JPH08119920A - Tricyclic anilide derivative - Google Patents

Abstract

PURPOSE: To obtain a new tricyclic anilide derivative having steroid 5α-reductase inhibitory action, thus useful as a medicine for prostatomegaly, prostate cancer, alopecia and acne. CONSTITUTION: This new tricyclic anilide derivative (or a pharmacologically permissible salt thereof) is expressed by formula I [R<1> , R<2> and R<4> are each H or an alkyl; R<3> is H, a halogen, nitro or an alkyl; A is CH or N; Y is CH2 CH2 , CH=CH, CH2 O, OCH2 , CH2 S, SCH2 , O, S or a single bond; Z<1> -Z<2> is C=O or CHOR<5> (R<5> is H, an alkyl or aralkyl). X is O or S(O)q ((q) is 0-2); (n) is 1-6], e.g. 4-[2-(6,11-dihydrodibenz[b,e]-oxepin-11-on-2-yl) carboxamidophenoxy]butyric ethyl ester. A compound of formula Ia, one of the compounds of formula I (where, R<1> is an alkyl), is obtained by reaction between a compound of formula II and a compound of formula III, and then a compound of formula Ib, another one of the compounds of formula I (where, R<1> is H) is obtained.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a tricyclic anilide 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,
The abundance of dihydrotestosterone suggests that dihydrotestosterone plays an important role in the development of benign prostatic hyperplasia, and steroid 5 is used for its treatment.
α-reductase inhibitors have been reported to be useful [The Prostate Supplement
Supplement), 2 , 95 (1989)].

Further, the growth of prostate cancer depends on dihydrotestosterone, not testosterone, and it has been reported that a steroid 5α-reductase inhibitor is useful [The Prostate, 9 , 343. (1
986)]. On the other hand, dihydrotestosterone is also known to play an important role in the development of acne and baldness [Trens in Pharmacologic.
Science (Trends Pharmacol. Sci.), 10 , 491 (1989)].

As the tricyclic anilide derivative, the general formula (A) is described in West German Patent 918,634.

[0005]

Embedded image

A compound represented by the formula: is disclosed as a component of the dye.

[0007]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel tricyclic anilide derivative having a steroid 5α-reductase inhibitory action or a pharmaceutically acceptable salt thereof.

[0008]

According to the invention, the formula (I)

[0009]

Embedded image

[Wherein R ¹ , R ² and R ⁴ are the same or different and each represents hydrogen or lower alkyl, R ³ represents hydrogen, halogen, nitro or lower alkyl, and A
Represents CH or N, Y _{is, -CH 2 CH 2 -, -} C
_{H = CH -, - CH 2} O -, - OCH 2 -, - CH 2 S
_{-, - SCH 2 -, -} O -, - represents S- or a single bond, Z ¹ -Z ² is, C = O, CHOR ⁵ (wherein, R ⁵ represents hydrogen or lower alkyl), C = CH ₂ or N-
R ⁶ (in the formula, R ⁶ represents hydrogen, lower alkyl optionally substituted by a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aralkyl), and X represents O or S.
(O) _q (wherein q represents an integer of 0 to 2),
n represents an integer of 1 to 6], and a tricyclic anilide derivative or a pharmaceutically acceptable salt thereof are provided.

In the definition of each group of the formula (I), the lower alkyl and the alkyl moiety of aralkyl are linear or branched and have 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl. , Sec-butyl, tert-butyl, pentyl, hexyl and the like. Examples of the aryl portion of aralkyl include phenyl and naphthyl, and examples of the heterocyclic group include pyridyl and
Pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl,
Examples thereof include pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, furyl and thienyl.
Examples of the substituent of the substituted aralkyl and the heterocyclic group include the same or differently substituted lower alkyl having 1 to 3 substituents, lower alkoxy, halogen, amino, mono- or di-lower alkyl substituted amino, etc., lower alkyl and lower alkoxy, The alkyl moiety of the mono- or di-lower alkyl-substituted amino has the same meaning as described above. Halogen is fluorine, chlorine,
Means each atom of bromine and iodine.

The pharmacologically acceptable salt of the compound (I) is a pharmacologically acceptable acid addition salt, for example, inorganic acid salts such as hydrochloride, sulfate and phosphate, and maleic acid. Organic salts such as salts, fumarates and citrates, and as pharmacologically acceptable base addition salts, for example, ammonium salts, lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, etc. can give.

Next, the method for producing the compound (I) will be described. In compound (I), compound (Ia) in which R ¹ is lower alkyl and compound (Ib) in which R ¹ is hydrogen are:
It can be obtained according to the manufacturing process shown below.

[0014]

[Chemical 4]

(In the formula, R ^1a represents lower alkyl in the definition of R ¹ , and R ² , R ³ , R ⁴ , A, Y, Z ¹ -Z ² , X and n have the same meanings as described above.) Step 1: 1 to compound (II) and compound (II)
5 equivalents of compound (III) and 1 to 2 equivalents, for example
1,3-dicyclohexylcarbodiimide, ethyl-N, N-dimethylaminopropylcarbodiimide / hydrochloride, iodide
2-chloro-1-methylpyridinium, N, N-bis (2-oxo-3
-Oxazolidinyl) phosphinic acid chloride and the like, and 1 to 3 equivalents of a base such as triethylamine, tributylamine, diisopropylamine, in the presence of an organic solvent such as dichloromethane, chloroform, 1,2-dichloroethane, from room temperature to room temperature. Compound (Ia) can be obtained by reacting for 30 minutes to 6 hours depending on the boiling point of the solvent used.

Alternatively, the compound (Ia) can be obtained by a method in which the compound (II) is converted into a reactive derivative of a carboxylic acid such as an acid chloride or a mixed acid anhydride and then condensed with the compound (III). Step 2: Compound (Ia) is used in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in an organic solvent such as methanol, ethanol or dioxane containing water from room temperature to the boiling point of the solvent used. Compound (Ib) can be obtained by reacting for 30 minutes to 6 hours.

The starting compound (II) can be prepared by a known method [eg, JP-A-60-6690, JP-A-2-9].
1040, EP Patent 549352, The Chemistry of Heterocyclic Compounds (The
Chemistry of Heterocyclic Compounds), 43 , 369-545 (198
4), John Wiley and Sons and The Journal of Organic Chemistry.
Chemistry), 25 , 747 (1960), etc.] or a method analogous thereto.

The starting compound (III) can be obtained, for example, according to the method described in JP-A-1-139558. The intermediates and target compounds in the above-mentioned production methods are purified by a method commonly used in synthetic organic chemistry such as filtration,
It can be isolated and purified by subjecting it to extraction, washing, drying, concentration, recrystallization, various chromatography and the like. 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, a suitable solvent is used. Dissolved or suspended in, add acid or base,
The produced salt may be isolated and purified. In addition, compound (I)
And the pharmacologically acceptable salts thereof may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention.

The compound (I) obtained by the above production method may have positional isomers and optical isomers, but the present invention includes all possible isomers including these isomers and mixtures thereof. It Specific examples of compound (I) obtained by the above production method are shown in Table 1. The compound numbers in the table correspond to the example numbers described below.

