JPH07206817A - Urea derivative - Google Patents

Abstract

PURPOSE:To obtain a new urea derivative and its pharmacologically permissible salt having steroid 5alpha-reductase inhibiting action and useful as an agent for the treatment of prostatomegaly, prostatic cancer, alopecia and acne. CONSTITUTION:This urea derivative is a compound of formula I [R<1> is H or a lower alkyl; R<2> is H or a halogen; A is group of formula V [Y<1>-Y<2>-Y<3> is R<4>C=CH-NR<3>, N=CH-NR<3> or R<3>N-CH=N [R<3> is CHR<5>R<6> (R<5> and R<6> each is H, an alkyl or an aryl); R<4> is H or CHR<7>R<8> (R<7> and R<8> each is H, an alkyl or an aryl)]] or formula VI (R<9> is H or CHR<5>R<6>); X is O or s(O)n (n is 0-2)] or its pharmacologically permissible salt, e.g. 4-[2-[3-[1-(4,4'-difluorobenzhydryl) indol-5-yl]ureido]phenoxy]butyric acid ethyl ester. The compound of formula I, the compound of formula Ia (the compound of formula I wherein R<1> is an alkyl) and the compound of formula Ib (the compound of formula I wherein R<1> is H) can be produced from a compound of formula IV and a compound of formula III derived from a compound of formula II.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel urea derivative having a steroid 5α-reductase inhibitory activity and useful as a drug for treating benign prostatic hyperplasia, a drug for treating prostate cancer, a drug for treating baldness and a drug for treating acne.

[0002]

2. Description of the Related Art In patients with benign prostatic hyperplasia, steroid 5α-reductase activity in prostate tissue is increased,
A large amount of dihydrotestosterone is accumulated in tissues, suggesting that dihydrotestosterone plays an important role in the development of benign prostatic hyperplasia, and it is reported that steroid 5α-reductase inhibitors are useful for the treatment. The Prostate Supplement
Prostate Supplement), 2 , 95 (1989)].

Further, the growth of prostate cancer depends on dihydrotestosterone rather than testosterone, and it has been reported that a steroid 5α-reductase inhibitor is useful [The Prostate, 9 , 343.
(1986)]. On the other hand, it is known that dihydrotestosterone also plays an important role in the development of acne and baldness [Trends Pharmacol.Sci.], 10 , 491 (198)
9)]. Japanese Unexamined Patent Publication (Kokai) No. 1-190659 discloses a compound of formula (A) as a raw material for a photographic light-sensitive material.

[0004]

[Chemical 4] Compounds represented by are disclosed.

[0005]

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

[0006]

According to the invention, the formula (I)

[0007]

[Chemical 5]

[In the formula, R ¹ represents hydrogen or lower alkyl, R ² represents hydrogen or halogen, and A is

[0009]

[Chemical 6]

[Wherein Y ¹ -Y ² -Y ³ is R ⁴ C = CH
-NR ^3, in N = CH-NR ³ or R ³ N-CH = N [wherein, R ³ is hydrogen or -CHR ⁵ R ⁶ (wherein, R ⁵ and R ⁶ are the same or different, hydrogen, an alkyl Represents a substituted or unsubstituted aryl), R ⁴ is hydrogen or —CHR ⁷ R ⁸ (in the formula, R ⁷ and R ⁸ are the same or different and represent hydrogen, alkyl, substituted or unsubstituted aryl). ) Represents]] or

[0011]

[Chemical 7]

[Wherein R ⁹ is hydrogen or --CHR ⁵ R ⁶
(In the formula, R ⁵ and R ⁶ are as defined above), and X represents O or S (O) n (in the formula, n represents an integer of 0 to 2)}. Urea derivative [hereinafter referred to as compound (I). The same applies to compounds of other formula numbers] or a pharmaceutically acceptable salt thereof.

In the definition of each group of the formula (I), as lower alkyl, linear or branched C1-C4, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert. -Butyl and the like. Alkyl has a straight or branched carbon number of 1
-10, for example methyl, ethyl, propyl, butyl,
Pentyl, hexyl, heptyl, octyl, nonyl, decyl, isopropyl, isobutyl, sec-butyl, tert-
Butyl, neopentyl, 1-methylbutyl, 1-ethylbutyl, 1-ethylpropyl, 1-methylpentyl, 1
-Ethylbutyl, 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-
Butyl pentyl and the like. Examples of aryl include phenyl and naphthyl. Halogen represents each atom of fluorine, chlorine, bromine and iodine.

The substituent in the substituted aryl is the same or different and has 1 to 4 substituents, for example, lower alkyl, lower alkoxy, lower alkylamino, trifluoromethyl, halogen, etc., and lower alkyl, lower alkoxy, lower The alkyl moiety of alkylamino and halogen have the same meanings as described above.

The pharmacologically acceptable acid addition salts of compound (I) include inorganic acid salts such as hydrochloride, sulfate and phosphate, acetate, maleate, fumarate, tartrate, Examples of organic salts such as citrates include metal salts such as alkali metal salts such as sodium salts, potassium salts and lithium salts, alkaline earth metal salts such as magnesium salts and calcium salts, ammonium salts, zinc salts and the like. Examples of the ammonium salt include salts of ammonium, tetramethylammonium and the like, and examples of the pharmacologically acceptable organic amine addition salt include addition salts of lysine, glycine, phenylalanine and the like.

Next, the method for producing the compound (I) will be described. The compound (Ia) in which R ¹ is lower alkyl and the compound (Ib) in which R ¹ is hydrogen in the compound (I) can be obtained according to the following production steps.

[0017]

[Chemical 8]

(In the formula, R ^1a represents lower alkyl in the definition of R ¹ , and R ² , A and X have the same meanings as described above.)

Step 1: Compound (II) is used in the presence of 1 to 5 equivalents of a base such as triethylamine and 1 to 3 equivalents of diphenylphosphoryl azide (DPPA) in a solvent such as benzene, toluene or xylene, usually at room temperature. Between the boiling points of the existing solvents 3
Compound (III) can be obtained by reacting for 0 minutes to 6 hours.

