KR20020030497A - Osthenol derivatives and composition for inhibiting 5-alpha reductase type ii comprising same - Google Patents

Abstract

PURPOSE: An ostenol derivative and a 5 alpha-reductase type II inhibiting composition containing it are provided, thereby effectively inhibiting the activity of 5 alpha-reductase type II and consequently treating the prostate disease. CONSTITUTION: The ostenol derivative inhibiting the activity of 5 alpha-reductase type 2 is represented by formula(1), in which R1 is hydrogen, unsubstituted or mono or multi substituted C1 to C5 alkyl, C2 to C6 alkenyl or C2 to C6 alkynyl; C1 to C7 alkylcarbonyl; benzyl; or C3 to C7 allylcarbonyl or C3 to C7 allylcarbamyl; R2 is hydrogen; or unsubstituted or hydroxy or C1 to C5 alkyl-OCO substituted C2 to C5 alkyl or C2 to C6 alkenyl; or OR1 and R2 are together unsubstituted or substituted oxygen containing 5 or 6 member hetero ring, provided that R1 and R2 are not hydrogen at the same time.

Description

OSTHENOL DERIVATIVES AND COMPOSITION FOR INHIBITING 5-ALPHA REDUCTASE TYPE II COMPRISING SAME

The present invention relates to austenol derivatives and pharmacologically acceptable salts thereof, 5α-reductase type II inhibitory compositions comprising the same, and pharmaceutical compositions useful for the prophylaxis or treatment of prostate diseases comprising the same.

Prostate diseases such as prostate hyperplasia and prostate cancer have been rapidly increasing worldwide in recent years as human life progresses gradually with the development of modern medicine. Prostatic hyperplasia is usually age-related and there are several causes of prostate cancer, one of which has been reported to be associated with androgen hormones. However, the development of prophylactic agents is more suitable than the development of therapeutic agents or treatment methods in that there is a lack of search data for the disease and have a long incubation period.

Sufficient amount of testosterone is absolutely required for the development and growth of the prostate gland (Cheng E. et al ., J. Endocrinology of the prostate.In : Lepor, H., Lawson, RK, editors.Prostate diseases. Philadelphia: Sanuders, 1993: 57-71). In most animal models of prostate cancer, the supply of androgen given externally is essential, and androgens are known to play an important role in the production of prostate cancer (Pollard M. et al . , Cancer Lett. 1989, 45: 209). -212 and Shirai T. et al ., Jpn. J. Cancer Res. 1995, 86: 645-648. 98% of the total testosterone produced is in the form of protein binding, and about 2% of the total amount of free testosterone is circulated through the blood. High concentrations of this free testosterone have been reported to increase the incidence of prostate cancer (Ross R. et al ., J. Nat'l. Cancer Inst. 1986, 76: 45-48) and Ellis. L.) and Nyborg, H. ( Steroids 1992, 57: 72-75). Therefore, one of the ways to treat prostate cancer is to remove androgens. Reducing the levels of androgens affects the inhibition of prostate cancer production, but side effects such as weakening male sexual function.

Testosterone is diffused into the prostate and converted to dihydrotestosterone (DHT) by an enzyme called 5α-reductase present in the prostate gland (Bruchovsky, N.) and Wilson, JD., J. Biol. Chem. 1968, 219: 277-279). DHT produced by this 5α-reductase binds to androgen receptors, enters the nucleus and acts as a transcription factor, which plays a larger role than testosterone in promoting growth and differentiation of the prostate and maintaining homeostasis and function. (See J. Endocrinology of the prostate. In: Lepor, H., Lawson, RK, editors. Prostate diseases. Philadelphia: Sanuders, 1993: 57-71). As age increases, male hormone testosterone is converted to DHT by 5α-reductase, which promotes the growth and differentiation of the prostate gland, resulting in prostate cancer, prostatic hypertrophy, difficulty urinating, weakness, frequent urination, and nocturia. It causes a variety of symptoms. 5α-reductase is classified into two isoforms of type I and type II, respectively. The type II of the two types is examined by examining the optimum pH and the reactivity against the homogenous layer of the adult prostate. It has been shown to be associated with the prostate gland, and this activity of type 5α-reductase type II has been shown to play an important role in the growth of the prostate and vulva (Andersson S. et al., Nature. 354: 150-161, 1991 and Proc. Nat'l. Acad. Sci. USA. 87: 3640-3644, 1990, Hisch KS et al., Proc. Nat'l. Acad., USA, 90: 5277- 5281, 1993 and Jenkins EP et al., J. Clin Invest. 89: 293-300, 1992).

In addition, the high incidence of prostate cancer also showed high activity of 5α-reductase (Wu AH et al ., Cancer Epidemiol. Biomarkers Prev. 1995, 4: 735-741) and Lookingbillbill (Lookingbill DP). Et al., J. Clin. Endocrinol. Metab., 1991, 72: 1242-1248), and prostate cancer patients have been shown to have a high rate of conversion of testosterone to DHT (Meikle AW et al. Prostate 1987, 10: 25-31). Therefore, various 5α-reductase inhibitors have been synthesized for the purpose of treating prostate cancer and enlarged prostate.

In particular, Merck's finasteride, the only US FDA approved to date, has been reported to lower the level of DHT in the prostate and have little effect on serum testosterone levels or sexual function ( Gormley GJ et al ., N. Engl. J. MEd. 1992, 327: 1185-1191. Finasteride-based Proscar® is already available as a prostate hypertrophy and based on these reports, many researchers have found that 5α-reductase inhibitors can be used to prevent prostate cancer. We are conducting research by synthesizing materials.

Synthesized 5α-reductase inhibitor, SK & F 105657, reported lowering prostate DHT levels to castrated levels when administered orally at 25 mg / kg (see Lamb JC et al., Prostate 1992, 21: 15-34). And 5α-reductase inhibitor FK 143 synthesized by Fujisawa Pharmaceutical Co., Ltd., Japan, have been reported to reduce the production of prostate cancer as a result of mixing for 60 weeks at a concentration of 20 ppm (Homma Y. et al. See J. Nat'l. Cancer Inst. 1997, 89: 803-807. PNU 157706, a 5α-reductase inhibitor, inhibited prostate cancer by 53% (2 mg / kg / day), 51% (10 mg / kg / day), and when castration reduced the concentration of DHT in the prostate by 95%, Treatment with PNU 157706 reduced 85-91%, demonstrating that 5α-reductase inhibitors can be used for hormonal treatment of prostate cancer (Zaccheo T. et al., J. Steroid Biochem. Mol. Biol. 1998, 64: 3-4, 193-198. Kyowa Hakko Kogyo has synthesized indole, benzimidazole derivatives (IC ₅₀ : 9.6, 13 nM) having IC ₅₀ values similar to finasterides (Takami H. et al ., Bioorg. Chem. 1998, 6: 12, 2441-2480).

The present inventors searched for plants whose activity is expected to be useful for the treatment of prostatic hypertrophy from natural resources, and as a result, various kinds of coumarins obtained by separating and purifying extract fractions of Angelica Koreana Maxim. It was confirmed that osthenol in Coumarin) compounds strongly inhibited the activity of 5α-reductase type II, an enzyme related to prostate disease (IC ₅₀ = 0.1 µg / ml).

Therefore, the present inventors have shown that the inhibitory effect of 5α-reductase type II, an enzyme related to prostate hypertrophy, of the austenol synthetic derivatives synthesized by SAR (structure activity relationship) method using austenol as a leading substance, and prostatic hyperplasia through animal experiments The present invention has been completed by confirming prostate disease treatment effects such as inhibitory effects.

It is an object of the present invention to provide an austenol derivative having a 5α-reductase type II inhibitory effect and a pharmacologically acceptable salt thereof.

Another object of the present invention is to provide a 5α-reductase type II inhibitor composition comprising the austenol derivative or a salt thereof.

Still another object of the present invention is to provide a composition for preventing or treating prostate disease, including the austenol derivative or a salt thereof.

1 is a graph comparing dorsal prostate weights of prostatic hypertrophy-induced male rats to which various compounds according to the present invention are administered,

2 is a graph comparing testis weights of prostatic hypertrophy-induced male rats administered various compounds according to the present invention.

Figure 3 is a graph comparing the concentration of LH (luteinizing hormone) in the blood of prostatic hypertrophy-induced male rats administered various compounds according to the present invention.

The present invention provides austenol derivatives of the general formula (1) and pharmacologically acceptable salts thereof.

Formula 1

Where

R ₁ is hydrogen; Unsubstituted or mono or polysubstituted (C ₁ -C ₅ ) alkyl, (C ₂ -C ₆ ) alkenyl or (C ₂ -C ₆ ) alkynyl; (C ₁ -C ₇ ) alkylcarbonyl; benzyl; Or (C ₃ -C ₇ ) allylcarbonyl or (C ₃ -C ₇ ) allylcarbamyl,

R ₂ is hydrogen; Or (C ₂ -C ₅ ) alkyl or (C ₂ -C ₆ ) alkenyl unsubstituted or substituted with hydroxy or (C ₁ -C ₅ ) alkyl-OCO-; or

OR ₁ and R ₂ together may form an unsubstituted or substituted oxygen containing 5 or 6 membered hetero ring,

Provided that R ₁ and R ₂ are not simultaneously hydrogen.

The term "(C ₁ -C ₅₎ alkyl" means a monovalent saturated hydrocarbon radical of a linear or branched group having 1 to 5 carbon atoms and, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, Tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl and the like.

The term "(C ₂ -C ₆ ) alkenyl" means a linear or branched divalent unsaturated hydrocarbon radical having 2 to 6 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1 -Butenyl, 2-butenyl, 3-butenyl, isobutenyl, secondary-butenyl, tert-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, iso Pentenyl, tert-pentenyl, 1-heptenyl, 2-heptenyl and the like.

The term "(C ₂ -C ₆ ) alkynyl" means a linear or branched trivalent unsaturated hydrocarbon radical of 2 to 6 carbon atoms, for example ethynyl, 1-propynyl, 2-propynyl, isopropynyl, 1 -Butynyl, 2-butynyl, isobutynyl, secondary-butynyl, tert-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, isopentinyl, 1 -Hexynyl, 2-hexynyl, 3-hexynyl and the like.

The term "(C ₁ -C ₇ ) alkylcarbonyl" means (C ₁ -C ₇ ) alkyl-CO- comprising a linear or branched monovalent saturated hydrocarbon radical having 1 to 7 carbon atoms, such as methylcarbonyl , Ethylcarbonyl, propylcarbonyl, butylcarbonyl, isobutylcarbonyl, secondary-butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl, heptylcarbonyl and the like. .

The term "single or multiple substituted (C ₁ -C ₅ ) alkyl, (C ₂ -C ₆ ) alkenyl or (C ₂ -C ₆ ) alkynyl" means one or more hydroxy, halogen, (C ₁ -C ₅ ) Substituted by alkylcarbonyl or the like.

The term "(C ₃ -C ₇ ) allylcarbonyl" means (C ₃ -C ₇ ) allyl-CO- containing unsaturated hydrocarbons having 3 to 7 carbon atoms containing allyl groups, such as benzoylcarbonyl and the like.

The term "(C ₃ -C ₇ ) allyl carbamyl" means (C ₃ -C ₇ ) allyl-NHCO- containing unsaturated hydrocarbons having 3 to 7 carbon atoms containing allyl groups, such as phenylcarbamyl and the like.

The term "(C ₂ -C ₅ ) alkyl" means a linear or branched monovalent saturated hydrocarbon radical of 2 to 5 carbon atoms, for example ethyl, propyl, isopropyl, butyl, isobutyl, secondary-butyl, tertiary -Butyl, pentyl, isopentyl, neopentyl, tert-pentyl and the like.

Unsubstituted or substituted oxygen containing 5 or 6 membered hetero rings which OR ₁ and R ₂ may form together are hydroxy, hydroxy- (C ₁ -C ₅ ) alkyl or benzoyloxy- (C ₁ -C ₅ ) Tetrahydrofuran, furan, tetrahydropyran, pyran ring and the like substituted with alkyl.

Pharmacologically acceptable salts refer to conventional pharmacologically acceptable salts.

Preferred compounds in the compounds of formula 1 according to the invention are those in which R ₁ is hydrogen, (C ₁ -C ₅ ) alkylcarbonyl, (C ₃ -C ₇ ) allylcarbonyl or (C ₃ -C ₇ ) allylcarbamyl Is an austenol derivative wherein R ₂ is CH ₂ = CHCH ₂ -or (C ₂ -C ₅ ) alkyl.

Most preferred compounds in the compounds of formula 1 according to the invention are those in which R ₁ is hydrogen, CH ₃ CO, C ₆ H ₅ CO or C ₆ H ₅ NHCO, and R ₂ is CH ₂ = CHCH ₂ -or C ₃ H _7- to be.

The structures of representative compounds of the present invention are shown in Table 1 below:

The austenol derivatives of the general formula (1) of the present invention are known as starting materials of 7-hydroxycoumarin (Compound 1) (M. Loufty, Pharmazie , 1979 , 34 , 672) Murry et al., Tetrahedron , 1971 , 27 , 1247), all of which are incorporated herein by reference.

The present invention also provides a 5α-reductase type II inhibitory composition comprising an austenol derivative of Formula 1 and a pharmaceutically acceptable salt effective amount thereof, and a pharmaceutically acceptable carrier.

In another aspect, the present invention provides a composition characterized in that the prostate disease for the prevention or treatment, comprising an effective amount of the austenol derivative of Formula 1 and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Prostate diseases that can be prevented or treated by the pharmaceutical composition of the present invention include prostate cancer, prostatic hyperplasia, prostatitis, prostatic seminal inflammatory disease, prostatic vasculitis, and the like.

The pharmaceutical composition may further include conventionally used excipients, disintegrants, sweeteners, lubricants, flavoring agents, etc., tablets, capsules, powders, granules, suspensions, emulsifiers, syrups, It may be formulated in unit dosage forms or in multiple dosage pharmaceutical formulations, such as liquid or parenteral formulations.

A 5α-reductase type II inhibitory composition or a composition for preventing and treating prostate disease, comprising the effective amount of the austenol derivative of Formula 1, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, Depending on the method can be parenteral administration or oral administration, the amount of 0.01 to 10g, preferably 1 to 5g per 1kg body weight per day as an active ingredient can be administered in one to several times. Dosage levels for a particular patient may vary depending on the patient's weight, age, sex, health condition, diet, time of administration, method of administration, rate of excretion, and severity of disease.

The present invention is illustrated by the following examples, but is not limited thereto. 300 MHz ¹ H NMR was used in the following experiment, and silica gel 60 (230-400 mesh ASTM) of Merck was used as the silica gel for the column.

Example 1

Synthesis of 7-allyloxy-chromen-2-one (Compound 2)

In 6 ml of anhydrous dimethylformamide (DMF), 500 mg (3.09 mmol) of natural product umbelliferon (7-hydroxycoumarin: Compound 1; Aldrich), 1.28 g (9.27 mmol) of K ₂ CO ₃ and 513 mg (3.09) of KI mmol) and allyl bromide 544 mg (4.5 mmol) were added and heated at 80 ° C. for 2 hours. The solid was filtered using 30 ml of ethyl acetate and the organic layer was washed with water. The residue obtained by evaporation under reduced pressure was vacuum dried to yield 618 mg (yield 99%) of the title compound as a white solid.

Melting Point: 86-88 ℃

¹ H NMR (CDCl ₃ ) δ7.56 (d, J = 9.3Hz, 1H), 7.30 (d, J = 8.7Hz, 1H), 6.78 (m, 2H), 6.18 (d, J = 9.6Hz, 1H ), 5.97 (m, 1H), 5.32 (m, 2H), 4.52 (m, 2H)

Example 2

Synthesis of 7-prop-2-ynyloxy-chromen-2-one (Compound 3)

500 mg (3.09 mmol) of natural product umbelliferone (7-hydroxycoumarin: compound 1), K ₂ CO ₃ 1.28 g (9.27 mmol), KI 513 mg (3.09 mmol) and propargyl bromide (80% by weight) in 6 ml of anhydrous DMF. 0.69 ml (4.635 mmol) was added and heated at 80 ° C. for 2 hours. The solid was filtered using 30 ml of ethyl acetate and the organic layer was washed with water. The residue obtained by evaporation under reduced pressure was vacuum dried to yield 615 mg (yield 99%) of the title compound as a white solid.

Melting point: 120-122 ℃

¹ H NMR (CDCl ₃ ) δ7.65 (d, J = 9.6Hz, 1H), 7.40 (d, J = 8.4Hz, 1H), 6.92 (m, 2H), 6.28 (d, J = 9.3Hz, 1H ), 4.77 (d, J = 2.4 Hz, 2H), 2.58 (t, J = 2.4 Hz, 1H)

Example 3

Synthesis of 7- (1,1-dimethyl-prop-2-ynyloxy) -chromen-2-one (Compound 4)

In 4 ml of anhydrous DMF, 500 mg (3.09 mmol) of natural product umbelliferon (7-hydroxycoumarin: Compound 1), 828 mg (6.0 mmol) of K ₂ CO ₃ and 1.0 ml (9.0 mmol) of 3-chloro-3-methyl-1-butyne ) Was added and heated at 90 ° C. for 24 h. After filtering the solid using 50 ml of ethyl acetate, the organic layer was washed twice with 10% aqueous HCl solution (20 ml), once with water and evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluate: hexane: ethyl acetate = 2: 1). Purification of the reaction product gave 564 mg (yield 80%) of the title compound as a pale yellow solid.

Melting Point: 134-138 ℃

¹ H NMR (CDCl ₃ ) δ7.58 (d, J = 9.3Hz, 1H), 7.29 (d, J = 8.7Hz, 1H), 7.24 (d, J = 2.1Hz, 1H), 6.98 (dd, J = 2.4, 8.7 Hz, 1H), 6.20 (d, J = 9.3 Hz, 1H), 2.60 (s, 1H), 1.64 (s, 6H)

Example 4

Synthesis of 7- (1,1-dimethyl-allyloxy) -chromen-2-one (Compound 5)

500 mg (2.19 mmol) of 7- (1,1-dimethyl-prop-2-ynyloxy) -chromen-2-one (Compound 4) obtained in Example 3 was dissolved in 10 ml of ethyl acetate, and 50 mg of quinoline ( 10 wt%) and 10 mg of Lindler catalyst were added. The reaction solution was stirred at room temperature under a hydrogen balloon for 5 hours, 50 ml of ethyl acetate was added, washed 3 times with 2N HCl aqueous solution (20 ml), washed once with water and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluate: hexane: ethyl). Purification with acetate = 2: 1) gave 500 mg (yield 100%) of the title compound as a white solid.

Melting point: 80-82 ℃

¹ H NMR (CDCl ₃ ) δ7.54 (d, J = 9.6Hz, 1H), 7.23 (d, J = 8.7Hz, 1H), 6.90 (d, J = 2.4Hz, 1H), 6.79 (dd, J = 2.4, 8.7 Hz, 1H), 6.16 (d, J = 9.3 Hz, 1H), 6.04 (dd, J = 10.8, 17.7 Hz, 1H), 5.15 (m, 2H), 1.46 (s, 3H)

Example 5

Synthesis of 7- (1,1-dimethyl-propoxy) -chromen-2-one (Compound 6)

49.5 mg (4.950 mmol) of 7- (1,1-dimethyl-allyloxy) -chromen-2-one (compound 5) obtained in Example 4 was dissolved in 3 ml of ethyl acetate, and 4 mg of 10% palladium carbon was added. did. The reaction solution was stirred at room temperature under a hydrogen balloon for 4 hours, the solid was filtered, and the residue filtered under reduced pressure was purified by short silica gel column chromatography (eluent: hexane: ethyl acetate = 4: 1) to give the title compound as a colorless liquid. 48 mg (95% yield) were obtained.

¹ H NMR (CDCl ₃ ) δ7.57 (dd, J = 0.3, 9.0Hz, 1H), 7.27 (d, J = 8.4Hz, 1H), 6.88 (d, J = 2.4Hz, 1H), 6.80 (dd , J = 2.1, 8.4 Hz, 1H), 6.21 (d, J = 9.3 Hz, 1H), 1.69 (q, J = 7.2 Hz, 2H), 1.30 (s, 6H), 0.93 (t, J = 7.2 Hz , 3H)

Example 6

Synthesis of 8-allyl-7-hydroxy-chromen-2-one (Compound 7)

8.0 g of 7-allyloxy-chromen-2-one (compound 2) obtained in Example 1 and 40 ml of xylene for reagents were added to a sealed tube container, and nitrogen was passed through for 20 minutes and heated in a 260 ° C. sand bath for 24 hours. It was. After cooling to room temperature, the resulting white crystals were filtered and washed with benzene to give 5.8 g (73% yield) of the title compound. The filtrate was distilled under reduced pressure, and then purified by silica gel chromatography (eluate: hexane: ethyl acetate = 1: 1) to give 0.8 g (yield 10%) of the title compound as a pale yellow solid, and 6-allyl-7-hydroxycoumarin 0.96 as a pale yellow solid. g (yield 12%) was obtained.

Compound 7: Melting point: 164-166 ° C., ¹ H NMR (CDCl ₃ ) δ7.65 (d, J = 9.3 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 8.7 Hz, 1H), 6.26 (d, J = 9.3 Hz, 1H), 6.03 (m, 1H), 5.16 (m, 2H), 3.67 (d, J = 6.3 Hz, 2H)

6-allyl-7-hydroxycoumarin: ¹ H NMR (CDCl ₃ ) δ7.65 (d, J = 9.0 Hz, 1H), 7.23 (s, 1H), 7.02 (s, 1H), 6.25 (d, J = 9.3 Hz, 1H), 6.00 (m, 1H), 5.15 (m, 2H), 3.45 (d, J = 6.3 Hz, 2H)

Example 7

Synthesis of Acetic Acid 8-allyl-2-oxo-2H-chromen-7-yl ester (Compound 8)

0.1 ml of pyridine and 0.1 ml of acetyl chloride were added to a solution of 100 mg (0.490 mmol) of 8-allyl-7-hydroxy-chromen-2-one (Compound 7) obtained in Example 6 in 3 ml of ether and 1 ml of THF. . After stirring the reaction solution at room temperature for 16 hours, the resulting solid was filtered, 20 ml of ethyl acetate was added to the organic layer, washed three times with 10% aqueous HCl solution (10 ml), and the residue obtained by evaporation under reduced pressure was subjected to silica gel chromatography (eluate: hexane). : Ethyl acetate = 5: 1) afforded 108 mg (yield 100%) of the title compound as a pale yellow solid.

Melting point: 92-96 ℃

¹ H NMR (CDCl ₃ ) δ7.62 (d, J = 9.6Hz, 1H), 7.32 (d, J = 8.4Hz, 1H), 6.97 (d, J = 8.7Hz, 1H), 6.33 (d, J = 9.3 Hz, 1H), 5.82 (m, 1H), 5.00 (m, 2H), 3.49 (m, 2H), 2.28 (s, 3H)

Example 8

Synthesis of Benzoic Acid 8-allyl-2-oxo-2H-chromen-7-yl ester (Compound 9)

24 mg (0.195) of 4- (dimethylamino) pyridine in a solution of 13.3 mg (0.065 mmol) of 8-allyl-7-hydroxy-chromen-2-one (Compound 7) obtained in Example 6 in 1.5 ml of carbon dichloride. mmol) and 14 mg (0.098 mmol) of benzoyl chloride. After stirring the reaction solution at room temperature for 3 hours, 20 ml of carbon dichloride was added to the organic layer, washed twice with a saturated NaCl aqueous solution (10 ml), and the residue obtained by evaporation under reduced pressure was subjected to silica gel chromatography (eluate: hexane: ethyl acetate = 5). Purification by 1) yielded 15.5 mg (yield 77%) of the title compound as a white solid.

Melting Point: 118-120 ℃

¹ H NMR (CDCl ₃ ) δ8.14 (m, 2H), 7.65 (d, J = 9.6Hz, 1H), 7.59 (m, 1H), 7.47 (m, 2H), 7.36 (d, J = 8.4Hz , 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.34 (d, J = 9.6 Hz, 1H), 5.85 (m, 1H), 4.94 (m, 2H), 3.54 (m, 2H)

Example 9

Synthesis of Phenyl-carbamic acid 8-allyl-2-oxo-2H-chromen-7-yl ester (Compound 10)

0.3 ml (3.75 mmol) of pyridine and 196 mg of phenyl isocyanate in a solution of 50 mg (0.245 mmol) of 8-allyl-7-hydroxy-chromen-2-one (Compound 7) obtained in Example 6 in 2.5 ml of carbon dichloride. (1.65 mmol) was added. After stirring the reaction solution at room temperature for 2 days, the resulting solid was filtered and the residue obtained by evaporating the organic layer under reduced pressure was purified by silica gel chromatography (eluent: hexane: ethyl acetate = 3: 2) to give 59 mg of the title compound as a white solid. (Yield 75%) was obtained.

Melting point: 122-126 ℃

¹ H NMR (CDCl ₃ ) δ 7.69 (d, J = 9.6 Hz, 1H), 7.37 (m, 5H), 7.17 (m, 2H), 6.39 (d, J = 9.6 Hz, 1H), 5.92 (m , 1H), 5.03 (m, 2H), 3.60 (br, d, J = 6.3 Hz, 2H)

Example 10

Synthesis of 8-allyl-7- (1,1-dimethyl-prop-2-ynyloxy) -chromen-2-one (Compound 11)

204 mg (1.0 mmol) of 8-allyl-7-hydroxy-chromen-2-one (Compound 7) obtained in Example 6 in 4 ml of anhydrous DMF, 276 mg (2.0 mmol) of K ₂ CO ₃ and 3-chloro-3 0.5 ml (4.5 mmol) of methyl-1-butyne were added and heated at 90 ° C. for 26 hours. After filtering the solid using 30 ml of ethyl acetate, the organic layer was washed twice with 10% aqueous HCl solution (20 ml), once with water and evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluate: hexane: ethyl acetate = 5: 1). Purified with 152 mg (57% yield) of the title compound as a yellow solid.

Melting point: 88-92 ℃

¹ H NMR (CDCl ₃ ) δ7.56 (d, J = 9.6Hz, 1H), 7.51 (d, J = 8.7Hz, 1H), 7.20 (d, J = 9.0Hz, 1H), 6.20 (d, J = 9.6 Hz, 1H), 5.86 (m, 1H), 4.95 (m, 2H), 3.51 (br, d, J = 6.1 Hz, 2H), 2.58 (s, 1H), 1.66 (s, 6H)

Example 11

Synthesis of 8-allyl-7- (1,1-dimethyl-allyloxy) -chromen-2-one (Compound 12)

A solution of 50 mg (0.185 mmol) of 8-allyl-7- (1,1-dimethyl-prop-2-ynyloxy) -chromen-2-one (Compound 11) obtained in Example 10 in 3 ml of ethyl acetate To this was added 5 mg of quinoline (10 wt%) and 2 mg of Lindler catalyst. The reaction solution was stirred at room temperature under a hydrogen balloon for 5 hours, 10 ml of ethyl acetate was added, washed 3 times with 2N HCl aqueous solution (10 ml), washed once with water, and the residue obtained by evaporation under reduced pressure was purified by silica gel chromatography (eluate: hexane: ethyl). Purification with acetate = 5: 1) gave 43 mg (yield 86%) of the title compound as a yellow solid.

Melting point: 58-62 ℃

¹ H NMR (CDCl ₃ ) δ7.53 (d, J = 9.3Hz, 1H), 7.09 (d, J = 8.7Hz, 1H), 6.98 (d, J = 8.7Hz, 1H), 6.16 (d, J = 9.3 Hz, 1H), 6.08 (dd, J = 10.8, 17.7 Hz, 1H), 5.88 (m 1H), 5.15 (m, 2H), 4.96 (m, 2H), 3.53 (d, J = 6.3 Hz, 2H), 1.47 (s, 6H)

Example 12

Synthesis of 8-allyl-7-benzyloxy-chromen-2-one (Compound 13)

In 6 ml of anhydrous DMF, 100 mg (0.49 mmol) of 8-allyl-7-hydroxy-chromen-2-one (Compound 7) obtained in Example 6, 138 mg (1.0 mmol) of K ₂ CO ₃ and 0.09 ml of benzylbromide ( 0.75 mmol) was added and heated at 60 ° C. for 3 hours. The solid was filtered using 30 ml of ethyl acetate and the organic layer was washed with water. The residue obtained by evaporation under reduced pressure was purified by silica gel chromatography (eluate: hexane: ethyl acetate = 2: 1) to give 145 mg (yield 100%) of the title compound as a pale yellow solid.

Melting point: 114-117 ℃

¹ H NMR (CDCl ₃ ) δ7.55 (d, J = 9.3Hz, 1H), 7.28 (m, 5H), 7.23 (d, J = 8.7Hz, 1H), 6.82 (d, J = 8.7Hz, 1H ), 6.18 (d, J = 9.3 Hz, 1H), 5.91 (m, 1H), 5.12 (s, 2H), 4.97 (m, 2H), 3.60 (m, 2H)

Example 13

Synthesis of 8-allyl-7-methoxy-chromen-2-one (Compound 14)

To 100 mg (0.49 mmol) of 8-allyl-7-hydroxy-chromen-2-one (Compound 7) obtained in Example 6, 2 ml of 95% ethanol, 15 mg (0.75 mmol) of NaOH and 0.047 ml (1 mmol) of dimethyl sulfate Was added. After stirring the reaction solution at room temperature for 24 hours, 20 ml of carbon dichloride was added to the organic layer, washed twice with an aqueous saturated NaCl solution (10 ml), and the residue obtained by evaporation under reduced pressure was subjected to silica gel chromatography (eluate: hexane: ethyl acetate = 2 :). Purification with 1) gave 68 mg (yield 60%) of the title compound as a pale yellow solid.

Melting Point: 136-140 ℃

¹ H NMR (CDCl ₃ ) δ7.56 (d, J = 9.6Hz, 1H), 7.26 (d, J = 8.4Hz, 1H), 6.78 (d, J = 8.4Hz, 1H), 6.17 (d, J = 9.3 Hz, 1H), 5.89 (m, 1H), 4.95 (m, 2H), 3.85 (s, 3H), 3.53 (m, 2H)

Example 14

Synthesis of 8-allyl-7- (2-hydroxy-ethoxy) -chromen-2-one (Compound 15)

100 mg (0.49 mmol) of 8-allyl-7-hydroxy-chromen-2-one (Compound 7) obtained in Example 6, 0.3 g (2.17 mmol) of K ₂ CO ₃ and 0.053 ml of 2-bromoethanol ( 0.75 mmol) was added 5 ml of acetone and heated to reflux for 24 hours. After cooling to room temperature, 30 ml of ethyl acetate was added, washed twice with 10% aqueous HCl solution (30 ml) and once with water. Then, the residue obtained by evaporation under reduced pressure was purified by silica gel chromatography (eluate: hexane: ethyl acetate = 1: 2) to give 110 mg (yield 91%) of the title compound as a white solid. Melting Point: 136-138 ℃

¹ H NMR (CDCl ₃ ) δ7.57 (d, J = 9.3Hz, 1H), 7.27 (d, J = 8.4Hz, 1H), 6.78 (d, J = 8.7Hz, 1H), 6.19 (d, J = 9.3 Hz, 1H), 5.92 (m, 1H), 4.96 (m, 2H), 4.12 (m, 2H), 3.92 (m, 2H), 3.57 (m, 2H)

Example 15

Synthesis of 8-allyl-7- (2-oxo-propoxy) -chromen-2-one (Compound 16)

200 mg (0.97 mmol) of 8-allyl-7-hydroxy-chromen-2-one (compound 7) obtained in Example 6, 0.3 g (2.17 mmol) of K ₂ CO ₃ and 0.093 ml (1.16 mmol) of chloroacetone 5 ml of acetone was added thereto, and the mixture was heated to reflux for 24 hours. After cooling to room temperature, 30 ml of ethyl acetate was added, washed twice with 10% aqueous HCl solution (30 ml) and once with water. Then, the residue obtained by evaporation under reduced pressure was purified by silica gel chromatography (eluate: hexane: ethyl acetate = 2: 1) to give 215 mg (yield 86%) of the title compound as a white solid.

Melting point: 116-118 ℃

¹ H NMR (CDCl ₃ ) δ7.56 (d, J = 9.3Hz, 1H), 7.25 (d, J = 8.4Hz, 1H), 6.60 (d, J = 8.7Hz, 1H), 6.21 (d, J = 9.3 Hz, 1H), 5.92 (m, 1H), 4.97 (m, 2H), 4.56 (s, 2H), 3.62 (m, 2H), 2.25 (s, 3H)

Example 16

Synthesis of 7-hydroxy-8-propyl-chromen-2-one (Compound 17)

40 mg of 10% palladium carbon was added to a solution of 1000 mg (4.950 mmol) of 8-allyl-7-hydroxy-chromen-2-one (compound 7) obtained in Example 6 in 30 ml of ethyl acetate. The reaction solution was stirred at room temperature under a hydrogen balloon for 10 minutes, the solid was filtered, and the residue filtered under reduced pressure was purified by short silica gel column chromatography (hexane: ethyl acetate = 2: 1) to yield 920 mg of the title compound as a white solid (yield). 92%) was obtained.

Melting Point: 136-140 ℃

¹ H NMR (CDCl ₃ ) δ 6.88 (d, J = 8.1 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 2.91 (m, 2H), 2.71 (m, 4H), 1.58 (m , 2H), 0.97 (t, J = 7.2 Hz, 3H)

Example 17

Synthesis of acetic acid 2-oxo-8-propyl-2H-chromen-7-yl ester (compound 18)

In a solution of 150 mg (0.73 mmol) of 7-hydroxy-8-propyl-chromen-2-one (Compound 17) obtained in Example 16 in 6 ml of THF, 0.24 ml (2.92 mmol) of pyridine and 0.16 ml of acetyl chloride ( 2.19 mmol) was added. After the reaction solution was heated to reflux for 2 hours, the resulting solid was filtered using 20 ml of ethyl acetate, the organic layer was washed twice with 5% aqueous HCl solution (10 ml), and the residue obtained by evaporation under reduced pressure was subjected to silica gel chromatography (eluate). : Hexane: ethyl acetate = 5: 1) afforded 165 mg (yield 92%) of the title compound as white needle crystals.

Melting point: 76-78 ℃

¹ H NMR (CDCl ₃ ) δ 7.69 (d, J = 9.6 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.39 (d, J = 9.3 Hz, 1H), 2.75 (m, 2H), 2.37 (s, 3H), 1.62 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H)

Example 18

Synthesis of 4- (7-hydroxy-2-oxo-2H-chromen-8-yl) -but-2-enoic acid methyl ester (compound 19)

A solution of 20 mg (0.101 mmol) of 8-hydroxy-8,9-dihydro-furo [2,3-h] chromen-2-one (compound 22) obtained in Example 21 below in CH ₂ Cl ₂ was dissolved. 40 mg (0.121 mmol) of (triphenylphosphanilidene) -acetic acid methyl ester was added thereto, followed by stirring at room temperature for 30 minutes. The residue obtained by evaporation under reduced pressure was purified by silica gel chromatography (eluate: hexane: ethyl acetate = 3: 2) to give 20 mg (yield 76%) of the title compound as a pale yellow solid. Melting Point: 164-170 ℃

¹ H NMR (CDCl ₃ ) δ7.62 (d, J = 9.6Hz, 1H), 7.21 (d, J = 8.4Hz, 1H), 7.11 (m, 1H), 6.77 (d, J = 8.4Hz, 1H ), 6.24 (d, J = 9.3 Hz, 1H), 5.91 (m, 1H), 3.75 (dd, J = 1.5, 6.6 Hz, 2H), 3.73 (s, 3H)

Example 19

Synthesis of 8- (2,3-dihydroxy-propyl) -7-hydroxy-chromen-2-one (Compound 20)

In 200 ml (0.97 mmol) of 8-allyl-7-hydroxy-chromen-2-one (Compound 7) obtained in Example 6 in 4 ml of THF, 0.2 ml (2.43 mmol) of pyridine, N-methylmorpholine oxide 176 mg (1.5 mmol) and 0.96 ml (0.045 mmol) of OsO ₄ (4% aqueous solution) were added and heated to reflux for 2 hours. After cooling to room temperature, 5 ml of aqueous NaHSO ₃ solution was added thereto, stirred for 30 minutes, 30 ml of ethyl acetate was added thereto, washed twice with water (15 ml), and the residue obtained by evaporation under reduced pressure was subjected to silica gel chromatography (eluate: CHCl ₃ : methanol =). 6: 1) to give 187 mg (yield 82%) of the title compound as a white solid.

Melting Point: 194-196 ℃

¹ H NMR (CD ₃ OD) δ 7.85 (d, J = 9.6 Hz, 1H), 7.35 (d, J = 8.7 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.18 (d, J = 9.3 Hz, 1H), 3.98 (m, 1H), 3.51 (m, 2H), 3.01 (d, J = 6.9 Hz, 2H)

Example 20

Synthesis of 8H-pyrano [2,3-f] chromen-2-one (Compound 21)

To 514 mg (2.57 mmol) of 7-prop-2-ynyloxy-chromen-2-one (Compound 3) obtained in Example 2 was added 10 ml of dimethylaniline and heated to reflux for 24 hours. After cooling to room temperature, 30 ml of ethyl acetate was added, the mixture was washed twice with 10% aqueous HCl solution (30 ml), once with water and evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluate: hexane: ethyl acetate = 2: 1). This gave 200 mg (39% yield) of the title compound as a white solid.

Melting point: 150-156 ℃

¹ H NMR (CDCl ₃ ) δ7.59 (d, J = 9.6 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.97 (m, 1H), 6.71 (dd, J = 0.6, 8.4 Hz , 1H), 6.24 (d, J = 9.6 Hz, 1H), 5.87 (m, 1H), 4.94 (m, 2H)

Example 21

Synthesis of 8-hydroxy-8,9-dihydro-furo [2,3-h] chromen-2-one (Compound 22)

In a solution of 200 mg (0.97 mmol) of 8-allyl-7-hydroxy-chromen-2-one (Compound 7) obtained in Example 6 in 2 ml of THF and 2 ml of water, 0.96 ml (0.045 ml) of OsO ₄ (4% aqueous solution) mmol) and NaIO ₄ 320 mg (1.5 mmol) were added and stirred at room temperature for 2 hours. 5 ml of aqueous NaHSO ₃ solution was added thereto, stirred for 30 minutes, 30 ml of ethyl acetate was added thereto, washed twice with water (15 ml), and the residue obtained by evaporation under reduced pressure was purified by silica gel chromatography (eluate: hexane: ethyl acetate = 2: 1). This gave 62 mg (yield 32%) of the title compound as a yellow solid. Melting point: 140-146 ℃

¹ H NMR (CDCl ₃ ) δ7.58 (d, J = 9.6Hz, 1H), 7.25 (d, J = 8.4Hz, 1H), 6.75 (d, J = 8.1Hz, 1H), 6.16 (d, J = 9.3 Hz, 1H), 3.43 (m, 2H)

Example 22

Synthesis of 8-hydroxymethyl-8,9-dihydro-furo [2,3-h] chromen-2-one (Compound 23)

After dissolving 8-allyl-7-hydroxychromen-2-one (Compound 7) obtained in Example 6 in 4 ml of CH ₂ Cl ₂ , 40 mg of NaHCO ₃ and 200 mg (1.16 mmol) of mCPBA (70%) were added. It was added and stirred at room temperature for 24 hours. 30 ml of ethyl acetate was added, washed twice with 1N aqueous NaOH solution (30 ml), once with water, and the residue obtained by evaporation under reduced pressure was purified by silica gel chromatography (eluent: hexane: ethyl acetate = 1: 1) to give the title compound (130 mg) as a white solid. (Yield 61%) was obtained.

Melting point: 102-108 ℃

¹ H NMR (CDCl ₃ ) δ7.56 (d, J = 9.6Hz, 1H), 7.20 (d, J = 8.1Hz, 1H), 6.68 (d, J = 8.1Hz, 1H), 6.14 (d, J = 9.6 Hz, 1H), 5.03 (m, 1H), 3.86 (br, d, J = 9.9 Hz, 1H), 3.72 (dd, J = 6.0, 12.3 Hz, 1H), 3.35 (dd, J = 7.5, 16.2 Hz, 1H), 3.11 (dd, J = 7.5, 16.2 Hz, 1H)

Example 23

Synthesis of Benzoic Acid 2-oxo-8,9-dihydro-2H-furo [2,3-h] chromen-8-ylmethyl ester (Compound 24)

A solution of 10 mg (0.045 mmol) of 8-hydroxymethyl-8,9-dihydro-furo [2,3-h] chromen-12-one (Compound 23) obtained in 1.5 ml of carbon dichloride. 24 mg (0.195 mmol) of 4- (dimethylamino) pyridine and 14 mg (0.098 mmol) of benzoyl chloride were added thereto. After stirring the reaction solution at room temperature for 3 hours, 20 ml of carbon dichloride was added to the organic layer, washed twice with saturated NaCl aqueous solution (10 ml), and the residue obtained by evaporation under reduced pressure was subjected to silica gel chromatography (eluate: hexane: ethyl acetate = 2: 1). Purification with 11 mg of a title compound as a colorless liquid (yield 76%).

¹ H NMR (CDCl ₃ ) δ 8.03 (d, J = 7.5 Hz, 1H), 7.88 (m, 1H), 7.57 (d, J = 9.6 Hz, 1H), 7.49 (m, 1H), 7.35 (m , 2H), 7.22 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.16 (d, J = 9.3 Hz, 1H), 5.26 (m, 1H), 4.50 (m , 2H), 3.49 (dd, J = 9.9, 16.2 Hz, 1H), 3.21 (dd, J = 6.6, 16.5 Hz, 1H)

By the following experiment, it was confirmed whether the austenol derivative of the present invention effectively inhibits 5α-reductase type II and is effective in treating prostate disease.

Test Example 1

Identification of inhibitory effects on prostate disease-related enzyme 5α-reductase type II

In order to investigate the inhibitory effect of the test substance on 5α-reductase type II, an enzyme associated with prostate disease induction, Smith and others were modified and applied (Smith CM. Et al., "" 5α-reductase expression by prostate cancer cell lines and benign prostatic hyperplasia in vitro ", J. Clinical Endo. Metabol. 1995, 81: 1361-1366). In other words, LNCaP (ATCC CRL-1740), a cell line expressing 5α-reductase type II, and RPMI-1640 (sigma) in which fetal bovine serum from which hormones such as testosterone were removed by activated carbon adsorption was added. After incubation for 48 hours in medium (Sigma), the substrate [ ³ H] testosterone and the test substance was treated at a concentration of 20, 8, 0.4, 0.16 ㎍ / ㎖ and incubated for another 12 hours. After the reaction was completed, the culture solution was extracted twice with ethyl acetate and separated using a developing solvent in which chloroform and methanol were mixed at 96: 4 using thin layer chromatography (Merck, silica gel 60 W), followed by an image plate. The amount of DHT produced via radiation was measured by transferring to an image plate reader (Fuji Film, BAS-1500). The 5α-reductase activity was calculated by comparing the rate at which testosterone was converted to DHT compared to the control treated with 0.5% DMSO (dimethylsulfoxide) instead of the test substance, and the comparative material, finasteride, a prostatic hypertrophy inhibitor approved by the US FDA. Used.

Finasteride

As a result of this test, the degree of inhibition of 5α-reductase activity of each compound is expressed as IC ₅₀ (μg / ml) as shown in Table 2 below:

Activity Inhibition of 5α-Reductase Type II of Ostenol Synthetic Derivatives compound IC ₅₀ (μg / ml) compound IC ₅₀ (μg / ml) Finasteride 19.8 12 2.6 0 0.1 13 > 4 One 4 14 > 4 2 > 20 15 > 20 3 > 20 16 > 20 4 9.2 17 0.11 5 0.3 18 0.12 6 2.4 19 1.9 7 1.0 20 > 20 8 0.16 21 > 20 9 0.3 22 > 4 10 0.3 23 > 20 11 > 4 24 13.8

Table 2 shows that the austenol derivative of the present invention effectively inhibits 5α-reductase type II.

Test Example 2

Therapeutic Effect of Prostatic Hypertrophy in Rats

Male rats (weight: 120g-180g) weighing 3 weeks were used to examine the effect of the test substance on prostate hypertrophy in a real animal model. Put a period. Actual experiments are described by Paule-Braquet M. et al., "Effect of Serenoa Repens extract on estradiol / testosterone-induced experimental prostate enlargement in the rat", 1996, Pharmacological research, 34: 171-179. Prostatic hyperplasia was induced by subcutaneous implantation of a silicone medical grading tubing (Dow-Corning, USA) filled with estradiol and testosterone (Sigma, USA). . In other words, 14 groups of rats, except the normal control group, were castrated and implanted subcutaneously with a 1 cm long medical silicone tube containing estradiol on day 7 and replaced with a 5 cm long medical silicone tube containing testosterone on day 21. Prostatic hypertrophy was induced, and the control group was implanted with an empty medical silicone tube. 10 mg / kg of Compound 0, 1 4 to 10, 12, 17 to 19 and 24 once daily for 30 days except for the prostatic hypertrophy-induced control group among the 14 groups that induced prostate hyperplasia It was administered orally at the concentration of body weight. Rats were weighed and recorded once a week during the experimental period, and each experimental animal was autopsied and the weight of the dorsal prostate and testis was measured and recorded at the end of the administration period. 1 and 2 are graphs showing the dorsal prostate weight and testis weight of the prostatic hypertrophy-induced male rats to which the test compound was administered, respectively, compared to that of the normal rats and the prostatic hypertrophy-induced male rats to which the test compound was not administered. As shown in Figures 1 and 2, it can be seen that the prostate hypertrophy is reduced when the compound of the present invention is administered to male rats that cause prostatic hyperplasia.

Blood samples of the rats were collected, coagulated, centrifuged, and serum was separated and used to measure the amount of luteinizing hormone (LH). To quantify LH, radioimmunoassay was used using NIAMDD-LH-RPL antiserum against LH in rats (Toomey RE. Et al., "An in vivo assay for conversion of testosterone to dihydrotestosterone by rat prostatic". steroid 5α-reductase and comparison of two inhibitors ", Prostate . 1991, 19: 63-72). Figure 3 is a graph showing the LH in the blood of the male rats induced prostatic hyperplasia administered with the compound of the present invention compared to the case of normal rats and prostatic hypertrophic male rats not administered the test compound. As shown in Figure 3, it can be seen that the amount of LH in the blood is reduced when the compound of the present invention is administered to male rats causing prostatic hyperplasia.

Test Example 3

Investigation of cytotoxicity of test substance

LNCaP (ATCC CRL-1740) cell line, a human prostate cancer cell line, T24 cell line (ATCC HTB-4), a human bladder cancer cell line, and Hepa-1c1c7 (ATCC CRL-), a mouse liver cancer cell line, on a microtiter plate. 2026) The cell lines were cultured and treated with 20 μg / ml of test substance, respectively. After 24 hours of treatment with the test substance, washed with PBS (phosphate buffered saline), stained with 30 μl / well of crystal violet solution for 10 minutes (37 ° C., incubator), and 200 μl of sodium dodecyl sulfate (SDS) solution ( 0.5% SDS in 50% ethanol) was added to each well and allowed to react for 1 hour (37 ° C., incubator) and the absorbance was measured at 610 nm with a microplate reader (Holobaugh PA et al. J. Immunol.Methods , 135, 95-99, 1990).

The cell line not injected with the test compound according to the present invention, that is, the cell line treated with only DMSO, was performed as a control, and the absorbance peak of the test compound was compared with the absorbance peak of the control group to determine the cytotoxicity of the compound of the present invention. The results are shown in Table 3 below:

Toxicity Results of Ostenol Synthetic Derivatives against Various Cancer Cell Lines compound Cell line name LNCaP T24 Hepa1c1c7 05 T20 = 20% T20 = 50% - 06 T20 = 80% T20 = 40% T20 = 40% 10 T4 = 60% - - 11 T20 = 80% - - 12 T20 = 80% - - 13 T20 = 70% - - 14 T20 = 30% - - 22 T20 = 50% - T20 = 80% T20: The rate at which cancer cells die at a compound concentration of 20 µg / ml. T4: The rate at which cancer cells die at a compound concentration of 4 µg / ml .'- ': No cytotoxicity at a compound concentration of 20 µg / ml.

As a result of the test, it can be seen that the compound of the present invention has selectively strong cytotoxicity against prostate cancer cell line.

The austenol derivative of Formula 1 of the present invention can effectively inhibit the activity of 5α-reductase type II to effectively treat prostate disease.

Claims (6)

Ostenol derivatives of Formula 1 or pharmacologically acceptable salts thereof: Formula 1 Where R ₁ is hydrogen; Unsubstituted or mono or polysubstituted (C ₁ -C ₅ ) alkyl, (C ₂ -C ₆ ) alkenyl or (C ₂ -C ₆ ) alkynyl; (C ₁ -C ₇ ) alkylcarbonyl; benzyl; Or (C ₃ -C ₇ ) allylcarbonyl or (C ₃ -C ₇ ) allylcarbamyl, R ₂ is hydrogen; Or (C ₂ -C ₅ ) alkyl or (C ₂ -C ₆ ) alkenyl unsubstituted or substituted with hydroxy or (C ₁ -C ₅ ) alkyl-OCO-; or OR ₁ and R ₂ together may form an unsubstituted or substituted oxygen containing 5 or 6 membered hetero ring, Provided that R ₁ and R ₂ are not simultaneously hydrogen. The method of claim 1, R ₁ is hydrogen, (C ₁ -C ₅ ) alkylcarbonyl, (C ₃ -C ₇ ) allylcarbonyl or (C ₃ -C ₇ ) allylcarbamyl, and R ₂ is CH ₂ = CHCH ₂ -or ( Ostenol derivatives which are C ₂ -C ₅ ) alkyl. The method of claim 1, Ostenol derivatives wherein R ₁ is hydrogen, CH ₃ CO, C ₆ H ₅ CO or C ₆ H ₅ NHCO, and R ₂ is CH ₂ = CHCH ₂ -or C ₃ H _7- . A 5α-reductase type II inhibitory composition comprising an effective amount of the austenol derivative of formula 1 according to claim 1 or a pharmacologically acceptable salt thereof and a pharmaceutically acceptable carrier. A composition for preventing or treating prostate disease, comprising an effective amount of the austenol derivative of formula 1 according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The method of claim 5, A composition wherein the prostate disease is prostate cancer, prostate hyperplasia, prostatitis, prostatic spermitis or prostatic vasculitis.