[0021]

[Table 1]

[0022]

[Table 2]

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 to one group of 3 dd male mice weighing 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.

[0024]

[Table 3]

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 volumes of 0.32 M sucrose, 1
Contains mM dithiothreitol and 0.05 mM dihydronicotinamide adenine dinucleotide phosphate (NADPH) 20
After homogenization with mM sodium phosphate buffer (pH 6.5), centrifugation (100,000 × g, 30 minutes) was performed. The above-mentioned buffer was added to the obtained precipitate to suspend it, and the 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), the above enzyme solution (10 μg protein).
And a total volume of 0.5 ml reaction solution containing test compound (40 mM Tris citrate buffer containing 1 mM dithiothreitol, pH
4.5) was incubated at 37 ° C for 10 minutes. The enzymatic reaction was stopped by adding 2 ml of ethyl acetate and centrifuged (1,000 × g,
5 minutes). After collecting the organic layer in a test tube and drying to dryness,
Ethyl acetate (25 μl) was added, and the mixture was separated by silica gel thin layer chromatography (TLC) (developing solvent; dichloromethane: diethyl ether = 1: 1). The radioactivity of testosterone and the produced dihydrotestosterone and androstanediol was measured using BAS2000 [Fuji Film Co., Ltd.], and the enzyme activity inhibition rate by the test compound (test compound concentration; 100 nM) was calculated from the following formula. did.

[0027]

[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.
Further, the conversion rate of the blank, during the measurement of the enzyme activity,
The conversion rates are shown when the enzyme is inactivated by adding 2 ml of ethyl acetate to the enzyme solution.) The results are shown in Table 3.

[0029]

[Table 4]

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 used for animals and humans. The route of administration is preferably the most effective route for treatment, and may be oral or rectal, buccal, subcutaneous, intramuscular, intravenous and the like parenteral.

Examples of dosage forms include capsules, tablets, granules, powders, syrups, emulsions, suppositories, and injections. 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 an antiseptic such as p-hydroxybenzoate, an antioxidant such as sodium bisulfite, sodium pyrosulfite, ascorbic acid and tocopherol, and flavors such as strawberry flavor and peppermint. Further, capsules, tablets, powders, granules and the like include excipients such as lactose, glucose, sucrose and mannitol, starches, disintegrating agents such as sodium alginate, lubricants such as magnesium stearate and talc,
It is prepared using a binder such as polyvinyl alcohol, hydroxypropyl cellulose, gelatin, a surfactant such as fatty acid ester, a plasticizer such as glycerin, and the like.

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 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 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 be added.

The effective dose of the compound (I) or a pharmaceutically acceptable salt thereof and the number of administrations will 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 mg per adult
Is administered once to 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 embodiments of the present invention will be described below with reference to Examples, Reference Examples and Preparation Examples.

【Example】

Example 1: Ethyl 4- [2- (6,11-dihydrodibenz [b, e] oxepin-11-one-2-yl) carboxamidophenoxy] butyrate (Compound 1) 4- (2-Aminophenoxy) butyric acid Ethyl ester 1.2
40 g of 3 g of dichloromethane and 2.25 of tributylamine
1.20 g of 2-chloro-1-methylpyridinium iodide was added to the mixed solution of ml. (6,11
Suspension of 1.0 g of dihydrodibenz [b, e] oxepin-11-one-2-yl) carboxylic acid in dichloromethane
After adding 10 ml dropwise, the mixture was heated under reflux and stirring at the same temperature for 1 hour. After cooling to room temperature, add 50 ml of water to the reaction solution,
Extracted with dichloromethane. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. By recrystallizing the obtained residue with hexane-ethyl acetate,
1.41 g of compound 1 was obtained.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 1.18 (t, 3H, J
= 7.1 Hz), 2.23-2.33 (m, 2H), 2.63 (t, 2H, J = 6.9
Hz), 4.08 (q, 2H, J = 7.1 Hz), 4.18 (t, 2H, J = 6.
3 Hz), 5.27 (s, 2H), 6.93 (dd, 1H, J = 2.0 Hz and
7.6 Hz), 6.99-7.11 (m, 2H), 7.19 (d, 1H, J = 8.9 H
z), 7.40-7.63 (m, 3H), 7.91 (dd, 1H, J = 1.3 Hz and 7.6 Hz), 8.15 (dd, 1H, J = 2.3 Hz and 8.6 Hz),
8.50 (dd, 1H, J = 2.0 Hz and 7.6 Hz), 8.71 (br, 1
H), 8.77 (d, 1H, J = 2.3 Hz).

Example 2: 4- [2- (6,11-dihydrodibenz [b, e] oxepin-11-one-2-yl) carboxamidophenoxy] butyric acid (Compound 2) The compound obtained in Example 1. A mixture of 1 (1.41 g), 10N aqueous sodium hydroxide solution (0.77 ml) and ethanol (42 ml) was heated under reflux with stirring for 1 hour. Ethanol was distilled off from the reaction solution under reduced pressure, the residue was dissolved in 30 ml of water, and the residue was dissolved in 4N hydrochloric acid.
The pH was adjusted to 3. This was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over magnesium sulfate,
The solvent was distilled off under reduced pressure. Isopropyl ether was added to the obtained residue, the mixture was stirred at room temperature, and the crystals were filtered to give compound 2
0.86 g was obtained.

Melting point: 159-160 ° C. Elemental analysis (%): C ₂₅ H ₂₁ NO ₆ Calculated value: C 69.60; H 4.91; N 3.25 Measured value: C 69.56; H 4.90; N 3.15 IR (KBr tablet) cm ^{− 1} : 3200, 1732, 1605, 1495, 1450, 130
1, 1245, 1175, 747.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 2.21-2.31 (m, 2
H), 2.62 (t, 2H, J = 6.8 Hz), 4.19 (t, 2H, J = 6.1H
z), 5.28 (s, 2H), 6.94 (dd, 1H, J = 1.7 Hz and 7.
8 Hz), 6.97-7.10 (m, 2H), 7.19 (d, 1H, J = 8.6 H
z), 7.42 (d, 1H, J = 7.8 Hz), 7.48-7.54 (m, 1H), 7.
91 (d, 1H, J = 6.3 Hz), 8.12 (dd, 1H, J = 2.3 Hz and 8.6 Hz), 8.47 (dd, 1H, J = 1.7 Hz and 7.8 Hz),
8.74 (s, 1H), 8.76 (d, 1H, J = 2.3 Hz).

Example 3: 4- [2- (10,11-dihydrodibenzo [a, d]]
Cyclohepten-5-one-2-yl) carboxamidophenoxy] butyric acid (Compound 3) 10,11-dihydrodibenzo [a, d] cyclohepten-5-one-2-carboxylic acid 0.60 g and 4- (2-
Aminophenoxy) butyric acid ethyl ester (0.74 g) was used, and 0.16 g of compound 3 was prepared according to the method of Examples 1 and 2.
Obtained.