Step 2: Compound (III) and 1 to 2 equivalents of compound (IV) (Production method: described in JP-A-1-139558) are used in a solvent such as benzene, toluene, xylene or the like, if necessary 1
The compound (Ia) can be obtained by reacting for 30 minutes to 6 hours at room temperature to the boiling point of the solvent used in the presence of 5 to 5 equivalents of a base such as triethylamine.

Step 3: The compound (Ia) is added to an organic solvent such as methanol, ethanol or dioxane containing water under alkaline conditions such as lithium hydroxide, sodium hydroxide or potassium hydroxide at 0 to 100 ° C., usually at 30 ° C. Compound (Ib) can be obtained by reacting for minutes to 24 hours.

Next, the method for producing the starting compound (II) will be described. In compound (II), A is

[0023]

[Chemical 9]

(In the formula, Y ^1a -Y ^2a -Y ^3a is HC = CH-
NR ^3a, represents N = CH-NR ^3a or R ^3a N-CH = N, the compound R ^3a is represented by a group other than hydrogen in the definition of R ³⁾ (IIa) are prepared as shown below It can be obtained according to the process.

[0025]

[Chemical 10]

[Wherein Y ^1a -Y ^2a -Y ^3a has the same meaning as described above, and Y ^1b -Y ^2b -Y ^3b is HC = CH-NH, N = CH
Represents —NH or HN—CH═N, R ¹⁰ represents lower alkyl, Z represents chlorine, bromine, iodine, methanesulfonyloxy, trifluoromethanesulfonyloxy or p
-Toluenesulfonyloxy, R ^3a has the same ^meaning as above]

Step 4: Compound (Va) [prepared from 5-indolecarboxylic acid and 5-benzimidazolecarboxylic acid (Aldrich) by a known esterification method] and compound (VI) in an amount of 1 to 1.5 equivalents In the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butylate, silver oxide, etc., in a solvent such as ether, tetrahydrofuran, dimethylformamide, dioxane, etc. Between boiling points,
Compound (VIIa) can be obtained by reacting for 30 minutes to 24 hours.
Can be obtained.

Step 5: Compound (VIIa) is treated with lithium hydroxide,
Compound (IIa) can be obtained by reacting in an organic solvent containing water, such as methanol, ethanol and dioxane at 0 to 100 ° C. for 30 minutes to 24 hours under alkaline conditions such as sodium hydroxide and potassium hydroxide. it can.

In compound (II), A is

[0030]

[Chemical 11]

[Wherein Y ^1c -Y ^2c -Y ^3c is R ^4a C = CH
-NH or ^{R 4a C = CH-NR 3a} ( wherein, R ^4a is R ⁴
The compound (IIab) represented by a group other than hydrogen in the definition of and R ^3a has the same meaning as described above can be obtained according to the production steps shown below.

[0032]

[Chemical 12]

(In the formula, Z ^a has the same definition as Z, and R a
^{3a, R 4a, Y 1c -Y} 2c -Y 3c, R 10 and Z are as defined above)

Step 6: Compound (Vab) [prepared from 5-indolecarboxylic acid (manufactured by Aldrich) by a known esterification method] and compound (VIII) are added in an amount of 1 to 1.5 equivalents of lithium hydroxide or hydroxide. In the presence of a base such as sodium, potassium hydroxide, sodium hydride, potassium tert-butylate, silver oxide, etc., in a solvent such as ether, tetrahydrofuran, dimethylformamide, dioxane, etc., between 0 ° C and the boiling point of the solvent used, 30 minutes Compound (VIIab) can be obtained by reacting for -24 hours.

Step 7: Compound (VIIab) and compound (VI) are combined with 1 to 1.5 equivalents of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert.
-In the presence of a base such as butyrate or silver oxide, in a solvent such as ether, tetrahydrofuran, dimethylformamide or dioxane, between 0 ° C and the boiling point of the solvent used, 30 minutes to
Compound (VIIac) can be obtained by reacting for 24 hours.

Step 8: Compound (VIIac) or Compound (VII
ab) under alkaline conditions such as lithium hydroxide, sodium hydroxide and potassium hydroxide in an organic solvent such as methanol, ethanol and dioxane containing water at 0 to 100 ° C.
Compound (IIab) can be obtained by reacting for 0 minutes to 24 hours.

In the compound (II), A is

[0038]

[Chemical 13]

(Wherein R ^9a represents a group other than hydrogen in the definition of R ⁹ and R ¹⁰ has the same meaning as defined above)
(IIb) can be obtained according to the manufacturing process shown below.

[0040]

[Chemical 14]

(In the formula, Z, R ^9a and R ¹⁰ are as defined above)

Step 9: Compound (Vb) (Tokyo Kasei) and compound
(IX) in the presence of a base such as 1 to 1.5 equivalents of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butyrate, in a solvent such as ether, tetrahydrofuran, dimethylformamide, 0 ° C
The compound (VIIb) can be obtained by reacting for 30 minutes to 24 hours at the boiling point of the solvent used in the above.

Step 10: Compound (VIIb) is added under alkaline conditions such as lithium hydroxide, sodium hydroxide and potassium hydroxide in an organic solvent containing water such as methanol, ethanol and dioxane at 0 to 100 ° C. for 30 minutes. Compound (IIb) can be obtained by reacting for -24 hours.

The intermediates and target compounds in the above-mentioned production method are isolated by purification methods commonly used in synthetic organic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography and the like. It can be purified. In addition, the intermediate may 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. When it is obtained in a free form, it is dissolved in a suitable solvent. Alternatively, it may be suspended and added with an acid or a base to form a salt. The compound (I) and 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 the compound (I) obtained by each production method are shown in Table 1.

[0047]

[Table 1]

[0048]

[Table 2]

[0049]

[Table 3]

[0050]

[Table 4]

Next, the pharmacological action of compound (I) will be described in Test Examples.

