JP4646739B2 - Hair tension / scrubbing improver and hair cosmetics - Google Patents

Description

  The present invention relates to a drug for improving hair tension and strain, and a hair cosmetic containing the drug, and more particularly, by activating cells of hair and hair follicles, more specifically, The present invention relates to a drug for improving hair tension and stiffness by increasing expression, and a hair cosmetic containing the drug.

  Problems related to hair include those related to the health condition of hair roots and hair follicles such as thin hairs and hair loss, and those related to physical properties of hair such as hard, soft, non-abrasive / stubborn, split ends, prickly hairs, and pasasuku. In addition, even if it is a problem related to the physical properties of hair, it is caused by direct damage to hair, such as damage caused by external factors, such as permanent or bleach treatment, exposure to ultraviolet light, exposure to air pollutants, combing friction, etc. And the case where an internal element in hair shaft formation is involved. The hair care in the latter case requires not only improving the quality of the hair but also taking care to improve the health of the hair root and the hair follicle itself. Therefore, even if it is said that the state of the hair is not good, the care method varies depending on the cause.

  The hair itself is made up of a cuticle covering the surface, fur inside it and occupying most of the hair, and medulla in the center. It has been clarified that cutil contributes greatly to the firmness and firmness of hair (Akira Sogabe et al., J. Soc. Cosmet. Chem. Japan, Vol. 36, No. 3 (2002)). pp. 207-216 “Study on physical properties of hair 1—Measurement of short and long diameters of hair and evaluation method of bending stress”). The cuticle is composed of various components such as fiber proteins such as acidic hair keratins Ha1 and Ha2, basic keratins Hb1 and Hb2, and modified enzymes such as transglutaminase, peptidylarginine diminase, and granule component tricohiarin S100. Is known. However, the relationship between each of these components and the hair quality, for example, the hair lump and the hair, has not been fully elucidated. If the mechanism that influences the hair quality is sufficiently elucidated at the biochemical / molecular biology level, it may be possible to provide a product that exhibits a more remarkable effect than existing hair quality improving agents.

  Examples of conventional hair cosmetics that are supposed to impart hair and strain to hair include, for example, silyl groups bonded with reactive functional groups as described in JP-A-11-302129 (Patent Document 1). A hair treatment composition containing a copolymer having a siloxane-bonded Si-O-Si by hydrolysis on the hair, thereby cross-linking the copolymer molecules, so There are things that give a firmness. However, these conventional cosmetics for hair are coated on the surface of the hair, and penetrate the hair or are absorbed by the hair follicles to activate the hair and hair follicle cells to activate the hair paste.・ It does not improve strain.

  On the other hand, a cell activator containing taurine as an active ingredient is disclosed in Japanese Patent Application Laid-Open No. 2002-97116 (Patent Document 2), and a cell activator containing N-methyltaurine as an active ingredient and a hair patch / strain improver are disclosed in WO2002 / 034253. In Japanese Patent Publication (Patent Document 3). The effects of these agents are described as hair cell control, hair growth period extension, hair cell proliferation activation, hair patch / strain improvement by activation of cell proliferation. The improvement effect is still evaluated by a physical property test (torsion torque) of hair. Therefore, there is a need for a novel hair patch / strain improving agent based on activity evaluation at the biochemical / molecular biology level.

JP-A-11-302129 JP 2002-97116 A WO2002 / 034253 publication

  An object of the present invention is to provide a novel hair patch / strain improving agent based on activity evaluation at the biochemical / molecular biological level.

  The present inventor has examined the correlation between hair tension and stiffness (hardness as a scale, more specifically, Young's modulus) and expression of hair-related genes. As a result, hair keratin genes, particularly hair keratin Ha2 gene, hair As the expression of each of the keratin Hb2 gene and / or keratin-related protein KAP5.1-5 increases, the expression of the hair keratin Ha2, KAP5.1, KAP5.2, or KAP5.4 gene increases more preferably. As the Young's modulus of hair increases, that is, it is found that the hair sticks and feels a little bit, a patent application has been filed for “a hair quality evaluation method using a hair keratin gene as an index” (Japanese Patent Application No. 2004). 164596).

  The present inventor has recently constructed a new assay system for evaluating the effects of various drugs on the expression of hair-related genes, and using this assay system, various compounds affect the expression of hair-related genes. As a result of intensive studies on the effect, it was found that a specific 3-aminoisoxazole derivative has an effect of increasing the expression of hair-related genes, and the present invention has been completed.

