JPH01125320A - Testosterone-5alpha-reductase inhibitor - Google Patents

Abstract

PURPOSE:To obtain the titled safe inhibitor having testosterone-5alpha-reductase inhibiting action, free from hormone-like side effect, etc., and useful for the remedy of prostatomegaly, alopecia, etc., by using a chalcone compound as an active component. CONSTITUTION:The objective inhibitor contains a compound of formula I (X and Y are H or together forma bond; R1 is H, isoprenyl or isopentyl; R2 is H or OH) as an active component. The compound of formula I can be produced by reacting a compound of formula II (A1 is OH or methoxymethoxy; A2 is H or isoprenyl A3 is H, methoxymethoxy or benzyloxy) with a compound of formula III (A5 is H or methoxymethoxy; A6 is methoxymethoxy or benzyloxy). The compound of formula I is an analog of chalcone compound derived from HOKOTSUSHI (a Chinese herb drug), is free from steroid structure or steroid- like structure and has high safety.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a testosterone-5α-reductase inhibitor that has a testomethylone-5α-reductase inhibitory effect and is useful for treating prostatic hypertrophy, alopecia, acne, etc. It is related to.

[Prior Art and Problems] In recent years, alopecia has attracted attention, and the demand for hair restorers is on the rise. In China, bone grafting fat is used as one of the treatments for alopecia, and has been highly effective when used in combination with ultraviolet irradiation. In addition, this bone graft has antibacterial and antifungal effects, and is said to have extremely low toxicity. [Dictionary of Chinese medicine.

Volume 4, Kamiyu Science and Technology Publishing, Shogakukan, Tokyo.

1985. pp. 2420-2423].

On the other hand, symptoms such as prostate enlargement, androgenetic alopecia, acne vulgaris, and seborrhea are known to be caused by increased stimulation of male hormones, and these symptoms are caused by testosterone-5α.
-It is thought that it can be reduced or prevented by inhibiting reductase activity, and testosterone-
Several inhibitors have been discovered and synthesized that specifically inhibit 5α-reductase. However, conventional inhibitors have a steroid structure or a steroid-like structure, and there are many cases where side effects such as hormone-like effects are a problem, and the development of highly safe drugs has been desired.

"Means for Solving the Problems" The present inventors focused on the above-mentioned points and conducted intensive research in order to obtain a substance that is highly safe and has excellent therapeutic effects without undesirable side effects such as hormone-like effects. As a result of repeated studies, we found that 2°,4,4'-trihydroxy-3°-(3-methyl-2-butenyl) chalcone, a chalcone compound extracted and isolated from bone fat, has a testosterone-5α-reductase inhibitory effect. , further synthesized analogs thereof, and confirmed that they also had a testosterone-5α-reductase inhibitory effect, leading to the completion of the present invention.That is, the present invention is based on the general formula (1) (where XSY is a hydrogen atom or represents a bond, R3 represents a hydrogen atom, an isoprenyl group, or an isopendel group, and R2 represents a hydrogen atom or a hydroxyl group6
) It is a testosterone-5α-reductase inhibitor containing a compound represented by (hereinafter referred to as a compound of formula I) as an active ingredient.

Compounds of formula I can be produced, for example, as follows.

Represented by the formula ■ A (where A represents a hydroxyl group or a methoxymethoxy group, A represents a hydrogen atom or an isoprenyl group, and A3 represents a hydrogen atom, a methoxymethoxy group, or a benzyloxy group) A compound (hereinafter referred to as a compound of formula 1) and a compound represented by formula (hereinafter referred to as compound 2)) in an organic solvent using a base, or by further subjecting the condensate after condensation to at least one operation such as reduction or deprotection. A compound of formula I is obtained.

The compound of formula (1), which is a raw material, can be prepared by starting from commercially available 2°,4'-dihydroxyacetophenone and, depending on the target substance, introducing an isoprenyl group and/or protecting the hydroxyl group with a methoxymethyl group or benzyl group. Obtainable.

More specifically, by adding a base such as potassium carbonate to 2',4'-dihydroquine acetophenone as it is or in an organic solvent such as anhydrous tetrahydrofuran, and reacting with prenyl chloride, prenyl is added to the 3° position. After introducing the group, in an organic solvent such as dimethylformamide, N,N
A compound of formula (1) is obtained by adding a base such as -diisopropylethylamine or potassium carbonate and reacting with chloromethyl methyl ether or benzyl bromide.

In the second reaction, dimethylformamide used as a solvent is hydrolyzed in the presence of a strong base, so when dimethylformamide is used, N, N,
Preferably, amines such as N-diisopropylethylamine or triethylamine are used. Further, the above reaction is usually carried out at a temperature of about -10 to 80°C.

The compound of formula (1) can be obtained by using commercially available p-hydroxybenzaldehyde or 3,4-dihydroxybenzaldehyde as a starting material and substituting it with a methoxymethyl group, benzyl group, etc. depending on the target substance.

As a specific example, p-hydroxybenzaldehyde or 3,4-dihydroxybenzaldehyde is added to a base such as N,N-diisopropylethylamine, potassium carbonate, or triethylamine in an organic solvent such as dimethylformamide, and then chloromethyl methyl ether or benzyl ether is added. By reacting the bromide, a compound of formula (1) is obtained.

In the above reaction, dimethylformamide used as a solvent is hydrolyzed in the presence of a strong base, so when dimethylformamide is used, N,N
It is preferable to use amines such as ~diisopropylethylamine or triethylamine.

The above reaction is carried out at a temperature range from -10°C to the boiling point of the solvent used.

Examples of producing compounds of formula (1) and formula (2) are shown below.

