JPH05194204A - Anti-male sex hormone preparation - Google Patents

Abstract

PURPOSE:To provide an anti-male sex hormone preparation of high safety, having no hormone-like activity, containing a rosewood extract or a neoflavone compound. CONSTITUTION:The objective anti-male sex hormone preparation containing a rosewood extract or a compound of formula I (R1 and R2 are each H, OH or methoxy) (e.g. latifoline). This compound, which has no hormone-like activity but has high anti-male sex hormone activity, is useful for the prevention and therapies of various diseases involving male sex hormone, therefore, can be used in wide applications such as medicines and cosmetics.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an antiandrogen agent using a rosewood extract or a neoflavone compound.

[0002]

2. Description of the Related Art In the skin, sebum is necessary for preventing the evaporation of water and keeping the skin smooth, and also has the role of preventing foreign substances from entering the body. Also, sebum is necessary for the scalp to maintain the beauty of hair.

However, if the secretion is excessive, it becomes sticky and easily soiled, and pathogenic bacteria are easily propagated. Seborrhea, acne, dandruff and itching on the scalp, and male pattern baldness are all due to increased sebum secretion.

[0004] It is considered that the increase in sebum secretion is caused by the hyperactivity of male hormones. In addition to this, from the past,
Hypertension, acne, seborrhea, benign prostatic hyperplasia, prostate tumor and the like are known as diseases in which male hormones are involved, and all are considered to be caused by excessive activity of male hormones. In particular, various studies have revealed that 5α-dihydrotestosterone (DHT), which is a metabolite of testosterone, causes disease. Various antiandrogens have been used for the treatment of these diseases, and their action inhibits, for example, the activity of 5α-reductase that reduces testosterone to highly bioactive DHT in the target organ, or This is due to inhibition of the binding between the produced DHT and the receptor in the target cell.

However, these antiandrogens, such as cyproterone acetate, oxendron,
Although chlormadinone acetate and the like are steroid hormone derivatives, the effects are recognized, but because of unfavorable side effects such as hormone action and safety problems, especially sebum secretion suppression, prevention and treatment of acne, dandruff on the scalp,
It is not suitable for blending into long-term products such as cosmetics which are effective in preventing itching and hair loss.

[0006]

DISCLOSURE OF THE INVENTION The present invention provides a highly safe anti-androgen agent having no hormone-like action.

[0007]

The anti-androgen agent of the present invention is characterized by containing a rosewood extract or at least one of the neoflavone compounds represented by the following chemical formulas 3 and 4.

[0008]

[Chemical 3] (R ₁ , R ₂ : hydrogen atom, hydroxyl group or methoxyl group)

[0009]

[Chemical 4] _{(R 3, R 4, R} 5, R 6: a hydrogen atom, a hydroxyl group or methoxyl group)

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The neoflavone compound of the present invention, which can be organically synthesized, is of the genus Dalbergia (Dalb).
ergia sp. ) The plant can be extracted and isolated. Dalbergia latifolia (Dalbergia latifolia) among plants of the genus Dalbergia
And Dalbergia Kokinkinensis (Dalber
Gia cochinchinensis) is a leguminous woody plant commonly called rosewood.

This extraction can be carried out by using water, a hydrophilic organic solvent, a water-containing hydrophilic organic solvent, other organic solvent, and the like. Particularly, lower alcohols such as methanol and ethanol, water-containing methanol, water-containing ethanol, Extraction using propylene glycol or the like is desirable.

Since the rosewood extract and the neoflavone compound of the present invention have excellent anti-androgen action and high safety, anti-androgen agents containing them are caused by excessive activity of androgen. It can be used safely and effectively for the treatment of various conceivable diseases, such as androgenetic alopecia, acne, and benign prostatic hyperplasia, and can also be used as a cosmetic for acne prevention and hair. You can also

The anti-androgenic agent of the present invention may contain, as the above-mentioned neoflavone compound, those obtained by synthesis or those isolated from plants containing these, but plants such as rosewood containing these. The above-mentioned neoflavone compound may be contained as an active ingredient by blending the extract as it is.

The dosage form of the anti-androgen of the present invention can be an internal preparation such as tablets, capsules, powders, oral solutions, fine granules and granules, and liniments, sprays and lotions. It can also be used as an external skin agent such as an agent or an ointment.

[0015]

INDUSTRIAL APPLICABILITY The rosewood extract and the neoflavone compound of the present invention have no hormone-like action and have high antiandrogen activity, and are useful for the prevention and treatment of various diseases involving androgen. It is used in a wide range of applications such as medicines and cosmetics.

[0016]

【Example】

Example 1 Dalbergia latifolia
atifolia) 2 kg are crushed and chloroform 10
After addition of liter, the mixture was stirred for 6 hours and filtered, 10 liters of chloroform was added to the residue, and the mixture was further stirred for 6 hours.
Then, the obtained extracts were combined and chloroform was removed under reduced pressure to obtain a crude extract (citrus extract) 148.
0 g was obtained.

