WO2013161978A1 - Hair growth agent - Google Patents

Hair growth agent Download PDF

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Publication number
WO2013161978A1
WO2013161978A1 PCT/JP2013/062332 JP2013062332W WO2013161978A1 WO 2013161978 A1 WO2013161978 A1 WO 2013161978A1 JP 2013062332 W JP2013062332 W JP 2013062332W WO 2013161978 A1 WO2013161978 A1 WO 2013161978A1
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group
hair
formula
carbon atoms
linear
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PCT/JP2013/062332
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French (fr)
Japanese (ja)
Inventor
室伏　きみ子
俊郎 諸星
茂行 今村
達郎 藤原
良彦 野方
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Ｓａｎｓｈｏ株式会社
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Priority to SG11201406911RA priority Critical patent/SG11201406911RA/en
Priority to JP2014512699A priority patent/JP6074411B2/en
Priority to CN201380022119.2A priority patent/CN104254317B/en
Priority to KR1020147032100A priority patent/KR102165591B1/en
Publication of WO2013161978A1 publication Critical patent/WO2013161978A1/en
Priority to HK15105548.9A priority patent/HK1204935A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/55—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth

Definitions

  • the present invention relates to a hair restorer containing cyclic phosphatidic acid or carbacyclic phosphatidic acid as an active ingredient.
  • Alopecia can be congenital or acquired, and many studies have been conducted on its cause and mechanism of alopecia. However, although there are many hair nourishing and hair restorers on the market today, there are many unclear points.
  • medicinal ingredients include vasodilators such as assembly extract, vitamin E acetate, stimulants such as pepper tincture, pantothenic acid, biotin and the like. Vitamins, hormonal agents, anti-inflammatory agents, bactericides, and the like are used. It is also known that lysophosphatidic acid or phosphatidic acid derivatives have a hair-growing action (Patent Documents 1 and 2). In addition, a hair nurturing agent containing a hyaluronic acid synthesis promoting component is known (Patent Document 3).
  • This invention makes it the subject which should solve the problem in the above-mentioned prior art, and to provide the hair restorer which shows the outstanding hair restoration and hair growth effect.
  • the present inventors have found that cyclic phosphatidic acid and its derivatives show an excellent hair nourishing / hair growth effect, and have completed the present invention.
  • the hair restorer which contains the compound shown by following formula (1) as an active ingredient is provided.
  • R is a linear or branched alkyl group having 1 to 30 carbon atoms, a linear or branched alkenyl group having 2 to 30 carbon atoms, or a linear or branched group having 2 to 30 carbon atoms.
  • An alkynyl group, and these groups may contain a cycloalkane ring or an aromatic ring, and X and Y each independently represent an oxygen atom or a methylene group; M is a hydrogen atom or an alkali metal atom.
  • X and Y are oxygen atoms.
  • one of X and Y is an oxygen atom, and the other is a methylene group.
  • the compound represented by the formula (1) is a compound having an acyl group composed of a fatty acid derived from soybean lecithin.
  • a hair growth method comprising administering a compound represented by the above formula (1) to a subject.
  • FIG. 1 shows changes in hair growth scores of the control group and the NcPA administration group.
  • FIG. 2 shows the hair growth state on the 25th day after administration of the control group.
  • FIG. 3 shows the hair growth state on the 25th day of administration in the NcPA administration group.
  • the hair restorer of the present invention can be used for the treatment of androgenetic alopecia, and contains cyclic phosphatidic acid, carbacyclic phosphatidic acid or a salt thereof as an active ingredient.
  • the cyclic phosphatidic acid or the carbcyclic phosphatidic acid or a salt thereof is not particularly limited as long as it exhibits the effects of the present invention, but preferably a compound represented by the following formula (I) can be used.
  • R is a linear or branched alkyl group having 1 to 30 carbon atoms, a linear or branched alkenyl group having 2 to 30 carbon atoms, or a linear or branched group having 2 to 30 carbon atoms.
  • An alkynyl group, and these groups may contain a cycloalkane ring or an aromatic ring, and X and Y each independently represent an oxygen atom or a methylene group; M is a hydrogen atom or an alkali metal atom.
  • specific examples of the linear or branched alkyl group having 1 to 30 carbon atoms represented by the substituent R include, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group.
  • linear or branched alkenyl group having 2 to 30 carbon atoms represented by the substituent R include an allyl group, a butenyl group, an octenyl group, a decenyl group, a dodecadienyl group, a hexadecatrienyl group, and the like.
  • linear or branched alkynyl group having 2 to 30 carbon atoms represented by the substituent R include, for example, 8-decynyl group, 8-undecynyl group, 8-dodecynyl group, 8-tridecynyl group, and 8-tetradecynyl group.
  • cycloalkane ring that can be contained in the alkyl group, alkenyl group, or alkynyl group
  • a cyclopropane ring a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, and a cyclooctane ring.
  • the cycloalkane ring may contain one or more heteroatoms, and examples thereof include an oxirane ring, an oxetane ring, a tetrahydrofuran ring, and an N-methylprolysine ring.
  • aromatic ring that can be contained in the alkyl group, alkenyl group, or alkynyl group include a benzene ring, a naphthalene ring, a pyridine ring, a furan ring, and a thiophene ring.
  • substituent R is an alkyl group substituted by a cycloalkane ring
  • substituent R is an alkyl group substituted by a cycloalkane ring
  • specific examples in the case where the substituent R is an alkyl group substituted by a cycloalkane ring include a cyclopropylmethyl group, a cyclohexylethyl group, an 8,9-methanopentadecyl group, and the like.
  • substituent R is an alkyl group substituted by an aromatic ring
  • substituent R is an alkyl group substituted by an aromatic ring
  • R is preferably a linear or branched alkyl group having 9 to 17 carbon atoms, a linear or branched alkenyl group having 9 to 17 carbon atoms, or a linear or branched alkynyl group having 9 to 17 carbon atoms. It is a group. R is more preferably a linear or branched alkyl group having 9, 11, 13, 15 or 17 carbon atoms, or a linear or branched alkenyl group having 9, 11, 13, 15 or 17 carbon atoms. is there. R is particularly preferably a linear or branched alkenyl group having 9, 11, 13, 15 or 17 carbon atoms.
  • X and Y in the compound represented by the formula (1) each independently represents an oxygen atom (—O—) or a methylene group (—CH 2 —), but X and Y do not simultaneously become a methylene group. . That is, there are the following three combinations of X and Y. (1) X is an oxygen atom and Y is an oxygen atom. (2) X is an oxygen atom and Y is a methylene group. (3) X is a methylene group and Y is an oxygen atom.
  • M in the cyclic phosphatidic acid derivative represented by the formula (I) is a hydrogen atom or an alkali metal atom.
  • alkali metal atom examples include lithium, sodium, potassium and the like, and sodium is particularly preferable.
  • Specific examples of the compound represented by the formula (1) used in the present invention include, as a 1-position acyl group, R is a stearoyl group having 17 carbon atoms, an oleoyl group, a linoleoyl group, a linolenoyl group, and R is the number of carbon atoms. 15 palmitoyl groups, palmitooleoyl groups, or cyclic phosphatidic acid derivatives having two or more of these fatty acids and having mixed fatty acid residues are preferred. Especially, the cyclic phosphatidic acid derivative which has an acyl group which consists of a fatty acid derived from soybean lecithin is especially preferable.
  • the compounds of formula (I) may have isomers such as positional isomers, geometric isomers, tautomers, or optical isomers depending on the type of substituent, but all possible Isomers and mixtures containing two or more of these isomers in any ratio are also within the scope of the present invention.
  • the compound of formula (I) may exist in the form of an adduct (hydrate or solvate) with water or various solvents, and these adducts are also within the scope of the present invention. is there. Furthermore, any crystalline form of the compound of formula (I) and salts thereof is within the scope of the invention.
  • compounds in which X and Y are oxygen atoms include, for example, JP-A-5-230088, JP-A-7-149772, JP-A-7-258278, and JP-A-9. It can be chemically synthesized according to the method described in Japanese Patent No. 25235.