Melting point: 155-161 ° C. Elemental analysis (%): C ₂₆ H ₂₃ NO ₅ .0.2H ₂ O Calculated value: C 72.18; H 5.45; N 3.23 Actual value: C 72.03; H 5.56; N 3.23 IR ( KBr tablets) cm ^-1 : 3360, 2930, 1730, 1635, 1596, 152
5, 1453, 1291, 1254, 749.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 2.14-2.24 (m, 2
H), 2.52 (t, 2H, J = 6.9 Hz), 3.25 and 3.28 (AB, 4
H, J = 8.9 Hz), 4.15 (t, 2H, J = 6.1 Hz), 6.91 (d
d, 1H, J = 1.3 Hz and 7.6 Hz), 6.97-7.10 (m, 2H),
7.24 (d, 1H, J = 7.6 Hz), 7.33 (t, 2H, J = 7.6 H
z), 7.45 (dt, 2H, J = 1.5 Hz and 7.6 Hz), 7.79 (d
d, 1H, J = 1.5 Hz and 7.6 Hz), 7.79 (dd, 1H, J = 1.
5 Hz and 7.6 Hz), 7.84 (s, 1H), 8.01 (d, 1H, J = 7.
6 Hz), 8.07 (d, 1H, J = 7.6 Hz), 8.49 (dd, 1H, J =
1.5 Hz and 7.6 Hz), 8.66 (s, 1H).

Example 4: 4- [2- (6,11-Dihydrodibenz [b, e] oxepin-11-one-8-yl) carboxamidophenoxy] butyric acid (Compound 4) 6,11-dihydrodibenz [B, e] Oxepin-1
0.64 g of 1-one-8-carboxylic acid and 0.75 g of 4- (2-aminophenoxy) butyric acid ethyl ester were used to obtain 0.65 g of compound 4 according to the methods of Examples 1 and 2.

[0044] mp: 139-142 ° C. Elemental analysis _{(%): C 25 H 21} NO 6 Calculated: C 69.60; H 4.91; N 3.25 Found: C 69.65; H 5.06; N 3.33 IR (KBr tablet) cm ^{- 1} : 3440, 2930, 1732, 1639, 1599, 153
6, 1454, 1303, 753.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 2.16-2.25 (m, 2
H), 2.53 (t, 2H, J = 6.9 Hz), 4.18 (t, 2H, J = 5.9
Hz), 5.32 (s, 2H), 6.95-7.03 (m, 2H), 7.09 (d, 2H,
J = 8.6 Hz), 7.16 (t, 1H, J = 7.1 Hz), 7.53 (s, 1
H), 7.53 (dt, 1H, J = 1.7 Hz and 7.8 Hz), 8.04
(d, 3H, J = 8.6 Hz), 8.41 (d, 1H, J = 6.6 Hz), 8.5
6 (s, 1H).

Example 5: 4- [2- (11-methylidene-6,11-dihydrodibenz [b, e] oxepin-2-yl) carboxamidophenoxy] butyric acid (Compound 5) 11-methylidene-6,11 -Dihydrodibenz [b,
e] Oxepin-2-carboxylic acid 1.17 g and 4- (2
-Aminophenoxy) butyric acid ethyl ester (1.45 g) and compound 5 (0.58 g) according to the method of Examples 1 and 2.
Obtained.

Melting point: 244 ° C. (decomposition) Elemental analysis (%): C ₂₆ H ₂₃ NO ₅ .0.5H ₂ O Calculated value: C 69.60; H 4.91; N 3.25 Measured value: C 69.56; H 4.90; N 3.15 IR (KBr tablets) cm ^-1 : 3440, 1578, 1542, 1494, 1451, 124
9, 751.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 1.90-2.10 (m, 2
H), 2.45-2.55 (m, 2H), 4.00-4.15 (m, 2H), 5.23 (s,
2H), 5.37 (s, 1H), 5.96 (s, 1H), 6.85-6.95 (m, 2
H), 7.00-7.15 (m, 2H), 7.35-7.46 (m, 4H), 7.85 (d,
2H, J = 7.3 Hz), 8.12 (s, 1H), 9.52 (s, 1H).

Example 6: 4- [2- (11-Methylidene-6,11-dihydrodibenz [b, e] oxepin-2-yl) carboxamidophenylthio] butyric acid (Compound 6) 11-Methylidene-6 11-dihydrodibenz [b,
e] Oxepin-2-carboxylic acid 1.17 g and 4- (2
-Aminophenylthio) butyric acid ethyl ester (1.55 g) was used to afford compound 6 (0.78) according to the method of Examples 1 and 2.
g got.

Melting point: 116-125 ° C. Elemental analysis (%): C ₂₆ H ₂₃ NO ₃ S.0.6H ₂ O Calculated value: C 68.43; H 5.34; N 3.07 Found value: C 68.40; H 5.54; N 3.04 IR (KBr tablets) cm ^-1 : 3450, 1580, 1525, 1490, 1437, 130
3, 1239, 759.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 1.68-1.80 (m, 2
H), 2.28 (t, 2H, J = 7.1 Hz), 5.16 (s, 2H), 5.31
(s, 1H), 5.78 (s, 1H), 6.84 (d, 1H, J = 8.6 Hz),
6.97 (t, 1H, J = 7.6 Hz), 7.26-7.33 (m, 5H), 7.55
(dd, 1H, J = 1.5 Hz and 7.6 Hz), 7.71 (dd, 1H, J
= 2.3 Hz and 8.6 Hz), 8.11 (d, 1H, J = 2.3 Hz), 8.
57 (dd, 1H, J = 1.3 Hz and 8.2 Hz), 9.33 (s, 1H).

Example 7: 4- [2- (6,11-Dihydrodibenz [b, e] oxepin-11-one-2-yl) carboxamidophenylthio] butyric acid (Compound 7) 6,11-dihydrodi Benz [b, e] oxepin-1
To a mixed solution of 2.24 g of 1-one-2-carboxylic acid chloride and 5.0 mg of dimethylaminopyridine, 1.3 ml of pyridine, and 32 ml of dichloromethane, a solution of 2.39 g of 4- (2-aminophenylthio) butyric acid ethyl ester in dichloromethane 10 ml was added under ice cooling. After stirring at room temperature for 12 hours, 50 ml of water was added to the reaction solution, and this was extracted with dichloromethane. The organic layer was washed successively with 2N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent: hexane: ethyl acetate = 3: 1) to obtain 1.74 g of ethyl ester of compound 7.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 1.18 (t, 3H, J
= 7.2 Hz), 1.80-2.10 (m, 2H), 2.45 (t, 2H, J = 6.9
Hz), 2.89 (t, 2H, J = 7.1 Hz), 4.06 (q, 2H, J = 7.
2 Hz), 5.25 (s, 2H), 7.12 (dd, 1H, J = 1.5 Hz and
7.5 Hz), 7.17 (d, 1H, J = 8.7 Hz), 7.27-7.60 (m, 5
H), 7.85-7.95 (m, 1H), 8.13 (dd, 1H, J = 2.4 Hz and 8.7 Hz), 8.55 (dd, 1H, J = 1.2 Hz and 8.2 H
z), 8.83 (d, 1H, J = 2.4Hz), 9.47 (br, 1H). This compound was hydrolyzed according to the method of Example 2 to obtain 0.91 g of compound 7. Melting point: 111-112 ° C Elemental analysis (%): C ₂₅ H ₂₁ NO ₅ S Calculated value: C 67.10; H 4.73; N 3.13 Measured value: C 67.31; H 4.60; N 2.94 IR (KBr tablet) cm ^-1 : 3430, 3335, 1732, 1668, 1643, 151
9, 1487, 1300, 1254, 1174, 763.