Test Example 1. Acute toxicity test A test compound was orally administered (300 mg / kg) to 3 groups of 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. The results are shown in Table 2.

[0053]

[Table 5]

Test Example 2. Steroid 5α-reductase inhibition test According to the method of T. Liang et al. [Endocrinology, 117 , 571 (1985)], the epididymis of a male rat was treated with 10 times volume of 0.32M sucrose, 1m
The mixture was homogenized with a 20 mM sodium phosphate buffer (pH 6.5) containing M dithiothreitol and 0.05 mM dihydronicotinamide adenine dinucleotide (NADPH), and then centrifuged (100,000 × g, 30 minutes). The obtained precipitate is suspended by adding the above-mentioned buffer solution to obtain an enzyme solution (10 to 20 mg protein / ml).
Was prepared.

The enzyme activity was measured by [4- ¹⁴ C] -testosterone (150 nM), NADPH (2 nM) and the above enzyme solution (10 μg).
Protein) and test compound in a total volume of 0.5 ml
(40 mM Tris citrate buffer, pH 4.5 containing 1 mM dithiothreitol) was incubated for 10 minutes at 37 ° C. Stop the reaction by adding 2 ml of ethyl acetate and centrifuge (1,000 xg, 5
Minutes). The organic 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 and the produced dihydrotestosterone and androstanediol was measured using BAS2000 (Fuji Film).

Test compound (test compound concentration; 100 n
The enzyme activity inhibition rate by M) was calculated from the following equation.

[0057]

[Equation 1]

(In the formula, the control conversion rate means the conversion rate in the absence of a test compound during the measurement of the above-mentioned enzyme activity.
The blank conversion rate represents the conversion rate when 2 ml of ethyl acetate was added to the enzyme solution to inactivate the enzyme during the measurement of the enzyme activity). The results are shown in Table 3.

[0059]

[Table 6]

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. Also,
The pharmaceutical preparations are for use in animals and humans. The route of administration is preferably the most effective route for treatment, and examples thereof include oral or rectal, intraoral, subcutaneous, intramuscular, intravenous and the like 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, oils such as sesame oil, olive oil and soybean oil, It is prepared using antiseptics such as p-hydroxybenzoic acid esters, antioxidants such as sodium bisulfite, sodium pyrosulfite, ascorbic acid and tocopherol, flavors such as strawberry flavor and peppermint. In addition, capsules, tablets, powders, granules, etc., are excipients such as lactose, glucose, sucrose, and mannitol,
Disintegrants such as starch and sodium alginate, lubricants such as magnesium stearate and talc, polyvinyl alcohol,
Binder such as hydroxypropyl cellulose, gelatin,
It is prepared using a surfactant such as a fatty acid ester and a plasticizer such as glycerin.

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

Formulations for enteral administration are prepared as suppositories with conventional carriers such as cocoa butter, hydrogenated fats, hydrogenated fatty carboxylic acids and the like. Also, in these parenteral agents,
One or more auxiliary components selected from diluents, fragrances, preservatives, antioxidants, excipients, disintegrants, lubricants, binders, surfactants, plasticizers, etc. exemplified as oral agents. It can also be added.

The effective dose of Compound (I) or a pharmaceutically acceptable salt thereof and the number of administrations 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. Parenteral administration, for example, for intravenous administration, 0.1 to 100 per adult
Administer mg once or several times daily. 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 embodiments of the present invention will be described below with reference to Examples, Reference Examples and Preparation Examples.

[0066]

【Example】

Example 1. Ethyl 4- {2- [3- [1- (4,4'-difluorobenzhydryl) indol-5-yl] ureido] phenoxy} butyrate (Compound 1)

The compound c (0.22 g) obtained in Reference Example 3 was dissolved in 4 ml of toluene, and 0.25 ml of triethylamine and 0.25 g of diphenylphosphoryl azide were added. After stirring at room temperature for 2 hours, the mixture was heated under reflux for 1 hour. 2 ml of a toluene solution containing 0.16 g of ethyl 4- (2-aminophenoxy) butyrate was added, and the mixture was further heated and refluxed for 2 hours and a half. After cooling, add water,
It was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain 0.27 g of oily compound 1.

IR (liquid film) cm ⁻¹ : 1721, 1599, 1537, 1510, 14
^{. 74,1453,1224 1 H-NMR (CDCl} 3) (δ, ppm): 1.28-1.22 (m, 3H), 2.01-2.10
(m, 2H), 2.52 (t, 2H, J = 7.2Hz), 4.01-4.06 (m, 2H), 4.14-4.1
9 (m, 2H), 6.47 (d, 1H, J = 3.5Hz), 6.64-7.34 (m, 16H), 7.58
(s, 1H), 7.76 (s, 1H), 8.29 (dd, 1H, J = 2.0 and 7.9Hz).

Example 2.4- {2- [3- [1- (4
4'-Difluorobenzhydryl) indol-5-yl] ureido] phenoxy} butyric acid (Compound 2)

The compound 1 (0.27 g) obtained in Example 1 was dissolved in 5 ml of ethanol, ice-cooled, and 0.12 ml of 10N aqueous sodium hydroxide solution was added. After stirring for 2.5 hours at room temperature, the reaction solution was concentrated under reduced pressure. After adding 20 ml of water to the residue,
The pH was adjusted to 4.2 with 4N hydrochloric acid. The precipitated crystals were collected by filtration, washed with water and dried to obtain 0.15 g of white crystalline compound 2.

Melting point: 106.5-109 ° C. Elemental analysis (%): C ₃₂ H ₂₇ F ₂ N ₃ O ₄ Calculated value: C 69.18, H 4.90, N 7.56 Measured value: C 69.10, H 4.87, N 7.16

IR (KBr) cm ⁻¹ : 3380, 1705, 1592, 1523, 1225. ¹ H-NMR (CDCl ₃ ) (δ, ppm): 1.98-2.08 (m, 2H), 2.44-2.52
(m, 2H), 4.07 (t, 2H, J = 6.6Hz), 6.44 (d, 1H, J = 3.3Hz), 6.86-
6.98 (m, 3H), 7.05-7.23 (m, 11H), 7.32 (d, 1H, J = 8.9Hz), 7.8
2 (d, 1H, J = 2.0Hz), 7.94 (s, 1H), 8.12-8.16 (m, 1H), 9.15 (s,
1H), 12.14 (br, 1H).