  • a compound in which X and Y are oxygen atoms is synthesized by allowing phospholipase D to act on lyso-type phospholipid according to the method described in Japanese Patent Application Laid-Open No. 2001-178489. You can also
  • the lyso-type phospholipid used here is not particularly limited as long as it is a lyso-type phospholipid capable of acting on phospholipase D. Many types of lyso-type phospholipids are known, those having different fatty acid types, and molecular types having ether or vinyl ether bonds are known, and these are available as commercial products.
  • phospholipase D those derived from higher plants such as cabbage and peanuts and those derived from microorganisms such as Streptomyces uschromofuscus and Actinomadula sp. Are available as commercially available reagents, but are extremely selected by the enzyme derived from Actinomadula sp. No.362.
  • cyclic phosphatidic acid is synthesized (Japanese Patent Laid-Open No. 11-367032).
  • the reaction between lyso-type phospholipid and phospholipase D is not particularly limited as long as the enzyme is capable of expressing the activity. For example, it is heated from room temperature in an acetate buffer solution (pH of about 5 to 6) containing calcium chloride. (Preferably at about 37 ° C.) for about 1 to 5 hours.
  • the produced cyclic phosphatidic acid derivative can be purified by extraction, column chromatography, thin layer chromatography (TLC) or the like according to a conventional method
  • a compound in which X is an oxygen atom and Y is a methylene group can be obtained by a method described in the literature (Kobayashi, S., et al., TetrahedronroLetters 34, 4047-4050 (1993)). ) And can be synthesized by the method described in International Publication WO2002 / 094286. An example of a specific synthesis route is shown below.
  • a compound in which X is a methylene group and Y is an oxygen atom is synthesized by the method described in JP-A No. 2004-010582 or WO 03/104246. can do.
  • the dosage form of the hair restorer of the present invention is not particularly limited as long as it is a dosage form that can be compounded with the compound represented by the following formula (1) and can be applied to the outer skin.
  • a suitable cosmetic base Alternatively, it can be blended with a pharmaceutical base and used as a liquid, emulsion, semi-solid or solid hair restorer.
  • it may be included in microcapsules or liposomes.
  • the form of the hair restorer of the present invention is arbitrary, and examples thereof include hair liquid, hair tonic, hair lotion, ointment, hair cream, mousse, gel, shampoo, rinse, etc., each of which is used as a suitable base for the present invention.
  • the cyclic phosphatidic acid derivative obtained can be added and can be produced by a conventional method.
  • the content of the cyclic phosphatidic acid derivative in the hair restorer of the present invention varies depending on the type of the cyclic phosphatidic acid derivative, but is usually 0.01 to 5.0% by weight, preferably 0.01 to 3.0% by weight, more. Preferably, it is 0.1 to 1.0% by weight.
  • Suitable bases for liquid dosage forms include those commonly used for hair restorers, such as purified water, ethyl alcohol, and polyhydric alcohols, and additives may be added as necessary.
  • the polyhydric alcohol include glycerol, 1,3-butylene glycol, propylene glycol and the like.
  • Additives include surfactants, vitamins, anti-inflammatory agents, bactericides, hormonal agents, herbal extracts, tinctures, refreshing agents, moisturizers, keratolytic agents, antioxidants, sequestering agents, fragrances, etc. It is done.
  • the surfactant is not particularly limited, and nonionic, anionic, cationic and amphoteric surfactants can be appropriately used.
  • vitamins examples include benzyl nicotinate, nicotinamide, D-pantothenyl alcohol, pantothenyl ethyl ether, biotin, pyridoxine hydrochloride, riboflavin and the like.
  • Anti-inflammatory agents include dipotassium glycyrrhizinate, ⁇ -glycyrrhetinic acid, allantoin, diphenhydramine hydrochloride, guaiazulene, 1-menthol and the like.
  • bactericides include trichlorohydroxydiphenyl ether, hinokitiol, triclosan, chlorhexidine gluconate, phenoxyethanol, resorcin, isopropylmethylphenol, azulene, salicylic acid, zinc pyrithione, benzalkonium chloride, photosensitizer 301, mononitroguaiacol sodium, etc. .
  • hormone agents include ethinyl estradiol, estrone, estradiol and the like.
  • Herbal extracts include assembly extract, garlic extract, carrot extract, aloe extract, kina extract and the like.
  • Examples of the tincture include chili tincture, ginger tincture, cantharis tincture and the like.
  • Examples of the refreshing agent include chili pepper tincture, 1-menthol and camphor.
  • humectant examples include L-pyrrolidone carboxylic acid, sodium hyaluronate, chondroitin sulfate, cordyceps extract, saffron extract and the like.
  • antioxidant examples include butylhydroxyanisole, isopropyl gallate, propyl gallate, erythorbic acid and the like.
  • sequestering agent examples include ethylenediaminetetraacetate or a salt thereof.
  • fragrances examples include natural fragrances such as orange oil, lemon oil, bergamot oil, lime oil, lemongrass oil, and lavender oil, and synthetic fragrances such as menthol, rose oxide, linalool, citral, and linalyl acetate.
  • a combustible gas, an incombustible gas, or the like can be used.
  • the combustible gas include LPG (liquefied petroleum gas) and dimethyl ether
  • examples of the non-combustible gas include nitrogen gas and carbon dioxide gas.
  • Semi-solid or solid dosage form bases include petrolatum, solid paraffin, vegetable oil, mineral oil, lanolin, wax, macrogol, etc. If necessary, the aforementioned additives, emulsifiers such as lecithin, ethyl alcohol A lower alcohol such as isopropyl alcohol may be added.
  • the dose of the hair restorer of the present invention varies depending on the subject's symptoms, administration method, etc., but is 0.1 to 250 mg, preferably 1 to 100 mg as the compound represented by the formula (1) at a time per adult. Is administered transdermally once to several times a day.
  • NcPA Native cPA
  • soybean phospholipid lecithin content: 70%
  • 1 M acetate buffer pH 6.5
  • Streptomyces phospholipase A2 100 ml
  • the reaction solution was adjusted to pH 2.5 to inactivate the enzyme, and then 100 ml of chloroform and 50 ml of methanol were added and mixed with sufficient stirring to extract lipid components.
  • the chloroform layer was collected and dried under reduced pressure on a rotary evaporator. 100 ml of acetone was added to the solid content to precipitate phospholipids and remove free fatty acids. Dissolve 5 g of the precipitate in 40 ml of chloroform, add 10 ml of 1M acetate buffer (pH 5.5), add 1500 units of phospholipase D derived from the genus Actinomadura, and perform the reaction with stirring at 40 ° C. for 18 hours. It was. 20 ml of 3M sodium chloride and 20 ml of 0.1M EDTA solution were added to the reaction solution and stirred at 40 ° C. for 1 hour.
  • the above cyclic phosphatidic acid sodium salt 500 mg was dissolved in 5 ml of chloroform containing 10% methanol, applied to a silica gel column, developed with the same solvent, further developed with chloroform containing 20% methanol, and fractionated into 10 ml fractions. Fractions containing cyclic phosphatidic acid sodium salt were confirmed and collected by the above TLC method, and dried under reduced pressure using a rotary evaporator to obtain 320 mg of cyclic phosphatidic acid sodium salt powder. The purity of the cyclic phosphatidic acid sodium salt of this sample was 95%.
  • the fatty acid composition of the high purity cyclic sodium phosphatidic acid obtained above was analyzed by gas chromatogram method.
  • the sample was dissolved in hydrochloric acid methanol so as to be 20 mg / ml, and heated at 65 ° C. for 30 minutes. After returning to room temperature, the water of the master beam and then the hexane of the master beam were added and mixed thoroughly with stirring. Centrifugation was performed at 3000 rpm for 5 minutes, and 2 ⁇ l of the hexane layer was injected into the capillary column to analyze the constituent fatty acids. The analysis is as follows. Fatty acid content (%) Palmitic acid 23.9 Stearic acid 5.4 Oleic acid 8.6 Linoleic acid 53.4 Linolenic acid 4.9 Other fatty acids 3.8
  • Test Example 1 Using the NcPA produced in Production Example 1, a hair growth effect test in mice was performed.
  • the administration route was transdermal administration.
