JPH07304736A - Indole derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound having steroid 5alpha-reductase-inhibiting action and useful for treating prostatic hypertrophy, prostate cancer and acne. CONSTITUTION:A compound of formula I {R<1> is H or lower alkyl ; A is NO2 or BR<2> [BR<2> is C0NHR<2>, COOR<2> or OR<2>; R<2> is H, CHR<3> or R<4> (R<3> and R<4> are each H, an alkyl or an aryl)] ; X is 0 or S(O)n; (n) is 0-2} or its salt, e.g. 4-{2-[[5-nitroindol-1-yl)acetyl]amino]phenoxy}lactic acid ethyl. The compound of formula I is obtained by reacting a compound of formula II (R<1a> is a lower alkyl) with a compound of formula III in the presence of a base (e.g. potassium tert-butylate) in a solvent (e.g., dimethylformamide) at deg.C to a boiling point of the solvent for 0.5-6 hr. The compound of formula I is administered at a daily dose of 1mg to 1g/adult in the case of oral administration, at a daily dose of 0.1-100mg in the case of parenteral administration, e.g. intravenous administration and at a daily dose of 10mg to 100mg in the case of dermal administration.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel indole derivative useful as a therapeutic agent for prostatic hypertrophy, a therapeutic agent for prostate cancer, a therapeutic agent for baldness and a therapeutic agent for acne, which is based on the steroid 5α-reductase inhibitory action.

[0002]

2. Description of the Related Art In patients with benign prostatic hyperplasia, steroid 5α-reductase activity in prostate tissue is increased,
Since a large amount of dihydrotestosterone is present and dihydrotestosterone plays an important role in the development of benign prostatic hyperplasia, it has been reported that a steroid 5α-reductase inhibitor is useful for its treatment [T
he Prostate Supplement, 2, 95 (1989)]. In addition, the growth of prostate cancer depends on dihydrotestosterone, not testosterone, and steroid 5α-reductase inhibitors have been reported to be useful [The Prostat
e, 9, 343 (1986)]. On the other hand, dihydrotestosterone is known to play an important role in the development of acne and baldness [Trends Pharmacol. Sci., 1
0 , 491 (1989)].

JP-A-4-190346 discloses a compound represented by the formula (A) as a raw material for a photographic light-sensitive material and the like. Further, JP-A-5-78315 discloses an indole derivative as a steroid 5α-reductase inhibitor.

[0004]

[Chemical 2]

[0005]

An object of the present invention is to provide a novel indole derivative having a steroid 5α-reductase inhibitory action.

[0006]

The present invention provides a compound of formula (I)

[0007]

[Chemical 3]

{In the formula, R ¹ represents hydrogen or lower alkyl, A is NO ₂ or BR ² [wherein BR ² is CON.
Represents HR ² , COOR ² or OR ² , R ² represents hydrogen or CHR ³ R ⁴ (in the formula, R ³ and R ⁴ are the same or different and represent hydrogen, alkyl, substituted or unsubstituted aryl) ], X is O or S (O) n
(In the formula, n represents an integer of 0 to 2)} or an pharmaceutically acceptable salt thereof.

The compound represented by the formula (I) is hereinafter referred to as the compound (I). The same applies to compounds having other formula numbers. In the definition of each group of formula (I), lower alkyl is
Linear or branched C1-C4, such as methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, te
rt-butyl and the like are included. Alkyl is a linear or branched C1-C10, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, isopropyl, sec-butyl, tert.
-Butyl, 1-methylbutyl, 1-ethylpropyl, 1
-Ethylbutyl, 1-methylpentyl, 1-methylhexyl, 1-ethylpentyl, 1-methylheptyl, 1-
Ethylhexyl, 1,2-dimethylpropyl, 1,2-dimethylbutyl, 2-methylbutyl, 3-methylbutyl, 4-methylpentyl, 5-methylhexyl, 1- (1-methylethyl) butyl, 1-butylpentyl, etc. Included.
Aryl includes phenyl, naphthyl and the like.

