WO1998056940A1

WO1998056940A1 - Hair growth activating composition

Info

Publication number: WO1998056940A1
Application number: PCT/JP1998/002525
Authority: WO
Inventors: Seigo Hanada; Mina Kanda; Megumi Furui; Masato Sugiyama
Original assignee: Mitsubishi Chemical Corporation; Sansho Seiyaku Co., Ltd.
Priority date: 1997-06-09
Filing date: 1998-06-08
Publication date: 1998-12-17

Abstract

A new hair growth stimulant or hair tonic, i.e. a hair growth activating composition containing one or more triprenylphenol derivatives of general formula (I), salts thereof, and hydrates and solvates of both as the active ingredient, wherein R1 is -H or -CH¿2?CH2OH, R?2¿ is -H or -OH, R3 is -CH=C(CH¿3?)2 or -CH2-COH(CH3)2, and R?4¿ is -H or -OH.

Description

Meisho '' Hair Restoration Active Composition Technical Field

TECHNICAL FIELD The present invention relates to a hair-growth active composition, and more particularly to a hair-growth active composition containing a triprenylphenylninol derivative as an active ingredient. Background art

Conventionally, hair growth and hair restoration agents containing various chemicals have been used. Representative active ingredients include vitamin E, which has a blood circulation improvement effect, and sempri extract, and female hormones such as cystine and methionine as amino acids that are nutritional supplements. Further, estradiol, ethinyl estradiol and the like are known, and a plurality of pharmacologically active ingredients corresponding to various causes of hair loss are used in combination for the prevention and treatment of alopecia.

The effects of these hair restorer and hair restorer vary greatly between individuals, and new hair restorer and hair restorer were required. Disclosure of the invention

The present inventors have focused on the fact that microorganisms produce a variety of physiologically active substances, and as a result of searching for substances having hair-growth activity in microbial metabolites, have found that an excellent hair-growth effect can be obtained in a culture solution of Stachybotrys. The present inventors have found a group of compounds having the compound, and have completed the present invention. That is, the gist of the present invention is represented by the following general formula (I)

OH general formula (; I)

(In the above general formula (I), R ¹ represents —H or one CH ₂ CH ₂ OH, 'R ² represents one H or one H,

R ³ represents —CH = C (CH ₃ ) ₂ or —CH ₂ —COH (CH ₃ ) ₂ ,

R ⁴ represents —H or —OH. )

Or a salt or a hydrate or solvate thereof as an active ingredient in a hair-growth active composition comprising as an active ingredient a triprenylphenol derivative represented by the formula:

In a preferred embodiment of the present invention, a triprenyl phenol derivative is used.

Any one or two or more hair-growth active compositions,

In particular, triprenylphenol derivatives are

[1] In the general formula (I), R ¹ is —H, R ^{2 is} —H, R ³ is —CH ₂ —COH (CH ₃ ) ₂ , and R ^{4 is} —H A hair-growth active composition,

[2] In the above general formula (I), R ^{1 is} —H, R ² is —0 H, R ^{3 is} —CH = C (CH ₃ ) ₂ , and R ⁴ is —H Hair restoration active compositions are preferred.

In addition, the triprenyl phenol derivative is

The hair-growth active composition is also preferable in the present invention.

Further, as another embodiment of the present invention, in the above general formula (I)

[1] A triprenylphenol derivative in which R ¹ is —H, R ² is —H, R ^{3 is} —CH ₂ —C 0 H (CH ₃ ) ₂ , and R ⁴ is —H , Its salts or their hydrates or solvates,

[2] A triprenylphenol derivative in which R ^{1 is} —H, R ² is —OH, R ^{3 is} —CH CHC (CH ₃ ) ₂ , and R ⁴ is —H, Salts or hydrates or solvates thereof are mentioned.

As still another embodiment of the present invention,

[3] A microorganism belonging to the genus Stachybotrys and capable of producing the triprenyl phenol derivative represented by the above general formula (I) is cultured in a medium, and the compound is produced and accumulated in the culture. And a method for producing a tribrenylphenol derivative represented by the general formula (I), wherein the compound is collected from the culture. A microorganism belonging to the genus Stachybotrys is cultured in a medium, a compound is produced and accumulated in the culture, the compound is collected from the culture, and subjected to structural analysis based on its physical properties. The structure of ~ 5 was determined. Compounds 1 and 3 are novel triprenylphenol derivatives, and compounds 2 and 5 have been reported as antibacterial actives by Xu et al. Of the University of Iowa (J. Org. Chem. 1992, 57, 6700-6703) Consistent with stakibotrins A and B, compound 4 was reported as a NGF action enhancer by Orii et al. Of Taisho Pharmaceutical Co., Ltd. (Japanese Patent Application Laid-Open No. 6-239896999). No.) It was consistent with NGF_2 4 3. However, there is no description of 'hair growth activity' in these reports.