  • a sample to be administered (control or test substance) was administered to the back skin of a mouse using a micropipette, and lightly smeared with a finger (control group: 10 animals; and 10 NcPA administration groups).
  • the administration liquid volume was 100 ⁇ l / site.
  • the administration frequency was once a day.
  • the administration period was 24 days, with the first day of administration being 1 day of administration.
  • the naked eye observation of the shaved part was based on the criteria shown in the following Table 1 on the day of grouping (1 day of administration), 5th, 7th, 10th, 13th, 16, 19, 22 and 25th. The score was scored and the average value ⁇ standard deviation was calculated for each group. In addition, a photograph was taken for each group on the score observation day. Photographing and score observation were performed before administration.
  • Results Table 2 and FIG. 1 show the results of the hair growth state score observation. The results of mouse photography are shown in FIGS.
  • the NcPA administration group in which 1100 ⁇ l / site / day of NcPA was administered transdermally for 24 days showed a higher tendency (P ⁇ 0.1) on the 19th and 25th administration than the control group. ) was observed, and the hair growth promoting action of NcPA was confirmed.

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Abstract

The purpose of the present invention is to provide a hair growth agent having an excellent hair-nourishing/hair-growing effect. The present invention provides a hair growth agent comprising cyclic phosphatidic acid or carbacyclic phosphatidic acid as an active ingredient.

Description

育毛剤Hair restorer
　本発明は、環状ホスファチジン酸又はカルバ環状ホスファチジン酸を有効成分とする育毛剤に関する。 The present invention relates to a hair restorer containing cyclic phosphatidic acid or carbacyclic phosphatidic acid as an active ingredient.
　脱毛症には、先天性のもの、後天性のものがあり、その発症原因、発生機序共に多くの研究がなされている。しかし今日、養毛・育毛剤は非常に多く市場に出てはいるものの、不明な点が多いのが現状である。 Alopecia can be congenital or acquired, and many studies have been conducted on its cause and mechanism of alopecia. However, although there are many hair nourishing and hair restorers on the market today, there are many unclear points.
　従来、脱毛症の予防及び治療に用いられている多くの養育毛剤における、薬効成分としては、センブリエキス、ビタミンＥアセテート等の血管拡張剤、トウガラシチンキ等の刺激剤、パントテン酸、ビオチン等のビタミン類、更には、ホルモン剤、抗炎症剤、殺菌剤等が使用されている。又、リゾホスファチジン酸又はホスファチジン酸誘導体が養育毛作用を有することも知られている（特許文献１，２）。その他にも、ヒアルロン酸合成促進成分を含有する養育毛剤が知られている（特許文献３）。 In many conventional hair nurturing agents used for the prevention and treatment of alopecia, medicinal ingredients include vasodilators such as assembly extract, vitamin E acetate, stimulants such as pepper tincture, pantothenic acid, biotin and the like. Vitamins, hormonal agents, anti-inflammatory agents, bactericides, and the like are used. It is also known that lysophosphatidic acid or phosphatidic acid derivatives have a hair-growing action (Patent Documents 1 and 2). In addition, a hair nurturing agent containing a hyaluronic acid synthesis promoting component is known (Patent Document 3).
　しかしながら、これらの養育毛剤の効果は必ずしも高くはなく、使用者に必ずしも満足する結果を与えていないという問題があった。近年、技術の進歩に伴い、更に養育毛効果に優れる養育毛剤が望まれている。 However, the effect of these hair nurturing agents is not always high, and there is a problem that the user is not always given satisfactory results. In recent years, with the advance of technology, a hair nurturing agent that is further excellent in hair nurturing effect is desired.
特公昭６３－４１３６３号公報Japanese Patent Publication No. 63-41363 国際公開ＷＯ２００１／０１２１４１International Publication WO2001 / 012141 特開２００３－８１７７８号公報JP 2003-81778 A
　本発明は、上記した従来技術における問題点を解消し、優れた養毛・発毛効果を示す育毛剤を提供することを解決すべき課題とする。 This invention makes it the subject which should solve the problem in the above-mentioned prior art, and to provide the hair restorer which shows the outstanding hair restoration and hair growth effect.
　本発明者らは、環状ホスフアチジン酸及びその誘導体が、優れた養毛・発毛効果を示すことを見出し、本発明を完成するに至った。 The present inventors have found that cyclic phosphatidic acid and its derivatives show an excellent hair nourishing / hair growth effect, and have completed the present invention.
　すなわち、本発明によれば、下記式（１）で示される化合物を有効成分として含有する育毛剤が提供される。
Figure JPOXMLDOC01-appb-C000002
 （式中、Ｒは、炭素数１～３０の直鎖状若しくは分岐状アルキル基、炭素数２～３０の直鎖状若しくは分岐状アルケニル基、又は炭素数２～３０の直鎖状若しくは分岐状アルキニル基であり、これらの基はシクロアルカン環又は芳香環を含んでいてもよい。Ｘ及びＹはそれぞれ独立に、酸素原子、又はメチレン基を示すが、Ｘ及びＹが同時にメチレン基になることはない。Ｍは、水素原子又はアルカリ金属原子である。） That is, according to this invention, the hair restorer which contains the compound shown by following formula (1) as an active ingredient is provided.
Figure JPOXMLDOC01-appb-C000002
 (In the formula, R is a linear or branched alkyl group having 1 to 30 carbon atoms, a linear or branched alkenyl group having 2 to 30 carbon atoms, or a linear or branched group having 2 to 30 carbon atoms. An alkynyl group, and these groups may contain a cycloalkane ring or an aromatic ring, and X and Y each independently represent an oxygen atom or a methylene group; M is a hydrogen atom or an alkali metal atom.)
　好ましくは、式（１）において、Ｘ及びＹが酸素原子である。
　好ましくは、式（１）において、Ｘ又はＹの一方が酸素原子であり、他方がメチレン基である。
　好ましくは、式（１）で示される化合物が、大豆レシチン由来の脂肪酸からなるアシル基を有する化合物である。 Preferably, in the formula (1), X and Y are oxygen atoms.
Preferably, in Formula (1), one of X and Y is an oxygen atom, and the other is a methylene group.
Preferably, the compound represented by the formula (1) is a compound having an acyl group composed of a fatty acid derived from soybean lecithin.
　本発明によればさらに、上記式（１）で示される化合物を、対象者に投与することを含む、育毛方法が提供される。 According to the present invention, there is further provided a hair growth method comprising administering a compound represented by the above formula (1) to a subject.
　本発明によればさらに、育毛剤の製造のための、上記式（１）で示される化合物の使用が提供される。 According to the present invention, there is further provided use of a compound represented by the above formula (1) for the production of a hair restorer.
　本発明によれば、優れた養毛・発毛効果を示す育毛剤を提供することができる。 According to the present invention, it is possible to provide a hair restorer that exhibits an excellent hair nourishing / hair growth effect.
図１は、コントロール群及びNcPA投与群の育毛スコアの変化を示す。FIG. 1 shows changes in hair growth scores of the control group and the NcPA administration group. 図２は、コントロール群の投与２５日の発毛状態を示す。FIG. 2 shows the hair growth state on the 25th day after administration of the control group. 図３は、NcPA投与群の投与２５日の発毛状態を示す。FIG. 3 shows the hair growth state on the 25th day of administration in the NcPA administration group.
　以下、本発明について更に具体的に説明する。
　本発明の育毛剤は、男性型脱毛症の治療などに使用することができ、環状ホスファチジン酸又はカルバ環状ホスファチジン酸又はそれらの塩を有効成分として含む。環状ホスファチジン酸又はカルバ環状ホスファチジン酸又はその塩としては本発明の効果を示すものであれば特に限定されないが、好ましくは、下記式（Ｉ）で示される化合物を使用することができる。 Hereinafter, the present invention will be described more specifically.
The hair restorer of the present invention can be used for the treatment of androgenetic alopecia, and contains cyclic phosphatidic acid, carbacyclic phosphatidic acid or a salt thereof as an active ingredient. The cyclic phosphatidic acid or the carbcyclic phosphatidic acid or a salt thereof is not particularly limited as long as it exhibits the effects of the present invention, but preferably a compound represented by the following formula (I) can be used.
