JP2791673B2 - 5α-reductase inhibitor - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a 5α-reductase inhibitor useful for the prevention or treatment of various diseases involving androgens.

[Conventional technology]

Conventionally, hair disorders such as androgenetic alopecia and hirsutism; skin diseases caused by enhanced sebum secretion function such as acne and seborrhea; purulent sweat glands which may be caused by dysfunction of apocrine glands Inflammation: In the diseases such as prostatic hypertrophy and prostate cancer, the action of androgen is considered to be the cause or exacerbating factor, and various antiandrogen drugs are used for the treatment of these diseases. The mechanism of action of antiandrogens is to inhibit testosterone from being reduced to more active dihydrotestosterone by 5α-reductase in these target organs of interest;
Methods for inhibiting the binding of testosterone or produced dihydrotestosterone to a receptor in a target cell are known. At present, therapeutic agents used as antiandrogens include, for example, oxendrone, chlormadinone acetate, 11α-hydroxyprogesterone,
Androsten-3-one-17β-carboxylate acid, cyproterone acetate, etc., and any of these may be either 5α-reductase inhibitory activity or receptor binding inhibitory activity, or both. The action inhibits the action of male hormones.

[Problems to be solved by the invention]

However, all of these antiandrogens are steroid hormone derivatives, and when administered to a living body, may cause side effects when used for a long time, such as when the drug itself or a metabolite thereof has a hormonal effect. There were many safety issues.

[Means for solving the problem]

Under such circumstances, the present inventors have conducted intensive studies to develop a highly safe antiandrogen having no steroid skeleton, and as a result, a high 5α-reductase inhibitory action was found in isoflavone compounds. The present inventors have found that there is a substance having the compound, and have completed the present invention.

That is, the present invention provides the following general formula (I) Wherein R ¹ , R ² and R ³ represent a hydrogen atom, a chain or alicyclic hydrocarbon group or an alkoxyl group having 1 to 6 carbon atoms, and A, B, C and D represent a hydrogen atom, a hydroxyl group Or a methoxyl group. However, R ² and C do not simultaneously become hydrogen atoms. ] It is intended to provide a 5α-reductase inhibitor characterized by containing an isoflavone compound represented by the following formula:

The isoflavones of the general formula (I) have excellent 5α-reductase inhibitory activity and are highly safe. Therefore, the 5α-reductase inhibitor containing the isoflavones may be caused by the action of male hormones or its exacerbation factor. Various diseases, for example, seborrhea and acne associated with increased sebum secretion function,
It can be used safely and effectively for the treatment of purulent sweat glanditis, armpit odor, hirsutism, benign prostatic hyperplasia, prostate cancer, and male pattern baldness.

The 5α-reductase inhibitor of the present invention is administered systemically or locally orally or parenterally according to the purpose. The dose of the isoflavone compound (I) varies depending on age, body weight, sex, symptom, therapeutic effect, administration method, treatment time, etc. In the case of treatment and / or prevention of benign prostatic hyperplasia, it is usually 1 per adult. 1 mg to 1 g, preferably 20 mg to 200 times
It is orally administered once to several times a day in the range of mg, or 100 µg to 200 mg, preferably 1 mg to 1
Parenteral administration is performed once to several times a day in the range of 0 mg. In addition, in the case of treatment and / or prevention of alopecia and acne, usually 10 μg to 100 mg, preferably 50 μg to 1 at a time per adult.
It is orally administered once to several times a day in the range of 0 mg. Of course, as described above, the dose varies under various conditions,
In some cases, an amount smaller than the above range may be sufficient, and in other cases it may be necessary to administer beyond the above range.

When the 5α-reductase inhibitor of the present invention is used as an oral drug, the compound (I) may be administered as it is, but the dosage forms such as tablets, powders, granules, capsules, and liquids should be further devised. Thus, the effect can be further enhanced. For example, solid dosage forms include lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, inert diluents such as magnesium metasilicate, lubricating agents such as magnesium stearate, and fibrous gluconic acid. A disintegrating agent such as calcium may be contained. Tablets or pills can be sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose,
It may be coated with a film of a gastric or enteric substance such as phthalate, or may be coated with two or more layers.