The substituents of the substituted aryl include lower alkyl, lower alkoxy, lower alkylamino, trifluoromethyl or halogen having 1 to 4 substituents which are the same or different, and alkyl in lower alkyl and lower alkoxy, lower alkylamino. The moiety has the same meaning as the above lower alkyl. Halogen means fluorine, chlorine, bromine or iodine.

The pharmaceutically acceptable salts of compound (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. Examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate and phosphate, and organic acid salts such as acetate, maleate, fumarate, tartrate, citrate and lactate, and metal salts. Examples of the salt include alkali metal salts such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt and zinc salt, and ammonium salts such as ammonium and tetramethylammonium. And the organic amine addition salts include addition salts of morpholine, piperidine, etc.
Amino acid addition salts include glycine, phenylalanine,
Examples thereof include addition salts of aspartic acid, glutamic acid, lysine and the like.

Next, a method for producing the compound (I) will be described. In the production method shown below, when the defined group changes under the conditions of the method for implementation or is inappropriate for performing the method, a method for introducing and removing a protecting group commonly used in synthetic organic chemistry [ For example, Protective Groups in Organic Synthesis
ps in Organic Synthesis), by Green (TW Greene),
The target compound can be obtained by using John Wiley & Sons Inc. (1981)]. Moreover, the order of the substituent introduction steps can be changed as necessary.

[0013]

[Chemical 4]

(In the formula, R ^1a represents lower alkyl in the definition of R ¹ , and A and X have the same meanings as described above.) In the compound (I), the compound (Ia) in which R ¹ is a lower alkyl group is It can be obtained by reacting compound (II) obtained from aniline with compound (III) in the presence of a base.

As the reaction solvent, ether, tetrahydrofuran, dimethylformamide, dimethylsulfoxide and the like are used. As the base, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butyrate, lithium diisopropylamide and the like can be used. Compound (II) and the base are used in 1 to 1.5 equivalents relative to compound (III). The reaction is carried out between 0 ° C. and the boiling point of the solvent used,
It ends in 0.5 to 6 hours.

By hydrolyzing compound (Ia) in the presence of a base, compound (Ib) in which R ¹ is hydrogen can be obtained. As the reaction solvent, water-containing methanol, ethanol, dioxane or the like is used. As the base, 1 to 5 equivalents of lithium hydroxide, sodium hydroxide, potassium hydroxide or the like is used. The reaction is performed at 0 to 100 ° C and is completed in 0.5 to 24 hours.

The compound (II) used as a raw material can be obtained by the following production method.

[0018]

[Chemical 5]

(Wherein R ¹ and X have the same meanings as described above) The compound (II) can be produced by a known method (for example, JP-A No. 1-1395).
No. 58), the compound (IV) can be obtained by reacting it with 1 to 2 equivalents of bromoacetyl bromide. As the reaction solvent, dimethylformamide, toluene, benzene and the like are used. Reaction is 10
It is carried out between 0 ° C and the boiling point of the solvent used, and is completed in 1 to 24 hours.

A compound (IIIa) in which A is B ¹ R ² (wherein B ¹ R ² is CONHR ² or COOR ² and R ² is as defined above) in the compound (III) used as a starting material ) Can be obtained by the following manufacturing method.

[0021]

[Chemical 6]

(Wherein B ¹ and R ² have the same meanings as described above) The compound (IIIa) is obtained by converting the compound (V) into the compound (VI).
It can be obtained by reacting with a condensing agent and a base. As a reaction solvent, dichloromethane,
Chloroform, 1,2-dichloroethane and the like are used. 2-Chloro-1-methylpyridinium iodide, isobutyl chlorocarbonate, etc. are used as the condensing agent, and triethylamine, tributylamine, diisopropylamine, etc. are used as the base. The compound (VI), the condensing agent and the base are used in 1 to 4 equivalents based on the compound (V). The reaction is carried out between 10 ° C and the boiling point of the solvent used, and is completed in 1 to 24 hours.

