JPH11246414A - Steroid 5-alpha-reductase ii-type-specific inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject inhibitor having excellent steroid 5 α-reductase II-type-specific inhibitory effect, and useful in e.g. hair growth stimulants, anti- acnevulgaris bacteria skin drugs, by including a triterpene compound as active ingredient. SOLUTION: This inhibitor is obtained by including a compound of formula I (R is a 1-6C alkyl) (e.g. a compound of formula II) as active ingredient which is afforded by separation from extracts of plants such as cuachalalate; juliania adstringens, Amphiptery gumadstringens or the like, belonging to the family Julianiaceae. When this inhibitor is to be used in e.g. medicaments/quasi-drugs and cosmetic compositions, it is preferable that its daily dose is 4-10 ml and the abovementioned extract(s) is included at 0.005-20 wt.% on a dry basis.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a steroid 5α-reductase type II-specific inhibitor containing triterpenes. INDUSTRIAL APPLICABILITY The inhibitor of the present invention can be effectively used in the fields of pharmaceuticals, quasi-drugs, cosmetics, and the like, particularly for hair restorer, anti-acne therapeutic agent and the like.

[0002]

Conventionally, male pattern baldness, alopecia, seborrhea and acne (acne vulgaris) are caused by male hormones and metabolites from male hormones. In particular, recent studies have revealed that testosterone, a major male hormone, is metabolized by 5α-reductase into 5α-dihydroxytestosterone (DHT), which causes various skin disorders.

[0003] For this reason, female hormonal agents such as estradiol and anti-androgenic agents have been used in conventional hair restorers.

[0004] Recently, the search for a substance that inhibits the activity of 5α-reductase, which controls the metabolism of testosterone to DHT, has been advanced.

[0005] In male pattern baldness, it has been found that the depilated crown has higher 5α-reductase activity than the undepilated temporal region, and DHT binds to nuclear receptors in cells. While promoting the growth of sebaceous glands, it also acts on hair mother cells to suppress cell growth and prevent hair growth.

[0006] Recent studies have revealed that human 5α-reductase has a type I isozyme that is present in all tissues and a type II isozyme that is also present in androgen target tissues such as the prostate. Was.

[0007] In human scalp hair follicles, both type I and type II isozymes are present, and both are thought to be involved in the progress of male pattern hair loss.

Recently, the search for substances that specifically inhibit 5α-reductase type I and type II has been advanced.

[0009]

However, in the above-mentioned prior art, hormonal agents must be used under the control of a physician from the viewpoint of side effects and safety, and cosmetics for general consumers have restrictions on the blending standards. There are limits to their use in cosmetics.

On the other hand, 5α-reductase activity inhibitors have been found in various plant extracts and have been reported (JP-A-60-146829 and JP-A-63-8).
No. 8121, No. 64-3125, Tokiko 6-4755
No. 4, etc.), however, none of these are inadequate in terms of their action and effect, or have not reached a level where they can be sufficiently satisfied in terms of safety and cost. Although various studies have been made on the active ingredients of these substances,
Many have not been identified, and no examples have found a type-specific inhibitory effect.

[0011]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, from plant extracts, 5α-reductase, which is extremely excellent, is specifically superior to type II. Successfully identified and identified a component having an inhibitory activity.

That is, the present invention provides the following general formula (I)

[0013]

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(Wherein R represents an alkyl group having 1 to 6 carbon atoms) or a steroid 5α-containing a pharmaceutically acceptable salt thereof as an active ingredient.
It relates to a reductase type II specific inhibitor.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.

The steroid 5α-reductase I of the present invention
The type I specific inhibitor has the following general formula (I)

[0017]

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(Wherein R represents an alkyl group having 1 to 6 carbon atoms) or a pharmaceutically acceptable salt thereof as an active ingredient.

In the above, the alkyl group having 1 to 6 carbon atoms may have any of a straight-chain structure and a branched structure, and specifically includes a methyl group, an ethyl group, an n-propyl group, an isopropyl group and a butyl group. , T-butyl group, pentyl group, hexyl group and the like. In the present invention, a methyl group is particularly preferred.