Production example 1 2°, 4°-dihydroxyacetophenone 14.9.9
5 g was dissolved in tetrahydrofuran, 409.269 g of anhydrous potassium carbonate and 150 d of prenyl chloride were added thereto, and the mixture was stirred at room temperature for 5 days under a nitrogen stream. After the reaction was completed, 3N hydrochloric acid was added to the reaction solution while cooling to make the aqueous layer acidic, followed by extraction with ether. This ether extract was sequentially washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off.

Next, hexane 8007d was added to the obtained residue and decantation was performed to remove hexane-soluble materials to obtain a colorless solid of 2°,4′-dihydroxy-3”-(3-methyl-2
-butenyl)acetophenone 98.559 was obtained (yield 45.4%).

Infrared absorption spectrum sea "a'xem-": 3168
．． 2968, 2912. +622°1590.1494
,14.52,1372°1320,+272. I
P64,1126゜1100.1056,1024.1
000°980.914,888,848,834°7
92.778,718,614 Proton nuclear magnetic resonance spectrum (δppm in acetone-do): 1.63
(3H, d, J=1.5Hz).

=7= 1.76 (3H, d, J=1.5Hz).

2.53 (3H, s).

3.34 (2H, d, J=7.3Hz).

5.2 5(I H,t , 5ept, Jt=7.3
Hz.

Js=1. 5 Hz).

6.49 (IH, d, J = 8.8 Hz).

7.63 (IH, d, J = 8.8 Hz).

9.31 (IH, brs), 13.10 (II (
, s) Mass spectrum: M/Z (%) 220 (M”, 62).

20 5 (21), 1 77 (30).

1 77 (30), l 6 5 (91).

149(32), 147(22).

Next, 5.00y of this 2°,4°-dihydroxy-3'-(3-methyl-2-butenyl)acetophenone was dissolved in 30M1 of dimethylformamide, and N,N-diisopropylethylamine 6,Od was added to 0° Cooled to C. Chloromethyl methyl ether 2.4- was added dropwise to this solution, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, water was added and extracted with ether. The extract was sequentially washed with dilute hydrochloric acid and then with water, dried over anhydrous sodium sulfate, and the solvent was distilled off to give 2°-hydroxy-4°-methoxymethoxy as a colorless oil. −
3'-(3-methyl-2-butenyl)acetophenone 6
．． 129 was obtained quantitatively.

Infrared absorption spectrum ν■1tα-1・3584.29
64,2916,2856°+632.1496,14
18.136B.

1334.1304,1260,1232°1202.
1154, 1130, 1092°1054, . 1012
,988,952,924°906.794,684 Proton nuclear magnetic resonance spectrum (δppm in CDCl5) 1.67 (3H, s), 1.79 (3H, s).

2.56 (3H, s).

3.38 (2H, d, J = 7.3 Hz).

3.47 (3H, s).

5, I 7-5.25 (IH, m).

5.2 6 (2H, s).

6.6 4 (] H1s, J = 8.8 H
z).

7.57 (IH9d, J=8.8Hz).

1 2.7 7 (I H,s) Mass spectrum: M/Z (%) 264. (M', 14).

2] 9 (26), 2] 7 (] 2).

+89 (7), 177 (12).

165(13), 45(100).

Production Example 2 5.09 grams of 2',4'-dihydroxyacetophenone and 6.379 grams of N,N-diisopropylethylamine were dissolved in 60 volumes of dimethylformamide. To this solution, 2.7277 g of tetraromethyl methyl ether was slowly added under water cooling, stirred for 20 minutes under water cooling, and further heated to room temperature for 1.
The reaction was allowed to proceed for 5 hours. After the reaction, the reaction mixture was extracted with 300 d of diethyl ether, and the diethyl ether layer was sequentially washed with water (1007 d x 3) and shaken with saturated brine (50 d).
X2), dried over anhydrous sodium sulfate, filtered, and evaporated to obtain a residue. This residue was subjected to silica gel column chromatography (diameter 3.5 cm; 72.8!?;n
-Hexane:ethyl acetate 4:1; 0.3 to 9/c
m2) to form a colorless oily substance, 2°-hydroxy-4°.
-Methoxymethoxyacetophenone 5.669 was obtained (
yield 87.8%).

Infrared absorption spectrum sheet “AScytt-”: 163
B, 1582, 1504, 1368° 1332.125
0.121g, 1154°1142.1082,106
2,994. .

942.922 Proton nuclear magnetic resonance spectrum (δppm in CDCl5): 2.56 (3H, s), 3.47 (3H2s).

5.20 (2H, s).

6.54 (IH, dd, J=8.8, 2.4Hz).

6.59 (IH, d, J=8.8, 2.4Hz).

7.65 (IH, d, J = 8.8 H2).

- Monthly 12.61 (disappeared with addition of IH, S, D20) Mass spectrum: M/Z (%) 196 (M'', 100).

151 (35), I 37 (10).

135(12), 65(12).

53(12), 51(10).

46(22), 43(47) Production Example 3 2″,4°-Dihydroxyacetophenone 456π9 was dissolved in dimethylformamide 3-, and after cooling to 0°C, N
, N-diisopropylethylamine 1.73- were added. Further, 0.6177 g of chloromethyl methyl ether was added, and the mixture was stirred for 18 hours to react. After the reaction was completed, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off to obtain a colorless and transparent liquid. - 707.911 g of bismethoxymethoxyacetophenone was obtained (yield: 9
8.3%).

Infrared absorption spectrum ν■4"cyx-': 2952.
1668. +604. I 574. .

1494-. 1398, 1358, 1258゜121B
, 1206, 1156, 1134° 1084.1058
,1008,924°844.816 Proton nuclear magnetic resonance spectrum (δppm in CDCl5): 2.60 (31(,s), 3.47(3H2s).

3.52 (3H, s), 5.19 (2H, s).

5.27 (2I-1, s).

6.71 (IH, dd, J=8.8.2.4Hz).

