative (I) and gelling agent according to the present invention can be used in various fields, such as cosmetics, pharmaceuticals, and pesticides, to increase the viscosity of liquids. In particular, since the urea derivative (I) is a low molecular weight compound, the gel formed with the urea derivative (I) and gelling agent according to the present invention exhibits thixotropy. For example, when spreading cosmetics on the skin or spraying pesticides, the viscosity is low, making spreading and spraying easy. However, after spreading or spraying, the viscosity increases, making dripping less likely. Furthermore, liquid drugs can be difficult for children and the elderly to take, but increasing the viscosity with the urea derivative (I) and gelling agent according to the present invention can make them easier to take. When culturing cells using a culture medium, shaking culture is sometimes used for efficient cell proliferation. However, if the viscosity of the culture medium is low, there is a risk of leakage due to shaking. Therefore, it is preferable to increase the viscosity of the culture medium with the urea derivative (I) and gelling agent according to the present invention. Fragrances, soil substitutes for plant cultivation, and electrolytes can also be improved in terms of usability by increasing their viscosity. Furthermore, if the urea derivative (I) and gelling agent according to the present invention are added to the engine's radiator fluid, the viscosity is high and circulation is difficult when the engine is stopped or started, thus reducing the possibility of overcooling the engine. On the other hand, when cooling is necessary while the engine is running, the viscosity decreases due to heat, allowing for efficient engine cooling. Thus, the urea derivative (I) and gelling agent according to the present invention are useful in various technical fields. [Examples]

[0040] The present invention will be described in more detail below with reference to examples, but the present invention is not limited by the following examples, and it is certainly possible to implement it with appropriate modifications within the scope that is consistent with the spirit of the preceding and following descriptions, and all such modifications are included within the technical scope of the present invention.

[0041] Example 1: Synthesis of dodecyl-urea-Gly-His Dipeptide Gly-His (840 mg) was weighed into a 110 mL vial, and pure water (2.4 mL), acetonitrile (21.6 mL), and methanol (8 mL) (total solvent 32 mL) were added. Triethylamine (600 μL) was then added to adjust the pH of the reaction solution to approximately 8. Dodecyl isocyanate (600 μL) was then added, the vial was immediately closed, and the reaction was carried out overnight in a shaking constant temperature water bath set to 60°C. Approximately two-thirds of the solvent was removed using an evaporator (Biochromat), and the mixture was freeze-dried. The resulting white powder (100 mg) was added to methanol (5 mL) and dissolved by heating to 60°C. After cooling to room temperature, diethyl ether (45 mL) was slowly added. The precipitate was collected by centrifugation or filtration and vacuum-dried. The process from dissolution in methanol to vacuum drying of the precipitate was repeated twice. The resulting white powder was dispersed in water and centrifuged at 11,000 rpm for 10 minutes to precipitate. The precipitate was freeze-dried to obtain dodecyl-urea-Gly-His (yield 31%).

[0042] Example 2: Synthesis of dodecyl-urea-carnosine Carnosine (540 mg) was weighed into a 110 mL vial, and distilled water (7.8 mL), acetonitrile (16.2 mL), and methanol (6 mL) (total solvent 30 mL) were added. Triethylamine (300 μL) was then added to adjust the pH of the reaction solution to approximately 8. Dodecyl isocyanate (477 μL) was then added, the lid was immediately closed, and the mixture was reacted overnight in a shaking constant temperature water bath set to 70°C. Approximately one-third of the solvent was removed using an evaporator (Biochromat), and the mixture was freeze-dried. The resulting white powder (975 mg) was dispersed in distilled water (100 mL) and heated to 80°C to dissolve. This aqueous solution was slowly added to acetonitrile (450 mL) to precipitate the target compound. The mixture was centrifuged at 15,000 g at 4°C for 10 minutes to allow it to precipitate. The solution was filtered using a Kiriyama funnel and No. 4 hard filter paper, and the precipitate was collected. The collected white powder (500 mg) was dispersed in pure water (10 mL). This was centrifuged at 15,000 g at 4 °C for 10 minutes to precipitate the suspension. The solution was filtered using a Kiriyama funnel and No. 4 hard filter paper, and the precipitate was collected. The precipitate was freeze-dried to obtain dodecyl urea-carnosine (yield 25%).

[0043] Comparative Example 1: Synthesis of N-lauroyl-Gly-His·TFA salt H-His(Trt)-Trt(2-Cl) resin (500 mg, 0.31 mmol, manufactured by Watanabe Chemical Industry Co., Ltd.) was added to a solid-phase synthesis column. This resin has 0.62 mmol of His added per gram of resin. Dichloromethane (5 mL) was added to the column, left overnight, and then washed with dimethylformamide (5 mL). Fmoc-Gly-OH (357 mg, 4x molar amount, manufactured by Watanabe Chemical Industry Co., Ltd.) was condensed using the Fmoc method to obtain H-Gly-His(Trt)-Trt(2-Cl) resin. Lauric acid (240 mg, 4x molar amount, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.), HOBt (144 mg, 7x molar amount), HBTU (358 mg, 7x molar amount), DMF (10 mL), and N,N-diisopropylethylamine (580 mg) were added to this resin. After shaking for 1 hour, the reaction solution was filtered off, and the resin was sequentially washed with dimethylformamide, dichloromethane, and methanol, and dried under reduced pressure. Trifluoroacetic acid (TFA, 3.8 mL), triisopropylsilane (0.1 mL), and pure water (0.1 mL) were added, and the mixture was stirred for 90 minutes using a shaker to cleave the peptide from the resin. Diethyl ether was gradually added to the solution containing this crude peptide to precipitate the crude peptide. The crude peptide was recovered by centrifugation and freeze-dried. The obtained crude peptide (approximately 30 mg) was dissolved in pure water (1.5 mL) and triethylamine (0.1 mL). Acetic acid was added to this solution to adjust the pH to 5-6, thereby precipitating the N-lauroyl-Gly-His·TFA salt. The N-lauroyl-Gly-His·TFA salt was recovered by centrifugation and freeze-dried (yield 26%).