As used herein, “pharmaceutically acceptable salts” include, for example, alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as calcium salts,
Magnesium salts and aluminum salts; various organic amines, i.e. amine salts formed from aliphatic or arylaliphatic primary, secondary or tertiary mono-, di- or polyamines or heterocyclic bases, such as triethylamine,
2-hydroxyethylamine, di- (2-hydroxyethyl) amine, tri- (2-hydroxyethyl) amine, 4-aminobenzoic acid-2-diethylaminoethyl ester, 1-ethylpiperidine, bicyclohexylamine, N, N ' -Dibenzyl-ethylenediamine, pyridine, collidine, quinoline, procaine, dibenzylamine, 1-ephenamine and salts derived from N-alkyl-piperidine, but are not limited thereto.

The present inventors have separated triterpenes represented by the above general formula (I) from plant extracts and succeeded in their identification. Plants that can be used include cuachalalate (Julianiaceae).
Juliania adstringens), Amphiptery gumadstringen
s, Orthopterygium huancuy and the like, among which quacharate is particularly preferably used. For the extraction, bark of these plants is preferably used, but not limited thereto.

It has been already clarified that the extract of quacharate has high safety and exhibits excellent hair-growth and hair-growth effects (Japanese Patent Laid-Open No. 6-24942). The present inventors have found a novel active ingredient having an extremely excellent inhibitory effect on 5α-reductase activity from these extracts, and succeeded for the first time in the separation and identification thereof (Japanese Patent Application No. 9-62).
393) have not found a type-specific activity inhibitory effect of 5α-reductase.

According to the present invention, a novel active ingredient having an excellent inhibitory activity specifically on type II of steroid 5α-reductase has been found from the above extracts,
The identification was successful. The specific method and the like will be described in detail in Examples.

Since the inhibitor of the present invention has an excellent inhibitory effect on the activity of steroid 5α-reductase type II specifically, it is particularly useful for the prevention and treatment of symptoms related to the activity of steroid 5α-reductase type II. Various pharmaceutical preparations in the field of medicines and cosmetics, can be used in cosmetics and the like, specifically, for example, cosmetics for the prevention and treatment of acne vulgaris, and comprehensive pharmaceutical preparations for the prevention and treatment of acne, It can be used for skin cosmetics, cosmetics for hair growth and hair growth, etc. Here, the term “hair growth” is used in a concept that includes the promotion of hair growth, prevention of hair loss, and further, the effects of suppressing dandruff and itch.

The inhibitor of the present invention can be used for the prevention or treatment of injuries and diseases caused by the action of steroid 5α-reductase, in particular, type II, other than those described above. Alternatively, a diluent, an excipient, and the like may be added according to the purpose of use. The dosage form is also arbitrary, and may be any of oral and parenteral dosage forms. For example, it can be a liquid, syrup-like or tablet dosage form. Particularly for preparing a liquid preparation, physiological saline, ethanol, and 1,3-butylene glycol can be used as a diluent or carrier.

The inhibitor of the present invention has the general formula (I)
The isomers of the compound represented by are also included in the scope of the present invention.

In order to prepare a creamy preparation, higher fatty acids, higher alcohols, esters and the like can be used as carriers.

When the inhibitor of the present invention is used for hair growth, in addition to alkoxycarbonylpyridine N-oxide, vasodilators such as carpronium chloride, assembly extract and acetylcholine derivatives, amino acids such as serine and methionine, vitamin B ₆ , vitamin E and its derivatives, vitamins such as biotin, pantothenic acid and its derivatives, glycyrrhetinic acid and its derivatives, nicotinic acid esters such as benzyl nicotinate, skin function enhancers such as cepharanthin, and female hormones such as estradiol at the same time. You may mix. Further, additives usually used for hair restoration, for example, hinokitiol, hexachlorophene,
Antibacterial agents such as benzalkonium chloride, cetylpyridinium chloride, undecylenic acid, trichlorocarbanilide and bithionol; cooling agents such as menthol; salicylic acid, zinc and its derivatives; drugs such as lactic acid and its alkyl esters; and organic acids such as citric acid. Acids, protease inhibitors such as tranexamic acid, amino acids such as arginine, olive oil, squalane, liquid paraffin, isopropyl myristate, oils such as higher fatty acids and higher alcohols, polyhydric alcohols such as glycerin and propylene glycol, and other interfaces Activators, fragrances, antioxidants, ultraviolet absorbers, dyes, ethanol, water, humectants, thickeners, etc.
It can be appropriately compounded within a range that does not impair the effects of the present invention.