Compound 1

Compound 2 Compound 3

Compound 4

Compound 5

BEST MODE FOR CARRYING OUT THE INVENTION

The triprenyl phenol derivative represented by the above general formula (I) can be used as an active ingredient of a hair restorer, a hair restorer or an agent for preventing or treating hair loss.

Examples of the salt that can be formed by the triprenylphenol derivative represented by the general formula (I) include alkali metal salts such as sodium salts and potassium salts, magnesium salts, magnesium salts, and the like. Examples include alkaline earth metal salts such as calcium salts, organic base salts such as tetramethylammonium salt, and ammonium salts. Further, the triprenyl phenylol derivative represented by the above general formula (I) and a salt thereof can also form a hydrate or a solvate.

Next, the method for producing the compound of the present invention will be described.

The triprenylphenol derivative represented by the above general formula (I) can be produced by a microorganism belonging to Stachybotrys. Examples of such microorganisms include microorganisms belonging to Stachybotrys ′ elegance, such as Stachybotrys elegans D1087. Stakibotris' Elegance D 1 087 is a microorganism isolated from the natural soil by the present inventors and deposited with the Institute of Biotechnology, National Institute of Advanced Industrial Science and Technology as FE RM BP-637 Have been.

Details of the deposited Stachybotrys elegance D1087 (Stachybotrys elegans D1087) are as follows.

① Depositary institution name: International Depositary Authority Biotechnology Industrial Technology Research Institute, Ministry of International Trade and Industry Tokujo '' Address: 1-3-3 Tsukuba East, Ibaraki, Japan (Zip code: 30-5-856)

6)

② Deposit date: June 2, 1997 (Hara Deposit)

Receipt of transfer from the original depositary deposit to the above international depositary institution on May 25, 1999

③ Accession number: FERMB P-6 3 7 3 (Transferred from P. No. P-162, 53, deposited on June 2, 1997)

The mycological properties of Sugi Kibotris' Elegance D 1 087 are as follows.

[Morphological properties]

Colonies grow rapidly and spread thinly. Colonies on Miura medium (LCA) reach 67 mm in diameter after culturing at 24 ° C for 5 days, producing no colorless and soluble pigment. Colony-The back side is also colorless and usually produces few conidia, but placing sterilized rice grains on agar medium produces a large amount of conidia on the rice grains and on the surrounding medium. Colony growth on potato dextroth agar is 24 and reaches 60 mm in diameter after 5 days of culture. The fluffy surface is covered with spots of salmon conidia. The back of the colony is light brown.

Conidiophores are finite, well-differentiated, solitary or rarely branched, erect, often slightly bent, number of partitions: 2-4, colorless, surface smooth, length 74-117 (average 99) m, width 3.8-4.7 m (average 3.9 m) at base, tapered 2.8-3.4 m (average 3.1) m at top. Three to seven phyllids are formed in a ring form from the top of the conidiophores, sub-club-shaped, the surface is smooth, 10.6-16.6 (average 13.7) m in length, 3.4-5.9 (average 4.3) in width〃 m.

Conidia apical, aggregate to produce a viscous conidium mass, colorless and transparent, smooth surface, unicellular, lemon-shaped or spindle-shaped, 9.4-12.5 (average 11.0) / urn x 3.8-5.6 (average 4.7) ra.

Conidia show apical and filo-type conidium formation, congregate at the apical end of the fiber to produce a viscous conidium mass, unicellular, lemon-shaped or spindle-shaped, colorless and transparent, and the surface is smooth and long. 9.4 ~ 12.5 (average 11.0) / m, width 3.8 ~ 5.6 (average 4.7) m.