（一般式（１）中、Ｒ₁は水素原子またはメチル基、Ｒ₂は水素原子、直鎖または分岐の炭素数１〜８のアルキル基、直鎖または分岐の炭素数２〜８のアルケニル基、炭素数３〜８のシクロアルキル基、炭素数７〜１０のアラルキル基、または炭素数６〜１４のアリール基、Ｒ₃は水素原子またはメチル基、Ｒ₄は水素原子、直鎖または分岐の炭素数１〜８のアルキル基、直鎖または分岐の炭素数２〜８のアルケニル基、または炭素数３〜８のシクロアルキル基、炭素数７〜１０のアラルキル基、炭素数６〜１４のアリール基、炭素数２〜８のアルキルカルボニル基、炭素数７〜１０のアリールカルボニル基をそれぞれ表す。また、上記のアラルキル基、アリール基、アリールカルボニル基のアリール部分は、炭素数１〜３個のアルキル基、炭素数１〜３個のアルコキシ基、および水酸基でそれぞれ置換されていてもよい。） That is, the present invention provides a cosmetic for hair comprising as an active ingredient at least one compound selected from the group consisting of a 3-aminoisoxazole derivative represented by the following general formula (1) and a pharmaceutically acceptable salt thereof. Regarding fees.

(In the general formula (1), R ₁ is a hydrogen atom or a methyl group, R ₂ is a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, a linear or branched alkenyl group having 2 to 8 carbon atoms. , A cycloalkyl group having 3 to 8 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, or an aryl group having 6 to 14 carbon atoms, R ₃ is a hydrogen atom or a methyl group, R ₄ is a hydrogen atom, linear or branched C1-C8 alkyl group, linear or branched C2-C8 alkenyl group, C3-C8 cycloalkyl group, C7-C10 aralkyl group, C6-C14 aryl Group, an alkylcarbonyl group having 2 to 8 carbon atoms, and an arylcarbonyl group having 7 to 10 carbon atoms, and the aryl part of the aralkyl group, aryl group, and arylcarbonyl group has 1 to 3 carbon atoms. Alkyl group, charcoal Number 1-3 alkoxy groups, and hydroxyl group may be substituted, respectively.)

  In a preferred embodiment, the hair cosmetic is a hair patch / strain improving agent.

  The present invention also provides a hair cosmetic comprising at least one compound selected from the group consisting of the 3-aminoisoxazole derivative of the above general formula (1) and a pharmaceutically acceptable salt thereof as hair or The present invention relates to a method for improving hair stickiness and strain, which comprises applying to the scalp.

  The present invention also provides hair by adding one or more compounds selected from the group consisting of the 3-aminoisoxazole derivative of the above general formula (1) and a pharmaceutically acceptable salt thereof to an aqueous phase or an oil phase. The present invention relates to a method for producing a cosmetic for hair, characterized by producing a cosmetic for hair.

  The 3-aminoisoxazole derivative and its pharmaceutically acceptable salt, which are active ingredients of the hair patch / strain improving agent and hair cosmetic composition of the present invention, penetrate into the hair by being used on the hair or scalp. Alternatively, it can be absorbed into hair follicles to enhance the expression of keratin-related protein KAP5 in cells and improve hair tension and strain.

  The present invention relates to a drug and a cosmetic for hair that activates hair and hair follicle cells, and more specifically increases hair-related genes by increasing the expression of hair-related genes, The present invention provides a novel hair squeeze / strain improving agent and hair cosmetic based on activity evaluation at the biochemical / molecular biology level, more specifically, based on an assay for the effect of regulating the expression of the keratin-related protein KAP5 gene.

  In order to investigate the correlation between hair hardness and various genes extracted from hair in Japanese Patent Application No. 2004-164596 “Hair quality evaluation method using hair keratin gene as an index”, the present inventor The Young's modulus, which is an index of hardness, was measured, and the relationship between the measurement results and the expression levels measured by RT-PCR of various genes was statistically analyzed using Spearman's rank correlation coefficient (Zar, JHJ Amer.Stat.Assoc.67: 578-580, 1970 "Significance testing of the Spearman rank correlation cofficient"). As a result, it was found that the Young's modulus of hair is statistically significantly increased when the expression level of hair keratin Ha2, KAP5.1, KAP5.2, and KAP5.4 gene is large. It was also found that the Young's modulus of hair is increased when the expression level of the hair keratin Hb2 gene is large, although it is not statistically significant. On the other hand, there was no correlation with the hardness of hair about the other structural protein of fur, for example, hair keratin Ha1. Therefore, it was suggested that the proportion of cuticle constituent proteins and related genes is involved in hair hardness compared to fur.

  The hair keratin Ha2 gene (NCBI GenBANK Source “X90761”) encodes an acidic protein that is a member of the keratin gene family. Hair keratin Ha2 is type I keratin, and heterodimerizes with type II keratin to form hair, nails and the like. Type I hekeratin is located in chromosome 17q12-q21 region.