¹ H-NMR (DMSO-d ₆ ) (δ, ppm): 1.69-1.93 (m,
2H), 2.36 (t, 2H, J = 7.1 Hz), 2.94 (t, 2H, J =
7.1 Hz), 5.40 (br, 2H), 7.15-7.32 (m, 3H), 7.40-7.
70 (m, 5H), 7.74 (d, 1H, J = 8.8 Hz), 8.17 (dd, 1H,
J = 2.2Hz and 8.6Hz), 8.78 (d, 1H, J = 2.2Hz).

Example 8: 5- [2- (6,11-Dihydrodibenz [b, e] oxepin-11-one-2-yl) carboxamidophenylthio] valeric acid (Compound 8) 6,11-dihydro Dibenz [b, e] oxepin-1
1-one-2-carboxylic acid chloride 1.64 g and 5-
(2-Aminophenylthio) valeric acid ethyl ester 2.2
1.17 of compound 8 was prepared according to the method of Example 7 using 8 g.
g got.

Melting point: 113-113.5 ° C. Elemental analysis (%): C ₂₆ H ₂₃ NO ₅ S Calculated value: C 67.66; H 5.02; N 3.03 Measured value: C 67.30; H 4.87; N 2.89 IR (KBr tablet) cm ^-1 : 3430, 3328, 1723, 1650, 1578, 153
0, 1488, 1434, 1298, 758.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 1.67-1.90 (m, 4
H), 2.33 (t, 2H, J = 6.6 Hz), 2.85 (t, 2H, J = 6.6
Hz), 5.26 (s, 2H), 7.08 (dt, 1H, J = 1.5 Hz and 7.
5 Hz), 7.18 (d, 1H, J = 8.6 Hz), 7.30-7.62 (m, 6
H), 7.92 (dd, 1H, J = 2.1 Hz and 6.4 Hz), 8.15 (d
d, 1H, J = 2.4 Hz and 8.6 Hz), 8.54 (dd, 1H, J =
1.1 Hz and 8.1 Hz), 8.81 (d, 1H, J = 2.4 Hz), 9.49
(s, 1H).

Example 9: 6- [2- (6,11-dihydrodibenz [b, e] oxepin-11-one-2-yl) carboxamidophenylthio] hexanoic acid (Compound 9) 6,11-dihydro Dibenz [b, e] oxepin-1
1-one-2-carboxylic acid chloride 1.64 g and 6-
(2-Aminophenylthio) hexanoic acid ethyl ester
Compound 9 was prepared according to the method of Example 7 using 1.92 g.
1.14 g was obtained.

Melting point: 135-136 ° C. Elemental analysis (%): C ₂₇ H ₂₅ NO ₅ S Calculated value: C 68.19; H 5.30; N 2.95 Measured value: C 68.22; H 5.20; N 2.81 IR (KBr tablet) cm ^-1 : 3440, 3336, 1732, 1642, 1578, 153
0, 1489, 1298, 1257, 1151, 760.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 1.54-1.90 (m, 6
H), 2.30 (t, 2H, J = 6.6 Hz), 2.84 (t, 2H, J = 6.8
Hz), 5.26 (s, 2H), 7.08 (dt, 1H, J = 1.4 Hz and 7.
4 Hz), 7.19 (d, 1H, J = 8.8 Hz), 7.25-7.62 (m, 6
H), 7.92 (dd, 1H, J = 2.1 Hz and 6.5 Hz), 8.16 (d
d, 1H, J = 2.4 Hz and 8.6 Hz), 8.54 (dd, 1H, J =
1.0 Hz and 8.3 Hz), 8.83 (d, 1H, J = 2.4 Hz), 9.50
(s, 1H).

Example 10: 2- [4- (6,11-Dihydrodibenz [b, e] oxepin-11-one-2-yl) carboxamidophenylthio] acetic acid (Compound 10) 6,11-dihydrodi Benz [b, e] oxepin-1
1-one-2-carboxylic acid chloride 1.64 g and 2-
(4-Aminophenylthio) acetic acid ethyl ester 1.52 g
Using Compound 1, 1.32 g of Compound 10 was prepared according to the method of Example 7.
Obtained.

Melting point: 202-204 ° C IR (KBr tablet) cm ^-1 : 3356, 1732, 1645, 1599, 1524, 149
8, 1278, 1249, 763. Elemental analysis (%): C ₂₃ H ₁₇ NO ₅ S Calculated value: C 65.86; H 4.09; N 3.34 Found: C 65.54; H 3.83; N 3.18 ¹ H-NMR (DMSO- d ₆ ) (δ, ppm): 3.73 (s, 2H), 5.40 (s, 2
H), 7.23 (d, 1H, J = 8.7 Hz), 7.38 (d, 2H, J = 8.6
Hz), 7.53-7.82 (m, 6H), 8.16 (dd, 1H, J = 2.1 Hz
And 8.7 Hz), 8.74 (d, 1H, J = 2.1 Hz).

Example 11: 3- [4- (6,11-dihydrodibenz [b, e] oxepin-11-one-2-yl) carboxamidophenylthio] propionic acid (Compound 11) 6,11-dihydro. Dibenz [b, e] oxepin-1
1-one-2-carboxylic acid chloride 1.64 g and 3-
Compound 11 was prepared according to the method of Example 7 by using 1.62 g of (3-aminophenylthio) propionic acid ethyl ester.
1.21 g was obtained.

Melting point: 113-115 ° C. Elemental analysis (%): C ₂₄ H ₁₉ NO ₅ S.0.2H ₂ O Calculated value: C 65.95; H 4.47; N 3.20 Measured value: C 66.23; H 4.87; N 2.95 IR (KBr tablets) cm ^-1 : 3360, 1715, 1630, 1599, 1535, 148
8, 1250, 1149, 754.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 2.60-2.70 (m, 2
H), 3.10-3.20 (m, 2H), 5.22 (d, 2H, J = 2.0 Hz),
5.80 (br, 1H), 7.09-7.19 (m, 1H), 7.17 (d, 1H, J =
8.8 Hz), 7.27-7.87 (m, 7H), 8.02-8.18 (m, 2H), 8.
68 (d, 1H, J = 2.4 Hz).

