JPS63139125A - Aromatase inhibitor - Google Patents

Abstract

PURPOSE:To obtain an inexpensive aromatase inhibitor useful for preventing and treating estrogen-dependent diseases such as mammary cancer, etc., containing a naphthoquinone compound. CONSTITUTION:A 1,4-naphthoquinone or a 1,2-naphthoquinone, a derivative thereof shown by formula I and/or formula II (R1 and R2 are H or OH; R3 is H or 1-6C hydrocarbon chain) as an active ingredient is blended with a carrier, excipient, etc., and pharmaceutically manufactured by a conventional procedure to give the aimed substance. The inhibitor can be administrated by various methods such as oral, hypodermic, intramuscular, percutaneous or rectal administration. The blend can be pharmaceutically manufactured in such a way that the active ingredient is released rapidly, continuously or in a delayed way.

Description

[Detailed description of the invention] (Industrial application field) The present invention relates to aromatase inhibitors.

More specifically, the present invention relates to naphthoquinone compounds for inhibiting aromatase or for treating or preventing estrogen-dependent diseases.

(Prior Art) Estrogens are synthesized from androgenic steroids. Aromatic ring formation is an essential step in the biosynthesis process of estrogen. Therefore, it is thought that if this aromatase (aromatic ring forming enzyme) reaction could be effectively inhibited, it would be useful in the treatment of estrogen-dependent diseases. (Cancer Research (Oaneer Re5e)
arch), Ll(s).

Special Issue, 3261S, 19a2) Estrogen-dependent diseases that can be treated with aromatase inhibitors include, for example, breast cancer, endometriosis, ovarian cyst disease, benign mastopathy, and endometrial cancer. The usefulness of anti-estrogens in breast cancer treatment has been established.

Its proliferation is estradiol dependent. Therefore, it is believed that estrogen production inhibitors can halt the progression of this disease. Furthermore, benign mastopathy is a disease also called fibrous mastopathy, and is thought to be dependent on ovarian steroid hormones, and it has been suggested that antiestrogens are effective against this disease.

Polycystic ovarian disease is one of the most common causes of infertility in women. It has been pointed out that the etiology of this disease appears to be abnormal steroid metabolism, and the main therapeutic agent is the anti-estrogen clomitene. lol
One of the orally effective antifungal compounds・◎・
It was found that ketoconazole inhibits steroid synthesis in the adrenal glands through its inhibitory effect on cholesterol biosynthesis. And recently, it has been shown that ketoconazole's action on aromatase, or that this compound is an inhibitor of estrogen synthesis (Biochemical Pharmacology, (BiochemicatPhar)
macotogy) 34. 1087. (198
5)).

(Object of the Invention) An object of the present invention is to provide an aromatase inhibitor that is inexpensive and inhibits estrogen synthesis in a smaller amount.

(Structure of the Invention) As a result of intensive studies aimed at achieving the above object, the inventors discovered that naphthoquinone compounds are effective as inhibitors for estrogen synthesis, leading to the completion of the present invention.

The present invention will be explained in detail below.

The naphthoquinone compound in the present invention is 1,4-naphthoquinone and its derivatives represented by the following general formula (1) (It).

1.2-naphthoquinone. Among the substituents represented by R3, the substituted or unsubstituted hydrocarbon chain having a straight chain or branched chain having 1 to 6 carbon atoms includes a methyl group, (C
H crystal c-cnaH, an(on)- group is preferred.

Examples of such compounds include 1,4-naphthoquinone, 1,2-naphthoquinone, 5-hydroxy-1,4-naphthoquinone, 5-hydroxy-2-methyl-1,4-naphthoquinone, 5,8-dihydroxy Examples include -1,4-naphthoquinone and shikonin. Preferably 1,4-naphthoquinone.

These are 1.2-naphthoquinone, 5-hydroxy-1,4-naphthoquinone, and 5-hydroxy-2-methyl-1,4-naphthoquinone.

Note that all of these compounds are known compounds.

The compounds of the present invention have human aromatase inhibitory activity and are therefore effective in preventing or treating estrogen-dependent diseases such as human breast cancer. Various administration methods are available, including oral, subcutaneous, intramuscular, intravenous, transdermal, and transrectal administration.

The compounds of the present invention are generally used in the form of pharmaceutical compositions.

These compositions are prepared by methods well known to the pharmaceutical arts and contain at least one compound of the above general formula. Such pharmaceutical compositions contain the active ingredient, a compound of the general formula above, and a pharmaceutically acceptable carrier.