The compound (IIIb) in which A is R ^2a O (in the formula, R ^2a is one in which hydrogen is excluded from the definition of R ² ) in the compound (III) can be obtained by the following production method. .

[0024]

[Chemical 7]

(In the formula, R ^2a has the same meaning as described above, Z is chlorine, bromine or iodine, and Me is methyl.) The compound (IX) is obtained by converting the compound (VII) into the compound (VII).
It can be obtained by reacting with I) in the presence of a base. As the reaction solvent, ether, tetrahydrofuran, methyl ethyl ketone, dimethylformamide, dioxane or the like is used. As the base, calcium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium t-butyrate or the like is used. Compound (VIII) and the base are used in 1 to 5 equivalents based on compound (VII). The reaction is 0 ° C
It is carried out between the boiling points of the solvents used in Example 1 and is completed in 0.5 to 24 hours.

The compound (X) can be obtained by reacting the compound (IX) with dimethylformamide / dimethylacetal in the presence of a base such as pyrrolidine in a solvent such as dimethylformamide. Dimethylformamide / dimethylacetal and a base are used in 1 to 5 equivalents relative to compound (IX). Reaction is 10 ℃
Between the boiling points of the solvents used in 1 to 24 hours and are completed in 1 to 24 hours.

The compound (IIIb) can be obtained by hydrogenating the compound (X) in the presence of a catalyst such as Raney nickel, palladium carbon, Lindlar catalyst or the like in a solvent such as methanol, ethanol or isopropanol. The catalyst is 5 to 20% (weight ratio) with respect to the compound (X).
Used. The reaction is carried out at 10 to 50 ° C. for 1 to 24
Finish in time.

The intermediates and the target compounds in the above-mentioned production methods are purified by conventional purification methods in synthetic organic chemistry, for example,
It can be isolated and purified by subjecting it to filtration, extraction, washing, drying, concentration, recrystallization, various chromatography and the like. In addition, the intermediate can be subjected to the next reaction without being particularly purified. When it is desired to obtain a salt of compound (I), when compound (I) is obtained in the form of a salt, it may be purified as it is, and when it is obtained in a free form,
It may be dissolved or suspended in an appropriate solvent, and an acid or a base may be added to form a salt.

The compound (I) or a pharmaceutically acceptable salt thereof may exist in the form of an adduct with water or various solvents, and these adducts are also included in the present invention. Specific examples of compound (I) obtained by each production method are shown in Table 1. In the table, Et and t-Bu mean ethyl and tert-butyl, respectively.

[0030]

[Table 1]

Next, the pharmacological action of compound (I) will be explained.

Test Example 1 Acute toxicity test A test compound was orally administered (300 mg / kg) to 3 male dd mice each having a body weight of 20 ± 1 g. The mortality situation 7 days after administration was observed and the minimum mortality (MLD) value was calculated. MLD of compounds 3 and 4 is> 300 mg / kg
(There were no deaths).

Test Example 2 Steroid 5α-reductase Inhibition Test According to the method of T. Liang et al. [Endocrinology, 117, 571 (1985)], male rat rat epikowamaru was mixed with 10 volumes of 0.32 M sucrose,
After homogenization with 20 mM sodium phosphate buffer (pH 6.5) containing 1 mM dithiothreitol and 0.05 mM dihydronicotinamide adenine dinucleotide (NADPH),
It was centrifuged (100,000 × g, 30 minutes). The above-mentioned buffer was added to the obtained precipitate and suspended to prepare an enzyme solution (10 to 20 mg protein / ml).