  The hair keratin Hb2 gene (NCBI GenBANK Source “Y19207”) encodes a basic protein that is a member of the keratin gene family. Hair keratin Hb2 is type II keratin, and it heterodimerizes with type I keratin to constitute hair, nails and the like. Type II hekeratin is located in chromosome 12q13 region.

  KAP5.1-5 gene (SEQ ID NO: 1-5) belonging to the human keratin-related protein (KAP) 5 family (Homo sapiens genomic DNA, chromosome 11 clone: RP11-684B2, complete sequences. ACCESSION: AP000867) is known only for its base sequence No human EST has been reported on its function. The relationship between increased KAP5.1-5 gene expression and hair hardness was unclear. Although not particularly bound by any theory, for example, the putative protein encoded by the KAP5.2 gene is cysteine-rich (about 35.5%) and is rich in the low molecular amino acids glycine and serine (18.8 each). % And 24.2%) because it consists of 186 amino acids, it does not form secondary structures such as α-helix, can easily penetrate between keratin fibers, and has many hydrogen bonds by OH groups of many serine residues. May also contribute greatly to the mechanical strength of the hair. Similarly, other KAP5 genes are rich in cysteine, glycine, and serine, and the expression product has a structure similar to that of KAP5.2 and is considered to contribute greatly to the mechanical strength of hair. Table 1 below shows the partial amino acid composition of the KAP5.1-5 gene predicted coding protein.

  KAP5.1 to 5.5 genes (SEQ ID NOs: 1 to 5) are a group of genes belonging to the human keratin-related protein KAP5 family and having relatively high homology with each other. The high degree of homology between the amino acid sequences of the putative proteins encoded by each gene is apparent from FIG. 4 and Table 2 below.

  The inventor of the present invention, among the hair keratin Ha2, Hb2 genes and human keratin-related proteins KAP5.1, KAP5.2, and KAP5.4 genes, which have been correlated with the hardness (Young's modulus) of hair, particularly KAP5. For one gene, a reporter assay system was newly constructed to evaluate the effect of various drugs on the expression of this hair-related gene. Using this assay system, the effects of various compounds on the expression of the KAP5.1 gene were studied earnestly. As a result, it has been found that 3-aminoisoxazole derivatives and pharmaceutically acceptable salts thereof have an effect of increasing the expression of KAP5.1 gene.

  As described above, the KAP5.1 to 5.5 genes (SEQ ID NOs: 1 to 5) are a group of genes belonging to the human keratin-related protein KAP5 family and having relatively high homology with each other. Further, as can be seen from FIG. 3, the sequence of the promoter region of the KAP5.1 gene and the sequences of the promoter regions of other KAP5.2-5.5 genes are very close to each other, and the control mechanism is the same. There is a high possibility. Therefore, it is highly likely that a drug that enhances the expression of the KAP5.1 gene also enhances the expression of other KAP5 genes.

  Furthermore, as described above, the higher the expression level of the KAP5.1 gene, the higher the hair Young's modulus is statistically significantly. Therefore, a drug that increases the expression of the KAP5.1 gene improves the hardness of the hair. And improve hair stickiness and stiffness.

The 3-aminoisoxazole derivative of the present invention is a known compound and can be easily obtained. Further, it can be easily synthesized by known methods such as Chem. Pham. Bull., 14 , 1277 (1966), Japanese Patent Publication No. 41-21147, Japanese Patent Publication No. 54-44723, Japanese Patent Publication No. 59-27343, and the like.

  The 3-aminoisoxazole derivative of the present invention is known for its use as a herbicide (Japanese Examined Patent Publication No. 54-44723). There is no known improvement.

  Examples of specific substance names of the 3-aminoisoxazole derivatives of the present invention include 3-aminoisoxazole, 3-amino-4-methylisoxazole, 3-amino-5-methylisoxazole, 3-amino- 5-ethylisoxazole, 3-amino-5-n-propylisoxazole, 3-amino-5-cyclopropylisoxazole, 3-amino-5-n-butylisoxazole, 3-amino-5-tert-butyl Isoxazole, 3-amino-5-n-pentylisoxazole, 3-amino-5-isoamylisoxazole, 3-amino-5-n-hexylisoxazole, 3-amino-5-cyclohexylisoxazole, 3-amino -5-n-octylisoxazole, 3-amino-5-phenylisothio Sazole, 3-amino-5- (p-methoxyphenyl) isoxazole, 3-amino-5- (p-methoxyphenethyl) isoxazole, 3-amino-4,5-dimethylisoxazole, 3-acetamidoisoxazole, 3-acetamido-4-methylisoxazole, 3-acetamido-5-methylisoxazole, 3-acetamido-5-tert-butylisoxazole, 3- (N-acetyl-N-methylamino) -5-methylisoxazole 3- (N-acetyl-N-methylamino) -5-tert-butylisoxazole, 3-acetamido-4,5-dimethylisoxazole, 3-propionylaminoisoxazole, 3-propionylamino-5-methyliso Oxazole, 3-propionyl No-5-tert-butylisoxazole, 3- (N-propionyl-N-methylamino) -5-methylisoxazole, 3- (N-propionyl-N-methylamino) -5-tert-butylisoxazole, 3-butyrylamino-5-methylisoxazole, 3-butyrylamino-5-tert-butylisoxazole, 3- (N-methylamino) -5-methylisoxazole, 3- (N, N-dimethylamino) -5 Examples include tert-butylisoxazole.