For preparing the compositions, the active ingredient is usually mixed with a carrier or enclosed within a carrier in the form of a container, such as a capsule, sachet, or the like.

When the carrier is a diluent, it is a solid, semi-solid or liquid material that acts as an excipient, excipient or medium for the active substance. For example, the compositions of the invention may be tablets, pills, powders, sachets, emulsions, solutions, ointments,
The dosage forms may include capsules, herbal medicines, sterile injectable solutions, and sterile packaged powders. Suitable carriers, excipients or diluents include, for example, lactose, sorbitol, mannitol,
Dextrose, calcium phosphate, alginate.

Calcium silicate, cellulose, gelatin, magnesium stearate, water and mineral oil can be mentioned. Furthermore, emulsifiers, suspending agents, preservatives, sweeteners, flavors, and the like may be added to the pharmaceutical preparations of the present invention.

The compositions of the invention can be formulated to release the active ingredient rapidly, sustainedly, or delayed after administration to a patient using methods well known to those skilled in the art. For the purpose of oral administration, the compounds of this invention can be mixed with carriers and diluents and made into tablets or gelatin capsules. Alternatively, the mixture may be dissolved in a liquid such as aqueous 10-dextrose solution, isotonic saline, and sterile water and administered intravenously or injected. This solution may be lyophilized and stored in sterile ampoules so that it can be reconstituted into an injection solution for intramuscular injection by adding sterile water at the time of use.

(Effects of the Invention) As described above, the present inventors have discovered that naphthoquinone and its derivatives inhibit the reaction from androgen to estrogen catalyzed by aromatase. The compounds of the present invention are cheaper than conventionally known aromatase inhibitors and exhibit effective medicinal efficacy in small doses, so they can be used to treat estrogen-induced tumors such as endometrial cancer and breast cancer. This is expected, and its industrial value is high.

(Examples) Hereinafter, the present invention will be explained in more detail using Examples, but the present invention is not limited only to these Examples.

Examples 1 to 6 As inhibitors, 1,4-naphthoquinone, 1,2-naphthoquinone, 5-hydroxy-1,4-naphthoquinone, 5-
Hydroxy-2-methyl-1,4-naphthoquinone, -8
-Dihydroxy-1,4-naphthoquinone and shikonin were used to evaluate the inhibitory activity of these substances by I, , Tan, N, and Mu.
A method using human placental microsomes (European Journal Opbiochemistry (Eur.
open Journal ofBiochemls
try), 156. 243 (1986)).

First, aromatase was obtained by isolating a microsomal fraction from a human placenta obtained from a normal parturient.

As a substrate, a mixture of radioactive [1β,2β-3H]-androstenedione and non-radioactive androstenedione was used. This substrate is converted to estrone by the action of aromatase, and at the same time 'H and O are liberated.

Next, these aromatase, substrate, and inhibitor dissolved in ethanol were mixed and reacted.

The reaction temperature was 37°C and the reaction time was 10 minutes.

The total volume of the reaction solution was α5, and the aromatase concentration was 1 r.
n9/,/, substrate concentration is 10 pmoLμ (40000
cpm), the inhibitor dissolved in ethanol was added to the reaction solution with α5 to give a final concentration of 0.01 to 100 μmOL/l.
Added votchi.

After adding 20 μm of activated carbon to the reaction solution to adsorb and remove the steroid (rxn÷π), liberated 3H20 was measured using a liquid scintillation spectrometer.

In addition, for comparison, only ethanol was added to the reaction solution without containing an inhibitor at an amount of El 5 vot%, and free 'H, O was measured in the same manner.

The effect of each inhibitor was determined by adjusting the final concentration in the reaction solution to 100 μmol.
Table 1 shows the inhibition rate in L/l. In addition,
Inhibition rate (@ was determined by the following formula.

-B Inhibition rate (%)--x 1o.

However, A: Measured value when no inhibitor is added B: Measured value when an inhibitor is added Comparative Example 1 Inhibitory activity when 2-hydroxy-1,4-naphthoquinone is used as an inhibitor Example 1 Table 1 shows the results measured using the same method.

Note that the final concentration of the inhibitor in the reaction solution was 100 μmoνt.

Table 1

Claims (1)

[Claims] (1) The following general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and/or ▲ Mathematical formulas,
Chemical formulas, tables, etc. are available▼ [However, R_1 and R_2 each independently represent a hydrogen atom or a hydroxyl group. R_3 represents a hydrogen atom or a substituted or unsubstituted hydrocarbon chain having a linear or branched chain having 1 to 6 carbon atoms. ] Aromatase inhibitor consisting of.