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000003
（式中、Ｒは、炭素数１～３０の直鎖状若しくは分岐状アルキル基、炭素数２～３０の直鎖状若しくは分岐状アルケニル基、又は炭素数２～３０の直鎖状若しくは分岐状アルキニル基であり、これらの基はシクロアルカン環又は芳香環を含んでいてもよい。Ｘ及びＹはそれぞれ独立に、酸素原子、又はメチレン基を示すが、Ｘ及びＹが同時にメチレン基になることはない。Ｍは、水素原子又はアルカリ金属原子である。） (In the formula, R is a linear or branched alkyl group having 1 to 30 carbon atoms, a linear or branched alkenyl group having 2 to 30 carbon atoms, or a linear or branched group having 2 to 30 carbon atoms. An alkynyl group, and these groups may contain a cycloalkane ring or an aromatic ring, and X and Y each independently represent an oxygen atom or a methylene group; M is a hydrogen atom or an alkali metal atom.)
　式（Ｉ）において、置換基Ｒが示す炭素数1～30の直鎖状若しくは分岐状アルキル基の具体例としては、例えば、メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基、ヘプチル基、オクチル基、ノニル基、デシル基、ウンデシル基、ドデシル基、トリデシル基、テトラデシル基、ペンタデシル基、ヘキサデシル基、ヘプタデシル基、オクタデシル基、ノナデシル基、エイコシル基などが挙げられる。 In the formula (I), specific examples of the linear or branched alkyl group having 1 to 30 carbon atoms represented by the substituent R include, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group. , Heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl and the like.
　置換基Ｒが示す炭素数２～３０の直鎖状若しくは分岐状アルケニル基の具体例としては、例えば、アリル基、ブテニル基、オクテニル基、デセニル基、ドデカジエニル基、ヘキサデカトリエニル基などが挙げられ、より具体的には、８－デセニル基、８－ウンデセニル基、８－ドデセニル基、８－トリデセニル基、８－テトラデセニル基、８－ペンタデセニル基、８－ヘキサデセニル基、８－ヘプタデセニル基、８－オクタデセニル基、８－イコセニル基、８－ドコセニル基、ヘプタデカ－８，１１－ジエニル基、ヘプタデカ－８，１１，１４－トリエニル基、ノナデカ－４，７，１０，１３－テトラエニル基、ノナデカ－４，７，１０，１３，１６－ペンタエニル基、ヘニコサ－３，６，９，１２，１５，１８－ヘキサエニル基などが挙げられる。 Specific examples of the linear or branched alkenyl group having 2 to 30 carbon atoms represented by the substituent R include an allyl group, a butenyl group, an octenyl group, a decenyl group, a dodecadienyl group, a hexadecatrienyl group, and the like. More specifically, 8-decenyl group, 8-undecenyl group, 8-dodecenyl group, 8-tridecenyl group, 8-tetradecenyl group, 8-pentadecenyl group, 8-hexadecenyl group, 8-heptadecenyl group, 8- Octadecenyl group, 8-icosenyl group, 8-docosenyl group, heptadec-8,11-dienyl group, heptadec-8,11,14-trienyl group, nonadeca-4,7,10,13-tetraenyl group, nonadeca-4, 7,10,13,16-pentaenyl group, henicosa-3,6,9,12,15,18-hexaenyl group, etc. It is.
　置換基Ｒが示す炭素数2～30の直鎖状若しくは分岐状アルキニル基の具体例としては、例えば、８－デシニル基、８－ウンデシニル基、８－ドデシニル基、８－トリデシニル基、８－テトラデシニル基、８－ペンタデシニル基、８－ヘキサデシニル基、８－ヘプタデシニル基、８－オクタデシニル基、８－イコシニル基、８－ドコシニル基、ヘプタデカ－８，１１－ジイニル基などが挙げられる。 Specific examples of the linear or branched alkynyl group having 2 to 30 carbon atoms represented by the substituent R include, for example, 8-decynyl group, 8-undecynyl group, 8-dodecynyl group, 8-tridecynyl group, and 8-tetradecynyl group. Group, 8-pentadecynyl group, 8-hexadecynyl group, 8-heptadecynyl group, 8-octadecynyl group, 8-icosinyl group, 8-docosinyl group, heptadec-8,11-diynyl group and the like.
　上記のアルキル基、アルケニル基又はアルキニル基に含有されうるシクロアルカン環の具体例としては、例えば、シクロプロパン環、シクロブタン環、シクロペンタン環、シクロヘキサン環、シクロオクタン環などが挙げられる。シクロアルカン環は、1個以上のヘテロ原子を含んでいてもよく、そのような例としては、例えば、オキシラン環、オキセタン環、テトラヒドロフラン環、Ｎ－メチルプロリジン環などが挙げられる。 Specific examples of the cycloalkane ring that can be contained in the alkyl group, alkenyl group, or alkynyl group include a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, and a cyclooctane ring. The cycloalkane ring may contain one or more heteroatoms, and examples thereof include an oxirane ring, an oxetane ring, a tetrahydrofuran ring, and an N-methylprolysine ring.
　上記のアルキル基、アルケニル基又はアルキニル基に含有されうる芳香環の具体例としては、例えば、ベンゼン環、ナフタレン環、ピリジン環、フラン環、チオフェン環などが挙げられる。 Specific examples of the aromatic ring that can be contained in the alkyl group, alkenyl group, or alkynyl group include a benzene ring, a naphthalene ring, a pyridine ring, a furan ring, and a thiophene ring.
　従って、置換基Ｒがシクロアルカン環によって置換されたアルキル基である場合の具体例としては、例えば、シクロプロピルメチル基、シクロヘキシルエチル基、８，９－メタノペンタデシル基などが挙げられる。 Therefore, specific examples in the case where the substituent R is an alkyl group substituted by a cycloalkane ring include a cyclopropylmethyl group, a cyclohexylethyl group, an 8,9-methanopentadecyl group, and the like.
　置換基Ｒが芳香環によって置換されたアルキル基である場合の具体例としては、ベンジル基、フェネチル基、ｐ－ペンチルフェニルオクチル基などが挙げられる。 Specific examples when the substituent R is an alkyl group substituted by an aromatic ring include a benzyl group, a phenethyl group, a p-pentylphenyloctyl group, and the like.
　Ｒは、好ましくは、炭素数９～１７の直鎖状若しくは分岐状アルキル基、炭素数９～１７の直鎖状若しくは分岐状アルケニル基、又は炭素数９～１７の直鎖状若しくは分岐状アルキニル基である。Ｒは、さらに好ましくは、炭素数９、１１、１３、１５又は１７の直鎖状若しくは分岐状アルキル基、又は炭素数９、１１、１３、１５又は１７の直鎖状若しくは分岐状アルケニル基である。Ｒは、特に好ましくは、炭素数９、１１、１３、１５又は１７の直鎖状若しくは分岐状アルケニル基である。 R is preferably a linear or branched alkyl group having 9 to 17 carbon atoms, a linear or branched alkenyl group having 9 to 17 carbon atoms, or a linear or branched alkynyl group having 9 to 17 carbon atoms. It is a group. R is more preferably a linear or branched alkyl group having 9, 11, 13, 15 or 17 carbon atoms, or a linear or branched alkenyl group having 9, 11, 13, 15 or 17 carbon atoms. is there. R is particularly preferably a linear or branched alkenyl group having 9, 11, 13, 15 or 17 carbon atoms.
　式(１)で示される化合物中のＸ及びＹはそれぞれ独立に、酸素原子（－Ｏ－）又はメチレン基（－ＣＨ2－）を示すが、Ｘ及びＹが同時にメチレン基になることはない。即ち、Ｘ及びＹの組み合わせは以下の３通りである。
（１）Ｘが酸素原子であり、Ｙが酸素原子である。
（２）Ｘが酸素原子であり、Ｙがメチレン基である。
（３）Ｘがメチレン基であり、Ｙが酸素原子である。 X and Y in the compound represented by the formula (1) each independently represents an oxygen atom (—O—) or a methylene group (—CH 2 —), but X and Y do not simultaneously become a methylene group. . That is, there are the following three combinations of X and Y.