Liquid preparations for oral administration include emulsions, solutions, suspensions, syrups, elixirs and the like. Such liquid preparations include, besides the active ingredient and the inert diluent, humectants, adjuvants such as suspending agents, sweeteners,
Flavoring agents, fragrances, preservatives and the like may be contained.

Other formulations for oral administration include sprays and the like.

Representative formulations for parenteral administration according to the present invention include injections. To make the active ingredient of the present invention an injection, an aqueous medium such as distilled water for injection or physiological saline; vegetable oils such as propylene glycol, polyethylene glycol and olive oil; alcohols such as ethanol; What is necessary is just to dissolve, suspend or emulsify in an aqueous medium. Preservatives, wetting agents,
Auxiliaries such as emulsifiers and dispersants may be included. The sterilization means required for the injection include filtration through a bacteria retaining filter, blending of a bactericide, irradiation and the like. They can also be used as a sterile solid composition which is dissolved in sterile water or a sterile injection solvent before use.

Other preparations for parenteral administration include topical solutions; ointments, lotions, tonics, sprays, suspensions,
Coating agents such as emulsions; suppositories for rectal administration; petsaries for vaginal administration; In particular, lotions, tonics, sprays, solutions, and ointments are preferred as preparations for treating or preventing alopecia or acne. These preparations contain, in addition to the active ingredient, distilled water; lower alcohols such as ethanol; higher alcohols such as cetanol; expensive alcohols such as polyethylene glycol and propylene glycol; celluloses such as hydroxypropyl cellulose; Vegetable fat; petrolatum;
Waxes; silicone; vegetable oils such as olive oil; surfactants; diluents such as zinc oxide; and adjuvants such as wetting agents, suspending agents, fragrances and preservatives.

[Action and effect of the invention]

The isoflavone represented by the general formula (I) has an excellent 5α
-Reductase inhibitory activity and, in addition to the known 5α-reductase inhibitor, an inhibitory effect on the binding of male hormones to receptors. In addition, the isoflavone compound (I) is
It is extremely safe. For example, no death was observed when 10 g / kg of tectorigenin, one of the compounds (I), was administered to 5-week-old ICR mice. Accordingly, the 5α-reductase inhibitor of the present invention containing the isoflavone as an active ingredient is useful as a hair restorer or an inhibitor of sebaceous gland activity, as well as male pattern baldness, hirsutism, purulent sweat glanditis, prostatic hyperplasia, prostate cancer, etc. Is useful for the treatment and prevention of diseases associated with male hormones.

〔Example〕

 Next, the present invention will be described with reference to examples.

Example 1 Luteone; R ¹ = R ³ = H in general formula (I),
R ² CHCH ₂ CHC (CH ₃ ) ₂ , A ＝ B ＝ C ＝ D ＝ OH (hereinafter abbreviated as compound (a)), hydroxygenistein (2′-
Hydroxygenistein; In the general formula (I), R ¹ = R ² = R ³ =
H, A = B = C = D = OH; hereinafter abbreviated as compound (b); and Tectorigenin (R ¹ = R ³ = C = H, R ² = OCH ₃ , A = B = D = OH; hereinafter abbreviated as compound (c)) as a test compound, and the test was carried out by the following method.

