WO2000045782A1

WO2000045782A1 - TESTOSTERONE-5α-REDUCTASE INHIBITORS, HAIR GROWTH STIMULANT/HAIR NOURISHMENT COMPOSITIONS AND COMPOSITIONS FOR WHITENING COSMETICS

Info

Publication number: WO2000045782A1
Application number: PCT/JP2000/000504
Authority: WO
Inventors: Kokki Sakai; Ryuichiro Kondo; Kuniyoshi Shimizu
Original assignee: Kansai Koso Co., Ltd.
Priority date: 1999-02-02
Filing date: 2000-01-31
Publication date: 2000-08-10
Also published as: AU2322800A

Abstract

TSR activity inhibitors, hair growth stimulant/hair nourishment compositions and compositions for whitening cosmetics expected as exerting various effects caused by the inhibition of the TSR activity when used in various cosmetics and drugs, which are testosterone-5α-reductase activity inhibitors, hair growth stimulant/hair nourishment compositions and compositions for whitening cosmetics containing compounds having prenyl.

Description

Specification

Test Tosuteron 5 _alpha - reductase activity inhibitors, hair growth, hair tonic compositions and whitening cosmetic composition

Technical field

The present invention provides a testosterone -5H-reductase (hereinafter abbreviated as TSR) activity inhibitor which can be expected to have a hair-growth / hair-growing action, a sebum secretion inhibitory action, a whitening action, etc., and which can be added to various cosmetics and pharmaceuticals. And a composition for hair growth and hair growth and a composition for whitening cosmetics containing the TSR activity inhibitor.

Conventional technology

Conventionally, various studies have been made on the action of TSR. For example, in studies on the mechanism of male hormone suppression, it is said that the male hormone activity in hair roots is 5 -dihydrotestosterone (hereinafter abbreviated as DΗ), which is produced by the reduction of testosterone by TSR. . This DHT is known to have several to several tens of times more potent androgenic effects than testosterone.This DHT binds to an intracellular receptor and acts on hair mother cells to suppress cell division. It is believed that doing so hinders hair growth.

Recently, it has been confirmed that TSR is expressed in melanocytes in vitro, and it is suggested that inhibition of this TSR activity may suppress melanin production, and that whitening effects can be expected (" THE JOURNAL OF INVESTIGATIVE DERMATOLOGY "Vol.110'No.1, JANUAEY (1998)).

Further, by inhibiting the TSR activity, a sebum secretion inhibitory effect and the like can be expected, and attempts have been made to blend TSR activity inhibitors into various cosmetics and pharmaceuticals, and some of them have been commercialized.

By the way, some substances relating to the mechanism of inhibiting TSR activity have been reported, but there is no report that a TSR activity inhibiting action can be obtained by having a presyl group.

Disclosure of the invention

The object of the present invention is to provide various cosmetics and pharmaceuticals with various An object of the present invention is to provide a τ SR activity inhibitor which can be expected to have a seed action, and a hair growth / hair restoration composition and a whitening cosmetic composition containing the TSR activity inhibitor.

The present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, have found that a compound having a prenyl group has TSR activity inhibitory ability. Further, as such a compound, a compound having a prenyl group and a polar group such as a hydroxyl group is preferable, and in particular, a compound having a prenyl group contained in a thick timber of the genus Artocarpus is preferable. The inventors have found that they have inhibitory ability and completed the present invention.

According to the present invention, there is provided a TSR activity inhibitor comprising a compound having a prenyl group. '

Further, according to the present invention, there is provided a composition for hair growth and hair growth comprising the TSR activity inhibitor.

Further, according to the present invention, there is provided a composition for whitening cosmetics containing the TSR activity inhibitor.

Preferred embodiments of the invention

Hereinafter, the present invention will be described in more detail.