Teleomorph was not observed. [Physiological properties] '' Growth temperature 10 ° C ~ 35 ° C (cultured on PDA for 10 days)

Optimal growth temperature 30. C

Growth PH 4 ~ 10 (cultured on LCA liquid medium for 10 days)

Optimal growth pH 6

[Taxonomic considerations]

This strain (D1087) has 1) formation of a filamentous conidium, 2) distinct differentiation, solitary or irregular branching, and 3) rotation of a filament at the upper end of the conidiophore. 4) Conidia are formed basophilically and have the characteristic that they aggregate at the ends of the phiride to form a viscous mass. Based on the above properties, this strain belongs to the Stachybotrys genus of the Deutero mycotina-Hyphomycetes class.

According to the monograph of the genus Stachybotrys by S. C. Jong & E. E. Davis (Mycotaxon vol. Ill, (3) 409-485, 1976), there are 11 species in this genus. These species are distinguished by the size, shape, surface structure or color of conidia, the size of conidia-forming cells and conidia, and so on.

A search of this strain (D1087) was performed based on the search table on pages 423 to 424 of the same document, and the characteristics were consistent with those of Stachybotrys elegans. This species is characterized by the formation of colorless conidia, but D1087 also forms colorless conidia, and the morphological characteristics of other parts of the conidium-forming organ. ゃ The colony characteristics of Stachybotrys elegans It is in good agreement with it.

According to S.C.Jongk E.E.Davis, this species is treated as S.bisbyi, but this species is classified as Stachybotrys elegans synonym by W. Gams. (W. Gams, Compendium of Soil Fungi, 1980). Therefore, this strain (D1087) was identified as Stachybotrys elegans.

In the present invention, the above bacteria are cultured in a medium containing nutrients that can be used by ordinary microorganisms. As nutrients, glucose, syrup, dextrin, sucrose, starch, molasses, animal and vegetable oils and the like can be used. As the nitrogen source, soybean flour, wheat germ, corn steep liquor, cottonseed birch, meat extract, peptone, yeast extract, ammonium sulfate, sodium nitrate, urea and the like can be used. Other, if necessary, It is beneficial to add sodium, calcium, calcium, magnesium, cobalt, chlorine, phosphoric acid, sulfuric acid and other inorganic salts capable of forming ions. In addition, organic and inorganic salts that assist the growth of the fungus and promote the production of the triprenylphenol derivative can be appropriately added.

As the culturing method in the present invention, a culturing method under aerobic conditions, particularly a liquid shin culture, is most suitable. The temperature suitable for culturing is 20 ° C to 30 ° C, but in most cases, culturing is performed at around 26 ° C to 29 ° C. The production of the triprenylphenol derivative varies depending on the culture medium and culture conditions, but usually the accumulation is maximum between 4 and 10 days. Stop the culture when the amount of accumulated triprenyl phenol derivative in the culture reaches the maximum, and purify the target substance from the culture solution.

Since the triprenyl phenol derivatives are fat-soluble, they can be purified from cultures by utilizing their properties. That is, a solvent extraction method using ethyl acetate, black form, etc., a synthetic adsorbent such as silica gel, alumina, octadecyl silica gel, Diaion HP-20 (manufactured by Mitsubishi Chemical Corporation), or Sephadex LH-2 0 Column chromatography using a gel filtration agent such as [Pharmacia] etc., and preparative chromatography using a silica gel as a carrier, and in some cases, recrystallization with various organic solvents or water are effective. It is.

The hair-growth active composition of the present invention needs to contain at least one compound selected from the compounds represented by the above general formula (I), but does not adversely affect the purpose of use. As far as possible, other active compounds and additives can be included.

The content of these compounds in the composition is not limited as it can vary according to the combination with other active compounds and additives and the dosage form. However, it is generally from 0.0001 to 20% by weight, preferably from 0.01 to 5% by weight, based on the total composition weight.

