JP2529850B2 - Testosterone 5α-reductase inhibitor - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [A] Object of the Invention The present invention relates to a testosterone 5α-reductase inhibitor.

“Industrial field of application” Testosterone 5α-reductase inhibitor according to the present invention (hereinafter, simply referred to as Ts-red inhibitor for convenience).
Is used in prescription of medicines, quasi-drugs, and cosmetics, and is useful for the treatment of male-type baldness and baldness.

"Prior Art" Studies on Ts-red inhibitors have recently been published, for example, as the following publications.

In vivo role of Ts-red inhibitor, or as a mechanism of action, for example, in terms of male-type baldness, and relationship with osteoporosis, testosterone, which is the main androgen, is testosterone 5α-reductase (hereinafter, For convenience, it is simply reduced to Ts-red.),
As a result, the condition due to the excess of dihydrotestosterone produced becomes persistent. Then, it is known that this induces hair loss.

Therefore, substances capable of suppressing the production of dihydrotestosterone from testosterone are said to be able to improve these symptoms, and the development of Ts-red inhibitors is progressing.

In addition to the above-mentioned hair loss mechanism, acne (acne vulgaris)
It is said that it is also involved in the onset of, for example, when the production of dihydrotestosterone is increased, sebum secretory capacity is enhanced, and therefore, the Ts-red inhibitor is acne or, by suppressing sebum secretory capacity, oil Application to alopecia areata, seborrheic glycospermia, seborrheic eczema, and seborrheic pruritus (souyo) is considered.

"Publications on Known Ts-red Inhibitors" (1) JB Hamilton: American Journal of Anatomi Vol. 71 451 (1942) (2) Adachi & Kanou: Biochemical and Biophysical Research Communication Vol. 41 88
4 (1970) (3) Masashi Inaba: Mainichi Life 74-80 November issue (198
2) (4) Masashi Inaba: Fragrance Journal 14-18 N
o.58 (1983) (5) Schweighert. HU & Wilson. JD: Journal of Clinical End Clinology.
And Metaporism Vol. 38 881 (1974) (6) Journal of Cosmetics Industry VOL.9 No.2P101-107 Yasuo Asada (1985) (7) Published patent publication: Sho 58-193689 (8) Published patent publication: Sho-60-081122 (9) Published patent publication: Sho 60-126218 (10) Published patent publication: Sho 60-146829 (11) Published patent publication: Sho 60-028925 (12) Published patent publication: Sho 60-064910 ( 13) Published patent gazette: Sho 60-142908 "Problems to be solved by the invention" The present invention aims to contribute to the fields of use for pharmaceuticals, quasi-drugs, and cosmetics as described above. Ts
-Development of substances that can be red inhibitors.

[B] Structure of the Invention The present invention is a Ts-red inhibitor containing eugenol.

“Means for Solving Problems” The present inventors have conducted research and development on eugenol-containing extracts and isolated components for effective utilization of animal- and plant-derived components, and as shown below, effective We have succeeded in developing a Ts-red inhibitor.

"Experimental Example 1" Testosterone 5α-reductase extracted from the liver of an SD male rat (7 weeks old) was used and measured under the conditions of the following reaction system.

(Reaction system) 3.0 μM of testosterone was dissolved in 10 drops of propylene glycol, 5 ml of Tris-HC1 buffer solution (pH 7.2) was added, and then 5 mg of NADPH and 1 ml of testosterone 5α-reductase solution were sequentially added, and the mixture was kept at 37 ° C for 30 minutes. React. After the reaction,
Dichloromethane is added to stop the reaction, and the whole is extracted with 50 ml of dichloromethane to obtain a dichloromethane layer. Next, dichloromethane is distilled off under reduced pressure, and the reaction amount is measured by gas chromatography.

The sample (the substance obtained in the example) is added to the reaction system after the testosterone is dropped. (GC: column
OV-17, column length 2m, column temperature 250 ℃, FID) (Note in Table 1) Inhibition rate: The reaction rate of the control is regarded as 100% (inhibition rate 0%), and the reaction amount including the inhibitor is calculated to obtain the inhibition rate. The formula is as shown below.

a: Control (peak area of testosterone) b: Control (peak area of dehydrotestosterone and androstanediol) a ': Peak area of testosterone (inhibitor addition) b': Peak area of dehydrotestosterone and androstanediol (inhibitor Addition) In addition, dehydrotestosterone is further metabolized,
Androstanediol was also included in the calculation in the peak area (amount) of the 5α-reductase metabolite for producing androstanediol.