The TSR activity inhibitor of the present invention contains a compound having a prenyl group as an active ingredient. As such a compound, a compound having a prenyl group and a polar group such as a hydroxyl group is preferable. In particular, a compound having a prenyl group included in Moraceae and a compound having a prenyl group included in a plant of the genus Aitocarims are preferable. The molecular weight of these compounds is preferably from 100 to 100 in number average molecular weight.

Examples of the above-mentioned plants of the genus Grass (ΜθΙΕ ££££) include the genus Fig (Ficus), the genus Altocarpus (Artocarpusl genus iBroussonetia), and the genus Cucuria (Cudria). These fruits are used for food and medicine. The altocarpus (A ocarpus) plant is an evergreen tree native to the tropics, and is eaten in the place of origin by growing its fruit or cooking it. In addition, altocalcus A. incisus, which contains a compound having a prenyl group, is toxic to cultured cells at 100 ppm. And low toxicity to the human body.

A. heterophyllus d.

heterophyllus), A. ko, somanis (A. communis), A. risita (A. rigidaV A. venenosa (A. venenosaV A. arilithris) (A. alitilis A. Nobilis (A. nobilis), A. incisus, etc. Examples of the compounds having a prenyl group included in these Artocarpus plant species are described below. Examples include compounds represented by Structural Formulas 1 to 62 and 188 to 192. These compounds can also be obtained from plants of the family other than the genus Altocarps.

In order to extract and purify a compound having a prenyl group from these plants, it can be easily obtained by appropriately selecting a known solvent extraction method and various purification methods.

Examples of the compound having a prenyl group include compounds represented by the following structural formulas 1-192. However, in the formula, R represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, an acyl group or a darkosyl group.

The TSR activity inhibitor of the present invention may contain a compound having a prenyl group capable of inhibiting TSR activity. Since this TSR activity inhibitor can be expected to have a hair-growing action, a hair-growing action, a whitening action, a sebum secretion-suppressing action, etc. Formulations, shampoos, rinses, hair tonics, conditioners, scalp treatments, foundations, bath preparations, body cleansers, lotions, facial cleansers, ishiken, nutritional creams, skin formulas and other cosmetics and pharmaceuticals Thereby, a desired effect can be exhibited. The blending ratio and form of the TSR activity inhibitor in preparing a cosmetic can be appropriately selected depending on the type of the above-mentioned cosmetics and the like. It is preferably at least 1% by weight.

The composition for hair growth and hair growth according to the present invention contains the TSR activity inhibitor, and is used, for example, for hair growth, hair growth, hair lotion, hair packs, tonics, shampoos, and hair and scalp such as rinses. It can be incorporated into various cosmetics and the like to be used. In the composition for hair growth and hair restoration, the compounding ratio of the TSR activity inhibitor It is only necessary that the content can be adjusted to 0.001% by weight or more when it is added to the ingredients. The hair-growth / hair-growing composition of the present invention may contain various known materials, which are usually added to cosmetics that are expected to grow and grow hair, if necessary. For example, other hair-growth, hair-growing agents, antibacterial agents, cooling agents, humectants, or mixtures thereof.

Other hair restorers include, for example, vitamin B ₆ , vitamin E and its derivatives, glycyrrhetinic acid and its derivatives, nicotinic esters such as benzyl nicotinate, cyclosporins, carpronium chloride, cepharanthin, oxen Delon, diazoxide, minoxidil, ethinyl estradiol, estradiol, animal and plant extracts containing these, and the like can be used, and they can be used alone or as a mixture.

Examples of the antibacterial agent include hinokitiol, pyrotatoolamine, pyrothione zinc, hexcloclofen, phenol, benzalkonium chloride, cetylpyridinium chloride, pendecylenic acid, trichlorocarbanilide, and mixtures thereof.

Examples of the cooling agent include menthol and the like.

Examples of humectants include polyhydric alcohols such as glycerin, propylene glycol, 1,3-butylene glycol, sonorebitone, man-tonore, polyethylene glycol, zipper pyrendalcol; amine acids, sodium lactate, pyrrolidone NMF components such as sodium carboxylate; hyaluronic acid; collagen; elastin; chondroitin sulfate; fibronectin; ceramides; heparin-like substances; water-soluble high-molecular substances such as chitosan or mixtures thereof.