Example 12: 4- [2- (11-Hydroxy-6,11-dihydrodibenz [b, e] oxepin-2-yl) carboxamidophenylthio] butyric acid (Compound 12) Obtained in Example 7. Compound 7 ethyl ester 1.83
88 mg of sodium borohydride was added to a mixed solution of g, 5.0 ml of tetrahydrofuran and 15 ml of ethanol under ice cooling. After stirring at room temperature for 12 hours, add 50 ml of water to the reaction mixture.
Was added, and this was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered,
It was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent: hexane: ethyl acetate =
3: 1) and purified the ethyl ester of compound 12 to 1.7
4 g was obtained.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 1.18 (t, 3H, J
= 7.2 Hz), 1.75-2.10 (m, 2H), 2.41 (t, 2H, J = 6.9
Hz), 2.82 (t, 2H, J = 7.0 Hz), 3.54 (brd, 1H, J =
2.9 Hz), 4.06 (q, 2H, J = 7.2 Hz), 5.08 and 5.99
(AB, 2H, J = 12.5 Hz), 5.84 (brd, 1H, J = 2.9 Hz),
6.94 (d, 1H, J = 8.6 Hz), 7.09 (dd, 1H, J = 1.3 Hz
And 7.5 Hz), 7.25-7.46 (m, 5H), 7.55 (dd, 1H, J
= 1.5 Hz and 7.7 Hz), 7.77 (dd, 1H, J = 2.3 Hz and 7.7 Hz), 8.05 (d, 1H, J = 2.3 Hz), 8.53 (dd, 1
H, J = 1.1 Hz and 7.9 Hz), 9.32 (br, 1H). This compound was hydrolyzed according to the method of Example 2 to obtain 0.89 g of compound 12. Melting point: 152-154 ° C Elemental analysis (%): C ₂₃ H ₁₇ NO ₅ S Calculated value: C 66.80; H 5.16; N 3.12 Found value: C 66.75; H 5.00; N 2.98 IR (KBr tablet) cm ^-1 : 3350, 1646, 1579, 1521, 1496, 143
6, 1316, 1238, 763.

¹ H-NMR (DMSO-d ₆ ) (δ, ppm): 1.67-1.90 (m,
2H), 2.34 (t, 2H, J = 7.1 Hz), 2.91 (t, 2H, J = 7.
1 Hz), 5.31 and 5.79 (AB, 2H, J = 12.3 Hz), 5.95
(s, 1H), 6.86 (d, 1H, J = 8.6 Hz), 7.15-7.70 (m, 9
H), 7.80 (dd, 1H, J = 1.3 Hz and 9.2 Hz), 8.12 (d,
1H, J = 1.3 Hz), 9.66 (s, 1H).

Example 13: 4- [2- (11-methoxy-6,11-dihydro-1)
1H-dibenz [b, e] oxepin-2-yl) carboxamidophenoxy] butyric acid (compound 13) 11-methoxy-6,11-dihydrodibenz [b,
e] Oxepin-2-carboxylic acid 1.0 g and 4- (2-
1.13 g of aminophenoxy) butyric acid ethyl ester was prepared according to the method of Examples 1 and 2 to give Compound 14.14.
g got.

Melting point: 63 ° C. (decomposition) Elemental analysis (%): C ₂₆ H ₂₅ NO ₆ .0.3 H ₂ O Calculated value: C 68.95; H 5.70; N 3.09 Found value: C 69.09; H 5.59; N 2.81 IR (KBr tablets) cm ^-1 : 3418, 2934, 1728, 1667, 1611, 153
7, 1503, 1452, 1240, 1208, 755.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 2.12-2.34 (m, 2
H), 2.58 (t, 2H, J = 6.4 Hz), 3.31 (s, 3H), 4.02-4.
09 (m, 1H), 4.16-4.24 (m, 1H), 4.91 and 6.08 (AB,
2H, J = 12.4 Hz), 5.22 (s, 1H), 6.89 (dd, 1H, J =
2.0 Hz and 7.6 Hz), 6.94 (d, 1H, J = 8.6 Hz), 6.97
-7.08 (m, 2H), 7.30-7.38 (m, 4H), 7.79 (dd, 1H, J =
2.3 Hz and 8.6 Hz), 7.96 (d, 1H, J = 2.3 Hz), 8.4
4 (br, 1H), 8.49 (dd, 1H, J = 2.3 Hz and 7.3 Hz).

Example 14: 4- [2- (5-methoxy-5,11-dihydro [1]]
Benzoxepino [3,4-b] pyridin-2-yl)
Carboxamidophenoxy] butyric acid (Compound 14) 5-methoxy-5,11-dihydro [1] benzoxepino [3,4-b] pyridine-2-carboxylic acid 0.5 g and 4- (2-aminophenoxy) butyric acid ethyl ester
0.58 g of compound 14 was obtained according to the method of Examples 1 and 2 using 0.58 g.

Melting point: 78-82 ° C. Elemental analysis (%): C ₂₅ H ₂₄ N ₂ O ₆ Calculated value: C 66.95; H 5.39; N 6.25 Measured value: C 66.69; H 5.54; N 6.02 IR (KBr tablet) cm ^-1 : 3428, 2934, 1607, 1535, 1500, 145
2, 1256, 1228, 745.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 2.21-2.30 (m, 2
H), 2.61 (t, 2H, J = 6.9 Hz), 3.39 (s, 3H), 4.08-4.
23 (m, 2H), 5.20 and 5.90 (AB, 2H, J = 13.2 Hz),
5.32 (s, 1H), 6.91 (dd, 1H, J = 2.0 Hz and 7.6 H
z), 6.97-7.09 (m, 3H), 7.20 (dd, 1H, J = 5.1 Hz and
7.8 Hz), 7.72 (dd, 1H, J = 1.7 Hz and 7.6 Hz), 7.8
4 (dd, 1H, J = 2.3 Hz and 8.6 Hz), 7.98 (d, 1H, J
= 2.3 Hz), 8.43 (dd, 1H, J = 1.7 Hz and 5.0 Hz), 8.
52 (dd, 1H, J = 2.1 Hz and 7.8 Hz), 8.56 (s, 1H).

Example 15: 4- [2- (5-benzyl-10,11-dihydrodibenz [b, f] azepin-2-yl) carboxamidophenoxy] butyric acid (Compound 15) Compound obtained in Reference Example 2 b 0.36 g and 4- (2-aminophenoxy) butyric acid ethyl ester 0.34 g,
According to the method of Examples 1 and 2, 0.27 g of compound 15 was obtained.

Melting point: 119 ° C. (decomposition) Elemental analysis (%): C ₃₂ H ₃₀ N ₂ O ₄ .0.2H ₂ O Calculated value: C 75.33; H 6.01; N 5.49 Actual value: C 75.40; H 6.25; N 5.35 IR (KBr tablets) cm ^-1 : 3434, 1716, 1608, 1534, 1496, 145
2, 1339, 749.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 2.14-2.23 (m, 2
H), 2.56 (t, 2H, J = 7.1 Hz), 3.27 (s, 4H), 4.11
(t, 2H, J = 6.1 Hz), 5.02 (s, 2H), 6.87 (dd, 1H, J
= 2.5Hz and 7.1Hz), 6.93-7.05 (m, 2H), 7.10-7.27
(m, 8H), 7.35-7.38 (m, 2H), 7.53 (dd, 1H, J = 2.2
Hz and 8.4 Hz), 7.64 (d, 1H, J = 2.2 Hz), 8.40
(s, 1H), 8.45 (dd, 1H, J = 2.3 Hz and 7.3 Hz).