Next, 20 g of the obtained extract was subjected to column chromatography using silica gel C-200 (500 g), developed with benzene, and the eluate was evaporated under reduced pressure to remove each fraction. By recrystallization, 0.89 g of yellow needle crystals (compound a) and white crystals (compound b) 1.
63 g are obtained. The structural formula and physical properties of the obtained compound are as follows.

Compound a Chemical name: 4-methoxydarbergion Structural formula: Chemical formula 5

[0019]

[Chemical 5]

Melting point: 114 to 116 ° C. (recrystallized with methanol) Elemental analysis (%): C H O theoretical value 75.59 5.51 18.90 measured value 74.93 5.61 19.46

Mass spectrum (m / z): 254 (maximum) UV absorption spectrum (ethanol): λmax = 20
1nm, 260nm

Infrared absorption spectrum (KBr tablet method):
As in Figure 1. Absorption peak, 3050 cm ^-1 , 1630c
m ^-1 , 1,600 cm ^-1

¹ HNMR (CDCl ₃ ): 3.81 (3
H, s), 4.93 (1H, dddd, J = 6.0,
1.5, 1.0, 1.0 Hz), 5.00 (1H, dd
d, J = 17.0, 1.5, 1.5 Hz), 5.27
(1H, ddd, J = 10.0, 1.5, 1.0H
z), 5.91 (1H, s), 6.10 (1H, dd
d, J = 17.0, 10.0, 6.0 Hz), 6.48
(1H, d, J = 1.0 Hz), 7.16 to 7.34
(5H, m)

In the infrared absorption spectrum, 3050
cm ^-1 is vinyl group, 1650 cm ^-1 is carbonyl group, 1
It shows an ether bond absorption at 600 cm ^-1 , and has a maximum absorption at 201 nm in the ultraviolet absorption spectrum. In the proton nuclear magnetic resonance spectrum, 7.16-
The signal of the phenyl group at 7.34 (5H, m), and 6.
At 48 (d, J = 1.0 Hz), 5.91 (1H, s), an olephinic proton signal of the disubstituted benzoquinone and at 3.81 (3H, s) a methoxyl proton signal was observed. .. In addition, 5.00 (ddd, J
= 17.0, 1.5, 1.5 Hz), 5.27 (dd
d, J = 10.0, 1.5, 1.0 Hz), 6.10
(Ddd, J = 17.0, 10.0, 6.0 Hz),
4.93 (dddd, J = 6.0, 1.5, 1.0,
A signal derived from the> CH—CH═CH ₂ group was observed at 1.0 Hz). Further, in mass spectrometry, m / z =
This substance was identified as the above-mentioned 4-methoxydarbegion based on the data such as the molecular ion peak at 254 and the carbon nuclear magnetic resonance spectrum.

Compound b Chemical name: Latiforin Structural formula: Chemical formula 6

[0026]

[Chemical 6]

Melting point: 122 to 123 ° C. (recrystallized from benzene) Elemental analysis (%): C H O theoretical value 71.32 6.29 22.39 measured value 71.35 6.41 22.24

Mass spectrum (m / z): 286 (maximum) UV absorption spectrum (ethanol): λmax = 20
2 nm

Infrared absorption spectrum (KBr tablet method):
As shown in FIG. Absorption peak, 3370 cm ^-1 , 2950c
m ^-1 , 1,600 cm ^-1

¹ HNMR (CDCl ₃ ): 3.84 (3
H, s), 3.86 (3H, s), 5.05 (1H, d
dd, J = 17.0, 1.5, 1.5 Hz), 5.20
(1H, ddd, J = 6.0, 1.5, 1.5Hz),
5.26 (1H, brs), 5.27 (1H, ddd,
J = 9.0, 1.5, 1.5 Hz), 6.04 (1H,
brs), 6.33 (1H, ddd, J = 17.0,
9.0, 6.0 Hz), 6.52 (1 H, s), 6.7
6 (1H, s), 6.82 (1H, dd, J = 8.0,
1.5 Hz), 6.88 (1H, ddd, J = 8.0,
8.0, 1.5 Hz), 7.11 (1H, ddd, J =
8.0, 8.0, 1.5Hz), 7.18 (1H, d
d, J = 8.0, 1.5 Hz)