The hair restoring / hair growing composition of the present invention may further contain various additives. Examples of additives include fats and oils, surfactants, alcohols, fatty acids, preservatives, antioxidants, pigments, fragrances, ultraviolet absorbers, chelating agents, pH regulators, buffers, and purified water. The amount can be appropriately selected.

The composition for whitening cosmetics of the present invention contains a TSR activity inhibitor containing the compound having a prenyl group, and includes, for example, whitening agents, body lotions, emulsions, cosmetic waters, packs, foundations, and baths. , Body cleanser, face wash, stone cleaner, It can be blended with various cosmetics and the like used for skin such as creams and skin oils. Examples of the compound having a prenyl group include the compounds listed in Structural Formulas 1 to 192, and examples of the whitening cosmetic composition include compounds represented by the Structural Formulas 1891 to 91. The embodiment which does not include the compound to be used is exemplified.

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In the composition for whitening cosmetics, the compounding ratio of the TSR activity inhibitor may be 0.0001% by weight or more when compounded with the above various cosmetics. The composition for whitening cosmetics of the present invention may be blended with a known whitening agent, anti-wrinkle agent, humectant or a mixture thereof.

Examples of whitening agents include kojic acid, ascorbic acid, hydroquinone, thiol compounds, and mixtures thereof.

The whitening cosmetic composition of the present invention may contain, if necessary, fats and oils, surfactants, alcohols, fatty acids, preservatives, bactericides, thickeners, anti-inflammatory agents, antioxidants, and pigments. , Fragrance, water-soluble polymer, UV absorber, chelating agent, pH adjuster, buffer, purified water Other components can be appropriately blended.

The TSR activity inhibitor of the present invention contains a compound having a prenyl group as an active ingredient, and can be expected to exert various actions caused by TSR activity inhibition when blended in various cosmetics and pharmaceuticals. In addition, the composition for hair growth and hair growth and the composition for whitening cosmetics of the present invention can be blended with various cosmetics in view of hair growth and hair growth or whitening.

Example

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1

For the compounds of structural formulas 1 to 192 listed as the above compounds having a prenyl group, the enzymatic activity using the microsomes (TSR) derived from female rat liver shown below was measured, and the TSR activity of each compound was measured. The inhibitory ability was measured. Each compound was extracted and purified from the natural world by an ordinary method, and R in the structural formula was a hydrogen atom.

The enzymatic activity was determined in a sodium phosphate buffer (pH 6.5) at a concentration of 100 mmol / L at a concentration of 150 zmol / L testosterone at the start of the enzymatic reaction. / L dithiothreitol was added to each and pre-incubated at 37 ° C. After 10 minutes, add NADPH so that the concentration at the start of the enzymatic reaction is 1667 μταο1 ZL, and then add the microsomal solution so that the added protein amount is 0.25 mg. To start the reaction. After reacting at 37 ° C. for 10 minutes, 3 Mo 1 ZL of NaOH solution was added to 1 Z30 volume of the reaction system to terminate the reaction. From this reaction system, dihydrotestosterone was extracted, the amount of reaction produced was measured by mass spectrometry (GC_mass spectrometry), and the enzyme reaction rate was determined.

The TSR activity inhibitory activity is measured by adding the compounds represented by Structural Formulas 1 to 192 in the above enzyme activity measurement before pre-incubation so that the concentration at the start of each reaction becomes 100 ppm. The enzyme reaction rate was measured in the same manner as in the other conditions, and the enzyme reaction rate was measured when the above compound represented by the structural formulas 1-192 was not contained. The inhibition rate was determined by calculation from the ratio with the enzyme reaction rate measured above. Tables 1 and 2 show the results.

From the results in Tables 1 and 2, it can be seen that the compounds having a prenyl group represented by Structural Formulas 1-192 have TSR activity inhibitory ability and can be used as an active ingredient of a TSR activity inhibitor.