Example 3.4- {2- [3- [1- (4
4'-Difluorobenzhydryl) indol-5-yl] ureido] -5-fluorophenoxy} butyric acid (Compound 3)

Using the compound c (0.62 g) obtained in Reference Example 3 and 0.49 g of ethyl 4- (2-amino-5-fluorophenoxy) butyrate, the amorphous compound 3 was prepared in the same manner as in Examples 1 and 2. 0.36g was obtained.

Elemental analysis (%): C ₃₂ H ₂₆ F ₃ N ₃ O ₄ 1.2H ₂ O Calculated value: C 65.70, H 5.32, N 6.68 Measured value: C 65.68, H 5.20, N 6.45 IR (KBr) cm ^-1 : 3380,1715,1605,1560,1415,1154.

¹ H-NMR (DMSO-d ₆ ) (δ, ppm): 1.99-2.13
(m, 2H), 2.44-2.50 (m, 2H), 4.09 (t, 2H, J = 6.4Hz), 6.44 (d, 1
H, J = 3.5Hz), 6.70-6.73 (m, 1H), 6.91-7.24 (m, 12H), 7.32
(d, 1H, J = 8.9Hz), 7.75 (s, 1H), 7.89 (s, 1H), 8.11-8.06 (m, 1
H), 9.12 (s, 1H).

Example 4.4- {2- [3- [3- (4
4'-Difluorobenzhydryl) indol-5-yl] ureido] phenoxy} butyric acid (Compound 4)

Using the compound b (1.0 g) obtained in Reference Example 2 and 0.60 g of ethyl 4- (2-aminophenoxy) butyrate, a white crystalline compound 4 was prepared in the same manner as in Reference Example 3 and Examples 1 and 2. Of 0.47 g was obtained.

Melting point: 253-256 ° C. Elemental analysis (%): C ₃₂ H ₂₇ F ₂ N ₃ O ₄ Calculated value: C 69.18, H 4.90, N 7.56 Measured value: C 68.84, H 4.89, N 7.34

IR (KBr) cm ⁻¹ : 3310,1705,1650,1600,155
^{. 5,1505,1453,1220 1 H-NMR (DMSO} -d 6) (δ, ppm): 1.99-2.04 (m, 2H), 2.43
(t, 2H, J = 7.3Hz), 4.03 (t, 2H, J = 6.3Hz), 5.67 (s, 1H), 6.60
(s, 1H), 6.81-6.97 (m, 3H), 7.08-7.30 (m, 11H), 7.87 (s, 1
H), 8.06-8.10 (m, 1H), 9.06 (s, 1H), 10.82 (s, 1H).

Example 5.4- {2- [3- [3- (4,
4'-Difluorobenzhydryl) indol-5-yl] ureido] -5-fluorophenoxy} butyric acid (Compound 5)

Obtained according to Reference Examples 2 and 3 [3-
(4,4'-Difluorobenzhydryl) indole-
5-yl] carboxylic acid 0.60 g and 4- (2-amino-5)
Using 0.50 g of ethyl -fluorophenoxy) butyrate, white crystalline compound 5 was obtained by the same method as in Examples 1 and 2.
0.67 g was obtained.

Melting point: 236-239 ° C. Elemental analysis (%): C ₃₂ H ₂₆ F ₃ N ₃ O ₄ Calculated value: C 67.01, H 4.57, N 7.33 Measured value: C 66.77, H 4.54, N 7.12 IR (KBr ) cm ^-1 : 3320,1702,1654,1554,1414,1275,1155.

¹ H-NMR (DMSO-d ₆ ) (δ, ppm): 1.95-2.05 (m,
2H), 2.45 (t, 2H, J = 7.4Hz), 4.07 (t, 2H, J = 6.5Hz), 5.68 (s, 1
H), 6.61 (d, 1H, J = 2.0Hz), 6.64-6.72 (m, 1H), 6.91 (dd, 1H, J
= 2.8 and 10.7Hz), 7.08-7.31 (m, 11H), 7.79 (s, 1H), 8.02-
8.31 (m, 1H), 8.99 (s, 1H), 10.82 (s, 1H), 12.11 (br, 1H).

Example 6.4- {2- [3- [3- (4,
4'-Difluorobenzhydryl) -1-methylindol-5-yl] ureido] phenoxy} butyric acid (Compound 6)

Using the compound b (1.5 g) obtained in Reference Example 2 and 0.30 g of ethyl 4- (2-aminophenoxy) butyrate, white crystals were obtained in the same manner as in Reference Examples 1 and 3 and Examples 1 and 2. 0.19 g of compound 6 was obtained.

Melting point: 193-194 ° C. Elemental analysis (%): C ₃₃ H ₂₉ F ₂ N ₃ O ₄ .H ₂ O Calculated value: C 67.45, H 5.32, N 7.15 Measured value: C 67.80, H 5.04, N 7.25 IR (KBr) cm ^-1 : 3360,1709,1657,1598,1519,1455,1211.

¹ H-NMR (DMSO-d ₆ ) (δ, ppm): 1.95-2.05 (m,
2H), 2.45 (t, 2H, J = 7.4Hz), 3.69 (s, 3H), 4.05 (t, 2H, J = 6.4H
z), 5.69 (s, 1H), 6.61 (s, 1H), 6.82-6.89 (m, 2H), 6.90-6.97
(m, 1H), 7.08-7.26 (m, 9H), 7.32 (s, 2H), 7.86 (s, 1H), 8.06-
8.09 (m, 1H), 9.07 (s, 1H), 12.15 (br, 1H).