6.82 (IH, d, J = 2.4 Hz).

7.77 (lH, d, J = 8.8 Hz) mass spectrum.

M/Z (%) 240 (M”, 5).

225(1), 209(1).

1B+(+), 180(3).

1 79 (2), I 6 5 (2).

164(2), 70(2).

61(3), 45(100).

4.3(22), 28(3) Production Example 4 40.00 g of 2',4°-dihydroxy-3'-(3-methyl-2-butenyl)acetophenone obtained as an intermediate in Production Example 1 was dissolved in dimethyl Formamide 250)
d, and add 27.61 g of anhydrous potassium carbonate to this solution.
g, and benzyl bromide 24.0- were added thereto, and the mixture was stirred at -5°C for 2 days under a nitrogen stream.

After the reaction was completed, water was added, the precipitate was collected by filtration, and n-
Recrystallization from hexane yields colorless needle-shaped crystals of 4°-benzyloxo-2°-hydroxy-3″-(3-methyl-2
-butenyl)acetophenone 4.8.559 was obtained (yield 86.1%).

Infrared absorption spectrum
068.3024, 2988.2964°29+2.2
852,1632,1614゜1530.1502,1
4.54.141B.

1394, l366.1330, 1306°1 288
．． 1 276.1 234,1 ] 64°113
0.11'06,1090,1072゜1 030.1
022,966.84.4,808°788.752
,728,690,640 Proton nuclear magnetic resonance spectrum (δppm in CDC13): 1.67 (3H, brs), 1.71 (3H, br
s).

2.54 (3H, s).

3.41 (2H, d, J=7.3Hz).

5.16 (2H, s).

5.23 (I H,brt,'J = 7.3 Hz
).

6.48 (IH, d, J = 8.8 Hz).

7.31-7.43 (5H, m).

7. 5 6 (I H, d, J =
8. 8 1-1z).

12.76 (IH,s) Mass spectrum: M/Z (%) 3 1 0 (M”, I 4).

255(5), 220(6).

219(41), 177(9).

1 6 5 (9), 9 2 (8), 91 (100)
, 43(37) Production Example 5 32.66 g of 3.4-dihydroxybenzaldehyde was dissolved in dimethylformamide 200-, and after cooling to -5°C, N,N-diisopropylethylamine 200- was added. Furthermore, chloromethyl methyl ether (70%) was gradually added, and the mixture was stirred overnight to react. After the reaction was completed, the reaction mixture was poured into ice water, extracted three times with ethyl acetate, and the organic layer was washed three times with water and then shaken with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off to obtain a residue. This residue was recrystallized from ethyl acetate to obtain 3,4-
Bismethoxymethquine benzaldehyde 41.2017
was obtained (yield 86.37%).

Infrared absorption spectrum νg S'A"3-'・2956
．． 2904, 2828.1694. .

+598. I 500.1434,1260゜I 35
2,1126.1076.984 Proton nuclear magnetic resonance spectrum (δppm in CDC13): 3.52 (6H, s), 5.29 (2H, s).

5.32 (2H, s).

7.28 (IH, d, J=8.3Hz).

7.50 (IH, dd, J=8.3, 1.5Hz).

7, e 7 (l H, d, J = 1.5 Hz)
.

9.85 (IH, s) Mass spectrum: M/Z (%) 226 (M”, 6).

166(5), 150(11).

14.9(5), 134-(3).

5 8 (19), 4 5 (100)'.

Production Example 6 2.4.4 g of p-hydroxybenzaldehyde and 5.069 g of triethylamine were dissolved in 40% of anhydrous dimethylformamide. To this solution, 3.229 g of chloromethyl methyl ether was slowly added dropwise over 10 minutes under water cooling, stirred for 1 hour under water cooling, and then returned to room temperature for 30 minutes.
The reaction mixture was stirred for hours. After the reaction was completed, the reaction mixture was extracted with ethyl acetate (400-), and the ethyl acetate layer was sequentially extracted with
Washing with water (200dX4), shaking with saturated saline (1007x)
2), drying with anhydrous sodium sulfate, filtering, and distilling off the solvent,
A yellow oily substance of p-methoxymethoxybenzaldehyde 3.3+9 was quantitatively obtained.

Infrared absorption spectrum c7'x c7/L -' :2
956.2900.282B, 1696°1600.1
580,1510,1444゜14-28.1394,
1316.124.4゜1214.1202,1150
,1108°1082.988,922.834,75
4° proton nuclear magnetic resonance spectrum (δppm in CDCl5): 3.48 (3H, s), 5.25 (2H, s).

7.14 (2H, d, J = 8.8 Hz).

7.83 (2H, d, J = 8.8 H2).

9.89 (IH, s) Mass spectrum: M/Z (%) I 6 6 (M”, 1 3).

1 3 5 (11), I 2 2 (27).

+21 (31), 93 (+6).

83(16), 72(41).

6 5 (+ 3), 4 6 (+ 0 0) Production Example 7 12.22 g of p-hydroxybenzaldehyde was dissolved in dimethylformamide 801d, and 17.66 g of anhydrous potassium carbonate and 13 benzyl bromide were added to this solution.
．． 077 was added, and the mixture was stirred at room temperature for 1 day under a nitrogen stream.

After the reaction, water was added, the precipitate was collected by filtration, and recrystallized from a dichloromethane-hexane mixed solvent to obtain colorless needle-like crystals of 4-pendyloquine benzaldehyde.
79 was obtained (yield 94.6%).

Infrared absorption spectrum ν'm'As2-': 3052.
3032, 2828, 2800° 2744.168B,
1600, 1576° 1510, +4.62.1454
, 1426.

1396.1320,1300,1260°12+4.
1166.1110.1020゜866.832.73
4,696,656 proton nuclear magnetic resonance spectrum (δppm in CDCl!l): 5.14 (2H, s).