The enzyme activity was measured by [4- ¹⁴ C] -testosterone (150 nM), NADPH (2 nM) and the above enzyme solution (10 μg).
The reaction solution (40 mM Tris citrate buffer containing 1 mM dithiothreitol, pH 4.5) containing a protein and a test compound in a total volume of 0.5 ml was incubated at 37 ° C. for 10 minutes. The enzymatic reaction was stopped by adding 2 ml of ethyl acetate, and then centrifuged (1,000 xg, 5 minutes). The ethyl acetate layer was collected in a test tube and dried to dryness, 25 μl of ethyl acetate was added, and the mixture was separated by silica gel thin layer chromatography (TLC) (developing solvent;
Dichloromethane: diethyl ether = 11: 1).
The radioactivity of testosterone, the produced dihydrotestosterone and androstendiol was measured using an image scanner BAS2000 (Fuji Film Co., Ltd.), and the enzyme activity inhibition rate was calculated. As a result, at a test compound concentration of 100 nM, 99% of compound 3 and 4% of compound 4
Showed an inhibition rate of 98%.

Compound (I) or a pharmaceutically acceptable salt thereof can be administered alone as it is, but it is usually preferable to provide it as various pharmaceutical preparations.
Further, those pharmaceutical preparations are used for animals and humans. The route of administration is preferably the most effective route for treatment, and examples thereof include oral or rectal, buccal, subcutaneous, intramuscular, and intravenous parenteral routes.

Examples of dosage forms include capsules, tablets, granules, powders, syrups, emulsions, suppositories, injections and the like. Liquid preparations such as emulsions and syrups suitable for oral administration include water, sugars such as sucrose, sorbitol and fructose, glycols such as polyethylene glycol and propylene glycol, sesame oil and olive. It can be produced by using oils such as oil and soybean oil, preservatives such as p-hydroxybenzoic acid esters, flavors such as Strawberry flavor and peppermint. Capsules, tablets, powders, granules, etc. are excipients such as lactose, glucose, sucrose, mannitol, etc., disintegrating agents such as starch, sodium alginate, etc., lubricants such as magnesium stearate, talc etc. , Polyvinyl alcohol, hydroxypropyl cellulose, gelatin and the like binder, fatty acid ester and the like surfactant, glycerin and the like plasticizer and the like.

Formulations suitable for parenteral administration preferably consist of a sterile water-based solvent containing the active compound which is isotonic with the blood of the recipient. For example, as an injection, a solution for injection is prepared by using a carrier such as a salt solution, a glucose solution or a mixture of salt water and a glucose solution. Topical formulations are prepared by dissolving or suspending the active compound in one or more vehicles, such as mineral oil, petroleum, polyhydric alcohols or other bases used in topical pharmaceutical formulations.

Formulations for enteral administration are provided as suppositories with conventional carriers such as cocoa butter, hydrogenated fats, hydrogenated fatty carboxylic acids and the like. Also in these parenteral preparations, selected from the diluents, fragrances, preservatives, antioxidants, excipients, disintegrants, lubricants, binders, surfactants, plasticizers, etc. exemplified for oral preparations. It is also possible to add one or more auxiliary ingredients.

The effective dose of the compound (I) or a pharmacologically acceptable salt thereof and the frequency of administration vary depending on the administration form, the age and weight of the patient, the nature or severity of the condition to be treated, but are usually administered. In the case of oral administration, 1 mg to 1 g per adult is administered once to several times a day. For parenteral administration, for example, intravenous administration, 0.1 to 100 m per adult
Administer g once or several times a day. In the case of transdermal administration, 10 μg to 100 mg is administered once to several times a day. However, these doses vary depending on the various conditions described above.

The following are examples, reference examples and formulation examples.

[0041]