  “Pharmaceutically acceptable salt” refers to a salt that retains substantially the same biological activity as a pharmaceutical compound and is not toxic. Examples of such salts include, but are not limited to, addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, oxalic acid, tartaric acid, succinic acid And addition salts formed with organic acids such as malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid and the like.

  There are no particular limitations on the form of hair hair and strain improving agents and hair cosmetics containing the 3-aminoisoxazole derivative of the present invention and pharmaceutically acceptable salts thereof, in order to improve hair strength and strain. Any of the forms commonly used in Examples thereof include liquid, emulsion, emulsion cream, cream, gel, wax, mist, foam, and aerosol. The hair patch / strain improving agent and hair cosmetic of the present invention can be applied as products such as hair liquid, hair tonic, hair cream, mousse, treatment, hair restorer, shampoo, rinse, cream, milky lotion, pack and the like.

  The amount of the 3-aminoisoxazole derivative of the present invention and a pharmaceutically acceptable salt thereof depends on the dosage form of the hair cosmetic, but is generally 0.001 to 20 in the total amount of the hair cosmetic. % By mass, preferably 0.01 to 5% by mass.

  The hair squeeze / scrubbing improver and hair cosmetics of the present invention are formulated by combining general ingredients of cosmetics, quasi-drugs, and pharmaceuticals as necessary within the range that does not impair the effects of the present invention. Can be prepared. General blending components are, for example, powder components, liquid fats and oils, solid fats and oils, waxes, hydrocarbon oils, higher fatty acids, higher alcohols, ester oils, silicone oils, anionic surfactants, cationic surfactants, amphoteric surfactants, non- Ionic surfactant, moisturizer, water-soluble polymer, thickener, film agent, ultraviolet absorber, sequestering agent, lower alcohol, polyhydric alcohol, sugar, amino acid, organic amine, polymer emulsion, pH adjuster Skin nutrients, vitamins, antioxidants, antioxidant aids, fragrances, water, etc.