7.07 (2H, d, J = 8.8 Hz).

7.31-7.4.5 (5H, m).

7.83 (2H, d, J=8.8Hz).

9.88 (IH,s) Mass spectrum: M/Z (%) 2 1 2 (M”, 39).

92 (64), 91 (100).

65 (95), 63 (19).

Next, the compounds of formula (1) and formula (2) obtained as described above are condensed in the presence of a base. Examples of the solvent used include ethanol or dimethyl sulfoxide, and specific examples of the base include potassium hydroxide, which may be added after being dissolved in the solvent used as appropriate.

The reaction temperature is suitably about -10 to 60°C. This reaction is an aldol condensation reaction between the acetyl group at the I° position in the compound of formula (1) and the pomyl group at the 1st position in the compound (2). The reaction proceeds in the same way regardless of which substituents are substituted. After the reaction, the compound of formula (1) can be obtained by a commonly used purification method.

Furthermore, at least one operation such as reduction or deprotection is performed to obtain a compound of formula I, and the combination and order of these operations can be adjusted as appropriate depending on the target substance.

Catalytic reduction can be used for reduction.

In the case of catalytic reduction, examples of the solvent used include organic solvents such as ethyl acetate, and palladium on carbon can be used as the catalyst. The reaction temperature is suitably about -10 to 60°C, and the reaction can be sufficiently achieved at normal pressure, but the reaction may be carried out under pressure depending on the case.

After the reaction, the compound of formula I can be obtained by a commonly used general purification technique.

Deprotection can be accomplished by adding acid and heating or by reduction. In particular, methoxymethoxy can be removed by adding an acid and heating. Specific examples of the acid include hydrochloric acid, and suitable solvents include alcohols such as methanol or tetrahydrofuran.

Furthermore, the benzyl group can be removed by the reduction operation described above.

Next, a specific example of the production of the compound of formula (1) will be shown.

Specific Example 1 2°-hydroxy-4'-methoxymethoxy-3"-(3-methyl-2-butenyl)acetophenone obtained in Production Example I 5.509 and p-methoxymethoxybenzaldehyde 3 obtained in Production Example 6 After dissolving .46 g in ethanol 507, it was cooled to 0°C, a 100% saturated potassium hydroxide solution in ethanol was added, and the solution was dissolved at room temperature under an argon atmosphere.
The mixture was stirred for several days. After the reaction was completed, the reaction solution was made acidic with dilute hydrochloric acid while cooling, and then extracted with ether. This ether extract was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off, the resulting residue was recrystallized from methanol, and yellow needle-like crystals of 2°-hydroxy-4,4°-bismethinemethoxy- 3°-(3-methyl-2-butenyl)chalcone 3
．． 339 was obtained (yield 38.8%).

Infrared absorption spectrum νWAX Q7/(-' :29
56.2916, 2852.2824°+634.16
10.1584. +562°1508.1490,14
54. +420°1374.1306,1292.12
74°1238.1198.1170.1I54. .

1114.1082. +048,1010°992.9
70,962,924,870°824.800,78
8,658,632°612.540,512 Proton nuclear magnetic resonance spectrum (δppm in acetone-da) 1.65 (
3H9s), 1.80(3I(,s).

3.40 (2H, d, J=7.3Hz).

3.45 (3H, s), 3.46 (3H, s).

5.21-5.28 (IH, m).

5.28 (2H, s), 5.35 (2H, s).

6.75 (IH, d, J=8.8Hz).

7.12 (2H, d, J=8.8Hz).

7.82 (2H, d, J=8.8Hz).

7.87 (2H, s).

8.11 (IH, d, J = 8.8 Hz).

13.75 (l H, s) Mass spectrum: M/Z (%) 412 (M', 18).

369(13), 367(12).

203(46), 161(9).

149(9), 45(100) Next, 2.879 of this 2°-hydroxy-4,4°-bismethoxymethoxy-3”-(3-methyl-2-butenyl)chalcone was dissolved in tetrahydrofuran 607d, Add 5-15% hydrochloric acid methanol reagent 15- to this,
The mixture was stirred at 50° C. for 6.5 hours under an argon stream. After the reaction was completed, the reaction solution was poured into ice water and extracted with ether. This extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (Merk 93g 5°197.39: elution solvent, n-
Hexane: Ediyl acetate 2:1; 0.5 kg7c
m”), fractionated in 60M portions, combined the 16th to 33rd fractions, and distilled off the solvent to obtain a yellow-orange solid of 2°C.
, 4,4°-trihydroxy-3'-(3-methyl 2-
butenyl) chalcone 2.249 was obtained (yield 99.1%)
).

Infrared absorption spectrum νHax (y-': 3392.2
972,29.16.1628゜1606, ] 554
,1512,1486°1444.1370.1320
,1292°1240.1170.1 + 10.10
96°104.0,828,790,626,538° Proton nuclear magnetic resonance spectrum (δpPmin in acetone-do) 1.65 (
3H,s), 1.79(3H,s).

3,・38 (2H, d, J = 7.3 Hz)
.

5.29 (I H, brt, J = 7.3 H2)
.

6.54 (IH, d, J=8.8Hz).

6.93 (2H, d, J=8.8Hz).

7.73 (2H,d, J = 8.8 Hz17.
74 (IH, d, J=15.6Hz).

7.86C11-1, d, J=15.6Hz).

7.98 (IH, d, J = 8.8 Hz).

9.02 (I) (, s), 9.36 (IH, s).

] 4.81 (IH9s) Mass spectrum: M/Z (%) 324 (M”, 70).

281(59), 269(24).

1 89 (19), 176 (21).

1.61 (29), 149 (+00) 147 (33
), ] 2ocs4).

The reaction of Specific Example J is illustrated as follows.