【Example】

Example 1 Ethyl 4- {2-[[(5-nitroindol-1-yl) acetyl] amino] phenoxy} butyrate (Compound 1) 3.14 g of 5-nitroindole was added to dimethylformamide.
Dissolved in 60 ml. Under ice-cooling, 2.7 g of potassium t-butyrate and 40 ml of a dimethylformamide solution of the compound a 6.68 g obtained in Reference Example 1 were added, and the mixture was stirred at room temperature for 30 minutes. Water was added under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the organic layer was concentrated under reduced pressure. The obtained crude crystals were recrystallized from methanol to obtain 5.11 g of compound 1 as white crystals. Melting point: 161-163 ℃ IR (KBr) cm ^-1 : 3282,2930,1738,1674,1599,1454,1268,12
27,1171. ¹ HNMR (CDCl ₃ ) (δ, ppm): 1.28 (t, 3H, J = 7.1 Hz),
1.70-1.79 (m, 2H), 2.15 (t, 2H, J = 6.9 Hz), 3.8
2 (t, 2H, J = 6.1 Hz), 4.12-4.20 (m, 2H), 5.05
(s, 2H), 6.74 (d, 1H, J = 6.6 Hz), 6.86 (s, 1H,
J = 3.1 Hz), 6.90-7.04 (m, 2H), 7.39 (d, 1H, J
= 3.1 Hz), 7.44 (d, 1H, J = 9.2 Hz), 7.93 (br, 1H
), 8.17 (dd, 1H, J = 2.1 and 9.2 Hz), 8.34 (d
d, 1H, J = 1.7 and 7.9 Hz), 8.64 (d, 1H, J = 2.3
Hz).

Example 2 4- {2-[[(5-nitroindol-1-yl) acetyl] amino] phenoxy} butyric acid (Compound 2) 2.0 g of the compound 1 obtained in Example 1 was dissolved in 40 ml of ethanol. . Add 1.5 ml of 10N sodium hydroxide solution to this.
Was added and stirred at 50 ° C. for 2 hours. After the reaction solution was concentrated under reduced pressure, water was added to the residue to adjust the pH to 3. The resulting solid was collected by filtration and recrystallized from ethanol-isopropyl ether to obtain 1.77 g of compound 2 as white crystals. Mp: 216-217.5 ℃ Elemental analysis _{(%): C 20 H 29} N 3 O 6 · 0.7 C 2 H 5 OH ^{IR (KBr) cm -1:.} 3272,1718,1675,1540,1515,1455,1338 1 HNMR (DMSO-d 6) (δ, ppm): 1.89-1.96 (m, 2H), 2.41
(t, 2H, J = 7.2 Hz), 4.02 (t, 2H, J = 6.7 Hz),
5.30 (s, 2H), 6.80 (d, 1H, J = 3.0 Hz), 6.85-7.
09 (m, 3H), 7.65-7.69 (m, 2H), 7.94 (d, 1H, J =
7.9 Hz), 8.06 (dd, 1H, J = 2.2 and 9.2 Hz),
8.60 (s, 1H), 9.10 (s, 1H), 12.19 (br, 1H).

Example 3 4- {2-[[(5-benzyloxyindol-1-yl) acetyl] amino] phenoxy} butyric acid (Compound 3) 4.5 g 5-benzyloxyindole and the compound obtained in Reference Example 1 From 6.9 g of a, in the same manner as in Examples 1 and 2, 1.27 g of compound 3 was obtained as white crystals. Melting point: 152.5-153.5 ° C Elemental analysis (%): C ₂₇ H ₂₆ N ₂ O ₅ IR (KBr) cm ^-1 : 3370,1720,1644,1540,1490,1240,1157. ¹ HNMR (DMSO-d ₆ ) (δ, ppm): 1.89 (t, 2H, J = 6.4 Hz),
2.29-2.34 (m, 2H), 3.91 (t, 2H, J = 5.9 Hz),
5.05 (s, 4H), 6.42 (d, 2H, J = 2.8 Hz), 6.85-7.
05 (m, 3H), 7.16 (d, 1H, J = 2.8 Hz), 7.21-7.52
(m, 8H), 8.03 (d, 1H, J = 6.9 Hz), 8.62 (s, 1H
), 12.19 (br, 1H).