Although not limited, other active compounds or additives that can be added to the composition of the present invention include various components commonly used in cosmetics, quasi-drugs, and pharmaceuticals, such as polyoxygen. Oils such as ethylene (8 mol) oleyl alcohol ether, glyceryl monooleate, etc., blood flow enhancers such as nicotinic acid amide, benzyl nicotinate, vitamin E-acetate, sempli extract, glycyrrhizic acid, Inflammatory agents such as Nokitiol, hormones such as ethinyl estradiol, i: "Hair root activator such as Yumin H, pantothenyl ethyl ether, sorbitan monolaurate, monono, sorbitan luminitate. , Sorbitan sesquioleate, polyoxyethylene sorbitan monolaurate, polyethylene glycol monooleate, polyoxyethylene alkyl ether, polyglycol gester, lauryljetanolamide, fatty acid isopropanolamide, etc. Nonionic surfactants, sodium palmitate, sodium laurate, sodium lauryl sulfate, potassium lauryl sulfate, triethanolamine alkyl sulfate, Oil, Ronia dodecylbenzene sulfate, polyoxyethylene cured Anionic surfactants such as macar oil maleic acid, semi-polar surfactants such as lauryl dimethyl amine oxide and olein dimethyl amine oxide, surfactants, moisturizers, thickeners, preservatives, antioxidants, fragrances And coloring agents.

The hair-growth active composition of the present invention in combination with such other active compounds and additives is not limited in its dosage form and is optional. For example, as a pharmaceutical preparation, hair growth promotion and It can be used as a therapeutic or preventive agent for hair loss or as a cosmetic preparation, as a hair tonic, hair cream, shampoo, rinse, etc. having a hair growth promoting and hair loss preventing effect. Example

Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples unless it exceeds the gist of the present invention.

Production example>

1) Culture

Seed culture: syrup 2.0%, soybean meal 1.0%, soybean oil 0.15%, Sangurei down _{_{0.25%, FeS0 4 - 7H 2}} 0 0.0005%, NiCl 2 · 6H 2 0 0.00005 CaC0 3 culture locations containing 0.1% (P H6 .0) was dispensed into two 200 ml Erlenmeyer flasks in 40 ml aliquots and autoclaved at 121 ° C. for 20 minutes. One platinum loop of Stachybotrys elegance D 1 087 (FE RM BP- 6 3 7 3) was inoculated on this, and the cells were cultured at 27 ° C for 3 days at 210 rpm. . Main culture: syrup 2.0%, soybean meal 1.0%, soybean oil 0.15%, Sangurei emissions _{0: 25%, FeS0 4 -} 7H 2 0 0.0005%, NiCl 2 · 6H 2 0 0.00005 CaC0 3 culture locations containing 0.1% ( pH 6.0) was dispensed into 100 ml 500 ml Erlenmeyer flasks in 80 ml aliquots and autoclaved at 121 ° C for 20 minutes. This was inoculated with 0.4 ml of a seed culture solution and cultured at 27 ° C. for 8 days at 210 rpm for 8 days.

2) Purification of hair growth active composition

Five liters of acetone was added to 5 liters of the culture solution obtained in 1), and the mixture was stirred. The mixture was allowed to stand for one day and night, and the bacterial cells were filtered off to obtain about 9 liters of the extract.

The obtained acetate extract was concentrated to 4 liters under reduced pressure. This was extracted with 4 liters of ethyl acetate, and ethyl acetate was distilled off under reduced pressure from the ethyl acetate layer to obtain about 20 ml of an oily substance.

This oily substance was applied to a glass column filled with 200 g of silica gel (Kieselgel 100; manufactured by Merck) and chromatographed by stepwise gradient using chloroform-form methanol as a developing solvent. Separation was performed.

The solvent was distilled off under reduced pressure from the fraction eluted with chloroform / methanol in silica gel chromatography to obtain a fraction A of about 30 Omg.

This fraction A was purified by high-performance liquid chromatography equipped with YMC J's HERE0DS-H80 (30 mm x 250 mm) [manufactured by YMC Corporation].

Dissolve 84 mg of Fraction A in 2 ml of methanol-water mixture (3: 1) and equilibrate 0.5 ml of it with methanol-water mixture (3: 1) The preparative high-speed chromatography was performed. The mixture was eluted at a rate of 9 ml / min using a methanol-water mixture (3: 1).

Separate fractions by 1 fraction per minute from 10 minutes after the start of separation. Fractions B-1 (fractions 13-14) containing compound 1 and fractions containing compound 1 Fraction B—2 (fraction 17), fraction B—3 containing compound 3—1 (fraction 37), fraction B—4 containing compound 3—2 (fraction B—4) Fractions 50—51), fractions B—5 containing compound 4 (fractions 65—66), and fractions containing compound 5 (fractions 75—7) 7) was obtained. 0.5 m for the remaining fraction A solution Each fraction was subjected to three times preparative preparative chromatography to obtain a picture containing each compound, and the solvents were distilled off under reduced pressure.