Example 16: 4- [2- (10,11-dihydro-5H-dibenz [b, f] azepin-2-yl) carboxamidophenoxy] butyric acid (Compound 16) Compound c 0.29 obtained in Reference Example 3 g and 4- (2-aminophenoxy) butyric acid ethyl ester 0.34 g,
0.23 g of compound 16 was obtained according to the methods of Examples 1 and 2.

Melting point: 163-165 ° C. Elemental analysis (%): C ₂₅ H ₂₄ N ₂ O ₄ .0.3H ₂ O Calculated value: C 71.18; H 5.88; N 6.64 Found value: C 71.16; H 6.12; N 6.35 IR (KBr tablets) cm ^-1 : 3366, 1714, 1647, 1522, 1503, 148
6, 1449, 1342, 1215, 749.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 2.17-2.26 (m, 2
H), 2.55 (t, 2H, J = 7.1 Hz), 3.09 and 3.13 (AB, 4
H, J = 8.4 Hz), 4.17 (t, 2H, J = 5.9 Hz), 6.79 (t,
1H, J = 7.3 Hz), 6.91-7.12 (m, 6H), 7.48 (s, 2H),
7.59 (t, 1H, J = 2.3 Hz), 7.62 (s, 1H), 7.77 (s, 1
H), 8.46 (dd, 1H, J = 1.7 Hz and 7.6 Hz), 8.57
(s, 1H).

Example 17: 4- [2- (5-Methyl-10,11-dihydrodibenz [b, f] azepin-2-yl) carboxamidophenoxy] butyric acid (Compound 17) Compound obtained in Reference Example 4 d 0.45 g and 4- (2-aminophenoxy) butyric acid ethyl ester 0.56 g,
According to the method of Examples 1 and 2, 0.51 g of compound 17 was obtained.

Melting point: 63 ° C. (decomposition) Elemental analysis (%): C ₂₆ H ₂₆ N ₂ O ₄ .0.1H ₂ O Calculated value: C 72.24; H 6.11; N 6.48 Measured value: C 72.19; H 6.24; N 6.51 IR (KBr tablets) cm ^-1 : 3422, 2928, 1600, 1536, 1508, 149
4, 1481, 1453, 1334, 1113, 748.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 2.15-2.25 (m, 2
H), 2.58 (t, 2H, J = 7.1 Hz), 3.15-3.23 (m, 4H),
3.41 (s, 3H), 4.13 (t, 2H, J = 6.1 Hz), 6.88 (dd,
1H, J = 2.0 Hz and 7.6 Hz), 6.92-7.20 (m, 8H), 7.6
6 (dd, 1H, J = 2.3 Hz and 9.4 Hz), 8.46-8.50 (m,
1H), 8.47 (s, 1H).

Example 18: 4- [2- (5-benzyl-8-isobutyl-10,1)
1-dihydrodibenz [b, f] azepin-2-yl)
Carboxamidophenoxy] butyric acid (Compound 18) Using Compound h 0.33 g obtained in Reference Example 8 and 4- (2-aminophenoxy) butyric acid ethyl ester 0.25 g,
According to the methods of Examples 1 and 2, 0.24 g of amorphous compound 18 was obtained.

Elemental analysis (%): C ₃₆ H ₃₈ N ₂ O ₄ .0.3H ₂ O Calculated value: C 76.11; H 6.85; N 4.93 Measured value: C 76.12; H 7.10; N 4.86 IR (KBr tablet) cm ^-1 : 3435, 2950, 1706, 1601, 1530, 149
3, 1452, 1334, 1250, 747.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 0.86 (d, 6H, J
= 6.4 Hz), 1.77-1.82 (m, 1H), 2.13-2.22 (m, 2H),
2.36 (d, 2H, J = 6.4 Hz), 2.55 (t, 2H, J = 7.1 H
z), 3.20-3.30 (m, 4H), 4.11 (t, 2H, J = 6.1 Hz),
5.00 (s, 2H), 6.85-7.30 (m, 11H), 7.36 (d, 2H, J =
8.3 Hz), 7.51 (d, 1H, J = 8.6 Hz), 7.64 (s, 1H),
8.38 (s, 1H), 8.44 (dd, 1H, J = 2.3 Hz and 7.3 Hz).

Example 19: 4- [2- (8-isobutyl-10,11-dihydro-
5H-dibenz [b, f] azepin-2-yl) carboxamidophenoxy] butyric acid (Compound 19) Using the compound h 0.25 g obtained in Reference Example 8 and 4- (2-aminophenoxy) butyric acid ethyl ester 0.34 g,
0.26 g of compound 19 was obtained according to the methods of Examples 1 and 2.

Melting point: 144-145 ° C. Elemental analysis (%): C ₂₉ H ₃₂ N ₂ O ₄ .0.1H ₂ O Calculated value: C 73.43; H 6.84; N 5.91 Found value: C 73.39; H 7.04; N 5.86 IR (KBr tablets) cm ^-1 : 3340, 2948, 1601, 1504, 1452, 134
8, 1249, 752.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 0.90 (d, 6H, J
= 6.8Hz), 1.78-1.84 (m, 1H), 2.17-2.24 (m, 2H), 2.3
8 (d, 2H, J = 6.8 Hz), 2.59 (t, 2H, J = 7.1 Hz),
3.03-3.13 (m, 4H), 4.14 (t, 2H, J = 5.9 Hz), 6.28
(brs, 1H), 6.69 (d, 1H, J = 7.9 Hz), 6.73 (d, 1H,
J = 8.5 Hz), 6.84 (s, 1H), 6.86-6.90 (m, 2H), 6.97
-7.06 (m, 2H), 7.57 (dd, 1H, J = 2.1 Hz and 8.5 H
z), 7.63 (d, 1H, J = 2.1Hz), 8.44 (s, 1H), 8.47-8.5
0 (m, 1H).

Example 20: 4- {2- [5- (2-pyridyl) methyl-10,11
-Dihydrodibenz [b, f] azepin-2-yl] carboxamidophenoxy} butyric acid (Compound 20) Using 0.27 g of compound i obtained in Reference Example 9 and 0.26 g of 4- (2-aminophenoxy) butyric acid ethyl ester,
0.28 g of compound 20 was obtained according to the method of Examples 1 and 2.

Melting point: 81 ° C. (decomposition) Elemental analysis (%): C ₃₁ H ₂₉ N ₃ O ₄ .0.4H ₂ O Calculated value: C 72.33; H 5.83; N 8.16 Measured value: C 72.24; H 6.05; N 8.03 IR (KBr tablets) cm ^-1 : 3416, 2930, 1602, 1598, 1525, 150
8, 1494, 1451, 1250.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 2.17-2.27 (m, 2
H), 2.59 (t, 2H, J = 7.1 Hz), 3.25 (brs, 4H), 4.14
(t, 2H, J = 5.8 Hz), 5.14 (s, 2H), 6.89 (d, 1H, J
= 8.9Hz), 6.98-7.07 (m, 3H), 7.12-7.18 (m, 4H),
7.34 (d, 1H, J = 8.3 Hz), 7.52-7.60 (m, 2H), 7.69
(d, 1H, J = 1.7 Hz), 8.45-8.48 (m, 2H), 8.52 (s, 1
H).