Example 4 4- {2-[[[5- (1-propylbutyroxy) indol-1-yl] acetyl] amino] phenoxy} butyric acid (Compound 4) 5.0 g of the compound c obtained in Reference Example 3 From 8.9 g of compound a obtained in Reference Example 1, 1.54 g of compound 4 was obtained as white crystals by the same method as in Examples 1 and 2. Melting point: 123.5-125.5 ℃ IR (KBr) cm ^-1 : 2934,1728,1640,1545,1482,1241,1183. ¹ HNMR (DMSO-d ₆ ) (δ, ppm): 0.87 (t, 6H, J = 7.3 Hz),
1.30-1.60 (m, 8H), 1.76-1.85 (m, 2H), 2.31 (t,
2H, J = 7.3 Hz), 3.90 (t, 2H, J = 6.1 Hz), 4.19
-4.27 (m, 1H), 5.08 (s, 2H), 6.39 (d, 1H, J =
3.0 Hz), 6.76 (dd, 1H, J = 2.2 and 8.9 Hz),
6.84-7.02 (m, 3H), 7.06 (d, 1H, J = 2.2Hz), 7.32
(d, 1H, J = 8.9 Hz), 7.37 (d, 1H, J = 3.0 Hz),
8.64 (s, 1H).

Example 5 4- {2-[[[5- (benzhydrylcarbamoyl)
Indol-1-yl] acetyl] amino] phenoxy} butyric acid (Compound 5) By the same method as in Examples 1 and 2 from 2.7 g of compound d obtained in Reference Example 4 and 2.9 g of compound a obtained in Reference Example 1. As a white crystal, 0.57 g of Compound 5 was obtained. Mp: 125.5-127.5 ℃ Elemental analysis _{(%): C 34 H 31} N 3 O 5 · 0.3 H 2 O · CH
₃ OH IR (KBr) cm ^-1 : 3380,1601,1542,1476,1456. ¹ H NMR (DMSO-d ₆ ) (δ, ppm): 1.86-1.89 (m, 2H), 2.30-
2.33 (m, 2H), 3.86-3.96 (m, 2H), 5.23 (s, 2H),
6.46 (d, 1H, J = 9.4 Hz), 6.63 (br, 1H), 6.85-
7.05 (m, 3H), 7.26-7.39 (m, 1H), 7.52 (br, 1H),
7.78 (d, 1H, J = 7.9 Hz), 8.00 (d, 1H, J = 8.9 Hz
), 8.29 (s, 1H), 8.99 (br, 1H), 9.13 (br, 1H).

Example 6 4- {2-[[[5- (t-butylcarbamoyl) indol-1-yl] acetyl] amino] phenoxy} butyric acid (Compound 6) From indole-5-carboxylic acid and t-butylamine 1.88 g of Nt-butyl-5-indolecarboxamide obtained according to Reference Example 4 and the compound a obtained in Reference Example 1
From 3.0 g, by the same method as in Examples 1 and 2,
0.71 g of compound 6 was obtained as white crystals. Melting point: 138-139 ° C Elemental analysis (%): C ₂₄ H ₂₉ N ₃ O ₅ IR (KBr) cm ^-1 : 3400,1684,1623,1540,1457. ¹ H NMR (DMSO-d ₆ ) (δ, ppm): 1.40 (s, 9H), 1.83-1.88
(m, 2H), 2.38 (t, 2H, J = 6.9 Hz), 3.96 (t, 2H, J
= 5.9 Hz), 5.19 (s, 2H), 6.59 (d, 1H, J = 2.5 Hz
), 6.85-7.04 (m, 3H), 7.46-7.55 (m, 2H), 7.58
(d, 1H, J = 8.4Hz), 7.99 (d, 1H, J = 7.9Hz), 8.
09 (s, 1H), 8.82 (br, 1H), 12.25 (br, 1H).