(1) X is an oxygen atom and Y is an oxygen atom.
(2) X is an oxygen atom and Y is a methylene group.
(3) X is a methylene group and Y is an oxygen atom.
　式（Ｉ）で示される環状ホスファチジン酸誘導体中のＭは、水素原子又はアルカリ金属原子である。アルカリ金属原子としては、例えば、リチウム、ナトリウム、カリウムなどが挙げられ、ナトリウムが特に好ましい。 M in the cyclic phosphatidic acid derivative represented by the formula (I) is a hydrogen atom or an alkali metal atom. Examples of the alkali metal atom include lithium, sodium, potassium and the like, and sodium is particularly preferable.
　本発明で用いられる式（１）で示される化合物の具体例としては、１位アシル基として、Ｒが炭素原子数１７のステアロイル基、オレオイル基、リノレオイル基、リノレノイル基、Ｒが炭素原子数１５のパルミトイル基、パルミトオレオイル基、又は、これら脂肪酸を2種以上含有する、混合脂肪酸残基を有する環状ホスファチジン酸誘導体が好ましい。なかでも、大豆レシチン由来の脂肪酸からなるアシル基を有する環状ホスファチジン酸誘導体が特に好ましい。 Specific examples of the compound represented by the formula (1) used in the present invention include, as a 1-position acyl group, R is a stearoyl group having 17 carbon atoms, an oleoyl group, a linoleoyl group, a linolenoyl group, and R is the number of carbon atoms. 15 palmitoyl groups, palmitooleoyl groups, or cyclic phosphatidic acid derivatives having two or more of these fatty acids and having mixed fatty acid residues are preferred. Especially, the cyclic phosphatidic acid derivative which has an acyl group which consists of a fatty acid derived from soybean lecithin is especially preferable.
　式（Ｉ）の化合物はその置換基の種類に応じて、位置異性体、幾何異性体、互変異性体、又は光学異性体のような異性体が存在する場合があるが、全ての可能な異性体、並びに２種類以上の該異性体を任意の比率で含む混合物も本発明の範囲内のものである。 The compounds of formula (I) may have isomers such as positional isomers, geometric isomers, tautomers, or optical isomers depending on the type of substituent, but all possible Isomers and mixtures containing two or more of these isomers in any ratio are also within the scope of the present invention.
　また、式（Ｉ）の化合物は、水あるいは各種溶媒との付加物（水和物又は溶媒和物）の形で存在することもあるが、これらの付加物も本発明の範囲内のものである。さらに、式（Ｉ）の化合物及びその塩の任意の結晶形も本発明の範囲内のものである。 The compound of formula (I) may exist in the form of an adduct (hydrate or solvate) with water or various solvents, and these adducts are also within the scope of the present invention. is there. Furthermore, any crystalline form of the compound of formula (I) and salts thereof is within the scope of the invention.
　式(１)で示される化合物のうちＸ及びＹが酸素原子である化合物は、例えば、特開平５－２３００８８号公報、特開平７－１４９７７２号公報、特開平７－２５８２７８号公報、特開平９－２５２３５号公報に記載の方法等に準じて化学的に合成することができる。 Among the compounds represented by the formula (1), compounds in which X and Y are oxygen atoms include, for example, JP-A-5-230088, JP-A-7-149772, JP-A-7-258278, and JP-A-9. It can be chemically synthesized according to the method described in Japanese Patent No. 25235.
　また、式(１)で示される化合物のうちＸ及びＹが酸素原子である化合物は、特開２００１－１７８４８９号公報に記載の方法に準じてリゾ型リン脂質にホスホリパーゼＤを作用させることによって合成することもできる。ここで用いるリゾ型リン脂質は、ホスホリパーゼＤを作用しうるリゾ型リン脂質であれば特に限定されない。リゾ型リン脂質は多くの種類が知られており、脂肪酸種が異なるもの、エーテル又はビニルエーテル結合をもった分子種などが知られており、これらは市販品として入手可能である。ホスホリパーゼＤとしては、キャベツや落花生などの高等植物由来のものやStreptomyces chromofuscus, Actinomadula sp.などの微生物由来のものが市販試薬として入手可能であるが、Actinomadula sp. No.362由来の酵素によって極めて選択的に環状ホスファチジン酸が合成される（特開平１１－３６７０３２号明細書）。リゾ型リン脂質とホスホリパーゼＤとの反応は、酵素が活性を発現できる条件であれば特に限定されないが、例えば、塩化カルシウムを含有する酢酸緩衝液（ｐＨ５～６程度）中で室温から加温下（好ましくは３７℃程度）で１から５時間程度反応させることにより行う。生成した環状ホスファチジン酸誘導体は、常法に準じて、抽出、カラムクロマトグラフィー、薄層クロマトグラフィー（ＴＬＣ）などにより精製することができる。 Further, among the compounds represented by the formula (1), a compound in which X and Y are oxygen atoms is synthesized by allowing phospholipase D to act on lyso-type phospholipid according to the method described in Japanese Patent Application Laid-Open No. 2001-178489. You can also The lyso-type phospholipid used here is not particularly limited as long as it is a lyso-type phospholipid capable of acting on phospholipase D. Many types of lyso-type phospholipids are known, those having different fatty acid types, and molecular types having ether or vinyl ether bonds are known, and these are available as commercial products. As phospholipase D, those derived from higher plants such as cabbage and peanuts and those derived from microorganisms such as Streptomyces uschromofuscus and Actinomadula sp. Are available as commercially available reagents, but are extremely selected by the enzyme derived from Actinomadula sp. No.362. Thus, cyclic phosphatidic acid is synthesized (Japanese Patent Laid-Open No. 11-367032). The reaction between lyso-type phospholipid and phospholipase D is not particularly limited as long as the enzyme is capable of expressing the activity. For example, it is heated from room temperature in an acetate buffer solution (pH of about 5 to 6) containing calcium chloride. (Preferably at about 37 ° C.) for about 1 to 5 hours. The produced cyclic phosphatidic acid derivative can be purified by extraction, column chromatography, thin layer chromatography (TLC) or the like according to a conventional method.
　また、式(１)で示される化合物のうちＸが酸素原子であり、Ｙがメチレン基である化合物は、文献記載の方法（Ｋｏｂａｙａｓｈｉ，Ｓ．，他，Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔｅｒｓ ３４，４０４７－４０５０（１９９３））に準じて合成することができ、また国際公開ＷＯ２００２／０９４２８６号公報に記載の方法により合成することができる。具体的な合成経路の一例を以下に示す。 Further, among the compounds represented by the formula (1), a compound in which X is an oxygen atom and Y is a methylene group can be obtained by a method described in the literature (Kobayashi, S., et al., TetrahedronｒｏLetters 34, 4047-4050 (1993)). ) And can be synthesized by the method described in International Publication WO2002 / 094286. An example of a specific synthesis route is shown below.
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
　上記においては、先ず、市販の(R)-ベンジルグリシジルエーテル(1)をBF3・Et2Oで活性化させ、メチルホスホン酸ジメチルエステルにn-BuLiを作用させて得られるリチオ体を反応させることでアルコール(2)を得る。
　得られたアルコールを、トルエン中で過剰のp-トルエンスルホン酸のピリジニウム塩を用いて80℃で反応させることにより、環化体(3)を得る。この環化体を、水素雰囲気下で20% Pd(OH)2-Cを用いて加水素分解し、脱ベンジル化を行う(4)。縮合剤として1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩を用いて、脂肪酸と反応させてカップリング体(5)を得る。次に、求核剤としてブロモトリメチルシランを用いて、メチル基だけを位置選択的に除去し、環状ホスホン酸(6)を得る。これをエーテルを用いて分液ロートに移しこみ、少量の0.02Nの水酸化ナトリウム水溶液を滴下して、分液操作を行い、ナトリウム塩(7)として目的化合物を抽出、精製する。 In the above, first, the commercially available (R) -benzyl glycidyl ether (1) is activated with BF 3 .Et 2 O, and the thio compound obtained by reacting n-BuLi with methylphosphonic acid dimethyl ester is reacted. To obtain alcohol (2).