The example of the component which can be specifically mix | blended is as follows. The hair patch / strain improving agent and the hair cosmetic are produced by a conventional method according to the intended dosage form by blending one or more of the following components as required.
Powders such as polyethylene powder, polymethyl methacrylate powder, and nylon powder. Inorganic pigments such as titanium dioxide, zinc oxide, synthetic mica, talc, kaolin, sericite, boron nitride. Organic pigments such as Red No. 226, Red No. 228 and Blue No. 404. Oils such as camellia oil, macadamia nut oil, olive oil and castor oil. Waxes such as jojoba oil, beeswax, candelilla wax, carnauba wax, lanolin. Hydrocarbon oils such as liquid paraffin, squalane, paraffin, ceresin, petrolatum, microcrystalline wax. Higher fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid and isostearic acid. Higher alcohols such as cetyl alcohol, stearyl alcohol, isostearyl alcohol, octyldodecanol. Ester oils such as isopropyl myristate and diisostearyl malate. Silicone oil such as methylpolysiloxane. Anionic surfactants such as higher fatty acid soap, higher alkyl sulfate ester salt, N-acyl sarcosinate, POE-alkyl ether sulfate. Cationic surfactants such as alkyltrimethylammonium chloride, dialkyldimethylammonium chloride, and benzalkonium chloride. Amphoteric surfactants such as alkyldimethylaminoacetic acid betaine and alkylamidopropyldimethylaminoacetic acid betaine. Nonionic surfactants such as polyoxyethylene type, polyhydric alcohol ester type, ethylene oxide / propylene oxide block copolymer. Moisturizers such as polyethylene glycol, propylene glycol, glycerin, 1,3-butylene glycol, sorbitol, sodium hyaluronate, sodium pyrrolidone carboxylate. Water-soluble polymers such as quince seed gum, xanthan gum, carboxymethyl cellulose, carboxyvinyl polymer. Coating agents such as polyvinyl alcohol, polyvinyl pyrrolidone, nitrocellulose, and polymeric silicone. UV absorbers such as PABA, cinnamic acid, salicylic acid, benzophenone, benzotriazole, and dibenzoylmethane. Metal ion sequestering agents such as sodium salt of ethylenediaminetetraacetic acid (EDTA). Light stabilizers such as 4,5-dimorpholinopyridazinone. Lower alcohols such as ethanol, propanol, isopropanol, isobutyl alcohol, t-butyl alcohol. Polyhydric alcohols such as 1,3-butylene glycol, xylitol, sorbitol, diethylene glycol, and polyglycerol. Monosaccharides such as tricarbon sugar, tetracarbon sugar, pentose sugar, hexose sugar, deoxy sugar, amino sugar and uronic acid. Oligosaccharides such as trehalose. Polysaccharides such as cellulose and chondroitin sulfate. Amino acids such as glycine, serine, lysine, cystine, cysteine, methionine, glutamic acid, proline and derivatives thereof. Organic amines such as monoethanolamine, diethanolamine, and triethanolamine. PH adjusting agents such as lactic acid-sodium lactate and citric acid-sodium citrate. Vitamins such as vitamin A, vitamin B ₁ , vitamin B ₂ , vitamin C, vitamin E, biotin, nicotinamide, and derivatives thereof. Antioxidants such as dibutylhydroxytoluene, butylhydroxyanisole, gallic acid ester, hypotaurine and thiotaurine. Preservatives such as paraoxybenzoates and phenoxyethanol. Various propellants such as liquefied petroleum gas (LPG), nitrogen gas, carbon dioxide gas. Anti-inflammatory agents such as glycyrrhizic acid derivatives, glycyrrhetinic acid derivatives, hinokitiol, and zinc oxide. Protease inhibitors such as tranexamic acid. Whitening agents such as arbutin, ascorbic acid glucoside, 4-methoxysalicylate, ellagic acid and lucinol. Anti-wrinkle agents such as retinol and α-hydroxy acid. Activators such as royal jelly, photosensitizers and cholesterol derivatives. Blood circulation promoters such as assembly extract, γ-oryzanol, cephalanthin, vitamin E and its derivatives, nicotinic acid benzyl ester, adenosine, minoxidil and the like. Local stimulants such as capsaicin, chili pepper tincture, ginger tincture, cantalis tincture, and noiric acid vanillylamide. Anti-androgen agonists such as estradiol and ethinyl estradiol. Pantothenic acid and its derivatives. Hair follicle activators such as allantoin and photosensitive element 301. Exfoliating / dissolving agents such as salicylic acid, sulfur, resorcin, selenium sulfide. Antiseborrheic agents such as vitamin B ₆ and its derivatives. Antipruritic agents such as diphenhydramine hydrochloride, chlorpheniramine maleate, camphor and menthol. Awaku, Auren, Shikon, Peonies, Birch, Sage, Loquat, Carrot, Aloe, Zeniai, Iris, Grape, Yokuinin, Loofah, Lily, Saffron, Senkyu, Pepper, Hypericum, Onionis, Garlic, Pepper, Chimney, Seaweed, Seaweed Various extracts such as.

  Hereinafter, the present invention will be described more specifically with specific examples. In addition, this invention is not limited by this.

Example 1
Construction of KAP5.1 reporter plasmid For KAP5.1, which was found to correlate with hair hardness (Young's modulus), a transcriptional regulatory region was amplified by PCR, and then a reporter plasmid was constructed.

A. PCR amplification of DNA fragments NM-F1 primer (SEQ ID NO: 6) and R2 primer obtained by adding a recognition site for restriction enzymes NotI and MluI to the 5 ′ end of a DNA fragment of about 15 kb containing the KAP5.1 and KAP5.2 genes (SEQ ID NO: 7) was used to amplify by PCR using commercially available human genomic DNA (obtained from Promega) as a template (FIG. 1-A).

  The conditions for the PCR reaction are as shown in the following table.

  The NM-F1 primer (SEQ ID NO: 6) and R2 primer (SEQ ID NO: 7) are as shown in the following table. The numbers shown in the table indicate the positions of the sequence numbers of Homo sapiens genomic DNA, chromosome 11 clone: RP11-684B2, complete sequences. ACCESSION: AP000867.5.