9.8 mg of crude powder of compound 1 from fraction B_1, 5.0 mg of coarse powder of compound 2 from fraction B-2, 2.4 mg of powder of compound 3-1 from fraction B-3, 2.2 mg of powder of compound 3-2 was obtained from fraction B-4, 3.3 mg of powder of compound 4 was obtained from fraction B_5, and 4.0 mg of powder of compound 5 was obtained from fraction B-6. Next, Compound 1 crude powder obtained from Fraction B-1 was further purified by high performance liquid chromatography.

Dissolve the coarse powder in 0.5 ml of a mixture of methanol and water (3: 1), attach YMC J 'shere 0 DS-H80 (30 mm x 250 mm) High-performance liquid mouth chromatography equilibrated with a mixture of ethanol and water (3: 2) was applied. The mixture was eluted at a rate of 9 ml / min using a mixture of methanol and water (3: 2), and fractionated one fraction per minute from 40 minutes after the start of separation.

The solvent was distilled off from fraction C (fraction 39-41) containing Compound 1 under reduced pressure to obtain 3.8 mg of Compound 1 powder. Compound 2 crude powder obtained from fraction B-2 was also purified by high performance liquid chromatography.

Dissolve the coarse powder in 0.4 ml of a mixture of methanol and water (3: 1), attach YM CJ 'sphere OD S—H80 (30 mm * 250 mm), and add methanol. High-performance liquid chromatography equilibrated with a water-water mixture (13: 7). The mixture was eluted at a rate of 9 ml / min using a methanol-rue water mixture (13: 7), and fractionated one fraction per minute from 40 minutes after the start of separation.

The solvent was distilled off from fraction D (fraction 38) containing compound 2 under reduced pressure to obtain 1.1 mg of compound 2 powder.

Similarly, Compounds 3-1 to 5 were obtained. The physical properties of the obtained compounds 1 to 5 are as follows. Compound 3-1 and compound 3-2 are stereoisomers. Compound 1

1) Appearance: white powder

2) Molecular weight: 4 0 3

3) Molecular formula: C ₂₃ H ₃₃ N0 ₅

4) EIMS: 4 0 3 ( M +), 3 8 5 [(M- H 2 0) +], 1 7 9 5) High-resolution SIMS: actual measured value 3 8 6.2 3 6 4

Calculated value 3 8 6. 2 3 3 0 [(M-H ₂ 0 + H) ⁺ ] 6) Ultraviolet absorption spectrum: in methanol

λma (nm): 303, 254, 214

7) Infrared absorption spectrum: KBr method

v (cm-one: 3422, 2938, 1672, 1615, 1466, 1362, 1080

8) Hydrogen nuclear magnetic resonance spectrum: in heavy metal

<5 ppm: 6.75 (1H, s), 5.17 (1H, m), 4.26 (1H, d, J = 17.7 Hz), 4.22 (1H, d, J = 17

.7Hz), 3.88 (1H, dd, J = 7.0, 5.6Hz), 2.99 (1H, dd, J = 17.7, 5.6Hz), 2.66 (1H, dd, J = 17.7, 7.OHz), 1.59 (3H, s), 1.28 (3H, s), 1.15 (6H, s)

9) Carbon nuclear magnetic resonance spectrum: in heavy metal

(5 ppm: 174.25, 157, 96, 150, 19, 136.36, 132.52, 125.48, 124.12, 113.51,

100.86, 80.20, 71.39, 68.42, 44.32, 44.20, 41.23, 38.58, 29.17, 2 7.76, 23.69, 22.57, 18.80, 15.78

Compound 2

1) Appearance: white powder

2) Molecular weight: 4 0 1

3) Molecular formula: C ₂₃ H ₃₁ N 0 ₅

4) SIMS: 402 ([M + H) ⁺ ]

5) High resolution S I MS: measured value 4 0 2 2 2 9 8

Calculated value 4 0 2 2 2 7 9 [(M + H) ⁺ ]

6) Ultraviolet absorption spectrum: in methanol

λmaX (nm): 303, 254, 214

7) Infrared absorption spectrum: KBr method

V (cmuri:

