JPH10245394A - New triterpenes and composition containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the new subject compound comprising specific triterpenes, having excellent testosterone 5α-reductase activity-inhibiting effects, and useful as a hair-growing agent and a therapeutic agent for pimple in the field of a drug, a quasi drug, a cosmetic, etc. SOLUTION: The objective compound is new triterpenes of the formula (R is a 1-6C alkyl), (e.g. 6-oxo-3α-hydroxyeupha-7,24-dien-26-oic acid), has excellent testosterone 5α-reductase activity-inhibiting effects, and is useful as a therapeutic agent of skin disorder such as a hair-growing agent and a therapeutic agent for pimple in the field of a drug, a quasi drug, a cosmetic, etc. The compound obtained by dipping a dried material of cuachalalate of a plant belonging to Julianiaceae in ethanol to extract the dried material of cuachalalate, drying the ethanol extract under reduced pressure, treating the dried extract with an adsorbing resin, further treating the treated extract with a silica gel column and purifying the treated extract by recrystallization to provide the objective triterpenes.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to novel triterpenes and compositions containing the same. INDUSTRIAL APPLICABILITY The novel compound of the present invention has particularly excellent testosterone 5α-reductase activity, and can be effectively used as a hair restorer, a therapeutic agent for anti-acne and the like in the fields of pharmaceuticals, quasi-drugs, cosmetics 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] In male pattern baldness, it has been revealed that the depilated crown has higher 5α-reductase activity than the undepilated temporal, 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.

[0004] Therefore, female hormonal agents such as estradiol and anti-androgenic agents have been used in conventional hair restoratives.

[0005] Recently, the search for a substance that inhibits the activity of 5α-reductase, which controls the metabolism of testosterone to DHT, has been advanced.

[0006]

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, testosterone 5α-reductase activity inhibitory substances have been found in various plant extracts and have been reported (JP-A-60-146829).
No. 63-88121, No. 64-3125, Japanese Patent Publication No. 6-47554, etc.), all of which are insufficient in action and effect or safety,
The cost has not yet reached a satisfactory level.
Although various studies have been made on the active ingredients of these substances, many have not been identified.

[0008]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that a specific structure having an extremely excellent 5α-reductase activity inhibitory effect can be obtained from a plant extract. Have found novel triterpenes. The present invention is based on these findings.

That is, the present invention provides a compound represented by the following general formula (I)

[0010]

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

[0011] The present invention also relates to a composition containing the above compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0012]

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

The compound of the present invention has the following general formula (I):

[0014]

Embedded image (Wherein, R represents an alkyl group having 1 to 6 carbon atoms).

In the above description, 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 alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as calcium, magnesium and aluminum salts; various organic amines; That is, the first, second or third aliphatic or arylaliphatic
Amine salts formed from mono-, di- or polyamines or heterocyclic bases, such as triethylamine, 2-hydroxyethylamine, di- (2-hydroxyethyl) amine, tri- (2-hydroxyethyl) amine, 4-aminobenzoate Acid-2-diethylaminoethyl ester, 1
-Ethylpiperidine, bicyclohexylamine, N,
N'-dibenzyl-ethylenediamine, pyridine, collidine, quinoline, procaine, dibenzylamine, 1-
Salts derived from ephenamine and N-alkyl-piperidine are meant.

The present inventors have separated triterpenes represented by the above general formula (I) from plant extracts and succeeded in identifying them. 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.

The present inventors have already clarified that the extract of Quacharate has high safety and excellent hair growth and hair growth effects (JP-A-6-2494).
No. 2), the separation and identification of the active ingredient has not been successful until now. The present inventors have now found a new active ingredient having an excellent inhibitory effect on testosterone 5α-reductase activity among these extracts, and succeeded for the first time in separating and identifying the same. The specific method and the like will be described in detail in Examples.