鮮=27-Specific Example 2 In a mixed solution of 2,089 of 2°-hydroxy-4-methoxymethoxyacetophenone obtained in Production Example 2, 1.949 of p-methoxymethoxybenzaldehyde obtained in Production Example 6, and 5 of ethanol. Under water cooling, saturated potassium hydroxide
Add 15 mQ of ethanol solution and cool for 30 minutes under water cooling.
The mixture was stirred and reacted at room temperature overnight.

After the reaction was completed, the reaction mixture was made acidic with dilute hydrochloric acid to obtain a yellow solid. This was recrystallized with methanol and a yellow prism product of 2'-hydroxy-4,4'-bismethoxymethoxychalcone 2. lIg was obtained (yield 57.8%).

Infrared absorption spectrum ν'4a"x I2-': 1
642.1602.156B, 1510°1358.1
278.1232,1196°1172.1158,3
142,1076°1000.920,832,798 Proton nuclear magnetic resonance spectrum (δppm in CDCl5): 3.49 (6H, s), 5.22 (4H, s).

6.58 (IH, dd, J=8.8, 2.4Hz).

6.64 (l H, d, J = 2.4 Hz).

7.08 (2H, d, J = 8.8 Hz).

7.47 (IH, d, J=15.6Hz).

7.60 (2H, d, J = 8.8 Hz).

7.84 (IH, d, J=8.8Hz).

7°86 (IH, d, J = 15.6Hz).

13.36 (I H,s , disappeared by addition of DyO) Mass spectrum: M/Z (%) 344 (M'', 100).

343(28), 299(25).

1 67 (15), 1 66 (16).

164(19), 151(7B).

147(55), 134(18).

Next, 1.09 of 2'-hydroxy-4,4'-bismethoxymethoxychalcone was dissolved in 7 d of tetrahydrofuran, 5 yd of 5-15% hydrochloric acid methanol reagent was added, and 50 d of
The mixture was heated at ℃ for 30 minutes to react. After the reaction was completed, the reaction mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution, extracted with 300 d of ethyl acetate, and the ethyl acetate layer was washed with water (+00 d).
X3), shaken with saturated saline (50 dx2), dried over anhydrous sodium sulfate, filtered, and evaporated to obtain a residue. This residue was subjected to silica gel column chromatography using a mixed solvent of n-hexane and ethyl acetate, and a yellow granular product of 2°, 4.4”-trihydroxychalcone 521
mg (yield 70%).

Infrared absorption spectrum si=en=e71+-': 3288
．． 1634,1590,1554゜1514.1370
．． 1276.1220°119B, 1174.1166
, +126 proton nuclear magnetic resonance spectrum (δppm in acetone-do): 6.37
(IH, d, J=2.4Hz).

6.47 (I H, dd, J = 9.0.2.4.
Hz).

6.93 (2H, d, J = 8.5 Hz).

7.7 4 (2H, d, J = 8.5 Hz).

7.75 (I H, d, J = 1 5.6 Hz
).

7.86 (IH, d, J=15.6Hz).

8.1 2 (I H, J = 9.0 Hz) Mass spectrum: M/Z (%') 256 (M'', 98).

255(61), 163(41).

150 (30), 137 (100) 1 2 0 (
49), 1 0 7 (2B).

91 (20), 45 (86) −31= The reaction of Example 2 is illustrated as follows.

Soil Specific Example 3 15.09% of 3,4-bismethoxymethoxybenzaldehyde obtained in Production Example 5 and 16.09% of 2゛,4°-bismethoxymethoxyacetophenone obtained in Production Example 3 were dissolved in 131yd of ethanol and poured into ice water. After cooling, 1507 d of saturated potassium hydroxide/ethanol solution was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was diluted with water, the pH was adjusted to about 6 with 6N hydrochloric acid while cooling with water, and the resulting precipitate was collected by filtration, washed with water, dried, and 2'',3,4.4'-tetrakis 23.39 g of methoxymethoxychalcone was obtained (yield 78.3%).

Infrared absorption spectrum 'As cll-': 29
36.2904, 2824.1648°1602.15
90.1510,1402゜1316.1256,12
42.1194°1152.1000.916 Proton nuclear magnetic resonance spectrum (δppm in CDCl5), 3.49 (3H, s), 3.50 (3H, s).

3.52 (6H, s), 5.21 (2H, s).

5.25 (4H, s), 5.27 (2H, s).

6.77 (I H, dd, J = 8.8.2.2
Hz).

6.86 (11-1, d, J = 2.2 Hz)
.

7.20 (I H, dd, J = 8.1.1.2
Hz).

7.21 (IH, d, J = 8.1 Hz).

7.36 (IH, d, J=15.9Hz).

7.45 (IH, d, J = 1.2 Hz).

7.59 (] H, d, J = 15.9Hz).

7.67 (l H,d , J = 8.8 Hz) Mass spectrum: M/Z (%) 448 (M'', 2).

327(2), 299(3).

2 + 1 (1), + 81 (2).

179(2), 135(1).

46(2), 45(100) Next, this 2°, 3.4.4°-tetrakismethoxymethoxychalcone 4049 was mixed with 36ml of hydrochloric acid methanol reagent.
and refluxed for 10 minutes. The reaction solution was poured into ice water, and the precipitated crystals were collected by filtration, washed with water, and then dried. This was subjected to column chromatography (Kieselge160 230-
400 mesh, 280 g; elution solvent, hexane:ethyl acetate-1:1, 0.4 kW/cm'),
The 32nd to 70th fractions were collected in 50-unit fractions to obtain 2', 3,4,4'-tetrahydroxychalcone 543.2xy (yield 22.1%).

Infrared absorption spectrum list-5α-1:3372.32
48,1632,1612゜1594.1550,15
12,1370°1284.1256,1220.11
82゜1144.1112.1032 Proton nuclear magnetic resonance spectrum (δppm in CD30D): 6.30 (I H,d, J = 2.44 Hz)
.