B. Cloning of DNA fragment into vector The amplified DNA fragment was double digested with restriction enzymes MluI and NheI and separated by agarose gel electrophoresis, and then a DNA fragment of about 4.9 kb was recovered. This DNA fragment was cloned between the MluI and NheI sites of a reporter vector pGL-3basic (obtained from Promega) having a gene encoding firefly luciferase (FIG. 1-B). Subcloning [Step 1: Subcloning the SacI / NcoI fragment (154 bp, FIG. 2) into pGL-3basic. Step 2: Insert a SacI fragment (about 4.0 kbp, FIG. 2) into the obtained plasmid] to construct a reporter plasmid pGL-3-KAP5.1 containing the 5 ′ upstream region (SEQ ID NO: 8) of KAP5.1. (FIG. 2).

Example 2
KAP5.1 reporter assay Immortalized outer root sheath cells (IORS) (obtained from JP 2000-89) are seeded in 800,000 cells in a 75 cm ² flask and cultured under conditions of 37 ° C. and 5% CO ₂ for 6 days. The medium is Keratinocyte-SFM medium (Gibco).
Day 1: Plasmid DNA introduction (transient). The cultured IORS cells were transformed into the above-constructed reporter plasmid pGL3-KAP5.1 (firely luciferase) and the commercially available internal standard plasmid pRL-TK (renilla luciferase) according to the Manual of Effectene Transfection Reagent (QIAGEN). Converted.
Day 2: Retransformed cells are seeded in a 24-well multi-well plate at 100 to 160,000 cells per well and cultured overnight at 37 ° C. and 5% CO ₂ .
Day 3: The medium in each well is replaced with a basal medium in which various drugs are dissolved, and cultured overnight at 37 ° C. and 5% CO ₂ .
Day 4: Assay. Using a Dual-Luciferase Reporter Assay System (Promega), the luciferase activity in each well is measured according to the manufacturer's manual. The luminometer uses AutoLumat LB953 (BERTHOLD).

  As a negative control, an assay under the same conditions was performed except that no drug was contained (K-SFM (−)). The assay results are shown in Table 5. The effect of enhancing gene expression was expressed as an enhancement rate (ratio when the negative control was 100).

  As shown in Table 5, the 3-aminoisoxazole derivative of the present invention was found to have the effect of enhancing the gene expression of KAP5.1.

  In this example, the assay results were shown only for KAP5.1, but as described above, the sequences of the promoter regions of the KAP5.1 gene and the promoter regions of the other KAP5.2-5.5 genes were very different from each other. (Fig. 3), and the control mechanism is likely to be equivalent. Therefore, a drug that enhances the expression of KAP5.1 also enhances the expression of other KAP5 genes, improving the stiffness and stiffness. Very likely.

Example 3
Preparation of hair cosmetics Formulation examples of the hair cosmetics of the present invention are shown below. In addition, a compounding quantity is the mass%. The hardness of the wax was measured with a card meter Max ME-415 manufactured by I-Techno Engineering Co., Ltd. (diameter: 5.6 mm; speed: 7 sec / inch; load: 200 g; temperature: 37 ° C.). The viscosity was measured at a temperature of 1287 at a single cylinder rotational viscometer manufactured by Shibaura System Co., Ltd. Note that gels, treatments, etc. with high viscosity are VS-H1 type (rotor No. 6/10 rpm), and mists, hair liquids, mousses, hair tonics, hair restoration agents, etc., have low viscosity, VS-A1 type (rotor No. 1/60 rpm) was used.

Example 3.1 Wax A wax containing the drug of the present invention was prepared by a conventional method according to the following formulation. Emulsion waxy, hardness 20. This wax had a good feeling of use, and an improvement in the feel of the wax and the stiffness was observed.
3-Amino-5-methylisoxazole 0.1
Liquid paraffin 10
Microcrystalline wax 10
Dimethylpolysiloxane 4
Stearyl alcohol 4
Propylene glycol 10
Carnauba 3
Isostearic acid 0.5
Stearic acid 4.5
Tetra-2-ethylhexanoic acid pentaerythlit 2
Polyoxyethylene hydrogenated castor oil 3
Polyoxyethylene oleyl ether phosphate 2
Self-emulsifying glyceryl monostearate 3
Triethanolamine 1
Paraoxybenzoic acid ester Appropriate amount Sodium polyacrylate Appropriate amount Purified water Residue Perfume Appropriate amount

Example 3.2 Mist A mist containing the drug of the present invention was prepared by a conventional method according to the following formulation. A mist (aerosol), viscosity 5. This mist had a good feeling of use, and an improvement in the feel of the beam and the stiffness was observed.
3-Amino-5-methylisoxazole 1
Acrylic resin alkanolamine solution 12
Lauric acid diethanolamide 0.5
Ethanol 57
Polyoxyethylene oleyl ether 0.5
Purified water residue