Since the triterpenes of the present invention have an effect of inhibiting testosterone 5α-reductase activity, various pharmaceutical preparations and cosmetics in the field of medicine and cosmetics for preventing and treating symptoms related to testosterone 5α-reductase activity. And the like. Specifically, for example, for example, cosmetics for the prevention and treatment of acne vulgaris, and comprehensive pharmaceutical preparations for the prevention and treatment of acne, skin cosmetics, hair growth and nourishment of hair It can be used for hair cosmetics and the like. 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 triterpenes of the present invention may further comprise
It can be used for the prevention or treatment of injuries and diseases caused by the action of testosterone 5α-reductase, and is not limited to external use on the skin, and may contain diluents, excipients, etc. according to the purpose of use. May be. 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. For preparing a creamy preparation, higher fatty acids, higher alcohols, esters and the like can be used as carriers.

The triterpenes represented by the above general formula (I) of the present invention include isomers thereof within the scope of the present invention.

When the triterpenes of the present invention are 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, female hormones such as estradiol, etc. You may mix | blend simultaneously. In addition, additives usually used for hair restoration, for example, hinokitiol, hexachlorophen, benzalkonium chloride, cetylpyridinium chloride, undecylenic acid, antibacterial agents such as trichlorocarbanilide and bitionol, refreshing agents such as menthol, salicylic acid, Drugs such as zinc and its derivatives, lactic acid and its alkyl esters, etc., organic acids such as citric acid, protease inhibitors such as tranexamic acid, amino acids such as arginine, olive oil, squalane, liquid paraffin, isopropyl myristate, higher fatty acids Oils such as higher alcohols, polyhydric alcohols such as glycerin and propylene glycol, other surfactants, fragrances, antioxidants, ultraviolet absorbers, dyes, ethanol, water, humectants, thickeners, etc. of the present invention. Suitable as long as the effect is not impaired. It can be formulated.

When the compound of the present invention is used in a composition, in particular, a pharmaceutical / quasi-drug or cosmetic composition, the dosage is specified because it can vary depending on the form of the composition or the purpose of use. Not generally, but generally 4 to 10 ml per day
It is about. Specifically, for example, when the compound of the present invention is obtained from an extract obtained according to the method described in Examples described later, the extract (dry weight) is generally used in pharmaceuticals and cosmetics.
0.005 to 20% by weight, preferably 0.001 to 10
% By weight. If it 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.

[0024]

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 the Compound of the Present Invention 2 kg of a dried product of quacharalate was placed at 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 this 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 5α-reductase inhibitory activity was measured by the following method. As shown in Table 1 below,
The fraction having high inhibitory activity (sample (6) in Table 1) was purified by silica gel column treatment and recrystallization according to a known method to obtain 40 mg of the present compound.

The compound of the present invention has the following ¹ H-NM
When the structure was determined from the physical properties of R and ¹³ C-NMR, a new compound represented by the following chemical formula 4 was obtained: 6-oxo-3α-hydro
It was found to be xyeupha-7,24-dien-26-oic acid.

[0029]

Embedded image ¹ H-NMR (400 MHz, pyridine-d ₆ , σ) 0.70 (3H, s, H-18), 0.94 (3H, s, H-19), 0.96 (3H, d,
J = 6.6Hz, H-21), 0.98 (3H, s, H-30), 1.24 (1H, m, H-
22), 1.28 (1H, m, H-16), 1.38 (1H, m, H-1), 1.40 (2H,
m, H-15), 1.41 (3H, m, H-20), 1.52 (1H, m, H-11),
1.53 (1H, m, H-17), 1.67 (1H, m, H-11), 1.73 (3H, s,
H-28), 1.73 (1H, m, H-12), 1.83 (1H, dd, J = 2.9, 14.0H
z, H-2), 1.98 (2H, m, H-2, 16), 2.16 (3H, s, H-27),
2.27 (1H, dt, J = 3.7, 11.4Hz, H-1), 2.78 (1H, m, H-2
3), 2.87 (1H, m, H-23), 2.95 (1H, m, H-9), 3.06 (1H,
s, H-5), 3.60 (1H, bs, H-3), 5.89 (1H, d, J = 11.4Hz,
H-7), 6.05 (1H, t, J = 6.6, 7.0, 7.3Hz, H-24), 8.56 (1
H, s, H-26) ¹³ C-NMR (100 MHz, pyridine-d ₆ , CDC
l ₃ , σ) 25.0 (C-30), 25.8 (C-2), 18.4 (C-21), 21.5 (C-27), 21.
7 (C-19), 22.2 (C-29), 25.0 (C-30), 25.8 (C-2), 27.0 (C
-23), 27.8 (C-16), 29.1 (C-28), 31.7 (C-1), 32.9 (C-1
2), 33.1 (C-15), 36.0 (C-22), 36.2 (C-20), 37.6 (C-4),
43.1 (C-13), 43.8 (C-10), 50.5 (C-9), 52.3 (C-14), 5
2.5 (C-17), 60.9 (C-5), 75.9 (C-3), 125.1 (C-7), 128.9
(C-25), 142.2 (C-24), 149.6 (C-8), 170.3 (C-26), 201.
5 (C-6) The 5α-reductase inhibitory activity measurement and tricogram test of the compound of the present invention were performed by the following methods.