In the infrared absorption spectrum, 3370
phenolic hydroxyl groups in cm ^-1, vinyl group 2950 cm ^-1, an absorption of an ether bond to 1600 cm ^-1, having a maximum absorption in 202nm ultraviolet absorption spectrum.
In the proton nuclear magnetic resonance spectrum, the signal derived from the aromatic ring was 6.76 (1H, s),
Signal of aromatic proton of 4-substituted benzene at 6.52 (1H, s), 6.82 (dd, J = 8.
0, 1.5 Hz), 6.88 (ddd, J = 8.0,
8.0, 1.5 Hz), 7.11 (ddd, J = 8.
0, 8.0, 1.5 Hz), 7.18 (dd, J = 8.
Signal of aromatic proton of 2-substituted benzene at 0,1.5 Hz, 3.86 (3H, s), 3.84
Two proton signals of the methoxyl group were observed at (3H, s). Also, 5.27 (ddd, J = 9.0,
1.5, 1.5 Hz), 5.05 (ddd, J = 17.
0, 1.5, 1.5 Hz), 6.33 (ddd, J = 1)
7.0, 9.0, 6.0 Hz, 5.20 (ddd, J
= 6.0, 1.5, 1.5 Hz)> CH-CH = CH
A proton signal derived from _two groups was observed. Furthermore, this substance was identified as the above-mentioned latiforin based on data such as a molecular ion peak at m / z = 286 in mass spectrometry and carbon nuclear magnetic resonance spectrum.

Test Example 1 5α-reductase activity inhibitory effect (1) Preparation of 5α-reductase solution Wistar male rats sacrificed by cervical dislocation (1
2 weeks old) prostate is removed, 50 mM Tris-HCl buffer (pH 7.4), 1.5 mM ethylenediaminetetraacetic acid,
After homogenization with a 5 volume (w / v) solution containing 1 mM dithiothreitol, 10 mM sodium molybdate and 10% (w / v) glycerol, 700
The supernatant obtained by centrifuging for 10 minutes at 4 ° C. was used as an enzyme solution.

(2) Measurement of 5α-reductase inhibitory activity [ ³ H] testosterone (2 μCi) 10 μl, 3.3
150 μl of mM NADPH (nicotinamide adenine dinucleotide phosphate reduction type) solution, 100 μl of sample samples of various concentrations and 250 μl of the enzyme solution obtained in (1) were added and shaken at 37 ° C. Then, 2 ml of a mixed solution of chloroform / methanol (2/1) was added to stop the reaction, and 700 ° C ×
The extract was separated by centrifugation at 10 g for 10 minutes. The peak area of testosterone and its metabolites (DHT, androstanediol) of this extract is measured with a thin layer chromatographic scanner, and the inhibition rate is calculated from the following equation 1.

[0034]

[Equation 1] The results are shown in Table 1.

[0035]

[Table 1]

Test Example 2: Effect of Inhibiting Androgen Receptor Binding to DHT This test is carried out by the method of Takayasu et al. (J. Steroy).
d Biochem. , Vol. 19, pll41-1
146, 1983).

(1) Preparation of Androgen Receptor Solution Wistar male rats (12 weeks old) were castrated to give 24
After a lapse of time, the prostate was removed, and 50 mM Tris-HCl buffer (pH 7.4), 1.5 mM ethylenediaminetetraacetic acid,
After homogenizing with a 4-fold (w / v) solution containing 1 mM dithiothreitol, 10 mM sodium molybdate and 10% (w / v) glycerol, 700
The resulting supernatant was collected by centrifugation at × g for 10 minutes at 4 ° C. This supernatant was further centrifuged at 105,000 × g at 4 ° C. for 1 hour to obtain a supernatant, which was used as an androgen receptor solution.

(2) Measurement of Androgen Receptor Binding Inhibitory Activity 1 nM [ ³ H] DHT (100 Ci / mmol) and 40
Add 4 nl of a mixed solution of 0 nM-DHT, the receptor solution according to the above item (1) and a specimen sample of various concentrations (total volume 250 μl).
After incubating at 16 ° C. for 16 hours, 5% (w / v) activated carbon and 0.5% (w / v) dextran (molecular weight 6
250 μl of a solution containing 0000 to 90,000) was added and centrifuged at 4 ° C. for 10 minutes to obtain a supernatant. This supernatant 2
After taking 00 μl and mixing with liquid scintillation cocktail, the specific binding amount of [ ³ H] DHT to the receptor was measured using a liquid scintillation counter.
Find the inhibition rate more.

[0039]

[Equation 2] B CONT: Receptor and [ ³ H] when sample is not added
Specific binding amount of DHT B SAMPLE: Receptor and [ ³ H] when sample is added
Table 2 shows the results of the specific binding amount of DHT.

[0040]

[Table 2]

As is clear from Tables 1 and 2, a high anti-androgen effect was observed for the crude extract (citrus extract), the compounds a and b of the present invention.

[Brief description of drawings]

FIG. 1 I of 4-methoxydalbergione (compound a)
It is an R spectrum.

FIG. 2 is an IR spectrum of latiforin (Compound b).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location C07C 43/23 C 8619-4H 50/30 9049-4H

Claims (2)

[Claims] 1. An anti-androgen agent containing an extract of rosewood extract. 2. An antiandrogenic agent comprising a neoflavone compound represented by Chemical formula 1 and / or a neoflavone compound represented by Chemical formula 2. [Chemical 1] (R ₁ and R ₂ : hydrogen atom, hydroxyl group or methoxyl group) _{(R 3, R 4, R} 5, R 6: a hydrogen atom, a hydroxyl group or methoxyl group)