6.42 (IH, dd, J=2.44, 8.79Hz)
.

6.82 (IH, d, J=8.3Hz).

7.1 1 (IH, dd, J=8.3, 1.95Hz)
.

7.1 8 (I H, d, J = I, 9
6 Hz).

7.52 (IH, d, J = 1 5.1 3 Hz).

7.73 (IH, d, J=15.39Hz).

7.93 (IH, d, J = 9.03 Hz) Mass spectrum: M/Z (%) 2 7 2 (M', 6 6).

271(23), 163(27).

・150 (29), +37 (100) 123 (1
2), 108(17).

8 9 (31), 6 9 (18).

5] (31), 45 (18) =36- The reaction of Specific Example 3 is illustrated as follows.

10OH Specific Example 4 6.31 g of 2°,4′-bismethoxyacetophenone obtained in Production Example 3 and p-methoxymethquinohendzaldehyde obtained in Production Example 64. ．． 00g to ethanol50
yd and cooled to 0° C., 30°C of a saturated potassium hydroxide/ethanol solution was added, and the reaction solution was returned to room temperature and stirred for 2 days. The reaction solution was diluted with water, neutralized with 6N hydrochloric acid, extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain a reaction mixture as a syrup. This was subjected to column chromatography (Kieselgel 6
0, 270-400 mesh, 320g, 0.5kg
/cm'; Elution solvent.

Hexane, ethyl acetate (1:l), fractionated 507d each, merged the 66th to 87th fractions, and 2°
4.4'-) Rismethoxymethquine chalcone 5.64
9 was obtained (yield 559%).

Infrared absorption spectrum ν4B'x, , -1.

2952.2904. , I 654,1604°+57
4.1510.1328,1314°+242.120
6.1154.1080°994.922 Proton nuclear magnetic resonance spectrum (δppm in CDC13): 3.47 (3H, s), 3.49 (6H, s).

5.20 (2H, s), 5.20 (2H, s).

5.23 (2H, s).

6.76 (I H, dd, J=8.55, 1.95Hz
).

6.85 (] H, d, J = 1.95 Hz)
.

7.04 (2H, d, J=8.30Hz).

7.34 (IH, d, J=15.63Hz).

7.53 (2H, d, J=8.79Hz).

7.62 (IH, d, J=15.63Hz).

7.65 (IH, d, J = 8.55 Hz) Mass spectrum M/Z (%) 389 (1).

388 (M', 4.).

195(13), 194(14).

-39 = Next, add 2.529% of 5% palladium on carbon to 50% of ethyl acetate.
77 and hydrogenated for 2 hours, then 2', 4
．． Hydrogenation was performed by adding 507d of an ethyl acetate solution of 4'-trismethoxymethoxychalcone 5.119. After the reaction, the palladium on carbon was filtered and concentrated under reduced pressure to give 1
-(2,4-bismethoxymethoxyphenyl13-(4
-Methoxymethoxyphenyl 11-propanone was obtained quantitatively.

Infrared absorption spectrum ν = 2952.16
68,1602,1574°1512.14.44,1
400,1312°1246.1234,1200.1
154°1+22.1078.1008 Proton nuclear magnetic resonance spectrum (δppm in CDC13): 3.00 (2H, t, J-7, 32Hz).

3.30 (2H, t, J=7.32Hz).

3.47 (9H, s), 5.13 (2H, s).

5.18 (2H, s), 5.22 (2H, s).

6.71 (IH, dd, J=8.3, 2.44Hz).

6.82 (I H,cl, J = 2.44 Hz
).

6.94 (2H, d, J=8.3Hz).

7.1 4 (2H, d, J = 8.3 H2).

7.7 2 (I H, d , J 8.3 Hz) Mass spectrum: M/Z (%) 390 (M', 2).

330(11), 181(68).

151 (16), 45 (100).

Furthermore, this 1-(2,4-bismethoxymethoxyphenyl)-3-(4-methoxymethoxyphenyl)-1-
Propanone 4.449 was dissolved in methanol, hydrochloric acid methanol reagent 38) d was added, and the mixture was stirred at 60°C for 30 minutes. After the reaction was completed, the reaction solution was poured into ice water, neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to obtain a reaction mixture. This was subjected to column chromatography (Kiese
lgel 60270-400 mesh, 699.0.
5 kg/Cm': elution solvent, hexane: ethyl acetate =
1:1) to obtain 1-(2,4-dihydroxyphenyl)-3-(4-hydroxyphenyl)-1-propanone 2.551j (yield: 86.7%).

Infrared absorption spectrum νm==,,-':3456.3
272,1626,1598°1514.1434. +
320.1294. .

1212.1162,1134,986°778.74
6,620 Proton nuclear magnetic resonance spectrum (δppm in acetone-do): 2.92
(2H, t), 3.22 (2H, t).

6.37 (IH, d, J=1.95Hz).

6.42 (I H, dd, J=8.79, 1.95Hz
).

6.76 (2H, d, J = 8.3 Hz).

7.11 (2H, d, J = 8.3 Hz).

7.78 (I H,d, J = 8.79 Hz)
.

12.82 (IH,br) mass spectrum M/Z (%) 259 (6).

258 (M”, 36).

239(II), 152(10).

137 (100), 120 (24) 107 (35
), 42(23) -43= The reaction of specific example 4 is illustrated as follows.