Example 7 4- {2-[[[5- (1-propylbutylcarbamoyl) indol-1-yl] acetyl] amino] phenoxy} butyric acid (Compound 7) Indole-5-carboxylic acid and 4-amino From 7 g of N-propylbutyl-5-indolecarboxamide obtained from heptane according to Reference Example 4 and 0.4 g of compound a obtained in Reference Example 1, Compound 7 was obtained as white crystals by the same method as in Examples 1 and 2. 0.14g was obtained. Mp: 174.5-175.5 ℃ Elemental analysis _{(%): C 28 H 35} N 3 O 5 · 0.3 H 2 O IR (KBr) cm ^-1 : 3264,2926,1718,1680,1633,1536,1456,12
61,753. ¹ HNMR (DMSO-d ₆ ) (δ, ppm): 0.95 (t, 2H, J = 7.2 Hz),
1.42-1.64 (m, 10H), 1.92 (t, 2H, J = 7.4 Hz), 3.
70 (t, 2H, J = 4.9 Hz), 4.11-4.26 (m, 1H), 4.97
(s, 2H), 6.06 (d, 1H, J = 8.8 Hz), 6.73 (d, 1H,
J = 3.2 Hz), 6.89-7.02 (m, 2H), 7.22 (d, 1H, J =
3.2 Hz), 7.35 (d, 1H, J = 8.4 Hz), 7.57 (dd, 1H,
J = 1.3 and 8.4 Hz), 7.71 (s, 1H), 8.05 (d, 1
H, J = 1.3 Hz), 8.36 (dd, 1H, J = 1.7 and 7.7 H
z).

Example 8 1-{[2- [3- (carboxy) propoxy] phenylcarbamoyl] methyl} indole-5-carboxylic acid (Compound 8) 1.35 g of methyl indole-5-carboxylate and obtained in Reference Example 1. From 2.67 g of the obtained compound a, 0.25 g of compound 8 was obtained as white crystals by the same method as in Examples 1 and 2. Mp: 283-288 ° C. Elemental analysis _{(%): C 21 H 20} N 2 O 6 · 0.4 H 2 O IR (KBr) cm ^-1 : 3300,1681,1600,1543,1456,1320,1284,12
_{^{59. 1 HNMR (DMSO-d 6}} ) (δ, ppm): 1.87-1.90 (m, 2H), 2.39
(t, 2H, J = 6.9 Hz), 3.96-3.98 (m, 2H), 5.22 (s,
2H), 6.65 (br, 1H), 6.85-7.10 (m, 3H), 7.52-7.
55 (m, 2H), 7.77 (d, 1H, J = 8.6 Hz), 7.98 (d, 1
H, J = 7.3 Hz), 8.26 (s, 1H), 8.96 (br, 1H), 12.
31 (br, 2H).

Reference Example 1 4-{[(2-bromoacetyl) amino] phenoxy}
Ethyl butyrate (Compound a) 5.0 g of ethyl 4- (2-aminophenoxy) butyrate was dissolved in 90 ml of toluene and 10 ml of dimethylformamide. Under ice-cooling, 3 ml of bromoacetyl bromide was added, and the mixture was heated under reflux for 1 and a half hours. After cooling, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentrating the organic layer under reduced pressure,
The residue was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1) to obtain 6.95 g of oily compound a. ¹ HNMR (CDCl ₃ ) (δ, ppm): 1.26 (t, 3H, J = 7.1 Hz),
2.14-2.24 (m, 2H), 2.60 (t, 2H, J = 7.1 Hz), 4.0
7 (s, 2H), 4.10-4.20 (m, 4H), 6.88 (dd, 1H, J =
1.3 and 7.9 Hz), 6.94-7.26 (m, 2H), 8.33 (d
d, 1H, J = 1.7 and 7.9 Hz), 8.92 (br, 1H).

Reference Example 2 3-Methyl-4-nitro-1- (1-propylbutyroxy) benzene (Compound b) 15.0 g of 3-methyl-4-nitrophenol was dissolved in 300 ml of dimethylformamide. To this, potassium carbonate
15.0 g and 29.0 g of 1-propylbutyl p-toluenesulfonate were added. After stirring at 60 ° C. for 4.5 hours, the solid was filtered off. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After the organic layer was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
Purification by 10: 1) gave 19.45 g of oily compound b. ¹ HNMR (CDCl ₃ ) (δ, ppm): 0.93 (t, 6H, J = 7.3 Hz),
1.26-1.70 (m, 8H), 2.62 (s, 3H), 4.34-4.38 (m, 1
H), 6.75 (s, 1H), 6.77-6.78 (m, 1H), 7.78-8.09
(m, 1H).