The obtained alcohol is reacted at 80 ° C. with an excess of pyridinium salt of p-toluenesulfonic acid in toluene to obtain a cyclized product (3). This cyclized product is subjected to hydrogenolysis using 20% Pd (OH) 2 —C under hydrogen atmosphere to perform debenzylation (4). Using 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride as a condensing agent, it is reacted with a fatty acid to obtain a coupled product (5). Next, using bromotrimethylsilane as a nucleophile, only the methyl group is regioselectively removed to obtain cyclic phosphonic acid (6). This is transferred to a separatory funnel using ether, and a small amount of 0.02N aqueous sodium hydroxide solution is added dropwise to carry out a liquid separation operation to extract and purify the target compound as a sodium salt (7).
　また、一般式(１)で示される化合物のうちＸがメチレン基であり、Ｙが酸素原子である化合物は、特開２００４－０１０５８２号公報又は国際公開ＷＯ０３／１０４２４６号公報に記載の方法により合成することができる。 Further, among the compounds represented by the general formula (1), a compound in which X is a methylene group and Y is an oxygen atom is synthesized by the method described in JP-A No. 2004-010582 or WO 03/104246. can do.
　本発明の育毛剤の剤型としては、下記式（１）で示される化合物を配合しうる剤型で、外皮に適用可能な剤型であれば特に限定されず、例えば、適当な化粧品基剤又は医薬基剤と配合して液状、乳液状、半固形状あるいは固形状の育毛剤として用いることができる。さらに吸収を高めるために、マイクロカプセルや、リポソームに包含してもよい。 The dosage form of the hair restorer of the present invention is not particularly limited as long as it is a dosage form that can be compounded with the compound represented by the following formula (1) and can be applied to the outer skin. For example, a suitable cosmetic base Alternatively, it can be blended with a pharmaceutical base and used as a liquid, emulsion, semi-solid or solid hair restorer. Furthermore, in order to enhance absorption, it may be included in microcapsules or liposomes.
　また、本発明の育毛剤の形態は任意であり、ヘヤーリキッド、ヘヤートニック、ヘヤーローション、軟膏、ヘヤークリーム、ムース、ジェル、シャンプー、リンス等があげられ、各々好適な基剤に本発明に用いられる環状ホスファチジン酸誘導体を添加し、常法により製造することができる。 The form of the hair restorer of the present invention is arbitrary, and examples thereof include hair liquid, hair tonic, hair lotion, ointment, hair cream, mousse, gel, shampoo, rinse, etc., each of which is used as a suitable base for the present invention. The cyclic phosphatidic acid derivative obtained can be added and can be produced by a conventional method.
　本発明の育毛剤中の環状ホスファチジン酸誘導体の含有量は、環状ホスファチジン酸誘導体の種類によって異なるが、通常０．０１～５．０重量％、好ましくは０．０１～３．０重量％、より好ましくは、０．１～１．０重量％である。 The content of the cyclic phosphatidic acid derivative in the hair restorer of the present invention varies depending on the type of the cyclic phosphatidic acid derivative, but is usually 0.01 to 5.0% by weight, preferably 0.01 to 3.0% by weight, more. Preferably, it is 0.1 to 1.0% by weight.
　液状剤型に好適な基剤としては、育毛剤に通常使用されているもの、例えば精製水、エチルアルコール、多価アルコール類があげられ、必要により添加剤を添加してもよい。
　多価アルコールとしては、グリセロール、１，３－ブチレングリコール、プロピレングリコール等があげられる。
　添加剤としては、界面活性剤、ビタミン類、消炎剤、殺菌剤、ホルモン剤、生薬エキス、チンキ類、清涼剤、保湿剤、角質溶解剤、酸化防止剤、金属イオン封鎖剤、香料等があげられる。 Suitable bases for liquid dosage forms include those commonly used for hair restorers, such as purified water, ethyl alcohol, and polyhydric alcohols, and additives may be added as necessary.
Examples of the polyhydric alcohol include glycerol, 1,3-butylene glycol, propylene glycol and the like.
Additives include surfactants, vitamins, anti-inflammatory agents, bactericides, hormonal agents, herbal extracts, tinctures, refreshing agents, moisturizers, keratolytic agents, antioxidants, sequestering agents, fragrances, etc. It is done.
　界面活性剤としては、特に限定されず、非イオン性、陰イオン性、陽イオン性、両性界面活性剤を適宜用いることができる。 The surfactant is not particularly limited, and nonionic, anionic, cationic and amphoteric surfactants can be appropriately used.
　ビタミン類としては、ニコチン酸ベンジル、ニコチン酸アミド、Ｄ－パントテニルアルコール、パントテニルエチルエーテル、ビオチン、塩酸ピリドキシン、リボフラビン等があげられる。 Examples of vitamins include benzyl nicotinate, nicotinamide, D-pantothenyl alcohol, pantothenyl ethyl ether, biotin, pyridoxine hydrochloride, riboflavin and the like.
　消炎剤としては、グリチルリチン酸ジカリウム、β－グリチルレチン酸、アラントイン、塩酸ジフェンヒドラミン、グアイアズレン、１－メントール等があげられる。
　殺菌剤としては、トリクロロヒドロキシジフェニルエーテル、ヒノキチオール、トリクロサン、クロルヘキシジングルコン酸塩、フェノキシエタノール、レゾルシン、イソプロピルメチルフェノール、アズレン、サリチル酸、ジンクピリチオン、塩化ベンザルコニウム、感光素３０１号、モノニトログアヤコールナトリウム等があげられる。 Anti-inflammatory agents include dipotassium glycyrrhizinate, β-glycyrrhetinic acid, allantoin, diphenhydramine hydrochloride, guaiazulene, 1-menthol and the like.
Examples of bactericides include trichlorohydroxydiphenyl ether, hinokitiol, triclosan, chlorhexidine gluconate, phenoxyethanol, resorcin, isopropylmethylphenol, azulene, salicylic acid, zinc pyrithione, benzalkonium chloride, photosensitizer 301, mononitroguaiacol sodium, etc. .
　ホルモン剤としては、エチニルエストラジオール、エストロン、エストラジオール等があげられる。
　生薬エキスとしては、センブリエキス、ニンニクエキス、ニンジンエキス、アロエエキス、キナエキス等があげられる。
　チンキ類として、トウガラシチンキ、ショウキョウチンキ、カンタリスチンキ等があげられる。
　清涼剤としては、トウガラシチンキ、１－メントール、カンフル等があげられる。 Examples of hormone agents include ethinyl estradiol, estrone, estradiol and the like.
Herbal extracts include assembly extract, garlic extract, carrot extract, aloe extract, kina extract and the like.
Examples of the tincture include chili tincture, ginger tincture, cantharis tincture and the like.
Examples of the refreshing agent include chili pepper tincture, 1-menthol and camphor.
　保湿剤としては、Ｌ－ピロリドンカルボン酸、ヒアルロン酸ナトリウム、コンドロイチン硫酸、冬虫夏草抽出物、サフラン抽出物等があげられる。
　酸化防止剤としては、ブチルヒドロキシアニソール、イソプロピルガレート、没食子酸プロピル、エリソルビン酸等があげられる。
　金属イオン封鎖剤としては、エチレンジアミンテトラアセテートまたはその塩等があげられる。 Examples of the humectant include L-pyrrolidone carboxylic acid, sodium hyaluronate, chondroitin sulfate, cordyceps extract, saffron extract and the like.
Examples of the antioxidant include butylhydroxyanisole, isopropyl gallate, propyl gallate, erythorbic acid and the like.
Examples of the sequestering agent include ethylenediaminetetraacetate or a salt thereof.
　香料としては、オレンジ油、レモン油、ベルガモット油、ライム油、レモングラス油、ラベンダー油等の天然香料およびメントール、ローズオキサイド、リナロール、シトラール、酢酸リナリル等の合成香料があげられる。 Examples of the fragrances include natural fragrances such as orange oil, lemon oil, bergamot oil, lime oil, lemongrass oil, and lavender oil, and synthetic fragrances such as menthol, rose oxide, linalool, citral, and linalyl acetate.
