JPH09301856A - Estrogen agonist - Google Patents

Abstract

(57) [Summary] (Modified) [PROBLEMS] To provide a phytoestrogen agonist having an excellent estrogen-like action and reducing side effects of conventional estrogen agonists. SOLUTION: The following formula (I) A pharmaceutical and food additive exhibiting estrogen-like activity, which comprises a compound represented by the formula (wherein R represents a hydrogen atom or an acyl group) or a salt thereof as an active ingredient.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a drug and a food additive that exert an estrogen effect by specifically binding to an estrogen receptor.

[0002]

2. Description of the Related Art Estrogen is a kind of female hormone, and is a general term for hormones having an estrus effect and substances having a similar effect. Estradiol is the major naturally occurring steroidal estrogen, but other steroidal estrogens such as estrone, estriol, ericin, homoestrone and ethinyl estradiol are known.
Further, as non-steroidal estrogen, for example, diethylstilbestrol, hexestrol and the like are known.

Among these estrogen agonists, steroidal estrogens are used as a drug for indications such as amenorrhea, anovulatory cycle, functional uterine bleeding, and uterine dysgenesis due to a decrease in estrogen. It is also used for the treatment of menopausal disorders and the suppression of lactation. In addition, nonsteroidal estrogens are mainly used as therapeutic agents for diseases such as prostate cancer and benign prostatic hyperplasia.

On the other hand, it is known that plants also contain estrogen acting substances, which are collectively called phytoestrogens. As such phytoestrogens, it has been reported that isoflavones such as genistein, daidzein and myloestrol exhibit relatively strong estrogenic activity (Chiharu Umehara, Takeo Sato, steroid hormones, clinical physiology of pharmaceuticals). , Estrogen, published by Nankodo, 1966). More recently, daily intake of plants containing these phytoestrogens has led to
It has been pointed out that it may contribute to a decrease in the expression of diseases such as osteoporosis and gynecological diseases, breast cancer, uterine cancer, prostate cancer, and benign prostatic hyperplasia, and further to a decrease in blood cholesterol level.

More recently, among the metabolites of certain microorganisms, 5,7-dihydroxy-2- (4-hydroxyphenyl) -3-methylchroman-4-one has been isolated and found to be estrogenic. It has been reported to have activity (JP-A-2-218678 and JP-A-2-3).
No. 00181).

[0006]

All the currently used estrogen agonists have a problem that they have side effects such as gastrointestinal disorders, thrombosis, uterine bleeding, and liver disorders.
It is known that uterine cancer, breast cancer, etc. may develop after long-term administration. Therefore, estrogen agonists with reduced side effects are desired.

An object of the present invention is to provide a phytoestrogen agonist having excellent estrogen-like activity and reduced side effects of conventional estrogen agonists.

[0008]

[Means for Solving the Problems] In order to solve the above problems, the present inventors searched for substances that antagonize estradiol in the binding of estradiol to the estrogen receptor from plant components. As a result, they have found that the compound of the following formula (I) has a strong estrogen-like activity.

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

[0010]

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An estrogen agonist which comprises a compound represented by the formula (wherein R represents a hydrogen atom or an acyl group) or a salt thereof as an active ingredient.

The chemical name of the compound of formula (I) in which R is hydrogen is 1,3-bis (4-hydroxyphenyl)-
It is 1,4-pentadiene (Hinokiresinol), and its trans form and cis form are known, but conventionally, it was known only to have c-AMP phosphodiesterase inhibitory activity (Planta medica, 43 , 18-23 ( 1981)). Either can be used for the purpose of the present invention.

Examples of the acyl group include an alkanoyl group such as acetyl and an aroyl group such as benzoyl.

The compound of formula (I) of the present invention may optionally be converted into a salt, preferably a pharmacologically acceptable salt.
Examples of such salts include metal salts such as alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, organic amine salts such as monomethylamine and triethylamine. Can be mentioned. In addition, hydrates of the compounds in free or salt form can be used.

The compound of the above formula (I) can be easily isolated and purified in a good yield from a naturally occurring plant material such as a trunk, root or leaf of a plant by a known method, or a known method. Thus, it can be easily synthesized in good yield.
For example, the trans form is Hirose, Y. et al., Tet. Lett.,
1965, 3665-3668 by the method described in cypress (Chamae
cyparis obtusa) heartwood can be extracted and isolated and purified. In addition, the cis form is Marini-Bettolo, GB et al., T
It can be extracted, isolated and purified from plants (Hypoxis nyasica) by the method described in etrahedoron, (1985), 41, 665-670. Alternatively, both trans and cis forms are Beracierta,
AP et al., Tet. Lett., (1976), 2367; Ameer, F., et
It can also be synthesized by the method described in al J. Chem. Soc. Perkin Trans. I (1988), 1425.

The compound of the above formula (I) exerts an estrogenic effect by specifically binding to the estrogen receptor.