Table 2

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1 1 6 7 0. 4 1 5 1 6 3.8 1 8 6 5 6.1

1 1 7 6 9.3 1 5 2 6 7.5 1 8 7 5 3.3

1 1 8 7 1.1 1 5 3 6 4.2 1 8 8 8 0.9

1 1 9 7 2.1 1 5 4 6 2.5 1 8 9 7 1.0

1 2 0 6 8.6 1 5 5 6 3.4 1 9 0 9 1.0

1 2 1 6 5.3 1 5 6 6 5.8 1 9 1 9 5.5

1 2 2 6 5.5 5 1 5 7 6 8. 8 1 9 2 9 2.0 Comparative example

The TSR activity inhibitory ability of the compounds having no prenyl group represented by the following structural formulas A to E was measured in the same manner as in Example 1. Table 3 shows the results.

Table 3

Example 2

A compound having a prenyl group represented by the above formula (188) wherein R is a hydrogen atom can Extracted and purified from the world by conventional methods. The obtained compound was dissolved in a mixture of propylene glycol: ethanol = 1: 6 (volume ratio) to a concentration of 0.25 M to prepare a test solution. As a control, a control test solution was prepared by dissolving kojic acid, which has a whitening effect, in a mixture of propylene dalicol: ethanol = 1: 6 (volume ratio) to a concentration of 0.25 M. Next, a pigmentation inhibition test shown below was performed using these test solutions to evaluate the whitening effect of each test solution. Table 4 shows the results.

The back of 10 brown guinea pigs aged 6 weeks was shaved, and the shaved back was irradiated with ultraviolet light for 3 days. Irradiation day 7 min was performed Ri by the ultraviolet ray quantity of 1 3 5 O m J / cm 2. Each test solution and the solvent were applied twice a day for 5 weeks (35 days) twice a day after irradiation with the ultraviolet rays, at a rate of 5 days a week, to a predetermined portion of the back of the shaved guinea pig irradiated with the ultraviolet rays. This predetermined location was determined so that all the liquid could be applied separately to the back of the same guinea pig, and the location of the separation was varied depending on the guinea pig. The evaluation of the pigmentation inhibitory effect was performed by visually observing the back of each guinea pig on the 15th, 22nd, 29th, and 35th days after the start of the application of the test solution, and by coloration. The evaluation was performed by using a color difference meter (manufactured by Minolta Co., Ltd., CR-100) to evaluate the change in the degree of blackening of the skin irradiated with ultraviolet rays.

In the evaluation with the naked eye, the degree of pigmentation was divided into five levels, and the inhibition rate in each guinea pig on each evaluation day was determined, and the average value was used as the evaluation result. On the other hand, in the evaluation using a colorimeter, the suppression rate was obtained from the measurement results at a predetermined location on each guinea pig on each evaluation day, and the average value was used as the evaluation result. The reference for each measurement was based on the back of each guinea pig to which the test solution was not applied, which was irradiated with ultraviolet rays.

Table 4

From the results in Table 4, the test solution of the present invention showed a whitening effect superior to kojic acid, which is known to have a whitening effect, in any of the evaluation methods.

Claims

The scope of the claims

1) Test comprising a compound having a prenyl group Tosuteron 5 _alpha - reductase activity inhibitors.

2) The inhibitor according to claim 1, wherein the compound having a prenyl group has a number average molecular weight of 100 to 100,000.

3) The inhibitor according to claim 1 or 2, wherein the compound having a prenyl group is a compound having a prenyl group contained in Artocarpus pork.

4) A composition for hair growth and hair growth comprising the testosterone- 15 α-reductase activity inhibitor according to any one of claims 1 to 3.

5) A composition for whitening cosmetics comprising a testosterone-5α-reductase activity inhibitor having a compound having a prenyl group.

6) The whitening cosmetic composition according to claim 5, wherein the compound having a prenyl group does not include a compound represented by the following formula.