　上記の液状剤型を噴霧剤として用いるときは、可燃ガス、不燃ガス等を用いることができる。可燃ガスとしては、ＬＰＧ（液化石油ガス）、ジメチルエーテル等があげられ、不燃ガスとしては、窒素ガス、炭酸ガス等があげられる。
　半固形状又は固体状剤型の基剤としては、ワセリン、固形パラフィン、植物油、鉱物油、ラノリン、ろう類、マクロゴール等があげられ、必要により前記の添加剤、レシチン等の乳化剤、エチルアルコール、イソプロピルアルコール等の低級アルコール等を添加してもよい。 When the above liquid dosage form is used as a spray, a combustible gas, an incombustible gas, or the like can be used. Examples of the combustible gas include LPG (liquefied petroleum gas) and dimethyl ether, and examples of the non-combustible gas include nitrogen gas and carbon dioxide gas.
Semi-solid or solid dosage form bases include petrolatum, solid paraffin, vegetable oil, mineral oil, lanolin, wax, macrogol, etc. If necessary, the aforementioned additives, emulsifiers such as lecithin, ethyl alcohol A lower alcohol such as isopropyl alcohol may be added.
　本発明の育毛剤の投与量は、対象者の症状や投与方法等により異なるが、成人一人当たり、一回に、式（１）で示される化合物として０．１～２５０ｍｇ、好ましくは１ｍｇ～１００ｍｇが一日一回から数回、経皮投与される。 The dose of the hair restorer of the present invention varies depending on the subject's symptoms, administration method, etc., but is 0.1 to 250 mg, preferably 1 to 100 mg as the compound represented by the formula (1) at a time per adult. Is administered transdermally once to several times a day.
　以下の実施例により本発明を具体的に説明するが、本発明は実施例によって限定されることはない。 The present invention will be specifically described by the following examples, but the present invention is not limited to the examples.
製造例１：
　本実施例で使用したnative cPA(以下、NcPAとも称する)は、以下の通り調製したものである（特願２０１１－１２６９０１の実施例１、３及び５を参照）。
　大豆リン脂質（レシチン含量：７０％）１０ｇを０．３M塩化カルシウムを含有する１００ｍｌの１M酢酸バッファー（ｐＨ６．５）で溶解させた後、６０００単位のストレプトマイセス属由来のホスホリパーゼA2を添加し、４０℃で１８時間攪拌して反応させた。反応液をpＨ２．５に調整して酵素を失活させた後、１００ｍｌのクロロホルム、５０ｍｌのメタノールを添加して十分攪拌混合し脂質成分を抽出した。クロロホルム層を集め、ロータリーエバポレータで減圧乾固させた。固形分に１００ｍｌのアセトンを加えリン脂質を沈殿させ遊離脂肪酸を除去した。沈殿物５gを４０ｍｌのクロロホルムに溶解させ、１M酢酸バッファー（pＨ５．５）１０ｍｌを加え、更に１５００単位のアクチノマジュラ属由来のホスホリパーゼDを添加して４０℃で１８時間攪拌しながら反応を行った。反応液に２０ｍｌの３M塩化ナトリウム、２０ｍｌの０．１M  EDTA溶液を添加して４０℃で１時間攪拌を行った。更に２０ｍｌのメタノールを添加して十分攪拌した後、３０００回転、５分間遠心分離してクロロホルム層を集めた。この溶液をロータリーエバポレータで減圧乾固させ環状ホスファチジン酸ナトリウム塩３．８ｇを得た。収率はレシチン含量７０％（１０g中７ｇ）から環状ホスファチジン酸Naを３．８ｇを得たので５４．３％であった。環状ホスファチジン酸ナトリウム塩の純度分析は、シリカゲルプレートを用い、クロロホルム：メタノール：酢酸：５％二亜硫酸ナトリウム（１００：４０：１２：５、V/V）で展開後、５％酢酸銅：８％燐酸：２％硫酸混合液に短時間浸漬し風乾後、１８０℃で約１０分加熱した後、生成したスポットをスキャナー（アトー社製）法によって行った。即ち、標準品(９７％純度品）をコントロールとして、薄層クロマトグラフのスポットをデンシトメーターにより測定し、面積比で定量した。上記工程で得られた生成物中環状ホスファチジン酸ナトリウム塩の純度は５４％であった。 Production Example 1:
Native cPA (hereinafter also referred to as NcPA) used in this example was prepared as follows (see Examples 1, 3 and 5 of Japanese Patent Application No. 2011-126901).
After dissolving 10 g of soybean phospholipid (lecithin content: 70%) in 100 ml of 1 M acetate buffer (pH 6.5) containing 0.3 M calcium chloride, 6000 units of Streptomyces phospholipase A2 was added. The reaction was stirred at 40 ° C. for 18 hours. The reaction solution was adjusted to pH 2.5 to inactivate the enzyme, and then 100 ml of chloroform and 50 ml of methanol were added and mixed with sufficient stirring to extract lipid components. The chloroform layer was collected and dried under reduced pressure on a rotary evaporator. 100 ml of acetone was added to the solid content to precipitate phospholipids and remove free fatty acids. Dissolve 5 g of the precipitate in 40 ml of chloroform, add 10 ml of 1M acetate buffer (pH 5.5), add 1500 units of phospholipase D derived from the genus Actinomadura, and perform the reaction with stirring at 40 ° C. for 18 hours. It was. 20 ml of 3M sodium chloride and 20 ml of 0.1M EDTA solution were added to the reaction solution and stirred at 40 ° C. for 1 hour. Further, 20 ml of methanol was added and sufficiently stirred, and then centrifuged at 3000 rpm for 5 minutes to collect a chloroform layer. This solution was dried under reduced pressure using a rotary evaporator to obtain 3.8 g of cyclic phosphatidic acid sodium salt. The yield was 54.3% because 3.8 g of cyclic phosphatidic acid Na was obtained from a lecithin content of 70% (7 g in 10 g). Purity analysis of cyclic phosphatidic acid sodium salt was carried out using silica gel plates with chloroform: methanol: acetic acid: 5% sodium disulfite (100: 40: 12: 5, V / V), 5% copper acetate: 8% After being dipped in a phosphoric acid: 2% sulfuric acid mixed solution for a short time, air-dried, and heated at 180 ° C. for about 10 minutes, the generated spots were formed by a scanner (manufactured by Atto Corporation) method. That is, using a standard product (97% purity product) as a control, the spot of the thin layer chromatograph was measured with a densitometer and quantified by the area ratio. The purity of cyclic phosphatidic acid sodium salt in the product obtained in the above step was 54%.
　上記の環状ホスファチジン酸ナトリウム塩５００ｍｇを５ｍｌの１０％メタノールを含むクロロホルムに溶解させ、シリカゲルカラムにかけ、同一溶媒で展開、更に２０％メタノールを含むクロロホルムで展開し、１０ｍｌの画分に分取した。上記のTLC法によって環状ホスファチジン酸ナトリウム塩を含有する画分を確認して集め、ロータリーエバポレータで減圧乾固させ環状ホスファチジン酸ナトリウム塩の粉末３２０ｍｇを得た。本試料の環状ホスファチジン酸ナトリウム塩の純度は９５％であった。 The above cyclic phosphatidic acid sodium salt 500 mg was dissolved in 5 ml of chloroform containing 10% methanol, applied to a silica gel column, developed with the same solvent, further developed with chloroform containing 20% methanol, and fractionated into 10 ml fractions. Fractions containing cyclic phosphatidic acid sodium salt were confirmed and collected by the above TLC method, and dried under reduced pressure using a rotary evaporator to obtain 320 mg of cyclic phosphatidic acid sodium salt powder. The purity of the cyclic phosphatidic acid sodium salt of this sample was 95%.