Example 21: 4- [2- (5-benzyl-10,11-dihydrodibenz [b, f] azepin-2-yl) carboxamide-
3-Nitrophenoxy] butyric acid (Compound 21) Compound b 1.0 g obtained in Reference Example 2 and 4- (2-amino-3-nitrophenoxy) butyric acid ethyl ester 1.06
Compound 21 was prepared according to the method of Examples 1 and 2 using g.
0.22 g was obtained.

Melting point: 83 ° C. (decomposition) Elemental analysis (%): C ₃₂ H ₂₉ N ₃ O ₆ .0.6H ₂ O Calculated value: C 68.34; H 5.41; N 7.47 Found value: C 68.38; H 5.37; N 7.24 IR (KBr tablets) cm ^-1 : 3414, 2920, 1708, 1606, 1537, 149
0, 1450, 1273, 1232, 733.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 2.10-2.16 (m, 2
H), 2.49 (t, 2H, J = 6.8 Hz), 3.29 (s, 4H), 4.14
(t, 2H, J = 5.9 Hz), 5.05 (s, 2H), 7.00 (dt, 1H, J
= 1.9Hz and 7.0Hz), 7.12-7.31 (m, 9H), 7.39 (d,
2H, J = 7.3 Hz), 7.57 (dd, 1H, J = 1.3 Hz and 8.3
Hz), 7.61 (dd, 1H, J = 2.2 Hz and 8.6 Hz), 7.69
(d, 1H, J = 2.2 Hz), 8.51 (s, 1H).

Example 22: 4- [2- (9-benzylcarbazol-3-yl) carboxamidophenoxy] butyric acid (Compound 22) 0.79 g of compound j obtained in Reference Example 10 and 4- (2-
Aminophenoxy) butyric acid ethyl ester (0.82 g) was used to prepare compound 22 (0.80 g) according to the method of Examples 1 and 2.
Obtained.

Melting point: 110-111 ° C. Elemental analysis (%): C ₃₀ H ₂₆ N ₂ O ₄ Calculated value: C 75.30; H 5.48; N 5.85 Measured value: C 75.38; H 5.59; N 5.76 IR (KBr tablets) cm ^-1 : 3430, 1727, 1599, 1542, 1453, 133
0, 756.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 2.15-2.25 (m, 2
H), 2.54 (t, 2H, J = 7.1 Hz), 4.15 (t, 2H, J = 6.1
Hz), 5.53 (s, 2H), 6.90 (dd, 1H, J = 2.6 Hz and 6.
9 Hz), 6.96-7.03 (m, 2H), 7.10-7.13 (m, 4H), 7.22-
7.31 (m, 4H), 7.38-7.47 (m, 3H), 7.98 (dd, 1H, J =
2.0 Hz and 8.6 Hz), 8.19 (d, 1H, J = 7.9 Hz), 8.55
(dd, 1H, J = 2.5 Hz and 7.1 Hz), 8.75 (brs, 2H).

Reference Example 1: 5-benzyl-10,11-dihydrodibenz [b,
f] Azepine-2-carboxylic acid methyl ester (compound a) 5-benzyl-10,11-dihydrodibenz [b,
f] Azepine-2-aldehyde [Chemical Abstracts, 7
6, 113221k (1972)] 12.9 g 2 defining potassium hydroxide in methanol solution 650ml of - methanol solution 100 ml and iodine 5.2 g was added, carried out a total of 4 times the operation of stirring under ice cooling for 24 hours until the reaction is complete It was After completion of the reaction, methanol was distilled off under reduced pressure by about 2/3. Water in the reaction solution
1.0 liter was added to adjust the pH of the reaction solution to 5, and this was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium thiosulfate solution and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give compound a 1
1.9 g was obtained.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 3.30 (s, 4H),
3.90 (s, 3H), 5.09 (s, 2H), 7.02-7.45 (m, 10H), 7.7
9 (dd, 1H, J = 1.5 Hz and 10.8 Hz), 7.85 (d, 1H, J
= 1.5Hz).

Reference Example 2: 5-benzyl-10,11-dihydrodibenz [b,
f] Azepine-2-carboxylic acid (compound b) 10.4 ml of 10N aqueous sodium hydroxide solution was added to 360 ml of an ethanol solution of 11.9 g of compound a, and the mixture was stirred at 50 ° C for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, water was added to the obtained residue, and the pH was adjusted to 2. The obtained crystals were collected by filtration to obtain 10.5 g of compound b.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 3.22 (s, 4H),
5.01 (s, 2H), 6.96-7.27 (m, 5H), 7.34 (d, 2H, J =
7.3 Hz), 7.72 (dd, 1H, J = 2.0 Hz and 9.6 Hz), 7.
77 (d, 1H, J = 2.0 Hz).

Reference Example 3: 10,11-Dihydro-5H-dibenz [b, f] azepine-2-carboxylic acid (Compound c) Compound b 5.0 g ethyl acetate 100 ml and acetic acid 100 ml
1.25 g of palladium carbon was added to the mixed solution of, and the mixture was stirred at room temperature for 48 hours under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain 4.0 g of compound c. ¹ H-NMR (CDCl ₃ ) (δ, ppm): 3.08 (s, 4H), 6.70-6.90 (m,
4H), 6.00-7.16 (m, 4H).

Reference Example 4: 5-Methyl-10,11-dihydrodibenz [b, f]
Azepine-2-carboxylic acid (compound d) Compound c 4.6 g in dimethylformamide (DMF) solution
To 93 ml, 2.0 g of sodium hydride was added under ice cooling. After stirring for 15 minutes under ice cooling, 2.9 ml of methyl iodide was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, water was added to the reaction solution and this was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 3: 1) to obtain 2.3 g of the methyl ester of compound d.

To 70 ml of an ethanol solution of 2.3 g of the obtained methyl ester was added 2.6N of 10N aqueous sodium hydroxide solution.
ml was added, and the mixture was stirred at 50 ° C. for 3 hours. After completion of the reaction, ethanol was distilled off under reduced pressure, and water was added to adjust the pH to 3. This was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 2.04 g of compound d.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 3.06-3.27 (m, 4
H), 3.38 (s, 3H), 6.85-7.06 (m, 5H), 7.73 (d, 1H,
J = 1.1 Hz), 7.79 (dd, 1H, J = 1.1 Hz and 8.6 H
z).