I. Measurement of 5α-reductase inhibitory activity The measurement of 5α-reductase inhibitory activity was performed by the method of Takayasu et al. (S. Takayasu, K. Adachi, “J. Clin. Endocrlnol. M.
etab. ", 34, pp. 1098-1101 (1972). That is, the amount of testosterone reduced to DHT is measured using human hair roots, and isolated and purified in Example 1. The obtained 6-oxo-3α-hydroxyeupha-7,24-dien-26-oic a
Testosterone-70% cid in ethanol
It can be evaluated by measuring the 5-α-reductase inhibitory activity and determining the inhibition rate according to the following formula. Table 1 shows the results
Shown in

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 a silica gel column and recrystallized to form 6-ethyl acetate. oxo-3α-hydroxyeupha-7,24-dien-26
40 mg of -oic acid were obtained.

[0032]

(Equation 1)

[Table 1] 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) The 6-oxo-3α-hydroxyeupha-7,24-dien- obtained in Example 1 was added to 70% by weight of 95% ethanol.
0.1% by weight of 26-oic acid and 0.5% by weight of an adduct of hydrogenated castor oil with ethylene oxide (40 mol) were 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, 6-oxo-3α-hydroxyeupha-7,24-dien-
A composition containing no 26-oic acid (control) 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. The telogen follicles are the hair follicles that have stopped growing, and it has been recognized that those who report hair loss have a higher percentage of these telogen follicles than 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 application for 6 months, 100 hairs were removed from each subject, and the proportion of resting roots before and after application was examined. Of the hair follicles) was measured and measured. Table 2 shows the results.

[0035]

[Table 2] 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) 6-oxo-3α-hydroxyeupha-7,24-dien-26-oic acid (Example 1) 1 Polyoxyethylene (60) hydrogenated castor oil 0.5 95% ethanol 20.5 Perfume Appropriate amount (Preparation method) Mix and dissolve each component of phase A, and add the mixed solution of phase B to this while stirring. A lotion was prepared as a homogeneous solution.

As a control, 6-oxo-3α-hydroxyeupha-7,24-dien-26-oic acid was used as a component of the lotion.
Was prepared without the addition of

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

[0039]

[Table 3] 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 Preservative Appropriate amount (phase B) Propylene glycol 2.0 Polyoxyethylene (60) hydrogenated castor oil 1.0 6-oxo-3α-hydroxyeupha-7,24-dien-26-oic acid 0 1.1 Purified water residue (Preparation method) Mix the ingredients of phase A, heat and dissolve at about 75 ° C, add the combined liquid of phase B heated to 75 ° C with stirring, and then heat to 45 ° C. Continue stirring while cooling to
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) 6-oxo-3α-hydroxyeupha-7,24-dien-26-oic acid 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 (Phase B) Cetyl isooctanoate 10.0 Squalane 5.0 Vaseline 2.0 Propylparaben 2.0 (C phase) Carboxyvinyl polymer 1% aqueous solution 30.0 Sodium hexametaphosphate 0.03 Ion exchange water 8.35 (D phase) Ion exchange water 4.5 (E phase) Kaseikari 0.12 Ion exchange Water residue (Production method) A phase and B phase are each heated and dissolved at 60 ° C.
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 restoration was subjected to a practical use test on humans in the same manner as in Example 2, it was confirmed that the hair restoration effect was excellent.