When the inhibitor of the present invention is used as a pharmaceutical, quasi-drug, or cosmetic composition, the dosage may vary depending on the dosage form of the composition, the purpose of use, and the like. However, it is generally about 4 to 10 ml per day. Specifically, for example, when the compound of the present invention is obtained from an extract obtained according to the method described in Examples described below,
In pharmaceuticals and cosmetics, the extract (dry weight) is generally 0.0
05 to 20% by weight, preferably 0.001 to 10% by weight
It is blended so that If the amount is less than 0.005% by weight, it is difficult to sufficiently exert the effects of the present invention, while if it exceeds 20% by weight, it is not preferable in terms of formulation.

[0030]

Next, the present invention will be described more specifically with reference to examples. The present invention is not limited by this. The compounding amount is% by weight.

Example 1 Isolation and Purification of a Compound of the Formula (I) 2 kg of a dried product of quacharate was added to a room temperature (about 23 ° C.)
Extraction by immersion in 2 liters of ethanol for 24 hours
Times to obtain an extract, and then the extract is dried under reduced pressure,
40 g of an ethanol extract were obtained.

For 40 g of the ethanol extract, 2 kg of “Diaion HP-20” (manufactured by Nippon Neruizu) was used.
The ratio of methanol to distilled water was changed from 40% to 100% to elute. The 100% methanol eluted fraction was collected and dried under reduced pressure to obtain 10 g of the dried product under reduced pressure.

10 g of the dried product under reduced pressure was fractionated using 1 kg of silica gel ("Wakogel C-200") while changing the ratio of hexane to ethyl acetate from 15: 1 to 1: 1.

Each fraction was dried under reduced pressure and the inhibitory activity of each type of 5α-reductase was measured by the following method. As shown in Table 1 below, a fraction having a high inhibitory activity (sample (6) in Table 1) was purified by silica gel column treatment and recrystallization according to a known method to obtain 60 mg of the compound of the general formula (I).
I got

With respect to this compound, ¹ H-NMR, ¹³ C-
The structure was examined from the physical properties of NMR.
Known 3α-hydroxyeupha-7,24-dien-26-oic aci
d (hereinafter referred to as “sinol”).

[0036]

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As far as the present inventors know, it has never been reported that sinol has a specific activity inhibitory effect on 5α-reductase type II.

The measurement of the inhibitory activity and the tricogram test of 5α-reductase of sinol by type were carried out by the following methods.

I. Measurement of inhibitory activity of each type of 5α-reductase The inhibitory activity of each type of 5α-reductase can be measured by the following method.

That is, for the measurement of the 5α-reductase type I-specific inhibitory activity, normal human liver cells (Chang Liver) or dermal papilla cells, which mainly produce type I, are preferably used, and 5α-reductase is preferably used. For measurement of the type II-specific inhibitory activity, human neonatal foreskin gland fibroblasts (Hs-68) and prostate cells, which mainly produce type II, are preferably used. In this example, normal human liver cells (Chang Liver) were used for type I measurement, and live human neonatal foreskin gland fibroblasts (Hs-68) were used for type II measurement.

Using each of these human-derived cells, the amount of testosterone reduced to DHT or the amount of androstenedione reduced to androstanedione was measured in the cell culture supernatant. The 70% ethanol solution of sinol obtained by separation and purification
The α-reductase inhibitory activity can be evaluated by measuring the inhibitory activity for each type and determining the inhibition rate according to the following formula. In this example, the measurement was performed by measuring the amount of androstenedione reduced to androstanedione. Table 1 shows the results.

In Table 1, sample (1) is the ethanol extract described in Example 1;
(4) each elution fraction at the end of the operation by "Diaion HP-20" column chromatography;
Samples (5) and (6) are elution fractions using sample (4); sample (7) was isolated and purified from sample (6). That is, from the results in Table 1, the highly polar fraction of the fraction 2 eluted with hexane: ethyl acetate (1: 1) had a high inhibitory activity, and the fractions were collected, treated with silica gel column and recrystallized to obtain 60 mg of sinol. I got

[0043]

(Equation 1)

[0044]

[Table 1]

II. Tricogram Test The effect of the present invention on hair restoration (that is, promotion of hair growth or prevention of hair loss) can be evaluated by performing the following tricogram test. (Preparation of test sample) 0.1% by weight of the sinol obtained in Example 1 and 0.5% by weight of a hydrogenated castor oil ethylene oxide (40 mol) adduct in 70% by weight of 95% ethanol
It was added and dissolved by stirring. Next, ion-exchanged water was added to 100% by weight and mixed to prepare a liquid hair nourishing material. As a control, a composition containing no sinol in the above hair restoration (control product) was prepared. (Evaluation by tricogram test) A tricogram test was performed by a male panel (18 persons) using the test samples (product of the present invention and control product).