Reference Example 5: 5-benzyl-2-isobutyryl-10,11-dihydrodibenz [b, f] azepine (compound e) 5-benzyl-10,11-dihydrodibenz [b, b
f] To 30 ml of a tetrahydrofuran (THF) solution containing 1.0 g of azepine-2-aldehyde, 3.2 ml of 2-isopropylmagnesium chloride (2.0 M THF solution) was added dropwise at -50 ° C. After stirring at the same temperature for 1 hour, water is added to the reaction solution.
ml was added and this was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in 50 ml of toluene, 2.8 g of active manganese dioxide was added thereto, and the mixture was heated under reflux for 3 hours. After completion of the reaction, the mixture was allowed to cool to room temperature, filtered through Celite, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent; hexane: ethyl acetate = 5: 1) to obtain 0.6 g of compound e.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 1.14 (d, 6H, J
= 6.7 Hz), 3.24 (s, 4H), 3.42-3.47 (m, 1H), 5.02
(s, 2H), 6.97-7.27 (m, 8H), 7.35 (d, 2H, J = 6.9 H
z), 7.62 (dd, 1H, J = 2.2 Hz and 8.6 Hz), 7.69
(d, 1H, J = 2.2 Hz).

Reference Example 6 5-Benzyl-2-isobutyl-10,11-dihydrodibenz [b, f] azepine (Compound f) 38 g of a solution of 2.5 g of compound e in trifluoroacetic acid was added to triethylsilane 11.4 at room temperature. ml was added dropwise, and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, the mixture was poured into ice water and extracted with toluene. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent: hexane: ethyl acetate = 10: 1) to obtain 2.4 g of compound f.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 0.85 (d, 6H, J
= 6.7 Hz), 1.63-1.82 (m, 1H), 2.34 (s, 2H), 3.18
(s, 4H), 4.88 (s, 2H), 6.74-6.82 (m, 3H), 6.90-7.2
0 (m, 8H), 2.30 (d, 2H, J = 7.2 Hz).

Reference Example 7: 5-Benzyl-8-isobutyl-10,11-dihydrodibenz [b, f] azepine-2-aldehyde (Compound g) In a mixed solution of 0.18 ml of phosphorus oxychloride and 0.5 ml of dichloroethane. , DMF 0.17 ml were added and the mixture was stirred at room temperature for 1 hour. To this, a solution of 0.5 g of compound f in dichloroethane 1.0
ml was added, and the mixture was stirred at 60 ° C. for 2 hours. This reaction solution was poured into 20 ml of an aqueous solution of 2.4 g of sodium acetate prepared beforehand, and the mixture was stirred at room temperature for 30 minutes. This was extracted with dichloromethane, the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 3: 1) to give 0.4 g of compound g.
Obtained.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 0.88 (d, 6H, J
= 6.7 Hz), 1.80-1.85 (m, 1H), 2.39 (d, 2H, J = 6.7
Hz), 3.19-3.27 (m, 4H), 5.05 (s, 2H), 6.91 (dd, 1
H, J = 1.9 Hz and 8.6 Hz), 6.92 (d, 1H, J = 1.9 Hz),
7.09 (d, 2H, J = 8.6 Hz), 7.17-7.39 (m, 5H), 7.51
(dd, 1H, J = 1.9 Hz and 8.6 Hz), 7.57 (d, 1H, J =
1.9 Hz).

Reference Example 8: 5-Benzyl-8-isobutyl-10,11-dihydrodibenz [b, f] azepine-2-carboxylic acid (Compound h) Using Compound g 0.4 g, Reference Examples 1 and 2 were prepared. 0.33 g of compound h was obtained according to the method.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 0.87 (d, 6H, J
= 6.8 Hz), 1.78-1.84 (m, 1H), 2.38 (d, 2H, J = 6.8
Hz), 3.22 (brs, 4H), 5.02 (s, 2H), 6.87-6.91 (m, 1
H), 6.91 (s, 1H), 7.01-7.08 (m, 2H), 7.16-7.28 (m,
4H), 7.35 (d, 2H, J = 6.9 Hz), 7.72 (dd, 1H, J = 2.
0 Hz and 8.6 Hz), 7.78 (d, 1H, J = 2.0 Hz).

Reference Example 9: 5- (2-pyridyl) methyl-10,11-dihydrodibenz [b, f] azepine-2-carboxylic acid (Compound i) Using the compound c 1.81 g, the method of Reference Example 4 According to the procedure described above, 1.28 g of compound i was obtained.

¹ H-NMR (CDCl ₃ ) (δ, ppm): 3.27 (brs, 4H),
5.16 (s, 2H), 6.95-7.00 (m, 1H), 7.04-7.18 (m, 5H),
7.35 (d, 1H), 7.52 (dt, 1H, J = 1.8 Hz and 7.7 Hz),
7.67 (dd, 1H, J = 2.1Hz and 8.4Hz), 7.75 (d, 1H, J
= 2.1 Hz), 8.51 (dd, 1H, J = 0.8 Hz and 4.8 Hz).

Reference Example 10: 9-benzylcarbazole-3-carboxylic acid (compound j) 9-benzylcarbazole-3-aldehyde [Chemical
and PharmaceuticalBulltin, 40 , 230 (1992)] 7.2 g,
To a mixed solution of 3.0 g of sodium dihydrogen phosphate, 144 ml of dioxane and 30 ml of water, 45 ml of an aqueous solution of 9.1 g of sodium chlorite was added dropwise at room temperature over 10 minutes. After stirring at the same temperature for 6 hours, the reaction solution was cooled to 0 ° C., and saturated aqueous sodium thiosulfate solution was added dropwise thereto. The crystals were collected by filtration, dried, heated under reflux with ethanol for purification, and filtered to obtain 7.6 g of compound j.

Melting point: 275-278 ° C. ¹ H-NMR (CDCl ₃ ) (δ, ppm): 5.61 (s, 2H), 7.11-7.26 (m,
6H), 7.39-7.53 (m, 3H), 8.03 (d, 1H, J = 8.6 Hz),
8.14 (d, 1H, J = 7.9 Hz), 8.75 (s, 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

[0121]

INDUSTRIAL APPLICABILITY According to the present invention, a tricyclic anilide derivative having a steroid 5α-reductase inhibitory action and useful as a therapeutic drug for benign prostatic hyperplasia, prostate cancer, baldness and acne and its pharmacologically acceptable The salt can be provided.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 31/40 ACV 31/44 31/55 C07D 209/82 8217-4C 223/22 311/82 313 / 12 401/06 223 491/044 7019-4C 498/04 116 513/04 381 391

Claims (1)

[Claims] 1. Formula (1): [In the formula, R ¹ , R ² and R ⁴ are the same or different and each represent hydrogen or lower alkyl, and R ³ is hydrogen, halogen,
Represents nitro or lower alkyl, A is CH or N
The stands, Y _{is, -CH 2 CH 2 -, -} CH = CH -, - C
_{H 2 O -, - OCH 2} -, - CH 2 S -, - SCH 2 -, -
O -, - represents S- or a single bond, Z ¹ -Z ² is, C =
O, CHOR ⁵ (wherein R ⁵ represents hydrogen or lower alkyl), C═CH ₂ or N—R ⁶ (wherein R ⁶ is substituted with hydrogen, a substituted or unsubstituted heterocyclic group) Optionally lower alkyl, which represents a substituted or unsubstituted aralkyl), X is O or S (O) _q (in the formula, q
Represents an integer of 0 to 2), and n represents an integer of 1 to 6], or a pharmaceutically acceptable salt thereof.