8) Hydrogen nuclear magnetic resonance spectrum: in heavy methanol

5 p p m: 6.75 (1H, s), 5.31 (1H, m), 5.09 (brs), 4.25 (2H, brs), 4.07 (2H, m),

3.89 (1H, dd, J = 7.0, 5.6Hz), 2.99 (1H, dd, J = 17.7, 5.6Hz), 2.66 (1H, dd, J = 17.7, 7.OHz), 1.64 (3H, s), 1.57 (3H, s), 1.28 (3H, s) 9) Carbon nuclear magnetic resonance spectrum: in heavy methanol

5 ppm: 174.25, 157, 99, 150, 13, 139.79, 132.55, 132.28, 128, 87, 125.43,

124.11, 113.51, 100.91, 80.15, 68.35, 59.85, 44.20, 38.90, 36.02, 27.92, 27.75, 25.84, 22.19, 18.77, 17.75

Compound 3-1

1) Appearance: white powder

2) Molecular weight: 4 0 1

3) Molecular formula: C ₂₃ H ₃₁ N 0 ₅

4) SIMS: 4 0 2 [ (M + H) +], 3 8 4 [(M- H 2 0 + H) +] 5) High resolution SIMS: Found 4 0 2 2 3 0 0

Calculated value 4 0 2 2 2 7 9 [(M + H) +]

6) Ultraviolet absorption spectrum: in acetonitrile

λmaX (nm): 300, 259, 214

7) Infrared absorption spectrum: KBr method

V (cm— ¹ ): 3424, 2924, 1672, 1618, 1460, 1352, 1082, 1034

8) Hydrogen nuclear magnetic resonance spectrum: in heavy acetonitrile

<5 ppm: 6.87 (1H, brs), 6.60 (IH, s), 5.84 (IH, brs), 5.13 (IH, m), 5.08 (IH, m), 3.86 (1H, dd, J = 6.4, 5.1 Hz), 2.89 (1H, dd, J = 17.6, 5.6Hz), 2.57 (IH, dd, J = 17.6, 6.4Hz), 1.65 (3H.s), 1.59 (3H, s), 1.57 (3H, s ), 1.26 (3H, s)

9) Carbon nuclear magnetic resonance spectrum: in heavy acetonitrile

<5 ppm: 169.93, 158.04, 150, 98, 136.18, 132.56, 132.18, 125.46, 125.26,

113.21, 100.55, 79.92, 77.69, 67.54, 40.35.38.11, 27.43, 27.40, 25.78, 22.20, 19, 13, 17.74, 16.03

Compound 3-2

1) Appearance: white powder

2) Molecular weight: 4 0 1

3) Molecular formula: C ₂₃ H ₃₁ N 0 ₅

4) SIMS: 4 0 2 [ (M + H) +], 3 8 4 [(M- H 2 0 + H) +] 5) High resolution SI MS: actual measured value 4 0 2.2 2 5 2 '

Calculated value 4 0 2.2 2 7 9 [(M + H) ⁺ ]

6) Ultraviolet absorption spectrum: in acetonitrile

λmaX (nm): 300, 259, 214

7) Infrared absorption spectrum: KBr method

v (cm- ¹ ): 3399, 2924, 1692, 1618, 1460, 1360, 1078

8) Nuclear nuclear magnetic resonance spectrum: heavy acetonitrile

<5 ppm: 6.88 (1H, brs), 6.60 (IH, s), 5.84 (1H, brs), 5.14 (IH, m), 5.07 (IH, m), 3.85 (1H, dd, J = 6.5, 5.4 Hz), 2.89 (IH, dd, J = 17.6, 5.4Hz), 2.56 (IH, dd, J = 17.6, 6.5Hz), 1.64 (3H, s), 1.57 (3H, s), 1.56 (3H, s ), 1.

26 (3H, s)

9) Carbon nuclear magnetic resonance spectrum: in heavy acetonitrile

5 ppm: 169.94, 158.02, 151.01, 136.11, 132.53, 132.19, 125.42, 125.24,

125.21, 113.40, 100.62, 79.96, 77.71, 67.59, 40.33, 37.99, 27.49, 27.37, 25.77, 22.24, 19, 06, 17.72, 15.94

Compound 4

1) Appearance: white powder

2) Molecular weight: 4 2 9

3) Molecular formula: C ₂₅ H ₃₅ N 0 ₅

4) SIMS: 4 3 0 [(M + H) ⁺ ]