　上記でで得られた高純度環状ホスファチジン酸ナトリウムの脂肪酸組成をガスクロマトグラム法により分析した。試料２０mg/mlになるように塩酸メタノールに溶解し、６５度Cで３０分間加温した。室温に戻した後、棟梁の水、次いで棟梁のヘキサンを加えて十分に攪拌混合した。３０００回転、５分間遠心分離を行い、ヘキサン層２μlをキャピラリーカラムに注入し構成脂肪酸を分析した。分析は以下である。
脂肪酸　　　　　　　　含量（％）
パルミチン酸　　　　　２３．９
ステアリン酸　　　　　５.４
オレイン酸　　　　　　８．６
リノール酸　　　　　　５３．４
リノレン酸　　　　　　４．９
その他の脂肪酸　　　　３．８ The fatty acid composition of the high purity cyclic sodium phosphatidic acid obtained above was analyzed by gas chromatogram method. The sample was dissolved in hydrochloric acid methanol so as to be 20 mg / ml, and heated at 65 ° C. for 30 minutes. After returning to room temperature, the water of the master beam and then the hexane of the master beam were added and mixed thoroughly with stirring. Centrifugation was performed at 3000 rpm for 5 minutes, and 2 μl of the hexane layer was injected into the capillary column to analyze the constituent fatty acids. The analysis is as follows.
Fatty acid content (%)
Palmitic acid 23.9
Stearic acid 5.4
Oleic acid 8.6
Linoleic acid 53.4
Linolenic acid 4.9
Other fatty acids 3.8
試験例１：
　製造例１で製造したNcPAを用いて、マウスにおける発毛効果試験を実施した。 Test Example 1:
Using the NcPA produced in Production Example 1, a hair growth effect test in mice was performed.
（１）投与検体
コントロール；５０％エタノール（エタノールと生理食塩液を等量で調製したもの）
被験物質：生理食塩液によりNcPAの１％水溶液を調製し、このNcPAの１％水溶液をエタノールで希釈し、０．５％濃度に調製したものを使用した。 (1) Administered sample control: 50% ethanol (ethanol and physiological saline prepared in equal volume)
Test substance: A 1% aqueous solution of NcPA was prepared with physiological saline, and this 1% aqueous solution of NcPA was diluted with ethanol to prepare a 0.5% concentration.
（２）試験動物及び飼育条件
　試験には、雄性Ｃ３Ｈ／ＨｅＮＣｒｌＣｒｌｊ（以下、Ｃ３Ｈ、ＳＰＦ、日本チャールス・リバー株式会社）（１８．８ｇ～２３．６ｇ）を使用した。動物は、群分け３日前（４７－４８週齢）にマウスの頸部から尾部までの背部（側腹は含まない）をシェービングフォームを用いてカミソリで剃毛した。動物は、設定温度２３℃、設定湿度５５％、明暗各１２時間、換気回数（１２回／時）に維持された動物飼育室で飼育した。飼料は固形資料（ＭＦ、ロット番号：１１１２０６、オリエンタル酵母工業株式会社）を自由に摂取させ、飲料水は水道水を自由に摂取させた。 (2) Test animals and rearing conditions Male C3H / HeNCrlCrlj (hereinafter, C3H, SPF, Charles River Japan Co., Ltd.) (18.8 g to 23.6 g) was used for the test. The animals were shaved with a razor using a shaving foam on the back (not including the flank) from the neck to the tail of the mice 3 days before grouping (47-48 weeks of age). The animals were bred in an animal breeding room maintained at a set temperature of 23 ° C., a set humidity of 55%, light and darkness for 12 hours each, and ventilation frequency (12 times / hour). For the feed, solid materials (MF, lot number: 111206, Oriental Yeast Co., Ltd.) were freely ingested, and for drinking water, tap water was freely ingested.
（３）投与
　投与経路は、経皮投与とした。投与検体（コントロール又は被験物質）を、マイクロピペットを用いてマウスの背部皮膚に投与し、指で軽く塗りこんだ（コントロール群：１０匹；及びNcPA投与群１０匹）。投与液量は１００μｌ／部位とした。投与回数は１日１回とした。投与期間は、投与開始日を投与１日とし、２４日間とした。 (3) Administration The administration route was transdermal administration. A sample to be administered (control or test substance) was administered to the back skin of a mouse using a micropipette, and lightly smeared with a finger (control group: 10 animals; and 10 NcPA administration groups). The administration liquid volume was 100 μl / site. The administration frequency was once a day. The administration period was 24 days, with the first day of administration being 1 day of administration.
（４）判定
　剃毛部の肉眼観察は、群分け日（投与１日）、投与５、７、１０、１３、１６，１９，２２および２５日に、以下の表１に示す判定基準を基にスコアで採点し、群毎に平均値±標準偏差を算出した。また、スコア観察日に群ごとに写真撮影を行った。写真撮影及びスコア観察は投与前に行った。 (4) Determination The naked eye observation of the shaved part was based on the criteria shown in the following Table 1 on the day of grouping (1 day of administration), 5th, 7th, 10th, 13th, 16, 19, 22 and 25th. The score was scored and the average value ± standard deviation was calculated for each group. In addition, a photograph was taken for each group on the score observation day. Photographing and score observation were performed before administration.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
（５）結果
　発毛状態のスコア観察の結果を表２及び図１に示す。また、マウスの写真撮影の結果を図２及び図３に示す。 (5) Results Table 2 and FIG. 1 show the results of the hair growth state score observation. The results of mouse photography are shown in FIGS.
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
　表２及び図１に示す通り、１１００μｌ／部位／日のＮｃＰＡを２４日間経皮投与したＮｃＰＡ投与群は、コントロール群と比較して、投与１９日と２５日に高値傾向（Ｐ＜０．１）が認められ、ＮｃＰＡの発毛促進作用が確認された。 As shown in Table 2 and FIG. 1, the NcPA administration group in which 1100 μl / site / day of NcPA was administered transdermally for 24 days showed a higher tendency (P <0.1) on the 19th and 25th administration than the control group. ) Was observed, and the hair growth promoting action of NcPA was confirmed.

Claims (4)

  1. 下記式（１）で示される化合物を有効成分として含有する育毛剤。
    Figure JPOXMLDOC01-appb-C000001
     （式中、Ｒは、炭素数１～３０の直鎖状若しくは分岐状アルキル基、炭素数２～３０の直鎖状若しくは分岐状アルケニル基、又は炭素数２～３０の直鎖状若しくは分岐状アルキニル基であり、これらの基はシクロアルカン環又は芳香環を含んでいてもよい。Ｘ及びＹはそれぞれ独立に、酸素原子、又はメチレン基を示すが、Ｘ及びＹが同時にメチレン基になることはない。Ｍは、水素原子又はアルカリ金属原子である。）     A hair restorer containing a compound represented by the following formula (1) as an active ingredient.
    Figure JPOXMLDOC01-appb-C000001
     (In the formula, R is a linear or branched alkyl group having 1 to 30 carbon atoms, a linear or branched alkenyl group having 2 to 30 carbon atoms, or a linear or branched group having 2 to 30 carbon atoms. An alkynyl group, and these groups may contain a cycloalkane ring or an aromatic ring, and X and Y each independently represent an oxygen atom or a methylene group; M is a hydrogen atom or an alkali metal atom.)
  2. 式（１）において、Ｘ及びＹが酸素原子である、請求項１に記載の育毛剤。 The hair restorer of Claim 1 whose X and Y are oxygen atoms in Formula (1).
  3. 式（１）において、Ｘ又はＹの一方が酸素原子であり、他方がメチレン基である、請求項１に記載の育毛剤。 The hair restoring agent according to claim 1, wherein in formula (1), one of X and Y is an oxygen atom and the other is a methylene group.
  4. 式（１）で示される化合物が、大豆レシチン由来の脂肪酸からなるアシル基を有する化合物である、請求項１から３の何れか１項に記載の育毛剤。 The hair restoring agent according to any one of claims 1 to 3, wherein the compound represented by the formula (1) is a compound having an acyl group composed of a fatty acid derived from soybean lecithin.
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WO2021132297A1 (en) * 2019-12-23 2021-07-01 大塚化学株式会社 Carbacyclic phosphatidic acid compound
US11958876B2 (en) 2019-12-23 2024-04-16 Otsuka Chemical Co., Ltd. Carbacyclic phosphatidic acid compound

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KR20150006852A (en) 2015-01-19
SG11201406911RA (en) 2014-11-27
JP6074411B2 (en) 2017-02-01
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