Example 7.4 4- {2- [3- [3- (4,
4'-Difluorobenzhydryl) -1-methylindol-5-yl] ureido] -5-fluorophenoxy} butyric acid (Compound 7)

Obtained according to Reference Examples 1 to 3 [3-
0.34 g of (4,4'-difluorobenzhydryl) -1-methylindol-5-yl] carboxylic acid and 4- (2
-Amino-5-fluorophenoxy) ethyl butyrate 0.27 g
Using the same procedure as in Examples 1 and 2, 0.45 g of white crystalline compound 7 was obtained.

Melting point: 216-219 ° C. Elemental analysis (%): C ₃₃ H ₂₈ F ₃ N ₃ O ₄ .0.5H ₂ O Calculated value: C 66.44, H 4.90, N 7.04 Measured value: C 66.29, H 4.66, N 7.35

IR (KBr) cm ⁻¹ : 3360,1702,1657,1547,149
^{. 3,1427,1212,1156 1 H-NMR (DMSO} -d 6) (δ, ppm): 1.95-2.05 (m, 2H), 2.44 (t, 2
H, J = 7.3Hz), 3.69 (s, 3H), 4.06 (t, 2H, J = 6.4Hz), 5.68 (s, 1
H), 6.60 (s, 1H), 6.63-6.69 (m, 1H), 6.87-6.91 (m, 1H), 7.07
-7.25 (m, 9H), 7.31 (s, 2H), 7.80 (s, 1H), 8.01-8.07 (m, 1H),
9.03 (s, 1H).

Example 8.4- {2- [3- [1- (1-
Propylbutyl) indol-5-yl] ureido] phenoxy} butyric acid (Compound 8)

Obtained according to Reference Examples 1 and 3 [1-
Using 0.40 g of (1-propylbutyl) indol-5-yl] carboxylic acid and 0.48 g of ethyl 4- (2-aminophenoxy) butyrate, 0.21 g of white crystalline compound 8 was prepared in the same manner as in Examples 1 and 2. Obtained.

Melting point: 75.6 ° C. Elemental analysis (%): C ₂₆ H ₃₃ N ₃ O ₄ .0.3H ₂ O Calculated value: C 68.34, H 7.41, N 9.20 Measured value: C 68.34, H 7.59, N 9.31 IR ( KBr) cm ^-1 : 3380,2905,1700,1564,1524,1452,1238,1
201.

¹ H-NMR (DMSO-d ₆ ) (δ, ppm): 0.82 (t, 6H, J =
7.3Hz), 1.04-1.18 (m, 4H), 1.74-1.84 (m, 6H), 2.22-2.28
(m, 2H), 3.87 (t, 2H, J = 5.6Hz), 4.20-4.32 (m, 1H), 6.46 (d, 1
H, J = 3.0Hz), 6.71-6.75 (m, 1H), 6.89-6.93 (m, 2H), 7.10-7.
13 (m, 2H), 7.30 (d, 1H, J = 8.6Hz), 7.44 (s, 1H), 7.52 (s, 1H),
7.57 (s, 1H), 8.14-8.18 (m, 1H).

Example 9.4- {5-fluoro-2- [3
-[1- (1-Propylbutyl) indol-5-yl] ureido] phenoxy} butyric acid (Compound 9)

Obtained according to Reference Examples 1 and 3 [1-
A white crystalline compound was obtained by the same method as in Examples 1 and 2 using 1.45 g of (1-propylbutyl) indol-5-yl] carboxylic acid and 1.60 g of ethyl 4- (2-amino-5-fluorophenoxy) butyrate. 2.13 g of 9 was obtained.

Melting point: 129 ° C. Elemental analysis (%): C ₂₆ H ₃₂ FN ₃ O ₄ .0.5H ₂ O Calculated value: C 65.26, H 6.95, N 8.78 Measured value: C 65.28, H 6.86, N 8.60 IR ( KBr) cm ^-1 : 2958,1701,1545,1430,1280,1202,1159,1
110.

¹ H-NMR (DMSO-d ₆ ) (δ, ppm): 0.84 (t, 6H, J
= 7.3Hz), 1.06-1.25 (m, 4H), 1.76-1.87 (m, 4H), 2.10-2.14
(m, 2H), 2.48 (t, 2H, J = 6.6Hz), 4.04 (t, 2H, J = 5.94Hz), 4.20
-4.32 (m, 1H), 6.43 (d, 1H, J = 3.1Hz), 6.57-6.63 (m, 2H), 7.1
1 (d, 1H, J = 3.1Hz), 7.21 (dd, 1H, J = 2.0 and 8.7Hz), 7.29
(d, 1H, J = 8.7Hz), 7.64 (br, 1H), 7.70 (d, 1H, J = 2.0Hz), 8.14
-8.19 (m, 2H).

Example 10.4- {2- [3- [1- (4
4'-difluorobenzhydryl) benzimidazol-6-yl] ureido] phenoxy} butyric acid (compound 10)

Obtained according to Reference Examples 1 and 3 [1-
White crystals were obtained in the same manner as in Examples 1 and 2 using 1.0 g of (4,4′-difluorobenzhydryl) benzimidazol-6-yl] carboxylic acid and 0.73 g of ethyl 4- (2-aminophenoxy) butyrate. 0.63 g of compound 10
Obtained.

Melting point: 222-224.5 ° C. Elemental analysis (%): C ₃₁ H ₂₆ F ₂ N ₄ O ₄ .H ₂ O Calculated value: C 64.80, H 4.91, N 9.75 Measured value: C 65.04, H 4.56, N 9.47

IR (KBr) cm ⁻¹ : 3320,1603,1542,1508,145
3,1228. ¹ H-NMR (DMSO-d ₆ ) (δ, ppm): 2.00-2.05 (m, 2H), 2.45-2.5
1 (m, 2H), 3.07 (t, 2H, J = 6.2Hz), 6.85-7.00 (m, 3H), 7.16-7.
28 (m, 11H), 7.59-7.65 (m, 1H), 7.86 (br, 1H), 8.01 (s, 1H),
8.09-8.13 (m, 1H), 9.42 (s, 1H).