Test method The prostate ventral lobe of a Wistar rat sacrificed by cervical dislocation was excised, minced with 20 mM phosphate buffer containing 0.32 M sucrose and 0.1 mM dithiothreitol, and homogenized.
The precipitate was collected by centrifugation at 000 × g for 1 hour. The precipitate contains 2 volumes of 5 mg / ml digitonin, 2 M sodium chloride, 40% glycerol, 1 mM dithiothreitol, 1 mM EDTA.
Add 0 mM phosphate buffer, stir well, and add 15000 × g
The supernatant obtained by centrifugation for an hour was used as an enzyme solution. This solution 10
Take 0 μl of tritium-labeled testosterone ( ³
H-testosterone) (25 pg / μl) 100 μl
And 100 μl of various concentrations of sample solutions, and heated at 37 ° C. for 45 minutes.Then, the reaction was stopped by adding 1 ml of ethyl acetate, and unreacted ³ H-testosterone and ³ H-dihydroxyl converted by the enzyme were added. Testosterone was recovered in the ethyl acetate phase. The solvent was distilled off under a nitrogen atmosphere, dissolved in methanol, and testosterone and dihydrotestosterone were separated by high performance liquid chromatography, and the amount of each was measured to calculate the enzyme inhibitory activity of the sample.

Results The results are shown in Table 1. The inhibition rate (%) in Table 1 is
It was determined by the following equation.

Example 2 Using the compound (a), hair tonics having the composition shown in Table 2 were produced, and the effects on the trichogram of hair were evaluated. Subject is worried about daily hair loss30
Twenty men aged 35 to 35 were targeted. In the evaluation method, the head was divided left and right from the midline, and the hair tonic was used on one side and the hair tonic base was used on the other side every day. On day 0, 1 month, 3 months and 6 months after the start of the test, tricograms of three 7 × 7 mm ² portions 3 cm away from the median line around the crown were measured, and the telogen rate and the hair group The number of growing hairs was determined. In aging and androgenetic alopecia, an increase in the rate of telogen hair and a decrease in the number of anagen hairs in the hair group were significantly observed (Hattori et al., The 85th Annual Meeting of the Japanese Dermatological Association,
(May 17, 1986, Kyoto).

Table 3 shows the results. In one month, no change was observed in the hair tonic treatment part and the base treatment part, but in the three and six months, a decrease in the telogen hair percentage was observed in the hair tonic treatment part. Also in the number of anagen hairs in the hair group, the proportion of the hair group consisting of one anagen hair was reduced in the hair tonic treatment part, and the proportion of the hair group consisting of the three anagen hairs was inversely proportional thereto. The ratio has increased, and it can be seen that the density of hairs has increased in the processing section.

Example 3 The compound (a) was evaluated for its effect on the growth of human prostate cancer-derived cells. The results are shown in Table 4. The product of the present invention significantly suppressed the growth of human prostate cancer-derived cells.

Example 4 A 10% ethanol solution containing 2.0 of compound (c) was produced and evaluated for its effect on axillary odor. Judgment of the effect
The test was performed according to Table 6 based on the increase and decrease of the armpit odor before and after the treatment.
The test period was two weeks, and the coating treatment was performed twice a day.

(Results) As shown in Table 6, with the product of the present invention, improvement in axillary odor was observed as compared with the 10% ethanol solution base.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor ▲ Yoshi ▼ Koichi Mura 2606 Kabane-cho Akabane, Haga-gun, Tochigi Kato Co., Ltd. (72) Inventor Takashi Kitahara 2606 Kaigamachi-Akabane, Haga-gun, Tochigi Kato Co., Ltd. Inside the research institute (72) Michihiro Hattori 2606 Akabane, Kaigamachi, Haga-gun, Tochigi Pref. Kao Co., Ltd. (56) References JP-A-1-96126 (JP, A) JP-A-64-16709 (JP, A JP, A 60-146829 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) A61K 31/35 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. The following general formula (I) Wherein R ¹ , R ² and R ³ represent a hydrogen atom, a chain or alicyclic hydrocarbon group or an alkoxyl group having 1 to 6 carbon atoms, and A, B, C and D represent a hydrogen atom, a hydroxyl group Or a methoxyl group. However, R ² and C do not simultaneously become hydrogen atoms. ] A 5α-reductase inhibitor comprising an isoflavone compound represented by the formula: