WO1999012540A1

WO1999012540A1 - Remedies for hormone-dependent diseases

Info

Publication number: WO1999012540A1
Application number: PCT/JP1998/004081
Authority: WO
Inventors: Makoto Yoshihama; Masamichi Nakakoshi; Junji Nakamura; Shouji Nakayama; Kousaku Takahashi
Original assignee: Snow Brand Milk Products Co., Ltd.
Priority date: 1997-09-11
Filing date: 1998-09-10
Publication date: 1999-03-18
Also published as: AU9001698A; JP4166433B2

Abstract

Remedies for hormone-dependent disease which have a 17β-HSD inhibitory activity and are useful, owing to this activity, in preventing and/or treating male and female hormone-dependent diseases, more particularly prostatic cancer, prostatic hypertrophy, masculinism, mammary cancer, mastitis, uterus cancer, endometriosis, ovarian cancer, etc. These remedies contain as the active ingredient compounds having an aurone skeleton.

Description

Specification

Hormone-dependent disease treatment

Technical field

The present invention relates to a therapeutic agent for a hormone-dependent disease, comprising a compound having an auron skeleton as an active ingredient. The agent of the present invention has 17-HSD inhibitory activity, and its activity prevents and / or treats male and female hormone-dependent diseases, specifically, prostate cancer, benign prostatic hyperplasia, virilization, breast cancer It is useful as a prophylactic and / or therapeutic agent for mastopathy, uterine cancer, endometriosis, ovarian cancer and the like.

Background art

In recent years, the increasing incidence of androgen-dependent diseases such as prostate cancer and prostatic hypertrophy and female hormone-dependent diseases such as breast cancer and endometriosis has become a problem in Japan. For example, the prostate cancer mortality rate for 1998

3.9, about 10% of non-white people in the United States, but their life expectancy has improved due to improvements in medical technology, etc., and their diet has gradually increased due to westernization in the United States. It is approaching the level of Europe and the United States at 6.7 per 100,000 people a year. By the way 2

The number of deaths from prostate cancer in 2001 is expected to be about four times the number in 1990, the worst increase in all cancers.

Many findings have already shown that androgen-dependent diseases are expected to improve subjective and objective symptoms by lowering blood androgens. For this reason, blood androgens have been reduced by blood pressure, and gonadotropin-releasing hormone LH-RH agonist secreted from the pituitary gland has been administered, and LH is desensitized by pituitary gland. Attempts to treat these diseases by lowering secretory capacity to lower blood androgens to castration levels, or by administering antiandrogens that antagonize the androgen receptor to suppress the action of androgens In fact, clinical effects have been widely recognized. However, castration results in poor quality of life and is currently practiced only in very limited cases. LH-RH agonists also have problems such as side effects such as bone pain and urinary dysfunction due to agonism's unique flare phenomenon (temporary increase in male hormones), and relapse due to the continued presence of male hormones derived from the adrenal gland. Has become. More anti-androgens Drugs have been shown to reduce therapeutic effects due to mutations in the androgen receptor during drug administration. For this reason, “complete androgen blockade therapy” has recently been proposed for more effective endocrine therapy. This aims to completely block the male hormones in the blood by combining several endocrine therapies, and is expected to have even more therapeutic effects.

Testosterone, which has the highest androgenic activity among C steroids having androgenic activity, is biosynthesized with 17-hydroxyxy tero id dehydrogenase (17? -HSD) using androstenedione as a substrate. Therefore, by inhibiting this 17-HSD, the testosterone in the blood can be directly reduced, so that a high therapeutic effect on the androgen-dependent disease described above can be expected. Also this enzyme, since also a C _{1 8} steroids most estrogenic activity biosynthetic enzymes estradiol strong in de having estrogenic activity, as well as women hormone such as breast and endometriosis A therapeutic effect on sexual diseases is also expected.

To date, steroid compounds and non-steroid compounds have been proposed as 17 ^ -HSD inhibitors. The non-steroid compounds include, for example, the flavones described in Biochemical 'and'Biophysical' Research'Communications (Vol. 211, pp. 113-114, pp. 1995). Isoflavones and the fatty acids described in the journal Obster 'Steroid' Biochemistry (Vol. 23, pp. 357-363, 1989) are known. However, the activity of these compounds has never been satisfactory, and more active substances were expected.

Disclosure of the invention

In view of the situation described above, the present inventors have conducted extensive searches and have found that a compound having an auron skeleton has an activity of inhibiting 17-HSD that causes a hormone-dependent disease. Accordingly, an object of the present invention is to provide a therapeutic agent for a hormone-dependent disease, comprising a compound having an auron skeleton as an active ingredient.

The present invention relates to a therapeutic agent for a hormone-dependent disease, comprising a compound having an auron skeleton as an active ingredient. The auron skeleton is represented by the following formula.

The agent of the present invention has a 17 / 9-HSD inhibitory activity, and its activity prevents and treats male and female hormone-dependent diseases, specifically, prostate cancer, prostatic hyperplasia-masculosis, It is useful as a prophylactic and therapeutic agent for breast cancer, mastopathy, uterine cancer, endometriosis, ovarian cancer and the like.

The compound used for the drug of the present invention is a compound having an auron skeleton, and particularly, the following compounds are used.

(1) 6—Hydroxy-1 2— (Phenylmethylene) -1 3 (2H) Benzofuranone

(2) 2 — [(4-hydroxyphenyl) methylene] 1-6-hydroxy 3 (2H) 1-benzofuranone

(3) 2-[(3-hydroxy-l 4- 4-methoxyphenyl) methylene] 16-hydroxyl 3 (2H) 1-benzofuranone

(4) 2 — ((4-hydroxyl-3-methoxyphenyl) methylene) 16-hydroxy3 (2H) benzofuranone

(5) 2 — [(3,4-dimethoxyphenyl) methylene] 1-6-hydroxyl 3 (2H) 1-benzofuranone

(6) 2-[(4-bromophenyl) methylene]-6-hydroxy-3 (2H) -benzofuranone

(7) 2 — [(4-Fluorophenyl) methylene] —6-hydroxy—3 (2H) —benzofuranone

(8) 2 — [(4-chlorophenyl) methylene] -16-hydroxy-3 (2H) -benzofuranone

(9) 2-[(3-hydroxy-14-methoxyphenyl) methylene] -16-hydroxy3 (2H) -benzofuranone

(10) 6-Hydroxy 2-pyridonylidene-3 (2H) -Benzofuranone (11) 2-[(4-methoxyphenyl) methylene] 1-6-acetoxy 3 (2H) 1-benzofuronone

(12) 2 — ((3,4-Dimethoxyphenyl) methylene) 1 6 —Methoxy 3 (2H) 1-benzofuranone

(13) 2 — [(4-Methoxyphenyl) methylene] 16-Methoxy 3 3 (2 H) 1 Benzofuranone

(14) 2 — [(3,5 — dimethoxyphenyl) methylene] 1 6 — methoxy-1 3 (2H) — benzofuranone

(15) 6—Methoxy—2—Pyrironlidene 3 (2H) Benzofuranone

(16) 2 — [(3,4-dihydroxyphenyl) methylene] 1-6 -hydroxy 3 (2 H)-benzofuranone (generic name: sulfretin)

(17) 2 -C (3,4,5—trimethoxyphenyl) methylene] 1 6—Hydroxy-3 (2H) 1-benzofuranone

(18) 2 — [(2,3-Dimethoxyphenyl) methylene] 1-6 —Hydroxy-3 (2H) —Benzofuranone

These compounds are all known substances and are described in J. Chromatography, 57, 166 (1971) (compounds (1) to (5), (10), (17) and (18)), J. Med. ., 35, 1330 (1992) (compounds (6) to (8)), J. Am. Chem. Soc., 79, 214 (1957) (compound (9)), Magy. Kem. Foly., 74 , 582 (1968) (Compound (11)), Orient. J. Chem., 11, 189 (1995) (Compounds (12) and (13)), Bull. Chem. Soc. Jpn., 54, 635 (1981) )

(Compound (14)), Bull. Chem. Soc. Jpn., 42, 1456 (1996) (Compound (15)) It can be obtained by a synthesis method according to each literature. Alternatively, a nucleus-substituted benzofuranone and a nucleus-substituted benzaldehyde are dissolved in a solvent such as methanol, ethanol, or propanol, concentrated hydrochloric acid is added, and the mixture is heated to reflux for 1 to 24 hours, and then cooled. It can be obtained by filtering out the precipitated crystals. At this time, if no crystals are precipitated, the crystals can be obtained by crystallizing out the crystals using water or an organic solvent in a conventional manner, and filtering the crystallized out. In addition, the compound of (16) is generally commercially available and available, or is extracted and purified from plants according to known methods (J. Am. Chem. Soc, 75, 1900 (1953)), or is chemically synthesized. (Ber., 92, 2847 (1959)) Can be obtained by

The drug of the present invention is safely orally and non-hyrotoxically administered to humans and animals as a medicament. Parenteral administration includes, for example, intravenous injection, intramuscular injection, subcutaneous injection, intraperitoneal injection, transdermal administration, pulmonary administration, nasal administration, enteral administration, buccal administration, mucosal administration, vaginal administration, etc. These formulations are administered. For example, injections, suppositories, aerosols, transdermal absorption tapes and the like can be mentioned. Tablets for oral administration

(Including sugar-coated tablets, coated tablets, buccal tablets), powders, capsules (including soft capsules), granules (including coated ones), pills, troches, liquids, or these And pharmaceutically acceptable sustained-release preparations. Liquid preparations for oral administration include suspensions, emulsions, syrups (including dry syrups), and elixirs. These preparations are administered as pharmaceutical compositions together with pharmaceutically acceptable carriers, excipients, disintegrants, lubricants, coloring agents and the like according to known pharmaceutical manufacturing methods. Examples of carriers and excipients used in these preparations include lactose, glucose, sucrose, mannitol, potato starch, corn starch, calcium carbonate, calcium phosphate, calcium sulfate, crystalline cellulose, canzo powder, gentian powder, and the like. Binders include, for example, starch, tragacanth gum, gelatin, lipstick. , Polyvinyl alcohol, polyvinyl ether, polyvinyl pyrrolidone, hydroxyfif. Disintegrators such as ropi resenorelose, methinoresenorelose, etinoresenorelose, canolevoximetylcellulose, etc. Lubricants such as magnesium stearate, talc, hydrogenated vegetable oils, macrogol, etc .; lubricating agents such as calcium carbonate, sodium bicarbonate, sodium alginate; Those that are permitted can be used. For tablets and granules, sucrose, gelatin, hydroxypropylcellulose, purified shellac, gelatin, glycerin, sorbitol, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, It may be coated with cellulose phthalate acetate, hydroxypropyl methylcellulose phthalate, methyl methacrylate, methacrylic acid polymer, or in a layer using two or more of these. It may be coated. Further, capsules made of a substance such as ethyl cellulose or gelatin may be used. When preparing injections, add a PH regulator, a buffer, a stabilizer, a solubilizer, etc. to the active drug as needed, and make each injection by a conventional method.

When the agent of the present invention is administered to a patient, it varies depending on conditions such as the degree of symptoms, age, health condition, and weight of the patient and is not particularly limited, but is about 1 mg to 100 mg, preferably 500 mg per day for an adult. 200 mg orally or parenterally once or more times daily.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a diagram showing the results of the example.

FIG. 2 is a diagram showing the results of the example.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be described in more detail with reference to the following examples, which are merely illustrative, and the present invention is not limited thereto.

Example 1

6—Hydroxy—2— (Phenylmethylene) —— 3 (2H) —— Preparation of benzofuranone

6-Hydroxy-2H-benzofuran-3-one (1 g) and benzaldehyde (848 mg) were dissolved in methanol (20 ml), and sodium hydroxide (6 g) was dissolved in water (6 ml). The solution was added, and the mixture was stirred under a nitrogen stream for 16 hours, and then water (40 Om1) was added, and the mixture was adjusted to pH 4 with concentrated hydrochloric acid. The precipitated crystals were separated from each other and dissolved in 25 ml of methanol at 60 ° C to give 5. After leaving at c for 4 hours, the crystals were discriminated, dried over phosphorus pentoxide under reduced pressure at 60 for 8 hours, and the target compound (compound (1)) 4 32.6 mg (mp 1 4 1 ') c) was obtained.

FA B MA S S; 2 3 9 (M + l)

1 H - NMR (ppm, in DMSO - d b); 6. 7 2 (1 H, dd, J = 1 0. 3, 1. 9 H z), 6. 7 4 (1 H, s), 6 7 8 (1 H, d, J = 1.5 Hz), 7.40 (1 H, t, 7.6 Hz), 7.47 (1 H, t, 7.6 Hz) ), 7.60 (1 H, d, 8.5 Hz), 7.91 (1 H, d, 7.6 Hz), 10.0.95 (1 H, s) Example 2

2-[(4-Hydroxyphenyl) methylene] -16-Hydroxy-1 3 (2H) -Benzofuranone

6-Hydroxy-2H-benzofuran-3-one (1 g) and 4-Hydroxybenz aldehyde (8.13 g) were dissolved in methanol (75 ml), and concentrated hydrochloric acid (50 ml) was added. After that, the solution was cooled to room temperature, added with 400 ml of water, and allowed to stand for 1 hour. The precipitated crystals were separated and dried over phosphorus pentoxide under reduced pressure at 60 ° C for 5 hours to obtain 1.08 g of the desired compound (compound (2)) (mp 2887) (decomposition). Was.

FAB MA S S; 2 5 5 (M + 1)

¹ H-NR (ppm, in DMS O— d ₆ ); 6.7 1 (1 H, dd J = 8.2, 1.8 Hz), 6.70 (1 H, s), 6. 7 9 (1 H, d, J 1.8 Hz), 6.88 (1 H, d, 10.8 Hz), 7.58 (1 Ht, 85 Hz), 7 . 7 9 (1 H, d, 8.6 H z)

Example 3

2-((3-Hydroxy-4-methoxyphenyl) methylene) Production of 6-Hydroxy-3 (2H) -benzofuranone

Dissolve 1.0 g of 6-hydroxy-1 2 H-benzofuran-3-one 1 g and 3-hydroxy-14-methoxybenzaldehyde in 75 ml of methanol and then add concentrated hydrochloric acid. After adding 50 ml and refluxing for 2 hours, the solution was cooled to room temperature, and 400 ml of water was added and left for 2 hours. The separated crystals were discriminated, dried over phosphorus pentoxide at 60 and 5 hours under reduced pressure, and 1.27 g of the desired compound (compound (3)) (mp 24 0 to 24 2 ° C) ).

FAB MA S S; 2 8 5 (M + 1)

^{1 H - NMR (ppm, H} z, in DM SO - d 6); 3. 8 3 (3 H, s), 6. 6 3 (1 H, s), 6. 7 1 (1 H, dd, J = 1 0.6, 2.2 Hz), 6.77 (1H, d, J = 2.1Hz), 7.01 (1H, d, J = 8.2H2 ), 7.33 (1 H, dd, J = 8.2, 2.1 Hz), 7.47 (1 H, d, J = 2.1 Hz), 7.58 (1 H, d, J = 8.2 Hz) Example 4

2-((4-Hydroxy-3-methoxyphenyl) methylene) -1 6-Hydroxy-3 (2H) -Benzofuranone

6-Hydroxy-2H-benzofuran-3-one 1 g, 4-Hydroxy-1-3-methoxybenzaldehyde 1.0 g was dissolved in methanol 5 ml, concentrated hydrochloric acid 5 After adding 0 ml and refluxing for 2 hours, the solution was cooled to room temperature, and 400 ml of water was added and allowed to stand for 2 hours. The precipitated crystals were discriminated, dried over phosphorus pentoxide at 60 at reduced pressure for 5 hours, and 0.851 g of the desired compound (compound (4)) (mp 262-262) ) Got.

F A B MA S S; 2 8 5 (M + 1)

Ή-MR (ppm, in DM S 〇-d ₆ ); 3.85 (3H, s), 6.70 (1H, s), 6.71 (1H, dd, J = 8) 2, 1.8 Hz), 6.78 (1 H, d, J = 8.2 Hz), 7.44 (1 H, dd, J = 8.5, 2.1 Hz ), 7.50 (1 H, d, J = 2.1 H 2), 7.57 (1 H, d, J = 9.6 Hz)

Example 5

2-[(3,4-Dimethoxyphenyl) methylene] — 6 —Hydroxy-1 3 (2Η) —Production of benzofuranone

6-Hydroxy-2Η-benzofuran-1--3-one (1 g, 3,4 dimethoxybenzaldehyde) (2.33 g) was dissolved in methanol (75 ml), and concentrated hydrochloric acid (50 ml) was added. After refluxing for 1.5 hours, the solution was cooled to room temperature, and 400 ml of water was added. The precipitated crystals were discriminated and dried over phosphorus pentoxide under reduced pressure at 6 O'c for 7 hours to obtain 0.85 g of the desired compound (compound (5)) (mp 22 1 ° C). .

F A B MA S S; 2 9 9 (M + 1)

Ή-NMR (pm, in DMS 0-d ₆ ); 3.80 (3 H, s), 3.81 (3 H, s), 6.68 (1 H, s), 6.7 2 (1 H, dd, J = 8.2, 1.8 Hz), 6.8 1 (1 H, d, J = 2.1 Hz), 7.02 (1 H, d, J = 9.6 Hz), 7.49 (2 H, m) 7.55 (1 H, d, J = 8.5 Hz) Example 6

2-[(4-butophyl mophenyl) methylene] 6-Hydroxy 3 (2Η) Production of 1-benzofuranone

6-Hydroxy-2Η-benzofuran-3 —one 1 g, 4-bromobenzaldehyde 1.36 g were dissolved in methanol 75 ml, and 50 ml of concentrated hydrochloric acid was added. 1.

After refluxing for 5 hours, the solution was cooled to room temperature, and 400 ml of water was added. The precipitated crystals were separated from each other, and dried over phosphorus pentoxide at 60 at reduced pressure for 4 hours to obtain 1.16 g of the desired compound (compound (6)).

F A B MA S S; 3 1 8 (M + 1)

^{1 H - NMR (ppm, in} DMS 0 - d 6); 6. 6 9 (1 H, dd, J = 7. 9, 1. 5 H z), 6. 7 2 (3 H, s), 6 7 5 (1 H, d, J = 1.8 H z), 7.δ 9 (1 H, d, J = 8.5 H z), 7.62 (2 H, d, J = 8 5 H z), 7, 8 2 (2 H, d, J = 8.5 H z), 1 1.2 1 (1 H, s)

Example 7

2-((4-Fluorophenyl) methylene) -16-Hydroxy-3 (2H) -Benzofuranone

6-Hydroxy 2 H-Benzofuran 1 3-one 1 g, 4-fluorobenzaldehyde 0.78 ml dissolved in methanol 75 ml; 1 plus 1. Refurbished for 5 hours. After the solution was cooled to room temperature, 400 ml of water was added. The precipitated crystals were separated by α, and dried over phosphorus pentoxide under reduced pressure at 60 ° C for 4 hours to obtain 0.74 g of the target compound (compound)).

F A B MA S S; 2 5 7 (M + 1)

'Η-NMR (ppm, H z, in DMS O— d ₆ ); 6.70 (1 H, dd, J = 8.5, 1.8 H z), 6.77 (1 H, d , J = 1.8 Hz), 6.78

(1 H, s), 7.30 (2 H, t, J = 8.8 Hz), 7.60 (1 H, d, J = 8.6 Hz), 7.97 ( 2 H, dd, J = 8.8, 5. H z), 1 1.20 (1 H, s)

Example 8 2 — ((4 — fucinyl) methylene) 1 6 — Production of hydroxy 3 (2 H) -benzofuronone

6—Hydroxy-2H—Benzofuran-1 3—one 1 g, 4—1.08 g of benzoaldehyde, dissolved in methanol 75 ml, and concentrated hydrochloric acid 5 0 ml was added and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and 400 ml of water was added. <The separated crystals were discriminated, dried over phosphorus pentoxide at 60 and 5 hours under reduced pressure to obtain the desired compound (compound (compound 8)) 0.82 g was obtained.

1 H - NMR (ppm, in DM SO - d 6); 6. 6 8 (1 H, dd, J = 8. 5, 1. 5 H z), 6. 7 2 (1 H, s), 6 7 4 (1 H, d, J = 1.8 H 2), 7.30 (2 H, d, J = 8.5 H z), 7.57 (1 H, d, J = 8 5 Hz), 7.87 (2 H, d, J = 8.8 Hz), 11.20 (1 H, s)

Example 9

2-[(4-methoxyphenyl) methylene] 1-6-Hydroxy 3 (2H)-Production of Veranone

6-Hydroxy-2H-benzofuran—3—On lg, 4—Methoxybenzaldehyde 1. 25 g was dissolved in 75 ml of methanol, and 50 ml of concentrated hydrochloric acid was added. 1. Reflux for 5 hours. The solution is cooled to room temperature, and the precipitated crystals are separated from each other by α. The crystals are dried under reduced pressure at 60 ° C. for 4 hours on phosphorus pentoxide to obtain 0.983 g of the target compound (compound (9)). Was.

F A B MA S S; 26 9 (M + 1)

Ή-NMR (ppm, in DMSO— d ₆ ); 3.79 (3 H, s), 6.69 (1 H, dd, J = 8.5, 2.1 H z), 6. 7 3 (1 H, s), 6.76 (1 H, d, J = 1.8 Hz), 7.00 (2 H, d, J = 9.1 Hz), 7.5 8 (2 H, d, J = 8.2 Hz), 7.86 (2 H, d, J = 9.1 Hz), 1 1.1 1 (1 H, s)

Example 10

6—Hydroxy—2—Pyrironlidene-1 3 (2H) —Benzofuranone Production

6—Hydroxy-2H—benzofuran—3—one 1 g, pironal 1.11 After dissolving 50 g in 75 ml of methanol, 50 ml of concentrated hydrochloric acid was added and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and the crystals separated out were discriminated from each other and dried under reduced pressure at 60 ° C. for 4 hours on phosphorus pentoxide to obtain 1.37 g of the target compound (compound (10)). . FAB MA SS; 2 8 3 (M + l)

Ή-NMR (ppm, in DMSO-d ₆ ); 6.08 (2 H, s), 6.

7 0 (1 H, dd, J = 8.2, 1.8 H z), 6.70 (1 H, s), 7.0 1 (1 H, d, J = 7.9 H z) , 7.44 (1 H, dd, J = 8.2, 1.8 Hz), 7.52 (1 H, d, J = 1.5 Hz), 7.58 (1 H , d, J = 8.2 Hz), 1 0.99 (1 H, s)

Example 1 1

2-((4-Methoxyphenyl) methylene-1-6-acetoxy-3 (2H) -1-Benzofuranone

2 — [(4-Methoxyphenyl) methylene] 1-6 -Hydroxy-3 (2H)-Benzofuranone (0.5 g) is dissolved in pyridine (5 ml) and acetyl chloride (0.172 ml) is dissolved. In addition, it was refluxed for 2.5 hours. After the solution was cooled to room temperature, 40 ml of ethyl acetate was added, and the mixture was washed twice with 15 ml of 2N-hydrochloric acid and three times with 15 ml of saturated saline. The ethyl acetate solution was dehydrated with magnesium sulfate and concentrated under reduced pressure. The resulting powder was fractionated by gel chromatography on silica gel (100 g silica gel, elution solvent: hexane: ethyl acetate = 1: i, eluted at 500 mi), and the pressure was reduced. It was concentrated to dryness at 40 and crystals were obtained. After dissolving the crystals in 10 ml of ethyl acetate, leaving them at room temperature for 2 hours, the precipitated crystals are discriminated, dried over phosphorus pentoxide, and dried under reduced pressure at 60 to 5 hours. Compound (compound (11)) 355.4 mg was obtained.

F A B MA S S; 3 1 1 (M + l)

^{1 H - NM R (ppm,} in CDC 1 3); 2. 3 3 (3 H, s), 3. 8 4 (3 H, s), 6. 8 5 (1 H, s), 6. 9 1 (1 H, d, J = 8.5, 1.

8 H z), 6.96 (2 H, d, J = 8.8 H z), 7.13 (1 H, d, J = 1.5 H z), 7.78 (2 H , d, J = 8.24 Hz), 7.84 (2 H, d, J = 8.8 Hz)

Example 1 2 2-[(3,4-Dimethoxyphenyl) methylene] 1-6-Methoxy-3 (2H) -Benzofuranone

2 — [(3,4—Dimethoxyphenyl) methylene] 16—Hydroxy-13 (2H) —benzofuranone 0.53 g and potassium carbonate 0.583 g to dimethylformamide 5 To the solution containing m1, add 0.24 g of methyl p-toluenesulfonate, stir at 60 for 2 hours, then add 100 ml of water, and add 50 ml of ethyl acetate twice. After extraction, the mixture was washed twice with 50 ml of a saturated saline solution, separated by dehydration with magnesium sulfate, and concentrated under reduced pressure at 40 to obtain a crude target compound as a powder. The resulting powder was fractionated by silica gel column chromatography (50 g of silica gel, elution solvent: hexane: ethyl acetate = 1: 1, eluted at 500 ml), and applied under reduced pressure of 40. The mixture was concentrated to dryness in c to obtain crystals. The crystals were dissolved in 2 ml of ethyl acetate and 1 Omi of hexane and left at room temperature for 2 hours. The precipitated crystals were separated from each other, and dried over phosphorus pentoxide under reduced pressure at 60'c for 4 hours to obtain 435.3 mg of the desired compound (compound (12)).

F A B MA S S; 3 1 3 (M + 1)

^{1 H - NMR (ppm, in} CDC 1 3); 3. 9 0 (3 H, s), 3. 8 1 (3 H, s), 3. 9 5 (3 H, s), 6. 7 2 (2 H, s), 6.76 (1 H, s), 6.90 (1 H, d, J = 8.5 Hz), 7.44 (1 H, dd, J = 8 .

2, 2.4 Hz), 7.45 (1H, d, J = δ.5Hz), 7.67 (1H, d, J = 8.2Hz)

Example 13

2 — [(4-Methoxyphenyl) methylene] -16 —Methoxy-3 (2H) —Benzofuranone

1 [(4-Methoxyphenyl) methylene] 1-6 -Hydroxy_3 (2H) -benzofuranone 0.452 g and potassium carbonate 0.583 g in dimethylformamide 0.24 g of methyl p-toluenesulfonate was added to the solution containing 5 ml, and the mixture was added to the solution. C, After stirring for 2 hours, add 100 ml of water, extract twice with 50 ml of ethyl acetate, wash twice with 50 ml of saturated saline, dehydrate with magnesium sulfate, and separate by π. After concentration under reduced pressure at 40 ° C, a crude target compound was obtained as a powder. The obtained powder was subjected to silica gel column chromatography (50 g of silica gel, elution solvent hexane: ethyl acetate = (1: 1 elution at 500 ml) and concentrated to dryness under reduced pressure at 40 to give crystals. The crystals were dissolved in ethyl acetate (2 ml) and hexane (10 ml) and left at room temperature for 2 hours. The precipitated crystals were separated from each other, and dried over phosphorus pentoxide at 60 at reduced pressure for 4 hours to obtain 315.0 mg of the desired compound (compound (13)).

F A B MA S S; 2 8 3 (M + 1)

Ή-NMR (pm, in CDC "); 3.84 (3 H, s), 3.90 (3 H, s), 6.72 (2 H, m), 6.78 (1 H, s), 6.94 (2H, d, J = 8.5Hz), 7.67 (1H, d, J = 8.5Hz), 7.83 (2

H, d, J = 8.5 Hz)

Example 14

2 — [(3,5—Dimethoxyphenyl) methylene] 1-6—Methoxyl 3 (2H) Manufacture of Benzofuranone

2 — ί (3, 5 — dimethyl phenyl) methylene] 1 6 — Hydroxy 1 3 (2Η) — benzofuranone 0.53 g and potassium carbonate 0.58 3 g dimethylformamide 0.25 4 g of methyl p-toluenesulfonate was added to the solution containing 5 ml, and the mixture was stirred at 60 for 2 hours, water 100 ml was added, and ethyl acetate 50 ml was added. Then, the mixture was washed twice with 50 ml of a saturated saline solution, separated by dehydration with magnesium sulfate, and concentrated under reduced pressure with 4 ml to obtain a crude target compound as a powder. The resulting powder was fractionated by silica gel column chromatography (silica gel 50 g, elution solvent: hexane: ethyl acetate = 1: 1, eluted at 500 ml), and the pressure was reduced to 40 g under reduced pressure. The solution was concentrated to dryness to obtain crystals. This crystal was dissolved in 2 ml of ethyl acetate and 1 O ml of hexane and left at room temperature for 2 hours. The crystals thus formed were discriminated from each other, and dried over phosphorus pentoxide under reduced pressure at 60 ° C for 4 hours to obtain 41.6 mg of the desired compound (compound (14)).

F AB MA S S; 3 1 3 (M + 1)

Ή - NMR (ppm, in CDC 1 3); 3. 9 3 (6 H, s), 3. 9 5 (3 H, s), 6. 7 2 (2 H, s), 6. 7 6 ( 1H, s), 6.90 (1H, d, J = 8.5Hz), 7.44 (1H, dd, J = 8.2, 2.4Hz), 7.

4 5 (1 H, d, J = 8.5 Hz), 7.6 7 (1 H, d, J = 8.2 Hz) 6 —Methoxy 2 —Pyrironlidene 3 (2H) Production of Benzofuranone

6 —Hydroxy-1 2 —Pi π-urilidene 3 (2H) —Benzofuranone 0.53 g and 0.476 g of potassium carbonate plus 5 ml of dimethylformamide in a solution of methyl p — Toluene sulfonate 0.25 4 ml and 60. c, After stirring for 2 hours, add 100 ml of water, extract twice with 50 ml of ethyl acetate, wash twice with 50 ml of saturated saline solution, and separate by dehydration with magnesium sulfate. The mixture was concentrated under reduced pressure at 40 to give a crude compound as a powder. The obtained powder was fractionated by silica gel column chromatography (50 g of silica gel, eluted with hexane: ethyl acetate = 1: 1 in 500 ml) and eluted at 500 ml under reduced pressure. Concentrated to dryness at 'C to obtain crystals. This crystal is methyl acetate 2 m

1. Hexane was dissolved in 10 ml and left at room temperature for 2 hours. The precipitated crystals were separated from each other, and dried over phosphorus pentoxide at 60 at reduced pressure for 4 hours to obtain 336.7 mg of the desired compound (compound (15)).

F A B MA S S; 2 9 7 (M + l)

Ή - NM R (ppm, in CDC 1 3); 3. 9 0 (3 H, s), 3. 8 1 (3 H, s), 3. 9 5 (3 H, s), 6. 7 2 (2 H, s), 6.76 (1 H, s), 6.90 (1 H, d, J = 8.5 Hz), 7.44 (1 H, dd, J == 8.

2, 2.Hz), 7.45 (1H, d, J = 8.5Hz), 7.67 (1H, d, J = 8.2Hz)

Example 16

2 — [(3,4,5—trimethoxyphenyl) Methylene: '— 6—Hydroxy 3 (2H) Production of Benzofuranone

6-Hyd α-xy 2 H-Benzofuranone 3 —one 17 g and 3,4,5 — Trimethoxybenzaldehyde 25 g are dissolved in methanol 200 ml, and concentrated hydrochloric acid 2Q 0 ml was added, and the mixture was refluxed for 1.5 hours. After cooling this solution to room temperature, the precipitated crystals are separated by π, dried over phosphorus pentoxide at 60 with reduced pressure for 18 hours, and the desired compound (compound (17)) 36.0 g I got

F A B MA S S; 3 2 9 (M + l)

Ή-NR (ppm, in DMS 0-d 6); 3.72 (3H, s), 3.83 (6H, s), 6.70 (2H, m), 6.7 8 (1 H, m), 7.25 (1 H, s), 7.27 (1 H, s), 7.56 to 7.59 (2 H, m), 1 1.1 1 (1 H, s)

Example 1

Preparation of 2-[(2,3-Dimethoxyphenyl) methylene] -16-hydroxy-13 (2H) -benzofuranone

6-Hydroxy-2H-benzofuranone-3-one 20 g and 2,3-Dimethoxybenzaldehyde 25 g were dissolved in methanol 250 ml, and concentrated hydrochloric acid 250 ml Was added and the mixture was refluxed for 1.5 hours, and then 200 mi of water was added. After the solution was cooled to room temperature, the precipitated crystals were separated and dried over phosphorus pentoxide at 60 to 18 hours under reduced pressure to obtain 33.3 g of the desired compound (compound (18)) Was.

F A B MA S S; 29 9 (M + 1)

¹ H-NMR (ppm, in DMS 0-d 6); 3.80 (3 H, t), 3.8 1 (2 H, s), 6.69 (1 H, dd, J = 8.5, 1.8 Hz), 6.76 (1H, d, J = 1.8 Hz), 6.95 (1H, s), 7.09 (1H, dd) , J = 8.2, 1.2 Hz), 7.16 (1 H, t, J = 7.9 Hz), 7.

6 0 (1 H, d J = 8.5 H z) 7.5 4 (1 H, d d, J = 7. 9, 1.2 H z), 1 1 2 0 (1 H, s)

Example 18

Tablet manufacturing

Compound 1 1 8 (one of them) 20 g

6 g of potato shostarch

Talc stearate 4 g

6% HPC lactose 170 g Total 200 g

The components were mixed to produce 400 mg of tablets containing 50 mg of the compound obtained in the example.

Example 19

Manufacture of granules Compound 1 to 18 (any one) 10 g

Lactose 1 8 7 g

Magnesium stearate 3 g Total 200 g

The components were mixed, compression molded, pulverized and sized to produce 20 to 50 mesh 5% condyle granules.

Example 20

Production of injections

Compound 1 to 18 (one of them) 15 g

Physiological saline 1 0 0 m i Total 1 5 g / 100 m 1

The compound obtained in the above example was dissolved in physiological saline, filled in a vial, and sterilized by heating to give an intravenous injection.

Example 2 1

In vitro 17 ^-HSD inhibitory activity test

The compounds (compounds 1 to 15, 17 and 18) obtained in Examples 1 to 17 and sulfretin (Funakoshi, Cat. No. 82-0000-8: compound 16) (hereinafter referred to as test substances) ) Was tested for 17-HSD inhibitory activity. That is, each of the test substances was dissolved in ethanol, placed in a test tube to a final concentration of 260 nM, and dried with nitrogen gas. This 1 0 0 mM chloride force Li um, I mM ethylenediamine integrators tiger acetate, 0. 5 mM reduced nicotinamide Ami de adenine dinucleotide phosphate (all manufactured by Wako Pure Chemical ^{Industries), 1 μ MC 4 - 14} C) We scan 10 mM phosphate buffer (PH7.5) 590 / ^ 1 provided by TRON (NEN Research Products), and the method of Thompson et al. In J. Biol. m., 2449, 5366-4-5370, 1974), add 10 M of microsomal fraction obtained from human placenta, and add The reaction was performed under shaking for minutes. Immediately after the completion of the reaction, 2 ml of dichloromethane was added, and the mixture was sufficiently stirred, and centrifuged at 300 rpm for 5 minutes. Layer was transferred to another test tube and dried with nitrogen gas. To this, add 100 mg of ethanol containing 100 mg of ester mouth and 20 g of estradiol, and add 20〃1 to TLC plate (silicone gel 60 F). ₂₅₄ , Merck Co., Ltd. _c After deploying this TLC plate with benzene: acetone (4: 1), spots corresponding to estrone and estradiol were cut out under ultraviolet light, and liquid scintillation was performed. - to down cocktail (filter count (trademark); fuse one column preparative Packard) was added, remaining in the liquid scintillation counter one ^[4-'4 C] E be sampled opening down amount, and was determined 1 7/9-HSD produced by enzymatic activity ^[4-14 C] estradiol amount. A control group was obtained by performing the same operation without adding the test substance. Assuming that the 17 / 9-HSD enzyme activity of the control group was 0% inhibition, the 17-HSD enzyme inhibition rate of the test substance was calculated as a percentage. The results are shown in FIGS. Example 22

In vivo serum estradiol measurement test

Serum estradiol levels were measured using gonadotropin-treated young female rats. That is, a 14-day-old SD female rat was preliminarily bred together with a nursing parent, weaned at the age of 20 days, and then dissolved at 21 days of age in physiological saline per kg of body weight at the age of 21 days. Gonadotropin was administered subcutaneously 600 international units. Twenty-four hours later, a single suspension of the test substance in 0.5% carboxymethylcellulose dissolved in physiological saline was orally administered at 1 Q Omg / kg body weight. At 4 and 24 hours after administration of the test substance, whole blood was collected from the posterior vena cava under ether anesthesia, and serum was separated by centrifugation at 300 Q rpm for 30 minutes. E2 kit "Daiichi" II (Daiichi Radioisotope Laboratories) was used to measure the amount of peristolol contained in the serum of the test substance administration rat. Serum of the test substance administration rat or estradiol (Wako Pure Chemical Industries, Ltd.) of a known concentration for a standard curve was added to each test tube, 3 ml of getyl ether was added, and the mixture was agitated sufficiently and allowed to stand for a while. When the ether layer and the aqueous layer were clearly separated, the bottom was immersed in dry ice-methanol to freeze only the aqueous layer, the ether layer was transferred to another test tube, and dried at 37 with nitrogen gas. . To this, 100 μl ¹²⁵ 1-estradiol and an anti-estradiol antibody contained in the kit were added, and reacted at room temperature for 90 minutes. After completion of the reaction, add 1 ml of the secondary antibody and react at room temperature for another 15 minutes. Was measured E scan Torajio Ichiru - 3 performs 0 0 0 rpm for 1 5 minutes centrifugation, complete removal of the supernatant by Asupireta, ^{1 2 5} 1 present sediment at r counter one. Drawing a standard curve from ^{1 2 5} Les estradiol amount of known concentration of estradiol, We scan Torajio contained in the sera of test substance administered rats - was Le amount (E 2 amount) was measured. The results are shown in FIGS.

Industrial applicability

From the above results, the present invention provides a therapeutic agent for a hormone-dependent disease, comprising a compound having an aurone skeleton as an active ingredient. The agent of the present invention has a 17-HSD inhibitory activity, and its activity is a prophylactic and / or therapeutic agent for male and female hormone-dependent diseases, specifically, prostate cancer, benign prostatic hyperplasia, androgenesis, breast cancer, breast gland It is useful as a prophylactic and / or therapeutic agent for diseases, uterine cancer, endometriosis, ovarian cancer and the like.

Claims

The scope of the claims

1. A therapeutic agent for hormone-dependent diseases, comprising a compound having an auron skeleton as an active ingredient.

2. The therapeutic agent for hormone-dependent disease according to claim 1, wherein the compound having an auron skeleton is any one of the following compounds.

(1) 6-hydroxy-2- (phenylmethylene) 13 (2H) -benzofuranone

(2) 2 — [(4-Hydroxyphenyl) methylene] -16-Hydroxy-13 (2H) —Benzofuranone

(3) 2— ((3-hydroxy-14-methoxyphenyl) methylene) 16-hydr α-xy 3 (2Η) 1-benzofuranone

(4) 2— [(4-hydroxyl 3- methoxyphenyl) methylene] — 6—hydroxy 3 (2Η) 1-benzofuranone

(5) 2 — ((3,4-dimethoxyphenyl) methylene) 1-6—hydroxy 3 (2Η) —benzofuranone

(6) 2 — [(4-Promophenyl) methylene] —6—Hydroxy 3 (2Η) —Benzofuranone

(7) 2 — [(4-Fluorophenyl) methylene] — 6-hydroxy-1 3 (2Η) —benzofuranone

(8) 2 -ί (4-chlorophenyl) methylene) — 6—Hydroxy-1 3 (2Η) -benzofuranone

(9) 2 — [(3-hydroxy-14-methoxyphenyl) methylene] 16-hydroxy3 (2Η) -benzofuranone

(10) 6—Hydroxy-1 2-Pyrironylidene-1 3 (2Η) —Benzofuranone

(11) 2— [(4-methoxyphenyl) methylene] 16-acetoxy3 (2Η) -benzofuranone

(12) 2 — [(3,4-Dimethoxyphenyl) methylene] -1 6-Methoxy-1 3 (2Η) Benzofuranone

(13) 2 — [(4-Methoxyphenyl) methylene] -16-Methoxy-3 (2Η) -benzofuranone (14) 2 — [(3,5-dimethoxyphenyl) methylene] 1-6-methoxy3 (2Η) -benzofuranone

(15) 6-Methoxy 2- 2-pyronylidene 3- (2Η) Benzofuranone

(16) 2 — [(3,4-dihydroxy α-oxyphenyl) methylene] 1-6-hydroxy-13 (2Η) -benzofuranone (generic name: sulfretin)

(17) 2 — [(3,4,5-trimethoxyphenyl) methylene] -1-6-hydroxy-3 (2Η) -benzofuranone

(18) 2 — [(2,3-Dimethoxyphenyl) methylene] -1-6-hydroxy-3 (2Η) -benzofuranone

Figure i

1T5-HSD Blood E 2 level (pg / rai), ¹ compound Structural formula Molecular formula Molecular weight Inhibitory activity

After 24 hours

Οι ₅ Η ₁₀ Ο ₃ 238.224 57.6 ± 8.1

C _{! 5} H ₁₀ O ₄ 254.244 T1.6 ± 3.2 3.0 ± 2.2 30.4 ± 7.3

Ci6n ₁₂ 0 ₅ 284.2T0 End 2.1 ± 3.8

_{_{_{G le n 12 0 5 284.2T0 72.4}}} ± 2.9 3.3 ± 3.9 39.3 ± 6.2

298.297 R 6.3 ± 9.2 0.8 ± 1.3 31.R ± 6.2

C, ₅ hgBr03 31 completed.140 35.6 ± 3.2

C ₁₅ h ₉ F03 256.235 3T.1 ± 1.1

C, ₅ H ₉ CI0 ₄ 272.689 41.4 ± 2.3 U.0 ± 3, 22.6 ± 4.1

C, _e H ₁₂ 0 ₃ 268.2T0 73.5 ± 9.9 19.6 ± U 41.0 ± 10.2

C, »H, ₀ O ₅ 282.254 54.0 ± 8.3 6.4 ± 3.6 13.5 ± 2.3

(* '. * ² ; average ± standard deviation) i / 2 Fig. 2

(«',« 2; average ± standard deviation)

2 /