Example 3.3 Gel A gel containing the drug of the present invention was prepared by a conventional method according to the following formulation. Transparent solid (gel), viscosity 30000. This gel had a good feeling of use, and an improvement in a feeling of tension and stiffness was observed.
3-Amino-5-methylisoxazole 1
Behenyl alcohol 1
Glycerin 5
1,3-butylene glycol 5
Polyoxyethylene hydrogenated castor oil succinic acid (50E.O.) 40
Potassium hydroxide 1
2-Ethylhexyl paramethoxycinnamate 0.1
Purified water Residue Fragrance Appropriate amount

Example 3.4 Hair Liquid A hair liquid containing the drug of the present invention was prepared by a conventional method according to the following formulation. Transparent solid, viscosity 8. This hair liquid had a good feeling of use, and an improvement in the feel of the beam and the stiffness was observed.
3-Amino-5-methylisoxazole 3
Ethanol 55
Propylene glycol 5
Polyoxyethylene, polyoxypropylene, pentaerythritol ether (5EO) 25
2-Ethylhexyl paramethoxycinnamate 0.5
Pigment appropriate amount Purified water Residue Fragrance

Example 3.5 Treatment A treatment containing the agent of the present invention was prepared by a conventional method according to the following formulation. Emulsion cream, viscosity 25000. This treatment also had a good feeling of use, and an improvement in a feeling of tension and stiffness was observed.
3-Amino-5-methylisoxazole 0.5
Liquid paraffin 10
Vaseline 3
Dimethylpolysiloxane 2
Propylene glycol 10
Polyoxypropylene (40) butyl ether 2
Tetra-2-ethylhexanoic acid pentaerythrit 3
Polyoxyethylene hydrogenated castor oil 2
Potassium hydroxide 0.1
Carboxyvinyl polymer 0.3
Purified water Residue Fragrance Appropriate amount

Example 3.6 Mousse According to the following formulation, a mousse containing the drug of the present invention was prepared by a conventional method. Stock solution / propellant 90/10. Foam (aerosol), viscosity 5. This mousse also had a good feeling of use, and an improvement in the feel of the beam and strain was observed.
Stock solution:
3-Amino-5-methylisoxazole 0.5
Volatile isoparaffin 0.5
Ethanol 10
Polyoxyethylene hydrogenated castor oil 0.5
Polyoxyethylene / polyoxypropylene decyl ether 0.5
Loquat leaf extract 0.1
Yuka Former SM 10
Purified water Residual propellant:
LPG

Example 3.7 Hair Tonic A hair tonic containing the agent of the present invention was prepared by a conventional method according to the following formulation. Transparent liquid, viscosity 7. This hair tonic had a good feeling of use, and an improvement in the feeling of tension and stiffness was observed.
3-Amino-5-methylisoxazole 3
Ethanol 60
Dipropylene glycol 2
Polyoxyethylene hydrogenated castor oil 0.5
Lactic acid appropriate amount Sodium lactate solution appropriate amount Glycyrrhizinate monoammonium 0.1
Nicotinamide 0.1
DL-α-tocopherol acetate 0.1
L-Menthol 0.2
Dye Appropriate amount Purified water Residue Fragrance Appropriate amount

Example 3.8 Hair Tonic A hair tonic containing the agent of the present invention was prepared by a conventional method according to the following formulation. Transparent liquid, viscosity 7. This hair tonic had a good feeling of use, and an improvement in the feeling of tension and stiffness was observed.
3-acetamido-5-methylisoxazole 2
Ethanol 60
Dipropylene glycol 2
Polyoxyethylene hydrogenated castor oil 0.5
Lactic acid appropriate amount Sodium lactate solution appropriate amount Glycyrrhizinate monoammonium 0.1
Nicotinamide 0.1
DL-α-tocopherol acetate 0.1
L-Menthol 0.2
Appropriate amount of pigment Purified water Residue Fragrance Appropriate amount.

Example 3.9 Hair Tonic A hair tonic containing the agent of the present invention was prepared by a conventional method according to the following formulation. Transparent liquid, viscosity 7. This hair tonic had a good feeling of use, and an improvement in the feeling of tension and stiffness was observed.
3-Amino-5-methylisoxazole 1
3-acetamido-5-methylisoxazole 1
2-acetamidothiazole 1
Ethanol 60
Dipropylene glycol 2
Polyoxyethylene hydrogenated castor oil 0.5
Lactic acid appropriate amount Sodium lactate solution appropriate amount Glycyrrhizinate monoammonium 0.1
Nicotinamide 0.1
DL-α-tocopherol acetate 0.1
L-Menthol 0.2
Dye Appropriate amount Purified water Residue Fragrance Appropriate amount