[0044] Comparative Example 2: Synthesis of N-lauroyl-carnosine·TFA salt N-lauroyl-carnosine·TFA salt was obtained in the same manner as in Comparative Example 1 (yield 29%), except that Fmoc-βAla-OH (373 mg, 4 times the molar amount, manufactured by Watanabe Chemical Industry Co., Ltd.) was used instead of Fmoc-Gly-OH (357 mg, 4 times the molar amount) in Comparative Example 1.

[0045] Test Example 1: Gelation Test The dried powders of the urea compounds from Examples 1 and 2, or the amide compounds from Comparative Examples 1 and 2, were placed in glass microtubes ("Microtube No. 2," manufactured by Maruemu Co., Ltd.). Considering the subsequent gelation behavior, 50 mM phosphate buffer (pH 7.4), 0.1 M hydrochloric acid (pH 1), or Tris buffer (pH 9) were added in increments of approximately 0.05 to 0.2 mass%, starting from 0.01 mass%, and the mixture was completely dissolved by immersion in a 90°C oil bath. After cooling to room temperature, the tubes were left for one day. The presence or absence of gelation was determined by inverting the microtubes and observing whether the mixture flowed along the inner wall. Table 1 shows the minimum concentration at which gelation was confirmed. In Table 1, "×" indicates that gelation was not observed within the tested range.

[0046] [Table 1]

[0047] As shown in the experimental results in Table 1, when comparing compounds with identical peptide portions, it became clear that simply changing the amide group to a urea group significantly improved the gelling ability.

[0048] Test Example 2: Toxicology Test HepG2 cells were seeded at a rate of 10,000 cells per well in a 96-well microplate ("MICROPLATE 96Well with Lid, 3860-096," IWAKI Corporation) with 100 μL of liquid medium per well. The culture medium used was a mixture of fetal bovine serum (Nichirei Biosciences, Inc.) (50 mL), penicillin / streptomycin mixture (Nacalai Tesque Co., Ltd.) (5 mL), and Dulbecco's modified Eagle medium (Nacalai Tesque Co., Ltd.) (500 mL). One day after seeding, the medium was aspirated and replaced with medium containing the gelling agents at the concentrations shown in Figures 1 and 2. The cells were then incubated at 37°C for 24 hours. Next, 10 μL of the viable cell counting reagent SF (Nacalai Tesque Co., Ltd.) was added to each well, and the color reaction was carried out in a CO2 incubator for 1 hour. After that, the absorbance at 450 nm was measured using a microplate reader ("SH-9000," Corona Electric Co., Ltd.), and the cell viability was calculated by comparing it with the absorbance at a reference wavelength of 600 nm. A mixture of culture medium (100 μL) and viable cell counting reagent SF solution (10 μL) was used as the blank. The viability when the gelling agent concentration was 0% by mass was set to 100%, and the relative viability when the gelling agent was added was calculated. The experimental results for dodecyl-urea-Gly-His (Example 1) and N-lauroyl-carnosine·TFA salt (Comparative Example 1) are shown in Figure 1, and the experimental results for dodecyl-urea-carnosine (Example 2) and N-lauroyl-carnosine·TFA salt (Comparative Example 2) are shown in Figure 2.

[0049] As shown in Figures 1 and 2, conventional gelling agents, such as amide derivatives, exhibited low cytotoxicity at relatively low concentrations, but became cytotoxic above a certain concentration. In contrast, the amide derivative according to the present invention did not exhibit strong cytotoxicity, at least within the experimentally tested concentration range, and was demonstrated to be safe.

Claims

1. A urea derivative or a salt thereof, characterized by being represented by the following formula (I). 【Chemistry 1】 [In the formula, R 1 is C 6-20 It shows an aliphatic hydrocarbon group, n represents an integer between 1 and 6 (inclusive).

2. R 1 C 10-14 The urea derivative according to claim 1, which is an alkyl group.

3. A gelling agent characterized by containing the urea derivative described in claim 1 or 2 as an active ingredient.

4. A cosmetic composition characterized by containing the gelling agent described in claim 3.

5. An aqueous electrolyte characterized by comprising the gelling agent and water described in claim 3.

6. An aqueous metal ion battery characterized by containing the aqueous electrolyte described in claim 5.

7. A method for producing urea derivatives or salts thereof, The urea derivative is represented by the following formula (I), A method characterized by comprising the step of reacting an isocyanate compound represented by the following formula (II) with a dipeptide compound represented by the following formula (III). 【Chemistry 2】 [In the formula, R 1 is C 6-20 It shows an aliphatic hydrocarbon group, n represents an integer between 1 and 6 (inclusive).

8. R 1 C 10-14 The method according to claim 7, wherein the alkyl group is used.

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