5) High resolution S I M S: Actual value 4 3 0 2 5 8 3

Calculated value 4 3 0 2 5 9 1 [(M + H) +]

6) Ultraviolet absorption spectrum: in the middle of methanol

λmaX (nm): 305, 258, 215

7) Infrared absorption spectrum: KBr method

v (cm-li: 3424, 2924, 1655, 1618, 1460, 1078

8) Hydrogen nuclear magnetic resonance spectrum: in heavy methanol

δ ppm: 6.74 (IH, s), 5.15 (IH, m), 5.07 (lH ₍ ra), 4.42 (IH, d, J = 17.2Hz), 4.3

9 (1H, d, J = 17.2Hz), 3.88 (1H, dd, J = 7.0, 5.5Hz), 3.78 (2H, t, J = 5.2 Hz), 3.68 (2H, t, J = 5.2Hz), 2.98 (1H, dd, J = 17.6, 5.5Hz), 2.65 (1H, dd, J = 17.6, 7.OHz), 1.64 (3H, s) , 1.59 (3H, s), 1.57 (3H, s), 1.27 (3H, s)

9) Carbon nuclear magnetic resonance spectrum: in heavy metal

5 ppm: 171.54, 157, 96, 149.93, 136.24, 132.82, 132.17, 125.49, 125.37,

122.02, 113.28, 100.85, 80.19, 68.43, 61.26, 50.14, 46.29, 40.81, 38.61, 27.76, 27.73, 25.84, 22.57, 18.77, 17.72, 15.95 Compound 5

1) Appearance: White powder

2) Molecular weight: 3 8 5

3) Molecular formula: C ₂₃ H ₃₁ N0 ₄

4) SI MS: 3 8 6 [(M + H) ⁺ ]

5) High resolution S I MS: actual measured value 3 8 6 2 3 6 6

Calculated value 3 8 6 2 3 3 0 [(M + H)]

6) Ultraviolet absorption spectrum: in methanol

λm a (n m): 302, 255, 214

7) Infrared absorption spectrum: KBr method

V (cm: 3485, 2920, 1672, 1615, 1466, 1362, 1080

8) Hydrogen nuclear magnetic resonance spectrum: in heavy methanol

5 p p m: 6.75 (IH, s), 5.15 (IH, m), 5.06 (IH, m), 4.26 (IH, d, J = 17.7 Hz), 4.2

2 (1H, d, J = 17.7Hz), 3.88 (IH, dd, J = 7.0, 5.6Hz), 2.98 (IH, dd, J = 17.6, 5.6Hz), 2.66 (1H, dd, J = 17.6, 7.OHz), 1.63 (3H, s), 1.58 (3H, s), 1.56C3H, s), 1.28C3H, s)

9) Carbon nuclear magnetic resonance spectrum: in heavy metal

(5 ppm: 174.26, 157, 97, 150, 20, 136.19, 132.51, 132.17, 125.51, 125.36,

124.12, 113.50, 100.86, 80.20, 68.42, 44.20, 40.80, 38.52, 27.78, 27.71, 25.83, 22.58, 18.84, 17.70, 15.89

Test example>

Test example 1: Measurement of hair growth effect using mouse Using 7-week-old male C 3 H mice, experiments were performed according to the method of Ogawa et al. (Normal and Abnormal Epidermal Differrentiation University of Tokyo Press). Three days before the start of the test, the entire back of the mouse was shaved with an electric barren force, and it was confirmed that the back hair of the animal was in a telogen phase. The control group was 10 animals / group, and the other groups were 5 animals.

The sample was prepared by dissolving 15 mg of dried matter in 150 ml of a solution of ethanol: propylene glycol = 8: 2. About 1501 of this test preparation was applied twice a day to the shaved area evenly with a brush twice a day for 5 days (the application was repeated for 5 consecutive days and then repeated for 2 days). The animals were observed daily during the test period, and the degree of hair growth was visually evaluated according to the following criteria in six steps, and the average value was determined. In addition, the animals were anesthetized on the last day of the test, and the areas of the shaved area and the hair growth area were measured with an image analyzer to determine the ratio of the hair growth area. The results are shown in Tables 1 and 2.