That is, the hair roots of the extracted hair before and after use of the test sample are observed under a microscope, the number of hair roots at the stasis stage is counted from the form of the hair root, and the hair growth effect of the hair nourishing agent is compared by increasing or decreasing the ratio. did. A telogen follicle is a hair follicle that has stopped growing, and it has been recognized that the proportion of this telogen follicle is higher in people who report hair loss than in normal people.

Specifically, the product of the present invention was applied to the scalp of 10 male panels and the control product was applied to the scalp of 8 other male panels twice a day, 2 ml at a time, for 6 months continuously. Immediately before application and immediately after the application for 6 months, 100 hairs were removed from each subject, and the percentage of resting roots before and after application was examined. Of the hair follicles) was measured and measured. Table 2 shows the results.

[0048]

[Table 2]

Example 2 Test for Improvement of Acne Vulgaris (Acne Symptoms) A lotion having the following composition was prepared as a test sample. In addition, the compounding amount is weight%. (Phase A) Sorbitol 3.0 Glycerin 5.0 Resorcin 0.02 Ion-exchanged water balance (Phase B) Sinol (Example 1) 0.1 Polyoxyethylene (60) hydrogenated castor oil 0.5 95% ethanol 20 0.5 Perfume Appropriate amount (Preparation method) Each component of phase A was mixed and dissolved, and a mixed solution of phase B was added thereto with stirring to prepare a lotion as a homogeneous solution.

As a control, a composition not containing sinol as a component of the lotion was prepared.

Using the test samples (products of the present invention and the control product), 40 male and 40 female ages 13 to 23 were used as panels.
After one week, the effect of improving acne symptoms was determined according to the following evaluation criteria. Table 3 shows the results. (Evaluation criteria) Complete cure: No symptoms at all Significant effect: Significant improvement effect was observed Effective: Symptoms were lightened overall Invalid: No change in symptoms before and after use

[0052]

[Table 3]

Example 3 Cream (Phase A) Beeswax 10.0 Paraffin Wax 6.0 Lanolin 3.0 Isopropyl Myristate 6.0 Squalane 8.0 Liquid Paraffin 26.0 Polyoxyethylene Sorbitan Stearate 2.0 Sorbitan Monostearate 4.2 Preservatives Adequate (Phase B) Propylene glycol 2.0 Polyoxyethylene (60) hydrogenated castor oil 1.0 Sinol 0.1 Purified water Residue (Preparation method) Mix ingredients of phase A After heating and dissolving at about 75 ° C., the mixed solution of phase B heated to 75 ° C. was added thereto with stirring, and then stirring was continued while cooling to 45 ° C.
The cream was obtained by standing.

When this cream was subjected to a practical use test on humans in the same manner as in Example 2, it was confirmed that the cream was excellent in improving acne symptoms.

Example 4: O / W emulsion type hair restorer (phase A) sinol 0.01 polyoxyethylene (60 mol) addition-hardened castor oil 2.0 glycerin 10.0 dipropylene glycol 10.0 1,3- Butylene glycol 5.0 Polyethylene glycol (molecular weight 1500) 5.0 (B phase) Cetyl isooctanoate 10.0 Squalane 5.0 Vaseline 2.0 Propylparaben 2.0 (C phase) 1% aqueous solution of carboxyvinyl polymer 30. 0 Sodium hexametaphosphate 0.03 Ion-exchanged water 8.35 (D-phase) Ion-exchanged water 4.5 (E-phase) Kaseikari 0.12 Residual ion-exchanged water (Preparation method) Heat and dissolve
The mixture was mixed and treated with a homomixer to obtain a gel substance. Phase D is gradually added thereto, and dispersed by a homomixer. Then, dissolved C phase is added thereto, and further dissolved E phase is added, and emulsified by a homomixer to obtain an O / W emulsion type hair restorer. Was.

When this hair growth preparation was subjected to a practical use test on humans in the same manner as in Example 2, it was confirmed that the hair growth action was excellent.