10 Specific Example 5 20.01 g of 4°-benzyloxy-2°-hydroxy-3°-(3-methyl-2-butenyl)acetophenone obtained in Production Example 4 and 15 p-benzyloxybenzaldehyde obtained in Production Example 7 .01 was dissolved in dimethyl sulfoxide 657, 130 d of saturated potassium hydroxide/ethanol solution was added, and the mixture was stirred at room temperature under a nitrogen stream for 25 hours. After the reaction was completed, 3N hydrochloric acid was added to the reaction solution diluted with water while cooling to make it gradually acidic. The precipitate was collected by filtration, and then recrystallized from a mixed solvent of benzene and ethanol to obtain yellow needles. As crystals, 4,4'-dibenzyloxy-2'-hydroxy-3'-(3-methyl-2
-Butenyl)chalcone 23.64g was obtained (yield 727
%).

Infrared absorption spectrum νW: S, -1°3028.2
9 + 2.2852.1638°1608.1566
．． 15+4. ．． 1498°1450.1426,138
8,1376°1356.1312. +292.126
0°1242.1 182. ! 164. ．． 1114
゜】080. ]066, ]028.978.858°8
26.780 Proton nuclear magnetic resonance spectrum (δT) pm in CDCl5): 1.67 (3H, s), 1.72 (3H, s).

3.45 (2H, d, J=7.3Hz).

5.10 (2H, s), 5.17 (2H, s).

5.27 (IH, brt, J = 7.3 Hz)
.

6.51 (] H, d, J = 8.8 Hz).

7.00 (2H, d,, J = 8.8 Hz).

7.29-7.44 (] OH, m).

7.44 (I H, d, J = 15.11 (z)
.

7.58 (2H, d, J = 8.8 Hz).

7.74 (IH, d, J = 8.8 Hz).

7.83 (IH, d, J =] 5.1 Hz).

] 3.47 (l H, S) Mass spectrum: M/Z (%) 5 04 (M”, I O).

4, 14(6), 4.13(17).

2 0 3 (27), 9 2 (8).

9] (100), 65 (6).

44, (9) Next, this 4.4
°-dibenzyloxy-2°-hydroxy-3°-(3
-Methyl-2-butenyl)chalcone (21.039 g) was added and stirred at room temperature for 6 hours to absorb hydrogen. After the reaction, the suspension was filtered to remove palladium on carbon, the solvent was distilled off, and the resulting residue was recrystallized from benzene to give 1-(2,4-dihydroxy- 3-isopendelphenyl)-3-(4-hydroxyphenyl I
11.85 g of I-propanone was obtained (yield: 866%).

Infrared absorption spectrum C71L-':3
172.2952,2864. +616°1584.1
514, 14.96. ] +4541366, l 324
,1294,1260°1240.1174,1152
．． 1118°]092. ]028.890.854.8
26°792.760,666.642,618 Proton nuclear magnetic resonance spectrum (δppm in acetone-d6) 0.94
(6H,d, J = 6.8 Hz).

1.36-], 4-7 (2H, m).

1.59 (] H, t, 5eptet.

J = 6.8 H2, J = 6.8 Hz).

2.66 (I H, dd, J=5.4, I O, 3H
z).

2.66 (IH, t, J = 7.8 Hz).

2.92 (2) I, t, J = 7.3 Hz).

3.24 (2H, t, J=7.3Hz).

6.47 (IH, d, J = 8.8 Hz).

6.75 (2H, d, J=8.8Hz).

7.12 (2H, d, J=8.8Hz).

7.68 (IH, d, J=8.8Hz).

8.48 (11-1, brs).

13.17 (I H,s disappears with addition of D20) Mass spectrum M/Z (%) 328 (M”, 4 ]).

272(21), 254(20).

208(12), 207(93).

1 8 9 (12), 1 6 6 (30).

165(46), 151(21).

1 4, 9 (20), I 4 7 (I I
).

120 (57), 107 (100) The reaction of specific example 5 is illustrated as follows.

Experimental Example 1 Preparation of Testosterone-5α-Reductase An 11-week-old F344 male rat was dissected and the prostate gland was removed. The obtained prostate capsule and adipose tissue were removed, and a 0.25 M sucrose solution was added thereto at a rate of 5 i/g, followed by homogenization using a cell crusher (POLYTRON). The obtained homogenate was filtered through gauze, and the filtrate was further homogenized using a Dounce homogenizer.
After sonication, the microsomal fraction was separated into 1# by centrifugation.
Ta. This microsomal fraction was dissolved in 0.05M potassium phosphate buffer containing 3.377 0.25M sucrose (
It was suspended in pl-(6,6) and used as an enzyme solution.

Measurement of testosterone-5α-reductase and toxic activity: To the above enzyme solution, add 0.05M potassium phosphate buffer (pH 6.6), NADPH (final concentration 10-'
M), glucose-6-phosphate (5X J D -3M
) Glucose-6-phosphate dehydrogenase (0,51
U), bovine serum albumin (091%), [4-”C]
- Testosterone and the compounds obtained in Examples 1 to 5 were added to make a total amount of 6007J. This mixture was heated to 60°C at 30°C.
After reacting for a minute, IN hydrochloric acid was added to terminate the reaction. Testosterone and 5α-dihydrotestosterone were then added as carriers, and the reaction product was extracted with 1.577 g of ethyl acetate. After concentrating the extract, testosterone and 5α-dihydrotestosterone were separated by thin layer chromatography, and the radioactivity of 5α-dihydrotestosterone was measured using a liquid scintillation counter. In addition, the inhibition rate was calculated using the following formula using as a control the same procedure as above except that the compound obtained in the specific example was not added. From the results, the 50% inhibitory concentration was determined and shown in Table 1.

-B Inhibition rate (%) - 1A x 100 A: Amount of 5α-dihydrotestosterone produced when the compound obtained in the specific example is not added B: Amount of 5α-dihydrotestosterone produced when the compound obtained in the specific example is added As is clear from the above results, the compound of formula I was found to inhibit the activity of testosterone-5α-reductase, and is expected to be effective in treating prostatic hypertrophy, alopecia, acne, and the like.