Example 11 4- {2- [3- [1- (1-propylbutyl) benzimidazol-6-yl] ureido] phenoxy} butyric acid (Compound 11)

Obtained according to Reference Examples 1 and 3 [1-
Using 0.30 g of (1-propylbutyl) benzimidazol-6-yl] carboxylic acid and 0.30 g of ethyl 4- (2-aminophenoxy) butyrate, 0.35 g of white crystalline compound 11 was prepared in the same manner as in Examples 1 and 2. g was obtained.

Melting point: 214-217 ° C. Elemental analysis (%): C ₂₅ H ₃₂ N ₄ O ₄ .0.5H ₂ O Calculated value: C 65.06, H 7.21, N 12.14 Measured value: C 65.39, H 7.22, N 11.98 IR (KBr) cm ^-1 : 3340,2950,1695,1600,1546,1505,1120.

¹ H-NMR (DMSO-d ₆ ) (δ, ppm): 0.83 (t, 6H, J
= 7.3Hz), 0.93-1.22 (m, 4H), 1.76-2.10 (m, 6H), 2.49-2.58
(m, 2H), 4.09 (t, 2H, J = 6.6Hz), 4.31-4.38 (m, 1H), 6.86-7.0
2 (m, 3H), 7.07 (dd, 1H, J = 1.3 and 8.6Hz), 7.55 (d, 1H, J = 8.6
Hz), 7.97 (s, 1H), 8.03 (s, 1H), 8.15 (dd, 1H, J = 2.3 and 7.3H
z), 8.19 (s, 1H), 9.43 (s, 1H).

Example 12.4- {2- [3- [1- (4
4'-Difluorobenzhydryl) benzimidazol-5-yl] ureido] phenoxy} butyric acid (Compound 12)

Obtained according to Reference Examples 1 and 3 [1-
White crystals were obtained in the same manner as in Examples 1 and 2 using 2.0 g of (4,4′-difluorobenzhydryl) benzimidazol-5-yl] carboxylic acid and 1.46 g of ethyl 4- (2-aminophenoxy) butyrate. 0.68 g of compound 12 of
Obtained.

Melting point: 121-124.5 ° C. Elemental analysis (%): C ₃₁ H ₂₆ F ₂ N ₄ O ₄ .0.5H ₂ O Calculated value: C 65.83, H 4.81, N 9.91 Measured value: C 65.87, H 5.08, N 9.25

IR (KBr) cm ⁻¹ : 3350,1691,1603,1538,1511,1453,1228. ¹ H-NMR (DMSO-d ₆ ) (δppm): 1.98-2.12 (m, 2H), 2.46- 2.5
6 (m, 2H), 4.08 (t, 2H, J = 6.7Hz), 6.85-7.02 (m, 3H), 7.15-7.
28 (m, 12H), 7.94 (br, 1H), 8.02 (s, 1H), 8.13-8.16 (m, 1H),
9.37 (s, 1H), 12.19 (br, 1H).

Example 13.4- {2- [3- [1- (1-
Propylbutyl) benzimidazol-5-yl] ureido] phenoxy} butyric acid (Compound 13)

[1- (1
-Propylbutyl) benzimidazol-5-yl] carboxylic acid (0.20 g) and ethyl 4- (2-aminophenoxy) butyrate (0.20 g) were used to obtain 0.35 g of white crystalline compound 13 in the same manner as in Examples 1 and 2. It was

Melting point: 102 ° C. (decomposition) Elemental analysis (%): C ₂₅ H ₃₂ N ₄ O ₄ .0.5H ₂ O Calculated value: C 65.06, H 7.21, N 12.14 Measured value: C 65.01, H 7.09, N 11.85 IR (KBr) cm ^-1 : 3350,2960,1691,1600,1535,1493,1453,1
200.

¹ H-NMR (DMSO-d ₆ ) (δ, ppm): 0.82 (t, 6H,
J = 7.3Hz), 0.92-1.24 (m, 4H), 1.75-2.10 (m, 6H), 2.45-2.51
(m, 2H), 4.09 (t, 2H, J = 6.6Hz), 4.33-4.44 (m, 1H), 6.85-7.0
6 (m, 3H), 7.23 (dd, 1H, J = 2.0 and 8.6Hz), 7.53 (d, 1H, J = 8.6
Hz), 7.95 (s, 1H), 8.13-8.16 (m, 1H), 8.22 (s, 1H), 9.23 (s, 1
H), 12.06 (br, 1H).

Example 14.4- {2- [3- [3- (4
4'-difluorobenzhydryloxy) phenyl] ureido] phenoxy} butyric acid (compound 14)

3-obtained according to Reference Examples 1 and 3
2.5 g of (4,4'-difluorobenzhydryloxy) benzoic acid and ethyl 4- (2-aminophenoxy) butyrate
1.75 g of white crystalline compound 14 was obtained by the same method as in Examples 1 and 2 using 2.0 g.

Melting point: 140-142.5 ° C. Elemental analysis (%): C ₃₀ H ₂₆ F ₂ N ₂ O ₅ Calculated value: C 67.66, H 4.92, N 5.26 Measured value: C 67.65, H 4.86, N 5.21 IR (KBr ) cm ^-1 : 3350,1706,1603,1545,1509,1454,1226,1
157.

¹ H-NMR (DMSO-d ₆ ) (δ, ppm): 2.00-2.05
(m, 2H), 2.45-2.54 (m, 2H), 4.08 (t, 2H, J = 6.4Hz), 6.50 (s, 1
H), 6.60 (dd, 1H, J = 1.5 and 7.9Hz), 6.85-7.01, (m, 4H), 7.0
8-7.26 (m, 5H), 7.31 (s, 1H), 7.43-7.59 (m, 4H), 7.98 (s, 1
H), 8.09 (dd, 1H, J = 2.0 and 7.4Hz), 9.25 (s, 1H), 12.08 (br,
1H).