Example 5: Creamy hair restorer (Phase A) sinol 1.0 Liquid paraffin 5.0 Cetostearyl alcohol 5.5 Glyceryl monostearate 3.0 EO (20 mol) -2-octyldodecyl ether 0 Propylparaben 0.3 Fragrance 0.1 (Phase B) Glycerin 8.0 Dipropylene glycol 20.0 Polyethylene glycol (Molecular weight 4000) 5.0 Sodium hexametaphosphate 0.005 Ion-exchanged water Residue (Production method) Phase A , B phase is heated and dissolved, respectively, and mixed,
The mixture was emulsified with a homomixer to obtain a creamy hair restorer. An actual use test was carried out on the human hair by the tricogram test described in Example 1, and it was confirmed that the hair growth effect was excellent.

Example 6: Hair tonic sinol 10.0 Peppermint (1,3-butylene glycol solution) 0.1 N, N-dimethyl-2-dodecylamine oxide 1.0 Hinokitiol 1.0 Vitamin B ₆ 0.2 Vitamin E acetate 0.02 Menthol 0.2 Assembly extract 1.0 Salicylic acid 0.1 Maika (ethanol extract) 0.5 Propylene glycol 2.0 Sodium hyaluronate 0.01 Polyoxyethylene (10 mol) monostearate 2 0.0 75% ethanol residue

Example 7: Hair tonic sinol 10.0 Althea (ethanol extract) 1.5 Yokuinin (ethanol extract) 1.5 N, N-dimethyl-2-tetradecylamine oxide 0.05 Hinokitiol 1.0 Vitamin B ₆ 0.2 Vitamin E acetate 0.02 Menthol 0.2 Salicylic acid 0.1 Caccon (ethanol extract) 0.5 Propylene glycol 0.01 Sodium hyaluronate 0.01 Polyoxyethylene (10 mol) monostearate 2.0 70% ethanol residue

Example 8: Hair tonic sinol 0.6 95% ethanol 50.0 Monoammonium glycyrrhizinate 0.05 Althea (ethanol extract) 0.05 Yokuinin (1,3-butylene glycol solution) 0.05 peppermint ( Ethanol extract) 0.05 Saffron (ethanol extract) 0.05 Rosemary (ethanol extract) 0.05 Sengyu (ethanol extract) 0.05 Touki (ethanol extract) 0.05 Jio (ethanol extract) 0.05 Maikai (ethanol extract) 0.05 Sodium lauryl sulfate 0.1 N, N-dimethyl-2-tridecylamine oxide 0.5 Hardened castor oil ethylene oxide (40 mol) adduct 0.5 Succinic acid Appropriate amount of fragrance Color appropriate amount of purified water Residue

Example 9: Aerosol hair growth (stock solution formulation) sinol 0.6 95% ethanol 50.0 glycyrrhetinic acid 0.1 Altea (ethanol extract) 0.05 ぺ permint (ethanol extract) 0.05 assembly extract 0.1 Sodium lauryl sulfate 0.1 N, N-dihydroxymethyl-2-0.2 Decylamine oxide Hydrogenated castor oil Ethylene oxide (40 mol) adduct 0.5 Sq lactate qs Sodium lactate qs Flavor qs Dye qs Purified water residue (filling formula) Undiluted solution 50.0 Liquefied petroleum gas 50.0 After dissolving the undiluted solution formulation, fill it in a can, fill it with a valve, and fill with gas. An actual use test was performed on this hair tonic by the above trichogram test, and it was confirmed that the hair growth effect was excellent.

[0062]

As described in detail above, the inhibitor of the present invention has a particularly excellent steroid 5α-reductase type II-specific inhibitory effect, and is useful in the fields of pharmaceuticals, quasi-drugs, cosmetics, etc. It can be effectively used as a therapeutic agent for acne and the like.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 7/06 A61K 7/06 7/48 7/48 // A61K 35/78 35/78 C C07J 9/00 C07J 9/00 (72) Inventor Yasuo Fujimoto 8-32-8 Oizumi Gakuen-cho, Nerima-ku, Tokyo

Claims (4)

[Claims] 1. A compound represented by the following general formula (I) (Wherein, R represents an alkyl group having 1 to 6 carbon atoms) or a steroid 5α-reductase type II specific inhibitor comprising, as an active ingredient, a compound represented by the formula: . 2. The steroid 5α-reductase II according to claim 1, wherein in the general formula (I), R is —CH _3.
Type-specific inhibitors. 3. The steroid 5α-reductase type II specific inhibitor according to claim 1, which is used as a hair restorer. 4. The steroid 5α-reductase II according to claim 1, which is used as a therapeutic agent for skin disorders.
Type-specific inhibitors.