Reference Example 3 5- (1-Propylbutyroxy) indole (Compound c) 19.45 g of the compound b obtained in Reference Example 2 was dissolved in 300 ml of dimethylformamide. To this, add 14 ml of dimethylformamide / dimethylacetal and pyrrolidine.
8.4 ml was added and the mixture was heated under reflux for 4 hours. After allowing to cool, it was concentrated under reduced pressure. The obtained residue was dissolved in 300 ml of ethanol. To this, 8.0 g of 10% palladium carbon (containing 50% water) was added,
The mixture was stirred under a hydrogen atmosphere for 4 hours. After the solid was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1),
14.92 g of oily compound c was obtained. ¹ HNMR (CDCl ₃ ) (δ, ppm): 0.93 (t, 6H, J = 7.1 Hz),
1.38-1.74 (m, 8H), 4.18-4.22 (m, 1H), 6.45-6.75
(m, 1H), 6.85 (dd, 1H, J = 2.5 and 8.6 Hz), 7.1
2-7.27 (m, 3H), 8.02 (br, 1H).

Reference Example 4 N-Benzhydryl-5-indolecarboxamide (Compound d) 3.2 ml of benzhydrylamine was dissolved in 20 ml of dichloromethane. To this was added 2.9 g of 2-chloro-1-methylpyridinium iodide and 5.3 ml of tributylamine.
Under heating under reflux, a suspension of 1.5 g of indole-5-carboxylic acid in 10 ml of methylene chloride was added, and the mixture was heated under reflux for 4 hours and a half. After cooling, water was added and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1),
2.76 g of compound d was obtained as yellow crystals. ¹ HNMR (CDCl ₃ ) (δ, ppm): 6.50-6.53 (m, 2H), 7.19-7.
54 (m, 12H), 7.73 (dd, 1H, J = 1.7 and 8.0 Hz
), 8.03 (d, 1H, J = 8.3 Hz), 8.23 (s, 1H), 10.59
(br, 1H).

Formulation Example 1 Tablet A tablet having the following composition is prepared by a conventional method. Compound 2 100 mg Lactose 60 mg Potato starch 30 mg Polyvinyl alcohol 2 mg Magnesium stearate 1 mg Tar dye Trace amount

Formulation Example 2 Powder A powder having the following composition is prepared by a conventional method. Compound 3 150mg Lactose 280mg

[0056]

INDUSTRIAL APPLICABILITY According to the present invention, a novel indole derivative which is useful as a therapeutic agent for prostatic hypertrophy, a therapeutic agent for prostate cancer, a therapeutic agent for baldness and a therapeutic agent for acne, which is based on the steroid 5α-reductase inhibitory action, or a pharmacologically acceptable derivative thereof. A salt is provided.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical indication C12N 9/99 (72) Inventor Akio Ishii Ube City, Yamaguchi Prefecture 2542 Fujikumi Fujimi (72) Inventor Hiromi Nonaka 580-71 Tokukura, Shimizu-cho, Sunto-gun, Shizuoka Prefecture (72) Inventor Hiroshi Kase 3-35-18 Maehara-cho, Koganei-shi, Tokyo

Claims (1)

[Claims] 1. A compound represented by the formula (I): {In the formula, R ¹ represents hydrogen or lower alkyl, and A is N
O ₂ or BR ² [wherein BR ² is CONHR ² , CO
Represents OR ² or OR ² , R ² is hydrogen or CHR ³
R ⁴ (wherein R ³ and R ⁴ are the same or different and represent hydrogen, alkyl, substituted or unsubstituted aryl)
And X represents O or S (O) n (in the formula, n represents an integer of 0 to 2)} or a pharmaceutically acceptable salt thereof.