Example 5: Hairy cream (phase A) 6-oxo-3α-hydroxyeupha-7,24-dien-26-oic acid 1.0 Liquid paraffin 5.0 Cetostearyl alcohol 5.5 Glyceryl monostea Rate 3.0 EO (20 mol) -2-octyldodecyl ether 3.0 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) A phase and B phase are each heated and dissolved 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 6-oxo-3α-hydroxyeupha-7,24-dien-26-oic acid 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 Mica (ethanol extract) 0.5 Propylene glycol 2.0 Sodium hyaluronate 0.01 Polyoxyethylene (10 mol) monostearate 2.0 75% ethanol Residue

Example 7: Hair tonic 6-oxo-3α-hydroxyeupha-7,24-dien-26-oic acid 10.0 Altea (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 6-oxo-3α-hydroxyeupha-7,24-dien-26-oic acid 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 Senkyu (ethanol extract) 0 .05 Touki (ethanol extract) 0.05 Diou (ethanol extract) 0.05 Silkworm (ethanol extract) 0.05 Sodium lauryl sulfate 0.1 N, N-dimethyl-2-tridecylamine oxide 0.5 Hydrogenated castor oil ethylene oxide (40 mol) adduct 0.5 succinic acid qs perfume qs pigment Volume Purified water Residue

Example 9: Aerosol hair growth (stock solution formulation) 6-oxo-3α-hydroxyeupha-7,24-dien-26-oic acid 0.6 95% ethanol 50.0 Glycyrrhetinic acid 0.1 Artair (ethanol extraction Liquid) 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) addition Product 0.5 Lactic acid proper amount Sodium lactate proper amount Fragrance proper amount Pigment proper amount Purified water residue (filling formula) Stock solution 50.0 Liquefied petroleum gas 50.0 After dissolving the stock solution formulation, fill it in a can and fill it with a valve. After mounting, fill with gas. An actual use test was performed on this hair tonic by the tricogram test described in Example 1 above, and it was confirmed that the hair growth effect was excellent.

[0049]

As described in detail above, the triterpenes of the present invention have a particularly excellent testosterone 5α-reductase activity inhibitory effect, and are used in the fields of pharmaceuticals, quasi-drugs, cosmetics, etc. for hair restoration and anti-acne. It can be effectively used as a therapeutic agent and the like.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/575 ADA A61K 31/575 ADA AED AED (72) Inventor Yoshiharu Tsuji 1050 Niiwacho, Kohoku-ku, Yokohama-shi, Kanagawa Prefecture Shiseido Co., Ltd. Inside the Daiichi Research Center (72) Inventor Akihiro Ishino 1050 Nippacho, Kohoku-ku, Yokohama, Kanagawa Prefecture Inside Shiseido Daiichi Research Center (72) Inventor Masahiro Tajima 1050 Nippacho, Kohoku-ku, Yokohama-shi, Kanagawa Shiseido Co., Ltd. Inside the Daiichi Research Center (72) Inventor Masahiro Ota 1050 Nippa-cho, Kohoku-ku, Yokohama-shi, Kanagawa Prefecture Inside Shiseido Daiichi Research Center (72) Inventor Tatsuya Tsuru 2-64-12 Izumigaoka, Iwaki-shi, Fukushima (72) Inventor Yasuo Fujimoto 7-7-1 Narashinodai, Funabashi-shi, Chiba (72) Inventor Yoshiyuki Ichinohe Kanagawa Cang City Fueda 235-11

Claims (8)

[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 pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein in the general formula (I), R is —CH ₃ , or a pharmaceutically acceptable salt thereof. 3. A composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 4. The composition according to claim 3, which is a pharmaceutical composition. 5. The composition according to claim 3, which is a cosmetic composition. 6. The composition according to claim 3, which is used as a testosterone 5α-reductase activity inhibitor. 7. The method according to claim 3, which is used as a hair restorer.
A composition according to any one of the preceding claims. 8. The composition according to claim 3, which is used as a therapeutic agent for skin disorders.