Example 3.10 Hair restorer A hair restorer containing the agent of the present invention was prepared by a conventional method according to the following formulation. Transparent liquid, viscosity 7. This hair-growth agent also had a good feeling of use, and an improvement in a feeling of tension and stiffness was observed.
3-Amino-5-methylisoxazole 3
Ethanol 80
Isostearyl alcohol 2
1,3-butylene glycol 3
Polyoxyethylene hydrogenated castor oil 1
Sodium lauryl sulfate 0.3
DL-malic acid appropriate amount β-glycyrrhetinic acid 0.2
Pantothenyl ethyl ether 0.1
Benzyl nicotinate 0.1
Nicotinamide 0.1
DL-α-tocopherol acetate 0.5
Decyltetradecyldimethylamine oxide solution (20%) 5
L-Menthol 1

Example 3.11 Hair restorer A hair restorer containing the agent of the present invention was prepared by a conventional method according to the following formulation. Transparent liquid, viscosity 7. This hair-growth agent also had a good feeling of use, and an improvement in a feeling of tension and stiffness was observed.
3-acetamido-5-methylisoxazole 2
Ethanol 80
Isostearyl alcohol 2
1,3-butylene glycol 3
Polyoxyethylene hydrogenated castor oil 1
Sodium lauryl sulfate 0.3
DL-malic acid appropriate amount β-glycyrrhetinic acid 0.2
Pantothenyl ethyl ether 0.1
Benzyl nicotinate 0.1
Nicotinamide 0.1
DL-α-tocopherol acetate 0.5
Decyltetradecyldimethylamine oxide solution (20%) 5
L-Menthol 1

Example 3.12 Hair restorer A hair restorer containing the agent of the present invention was prepared by a conventional method according to the following formulation. Transparent liquid, viscosity 7. This hair-growth agent also had a good feeling of use, and an improvement in a feeling of tension and stiffness was observed.
3-acetamido-5-methylisoxazole 2
Ethanol 80
Isostearyl alcohol 2
1,3-butylene glycol 3
Polyoxyethylene hydrogenated castor oil 1
Sodium lauryl sulfate 0.3
DL-malic acid appropriate amount β-glycyrrhetinic acid 0.2
Pantothenyl ethyl ether 0.1
Benzyl nicotinate 0.1
Nicotinamide 0.1
DL-α-tocopherol acetate 0.5
Decyltetradecyldimethylamine oxide solution (20%) 5
L-Menthol 1

  The hair patch / strain improving agent and hair cosmetic composition of the present invention can be used for the hair or scalp to penetrate into the hair or be absorbed by the hair follicle to improve the hair patch / strain. Useful as a beauty method.

FIG. 2 is a schematic diagram showing the construction and construction of a KAP5.1 reporter plasmid. FIG. 1-A is a diagram showing PCR amplification of DNA fragments containing KAP5.1 gene and KAP5.2 gene, and FIG. 1-B is a diagram showing cloning of amplified DNA fragment into reporter plasmid vector pGL-3basic. is there. FIG. 2 is a construction diagram of a KAP5.1 reporter plasmid subsequent to FIG. 1, showing deletion of the KAP5.1 gene translation region (after the start codon) by subcloning. It is a figure which shows the expression regulation of a KAP5 gene group. It is a figure which shows the amino acid sequence comparison of the putative coding protein of human KAP5.1-5.1 gene.

Claims (2)

A cosmetic for hair containing, as an active ingredient, one or more compounds selected from the group consisting of 3-aminoisoxazole derivatives represented by the following general formula (1) and pharmaceutically acceptable salts thereof:

(In the general formula (1), R ₁ is hydrogen atom or a methyl group, R ₂ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, straight-chain or branched alkenyl group having 2 to 8 carbon atoms , A cycloalkyl group having 3 to 8 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, or an aryl group having 6 to 14 carbon atoms, R ₃ is a hydrogen atom or a methyl group, R ₄ is a hydrogen atom, linear or branched C1-C8 alkyl group, linear or branched C2-C8 alkenyl group, C3-C8 cycloalkyl group, C7-C10 aralkyl group, C6-C14 aryl Group, an alkylcarbonyl group having 2 to 8 carbon atoms, and an arylcarbonyl group having 7 to 10 carbon atoms, and the aryl part of the aralkyl group, aryl group, and arylcarbonyl group has 1 to 3 carbon atoms. Alkyl group, charcoal Number 1-3 alkoxy groups, and hydroxyl group may be substituted, respectively.).   A hair patch / strain improvement comprising, as an active ingredient, one or more compounds selected from the group consisting of a 3-aminoisoxazole derivative of the general formula (1) defined in claim 1 and a pharmaceutically acceptable salt thereof. Agent.

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