Furthermore, when the compound of formula I was orally administered to ddY male mice and Wistar rats on 19/19, no mortality was observed in any of them.

Thus, the compound of formula (1) has low toxicity and high safety.

Dosage and formulation of compounds of Formula I will now be described.

The compound of formula I, which is the active ingredient of the medicament of the present invention, can be administered to animals and humans as is or together with conventional pharmaceutical carriers. There are no particular limitations on the dosage form;
The tablets, capsules,
Examples include oral preparations such as granules, fine granules, and powders, and parenteral preparations such as injections and suppositories.

In order to exert the desired effect as an oral agent, it depends on the age, weight, and severity of the disease of the patient, but it is usually necessary for adults to use formula I.
It seems appropriate to take 100 to 450 R9 by weight of the compound in divided doses several times a day.

In the present invention, oral preparations such as tablets, capsules, and granules are manufactured according to conventional methods using, for example, starch, lactose, sucrose, mannitol, carboxymethyl cellulose, cornstarch, inorganic salts, and the like.

In addition to the excipients mentioned above, binders, disintegrants, surfactants, lubricants, fluidity promoters, flavoring agents, coloring agents, fragrances, and the like can be used in this type of preparation as appropriate. Specific examples of each are shown below.

[Binder] Starch, dextrin, gum arabic powder, gelatin,
Hydroxypropyl starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol.

[Disintegrant] Starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, low substituted hydroxypropyl cellulose.

[Surfactant] Sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 80° [Lubricant] Talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, Polyethylene glycol.

[Fluidity promoters: light silicic anhydride, dry aluminum hydroxide gel, synthetic aluminum silicate, magnenium silicate.

The compound of formula I can also be administered as a suspension, emulsion, syrup, or elixir, and these various dosage forms may contain flavorings and colorants.

In order to exert the desired effect as a parenteral agent, the compound of the present invention should be intravenously injected or dripped in an amount of 2 to 30 m9 per day for adults, although this will vary depending on the age, weight, and severity of the disease of the patient. Intravenous, subcutaneous, and intramuscular injections are considered appropriate.

This parenteral preparation is manufactured according to a conventional method, and generally uses distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc. as a diluent. be able to. Furthermore, a bactericide, a preservative, and a stabilizer may be added as necessary. In addition, from the viewpoint of stability, this parenteral preparation may be filled into a vial or the like, then frozen, water removed by ordinary freeze-drying techniques, and a liquid preparation prepared from the freeze-dried product immediately before use. Furthermore, isotonizing agents, stabilizers, preservatives, soothing agents, etc. may be added as appropriate.

Other parenteral preparations include liquid preparations for external use, liniments such as ointments, suppositories for rectal administration, and the like, which are manufactured according to conventional methods.

The present invention will be explained in more detail with reference to Examples below.
The present invention is not limited to this in any way.

Example 1 ■Corn starch 39g ■Crystalline cellulose 309 ■Carboquine methyl cellulose calcium 59 ■Light anhydrous silicic acid 0.5g ■Magnesium stearate 0.596 l
25 total 100g According to the above recipe, ① to ② were mixed uniformly and compressed using a tablet machine to obtain one tablet of 200119.

These tablets contain Compound 50-9 obtained in the specific example, and are taken by adults in 2 to 9 tablets a day in several doses.

Example 2 ■ Crystalline cellulose 69g ■ Magnesium stearate Ig ■ Calcium carboxymethyl cellulose 59 25 Total 100g According to the above recipe, parts of ■, ■, and ■ were uniformly mixed, compressed, and then crushed. The remaining amounts of , (2) and (2) were added and mixed, and the mixture was compressed and molded using a tablet machine to obtain 200 to 200 tablets.

This tablet contains 50m9 of the compound obtained in the specific example, and is taken by adults in 2 to 9 tablets a day in several doses.

591 Example 3 ■ Crystalline cellulose 44.59 ■ 10% hydroxypropyl cellulose ethanol solution 251i1 ■ Carboxymethyl cellulose calcium 5 g ■ Magnesium stearate 0.5 g
25g Total 100g Mix ■, ■, and ■ uniformly according to the above recipe, and then net it by a conventional method. After granulating it with an extrusion granulator, drying and crushing it, mix ■ and ■. Compression molding was performed using a tablet machine to obtain tablets each weighing 200 R9.

This tablet contains 50 to 50 of the compounds obtained in the specific examples, and is taken by adults in 2 to 9 tablets a day in several doses.

601 Example 4 (1) Crystalline cellulose 85 g (2) 10% hydroxypropyl cellulose ethanol solution 59 3 4 diluted with 10 total 1009 Items (1) to (2) were uniformly mixed according to the above recipe and were made into a paste. After granulation using an extrusion granulator, the mixture was dried and sieved to obtain granules.

This granule fg contains the compound 100R9 obtained in the specific example, and is administered in doses of 1 to 4.5 g in several doses per day for adults.

Example 5 ■Corn starch 74.59■Light silicic anhydride 0.5g I5'Tahi'' 25 Total 10'Og Mix ■~■ uniformly according to the above recipe, 200Rg
was filled into a No. 2 capsule.

One capsule of this capsule contains the compound 5 obtained in the specific example.
It contains 0m9, and adults should take 2 to 9 capsules a day in several doses.

Example 6 ■ Distilled water for injection Appropriate amount ■ Glucose 2001193 [
I de'tahim 5M total amount 5
d After dissolving ■ and ■ in distilled water for injection, they were injected into an ampoule of 5- and autoclaved at 121° C. for 15 minutes to obtain an injection.

Claims (1)

[Claims] General formula I ▲Mathematical formulas, chemical formulas, tables, etc.▼ I and R_2 represents a hydrogen atom or a hydroxyl group.) Testosterone-5 whose active ingredient is a compound represented by
α-reductase inhibitor.