Example 15.4- {2- [3- [4- (4,
4'-Difluorobenzhydryloxy) phenyl] ureido] phenoxy} butyric acid (Compound 15)

4-obtained according to Reference Examples 1 and 3
(4,4'-Difluorobenzhydryloxy) benzoic acid 3.0 g and ethyl 4- (2-aminophenoxy) butyrate
Using 2.4 g, and in the same manner as in Examples 1 and 2, 2.59 g of white crystalline compound 15 was obtained.

[0123] mp: 153.5-154.5 ℃ IR (KBr) cm -1:. 3390,1702,1605,1550,1507,1455,1219 1 H-NMR (DMSO-d 6) (δ, ppm): 2.00-2.09 (m, 2H), 2.50-2.
59 (m, 2H), 4.02-4.11 (m, 2H), 6.48 (s, 1H), 6.82-6.96 (m, 4
H), 6.82-6.96 (m, 4H), 7.13-7.23 (m, 4H), 7.31 (d, 2H, J = 8.4
Hz), 7.48-7.53 (m, 4H), 7.89 (s, 1H), 8.08 (dd, 1H, J = 2.0 and 7.4Hz), 9.10 (s, 1H), 12.07 (br, 1H).

Example 16.4- {2- [3- [4- [1-
[4- (2-Methylpropyl) phenyl] ethoxy] phenyl] ureido] phenoxy} butyric acid (Compound 16)

4- {1 obtained according to Reference Examples 1 and 3
-[4- (2-Methylpropyl) phenyl] ethoxy}
Using 49 g of benzoic acid and 2.2 g of ethyl 4- (2-aminophenoxy) butyrate, 3.49 g of white crystalline compound 16 was obtained in the same manner as in Examples 1 and 2.

Melting point: 144-146 ° C. Elemental analysis (%): C ₂₉ H ₃₄ N ₂ O ₅ Calculated value: C 71.00, H 6.99, N 5.71 Actual value: C 71.18, H 7.35, N 5.65

IR (KBr) cm ⁻¹ : 3380,2954,1713,1602,1545,1510,1454. ¹ H-NMR (DMSO-d ₆ ) (δ, ppm): 0.84 (d, 6H, J = 6.4 Hz), 1.52
(d, 3H, J = 6.4Hz), 1.74-1.89 (m, 1H), 2.01-2.04 (m, 2H), 2.4
1 (d, 2H, J = 6.9Hz), 2.49-2.50 (m, 2H), 4.06 (t, 2H, J = 6.2H
z), 5.36 (q, 1H, J = 6.3Hz), 6.81-6.98 (m, 7H), 7.11 (d, 2H,
J = 7.9Hz), 7.25-7.31 (m, 3H), 7.86 (s, 1H), 8.08 (d, 1H, J =
6.9Hz), 9.04 (br, 1H), 12.06 (br, 1H).

Example 17.4- {2- [3- [3- [1-
[4- (2-Methylpropyl) phenyl] ethoxy] phenyl] ureido] phenoxy} butyric acid (Compound 17)

3- {1 obtained according to Reference Examples 1 and 3
-[4- (2-Methylpropyl) phenyl] ethoxy}
3.13 g of white crystalline compound 17 was obtained by the same method as in Examples 1 and 2 using 2.5 g of benzoic acid and 2.2 g of ethyl 4- (2-aminophenoxy) butyrate.

Melting point: 174.5-176 ° C. Elemental analysis (%): C ₂₉ H ₃₄ N ₂ O ₅ Calculated value: C 71.00, H 6.99, N 5.71 Measured value: C 71.05, H 7.07, N 5.41 IR (KBr) cm ^-1 : 3350,2958,1708,1668,1600,1543,1493,1
453.

¹ H-NMR (DMSO-d ₆ ) (δ, ppm): 0.85 (d, 6H, J
= 6.4Hz), 1.54 (d, 3H, J = 5.9Hz), 1.83-1.92 (m, 1H), 2.04-2.
10 (m, 2H), 2.41 (d, 2H, J = 6.9Hz), 2.49-2.55 (m, 2H), 4.08-
4.15 (m, 2H), 5.39-5.42 (m, 1H), 6.49-6.52 (m, 1H), 6.87-7.
13 (m, 8H), 7.20 (s, 1H), 7.30 (d, 2H, J = 7.9Hz), 7.95 (s, 1H),
8.08 (d, 1H, J = 1.9Hz), 9.20 (br, 1H), 12.06 (br, 1H).

Example 18.4- {2- [3- [4- (1-
Propylbutyloxy) phenyl] ureido] phenoxy} butyric acid (Compound 18)

4- (2 obtained according to Reference Examples 1 and 3
-Propylbutyloxy) benzoic acid 1.5 g and 4- (2
Example 1 using 1.7 g of -aminophenoxy) ethyl butyrate
1.88 of white crystalline compound 18 in the same manner as in 1. and 2.
g was obtained.

Melting point: 136-138 ° C. Elemental analysis (%): C ₂₄ H ₃₂ N ₂ O ₅ .H ₂ O Calculated value: C 66.99, H 7.54, N 6.51 Actual value: C 66.91, H 7.77, N 6.16 IR (KBr) cm ^-1 : 2956,1717,1659,1603,1557,1508,1455,1
247.

¹ H-NMR (DMSO-d ₆ ) (δ, ppm): 0.88 (t, 6H, J
= 7.2Hz), 1.28-1.62 (m, 8H), 2.00 (t, 2H, J = 6.9Hz), 2.48-2.
51 (m, 2H), 4.07 (t, 2H, J = 6.4Hz), 4.19-4.27 (m, 1H), 6.83-
7.19 (m, 5H), 7.33 (d, 2H, J = 8.9Hz), 7.93 (s, 1H), 8.11-8.13
(m, 1H), 9.16 (s, 1H), 12.19 (br, 1H).