The estrogen agonist of the present invention is used, for example, as a therapeutic or prophylactic agent for amenorrhea, anovulatory cycle, functional uterine bleeding, uterine dysgenesis, etc. due to a decrease in estrogen. It can also be used as a therapeutic or prophylactic agent for menopausal disorders or osteoporosis, or as a milk secretion inhibitor. Further, it can be used as a therapeutic or prophylactic agent for prostate cancer, prostatic hypertrophy, etc.

Further, the food additive fortified with the estrogen agonist of the present invention can be used as a food additive for promoting the health of humans with symptoms associated with menopause or hypercholesterolemia.

The dosage form of the medicament of the present invention is, for example, a pharmaceutical composition suitable for oral administration such as tablets, capsules, granules, powders or syrups, or a pharmaceutical composition suitable for parenteral administration such as injections. I can list things. These pharmaceutical compositions include excipients (eg lactose, mannitol, corn starch, crystalline cellulose etc.), binders (eg cellulose derivatives, gum arabic, gelatin etc.),
Used with additives such as disintegrants (eg, carboxymethyl cellulose calcium), lubricants (eg, talc, magnesium stearate, etc.), stabilizers, flavoring agents, injectable solvents (eg, water, ethanol, glycerin, etc.) It is manufactured by a known method. When the medicament of the present invention is used as a therapeutic or prophylactic agent for the above-mentioned diseases, the dose varies depending on symptoms, age, etc., but is 1 to 1,0 per day for an adult.
00 mg, preferably 5-500 mg, can be administered, and can be administered once daily or in several divided doses.

[0020]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

[Estradiol antagonistic activity] The estradiol antagonistic activity can be determined by the method described in JP-A-5-229983 and the method by Thibodeau, SN et al. (Clin. Chem. 27, 68).
7-691 (1981)) was partially modified. That is, the test was performed using the estrogen receptor (estrogen binding protein) in the cell-soluble fraction obtained by grinding bovine uterus and ultracentrifuging at 100,000 g for 1 hour.

Dilute to a final concentration of 1 nM [ ³
H] estradiol (136 Ci / mmol) solution 10 μl,
A reaction solution containing 10 μl of a sample solution containing a trans isomer or a cis isomer of the compound of the formula (I) in which R is hydrogen was mixed with the reaction solution containing 200 μl of the cell-soluble fraction, and then stored at 4 ° C. overnight. After free [ ³ H] estradiol in the reaction solution was adsorbed and removed with dextran (Dextran T70, Pharmacia) -coated activated carbon (C4386, Sigma), the amount of [ ³ H] estradiol bound to the estrogen receptor was measured by liquid scintillation. The amount of [ ³ H] estradiol bound to the estrogen receptor was determined by measuring with a counter. As a control, the amount of [ ³ H] estradiol was measured in the same manner except that a solvent containing no sample was added instead of the sample solution.

For non-specific binding measurement, a 500-fold excess of unlabeled estradiol over [ ³ H] estradiol was added in place of the sample solution, and the same measurement was carried out.

The affinity of the sample for the estrogen receptor was determined by the following formula as the inhibition rate of [ ³ H] estradiol binding to the estrogen receptor. Binding inhibition rate = 100− (a / b × 100) a: dpm with sample addition-dpm with non-specific binding d: dpm without sample-dpm with non-specific binding dpm: number of decays per minute of radioactive substance

Furthermore, the final concentration of the sample (1 nM to 10 μM)
The binding inhibition rate was plotted against the logarithmic value of
The inhibitory concentration (IC ₅₀ value) was determined.

As a result, the IC ₅₀ of the trans form and the cis form of the present invention were 0.8 μM and 0.08 μM, respectively. This indicates that the compound of the formula (I) of the present invention has an estrogen-like activity which is almost the same as that of genistein which is a phytoestrogen of the following formula to about 1/10.

[0027]

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[0028]

INDUSTRIAL APPLICABILITY The compound of formula (I) of the present invention binds strongly to the estrogen receptor and exhibits estrogen-like activity. Therefore, it can be used as an estrogen agonist, for example, as a therapeutic or prophylactic agent for gynecological diseases, osteoporosis, prostate cancer or benign prostatic hyperplasia caused by a decrease in estrogen. In addition, these compounds can be used as a food additive for promoting the health of humans with symptoms associated with menopause or hypercholesterolemia.

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Claims (5)

[Claims] (1) The following formula (I): An estrogen agonist comprising a compound represented by the formula (wherein R represents a hydrogen atom or an acyl group) or a salt thereof as an active ingredient. 2. The medicine according to claim 1, which is used for treating and preventing a disease caused by a decrease in estrogen. 3. The medicine according to claim 1, which is used for treating or preventing prostate cancer or benign prostatic hyperplasia. 4. The medicine according to claim 1, which is used for treatment and prevention of osteoporosis or gynecological diseases. 5. A food additive containing the estrogen agonist according to claim 1.