(Experimental Results) Based on the above-mentioned Experimental Example 1, the one showing the Ts-red inhibitory activity was screened, and the finally marked botanical herb was listed by the Japanese Pharmacopoeia: Clove (Clove) Syzygium aromatic.
This is a bud of um Merrill et perry just before flowering.

The main active substance contained in the extract obtained from the clove is eugenol, and this is Ts-red.
It was discovered that it could be an inhibitor.

Therefore, we examined cloves based on various corresponding extraction solvents. And, for example, according to the method shown in the following examples, the resulting extract, although a simple method, contains eugenol, excellent Ts
We were able to find that it could be a -red inhibitor.

"Example 1" As a method for extracting a solution that can be a Ts-red inhibitor from clove, crushed clove and then clove powder 1
30 v / v% ethanol or 5 parts of ethanol was added to each part, immersed at room temperature, filtered, and the filtrate was frozen (-20 ° C to -10 ° C) and filtered again. Then, the clove extract is used as a Ts-red inhibitor.

Furthermore, the extract obtained by using methanol, acetone, ethyl acetate or the like instead of ethanol is also Ts-red.
It can be used as an inhibitor.

[Example 2] Cloves were crushed, and 10 parts of various water-immiscible organic solvents (for example, n-hexane, benzene, chloroform, ether) were added to 1 part of clove powder, and the mixture was immersed at room temperature. After that, filtration is performed, and then the organic solvent is distilled off to obtain a clove extract (oil).

[Example 3] After crushing the clove, the clove powder is steam-distilled to obtain clove oil (essential oil) containing 70 to 85% of eugenol.

"Experimental Example 2" Clove extracts obtained by extraction with various organic solvents were subjected to gas chromatography for quantification of eugenol, and the results shown below were obtained.

(Gas chromatography measurement conditions) Column: OV-17 Column length: 2.0 m Column temperature: 120 ° C Injection temperature: 200 ° C Carrier gas: Nitrogen flow rate: 30 ml / min Detection: FID As shown in Table 2, the clove extract obtained by extraction with various organic solvents is in a state of containing eugenol although there is a slight difference depending on the extraction solvent. The extract according to the above-mentioned Example 1 can be used as a more concentrated solution.

[Example 3] Male bald males (young bald males) (male bald from the frontal region) 25-55 year old volunteers prepared the following samples and administered by topical application. During the period, the use of other hair growth agents was stopped.

(Preparation concentration of sample) Eugenol 0.1 g was dissolved in 100 ml of ethanol solution to prepare a sample.

[Results of results] The administration period was one month for 6 months, and the application period was roughly twice in the morning and the evening, and the sample was well applied and rubbed only on the hair loss site. .

The results of the results are as shown in Table 4. If we consider the results of the study, it was of course that no side effects were observed during the period.
Almost the hair growth effect is seen against the baldness of young men, but the hair growth is mainly made of downy hair. In terms of age, it was less effective against baldness after about 50 years old.

(Note in Table 4) X / Y (Z) X: Number of hair growers Y: Number of sample administrators Z: Number of downy hair (hair growers) [C] Effect of the invention The present invention is in natural products The active ingredient was sought from a wide variety of animal- and plant-derived ingredients, and eugenol contained in Clove can be used as a novel Ts-red inhibitor.

As shown in Table 1, eugenol or clove powder extract containing eugenol completely inhibited Ts-red and did not produce dihydrotestosterone. On the other hand, isoeugenol, which is an isomer of eugenol, has a slightly inhibitory action, but is not suitable for use as a Ts-red inhibitor.

Furthermore, in Table 1, it was compared with various conventionally used agents for hair nourishing agents or hair styling agents, but methyl eugenol, vanillin, phenol, pyrogallol resorcinol and squalane had almost no inhibitory effect. Rather, the results were obtained that seemed to promote the production of dihydrotestosterone.

In addition to this, as a plant-derived component (extract) containing eugenol, there are Synechumaceae (Lauraceae)
There are some of the essential oils in the bark of the tree, the trunk of the quinque tree (Camellia family), the essential oil of the bark, or parts of the Ravensala raomatica Gmel (Camellia family), called Madagascar Dinga, and of course, these extracts are also Ts- It is considered to be effective as a red inhibitor.

Claims (1)

(57) [Claims] 1. A testosterone 5α-reductase inhibitor containing eugenol.