Example 19.4- {2- [3- [3- (1-
Propylbutyloxy) phenyl] ureido] phenoxy} butyric acid (Compound 19)

3- (1 obtained according to Reference Examples 1 and 3
-Propylbutyloxy) benzoic acid 3.0 g and 4- (2
Example 1 using 3.4 g of ethyl-aminophenoxy) butyrate
3.49 of white crystalline compound 19 in the same manner as in Steps 2 and 3.
g was obtained.

Melting point: 105-109.5 ° C. Elemental analysis (%): C ₂₄ H ₃₂ N ₂ O ₅ Calculated value: C 67.26, H 7.53, N 6.54 Measured value: C 67.92, H 7.70, N 6.45 IR (KBr) cm ^-1 : 2960,1713,1677,1598,1538,1493,1455,1
423.

¹ H-NMR (DMSO-d ₆ ) (δ, ppm): 0.89 (t, 6H, J
= 7.2Hz), 1.32-1.48 (m, 4H), 1.50-1.58 (m, 4H), 2.01-2.06
(m, 2H), 2.48-2.50 (m, 2H), 4.08 (t, 2H, J = 6.4Hz), 4.27 (t, 1
H, J = 5.7Hz), 6.52 (d, 1H, J = 7.9Hz), 6.85-7.17 (m, 5H), 7.23
(s, 1H), 8.00 (s, 1H), 8.11 (d, 1H, J = 7.4Hz), 9.31 (s, 1H), 1
2.18 (br, 1H).

Reference Example 1. Methyl [1- (4,4'-difluorobenzhydryl) indol-5-yl] carboxylate (Compound a)

0.7 g of methyl 5-indolecarboxylate was dissolved in 10 ml of dimethylformamide (DMF), and 0.25 g of potassium tert-butyrate was added under ice cooling. After stirring for 30 minutes, 4 ml of a DMF solution containing 0.69 g of 4,4′-difluorobenzhydryl bromide was added dropwise at the same temperature. After stirring overnight at room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 0.35 g of white crystalline compound a.
Obtained.

¹ H-NMR (DMSO-d ₆ ) (δ, ppm): 3.90 (s, 3H),
6.59 (dd, 1H, J = 0.2 and 3.4Hz), 6.81 (d, 1H, J = 1.7Hz), 6.8
6-7.39 (m, 10H), 7.84 (dd, 1H, J = 1.6 and 8.6Hz), 8.41 (d, 1
H, J = 0.6Hz).

Reference Example 2. Methyl [3- (4,4'-difluorobenzhydryl) indol-5-yl] carboxylate (Compound b)

2.68 g of methyl 5-indolecarboxylate was dissolved in 45 ml of dioxane, and 3.5 g of silver oxide and 4,4'-
10 ml of a solution of 4.2 g of difluorobenzhydryl bromide in dioxane was added. After stirring at 50 ° C. for 13 hours, the solid was separated by filtration through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain 2.69 g of white crystalline compound b.

¹ H-NMR (DMSO-d ₆ ) (δ, ppm): 3.86 (s, 3H),
5.68 (s, 1H), 6.60 (d, 1H, J = 0.3Hz), 6.86-7.25 (m, 10H), 7.3
5 (d, 1H, J = 8.5Hz), 7.89 (dd, 1H, J = 1.3 and 8.5Hz), 7.99
(s, 1H), 8.22 (br, 1H).

Reference Example 3. [1- (4,4'-Difluorobenzhydryl) indol-5-yl] carboxylic acid (Compound c)

A mixture of 0.35 g of the compound a obtained in Reference Example 1, 0.3 ml of 10N aqueous sodium hydroxide solution and 5 ml of ethanol was stirred at 60 ° C. for 9 hours, and the reaction solution was concentrated under reduced pressure. 20 ml of water was added and the pH was adjusted to 5.5 with 4N hydrochloric acid.
The precipitated crystals were collected by filtration, washed with water and dried to obtain 0.28 g of white crystalline compound c.

¹ H-NMR (DMSO-d ₆ ) (δ, ppm): 6.60 (d, 1H, J
= 3.3Hz), 7.13-7.40 (m, 10H), 7.51 (d, 1H, J = 8.7Hz), 7.72 (d
d, 1H, J = 1.5 and 8.7Hz), 8.26 (d, 1H, J = 1.3Hz).

Formulation Example 1. Tablet A tablet having the following composition was 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. Powders A powder having the following composition was prepared by a conventional method. Compound 3 150mg Lactose 280mg

[0151]

EFFECTS OF THE INVENTION According to the present invention, there is provided a urea derivative having a steroid 5α-reductase inhibitory activity and useful as a drug for treating benign prostatic hyperplasia, a drug for treating prostate cancer, a drug for treating baldness and a drug for treating acne. You can

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07C 275/34 9451-4H C07D 209/10 8217-4C 235/08 (72) Inventor Akio Ishii Yamaguchi 2542 Fujimagari, Ube, Ube Prefecture (72) Inventor Hiromi Nonaka 580-71 Tokukura, Shimizu-cho, Sunto-gun, Shizuoka Prefecture (72) Hiroshi Kase 3-35-18 Maehara-cho, Koganei-shi, Tokyo

Claims (1)

[Claims] 1. Formula (I): {In the formula, R ¹ represents hydrogen or lower alkyl, R ² represents hydrogen or halogen, and A represents Wherein, Y ¹ -Y ² -Y ^{3 is, R 4 C = CH-NR} 3, N =
During CH-NR ³ or R ³ N-CH = N [wherein, R ³ is hydrogen or -CHR ⁵ R ⁶ (wherein, R ⁵ and R ⁶ are the same or different, hydrogen, alkyl, substituted or unsubstituted represents aryl), R ⁴ is hydrogen or -CHR ⁷ R ⁸
(In the formula, R ⁷ and R ⁸ are the same or different and each represents hydrogen, alkyl, substituted or unsubstituted aryl)] or [Wherein R ⁹ represents hydrogen or —CHR ⁵ R ⁶ (in the formula, R ⁵ and R ⁶ have the same meanings as defined above)], and X represents O or S (O) n (wherein n Represents an integer of 0 to 2) or a pharmacologically acceptable salt thereof.