0: Not growing at all

1: Slightly growing

2: growing up to 1/3

3: 1/3 to 2/3 are growing

4: 2/3-almost growing

5: All are growing

In Tables 1 and 2, the term “mixture” refers to a sample containing compounds 1 to 5 in a weight ratio of 40: 10: 25: 25: 30: 40.

table 1

Table 2

Test example 2: Measurement of hair growth effect using mouse

Using 7-week-old male C 3 H mice, experiments were carried out according to the method of Ogawa et al. (Normal and Abnormal Epidermal Differrent iation Tokyo University Press). Three days before the start of the test, the entire back of the mouse was shaved with an electric barren force, and it was confirmed that the back hair of the animal was in a telogen phase. The control group was 10 animals / group, and the others were 5 animals.

The test samples were dissolved in 100 ml of a solution of ethanol: propylene glycol = 8: 2 so as to have the concentrations shown in Table 3, respectively. About 1501 of this test preparation was applied to the shaved area evenly with a brush twice a day for 5 days / week (after 5 consecutive days of application) No application for 2 days). The animals were observed daily during the test period, and the degree of hair growth was visually evaluated according to the following criteria in six steps, and the average value was determined. In addition, the animals were anesthetized on the last day of the test, and the areas of the shaved area and the hair growth area were measured with an image analyzer to determine the ratio of the hair growth area. Tables 3 and 4 show the results.

0 Not growing at all

1 Slightly growing

2 to 1/3 growing

3 1/3 to 2/3

4 2/3-Almost growing

5 All are growing

In Tables 3 and 4, noxidil was purchased from Sigma. Table 3

氺 W / W Table 4

Industrial applicability

The triprenylphenol derivative obtained from the culture solution of Stachybotrys elegans has an excellent hair-growth effect and is expected to be applied as a hair-growth agent.

Claims

The scope of the claims

1. The following general formula (I)

0H General formula (I)

(In the above general formula (I), R ′ represents 1 H or —CH ₂ CH ₂ OH,

R ² represents 1 H or — 0H,

R ³ represents one CH = C (CH ₃ ) ₂ or one CH ₂ _C〇H (CH ₃ ) ₂ ;

R ⁴ represents —H or —0H. )

A hair-growth active composition comprising, as an active ingredient, one or more of a triprenyl phenol derivative represented by the following formula, a salt thereof, or a hydrate or solvate thereof.

2. The triprenylphenol derivative is

Any one or two or more at which hair growth active composition range first claim of claim of ₍

3. The triprenylphenol derivative is

3. The hair-growing active composition according to claim 1 or 2, which is:

4. The method according to claim ^{1, wherein} R ¹ is —H, R ² is —H, R ^{3 is} —CH ₂ —COH (CH ₃ ) ₂ , and R ⁴ is —H. Hair restoration active composition.

5. The hair-growth activity according to claim ^{1, wherein} R ¹ is —H, R ^{2 is} —OH, R ³ is —CH = C (CH ₃ ) ₂ , and R ⁴ is —H. Composition.

6. A microorganism belonging to the genus Stachybotrys and capable of producing a triprenylphenol derivative represented by the following general formula (I) is cultured in a medium, and the compound is produced and accumulated in the culture. A method for producing a triprenylphenol derivative represented by the following general formula (I), wherein the compound is collected from the culture.

'General formula (I)

(In the above general formula (I), R ¹ represents 1 H or —CH ₂ CH ₂ OH,

R ² represents _ H or — 0 H,

R ³ represents one CH = C (CH ₃ ) ₂ or one CH ₂ —C OH (CH ₃ ) ₂ R ⁴ represents —H or —OH. )

7. The method according to claim 6, wherein R ^{1 is} —H, R ² is —H, R ³ is —CH ₂ —COH (CH ₃ ) ₂ , and R ⁴ is —H. Production method.

8. The method according to claim 6, wherein R ^{1 is} -H, R ^{2 is} -OH, R ^{3 is} -CH = C (CH ₃ ) ₂ , and R ⁴ is -H. .

OH general formula (I)

In the general formula (I), R ^{1 is} -H, R ² is -H, R ³ is _CH ₂ _C 0 H (CH 3) 2, and R ⁴ is -H. Riprenyl phenol derivative, its salt or hydrate or solvate thereof.

10 0 OH General formula (I)

In the above general formula (I), R ¹ is —H, R ² is —0H, R ³ is —CH = C (CH 3) 2, and R ⁴ is —H. Nol derivatives, their salts or hydrates or solvates thereof.