JPH0789961A - Benzoazepinone derivative - Google Patents

Abstract

PURPOSE:To obtain the novel derivative effective for preventing and treating diseases such as myocardial infarction, acute renal failure, bronchial asthma, etc., comprising a specific benzoazepinone derivative. CONSTITUTION:A novel benzoazepinone derivative (salt) of formula I [Z is CH; X is single bond or Z and X are bonded to form the formula C=CH; R<1> and R<2> are H, lower alkyl,l lower alkenyl, hydroxy, lower alkoxy, lower alkylthio, halogen, etc.; R<3> is H, lower alkyl, lower alkenyl or (substituted) aralkyl; (n) is 0-10 integer; (a) is N,N-oxido] [e.g. 11-formyl-6-methyl-5,11,- dihydropyrido[4,3-c]] [1]benzoazepin-5(6H)-one]. The compound is obtained by treating a 11-epoxy derivative of formula II with a Lewis acid and is useful for preventing and treating myocardial infarction, acute renal failure, bronchial asthma, etc., as an endothelin receptor antagonism.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a benzazepinone derivative having an endothelin receptor antagonistic action or a pharmacologically acceptable salt thereof.

[0002]

2. Description of the Related Art With respect to therapeutic agents for hypertension and stroke, therapeutic agents for asthma, etc., development of more potent agents with less side effects is desired. Recently, endothelin was found in vascular endothelial cells [Nature, 332, 411].
(1988)]. This substance strongly contracts various smooth muscles (eg, bronchial smooth muscles) including major blood vessels of humans (eg, coronary arteries, aortas, basilar arteries, etc.), and its action is angiotensin II, vasopressin. , 10 times more potent than known contractile peptides such as Neuropeptide Y.
It also exhibits blood pressure increasing activity and contractile force enhancing action on myocardium. On the other hand, endothelin is considered as one of mediators for myocardial infarction [Nature, 344, 114 (1990)] or acute renal failure [Life science, 46, 1611 (1990)]. Furthermore, it has recently become clear that it has not only smooth muscle contraction but also various physiological effects. Therefore, a compound having an endothelin antagonism is considered to be useful for preventing and treating diseases related to endothelin such as myocardial infarction, acute renal failure, and bronchial asthma.

As an endothelin receptor antagonist, for example, an anthraquinone derivative is disclosed in JP-A-3-47163.
Peptide derivatives in JP-A-3-130299, JP 4-13
Japanese Patent No. 4048 discloses TAN-1415 derivatives. Also,
The tricyclic benzazepinone derivative related to the present invention is disclosed in JP-A-1-319464.

[0004]

DISCLOSURE OF THE INVENTION Novel and useful endothelin receptor antagonists are expected and required to have preventive and therapeutic effects on a wide range of diseases. An object of the present invention is to provide a novel benzazepinone derivative having an endothelin receptor antagonistic action or a pharmacologically acceptable salt thereof.

[0005]

The present invention provides a compound of formula (I)

[0006]

[Chemical 2]

(Wherein Z represents CH and X represents a single bond, or Z and X together represent C = CH, R ¹ and
R ² is the same or different and represents hydrogen, lower alkyl, lower alkenyl, hydroxy, lower alkoxy, lower alkylthio or halogen, or R ¹ and R ² together represent methylenedioxy, R ³ is hydrogen, A lower alkyl, a lower alkenyl or a substituted or unsubstituted aralkyl, n represents an integer of 0 to 10, and a represents N or N-oxide).
It is called 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), the alkyl moiety in lower alkyl, lower alkoxy and lower alkylthio has a linear or branched carbon number of 1 to 1.
6, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
Pentyl, isopentyl, hexyl and the like are included. The lower alkenyl includes, for example, vinyl, allyl, propenyl, butenyl, pentenyl, hexenyl and the like having 2 to 6 carbon atoms, and halogen means each atom of fluorine, chlorine, bromine and iodine. For aralkyl,
C7-C13 such as benzyl, phenethyl and benzhydryl are included, and the aralkyl substituents are the same or different and have 1 to 3 substituents such as lower alkyl, lower alkoxy, lower alkenyl and trifluoro. Examples include methyl, halogen, methylenedioxy and the like. In the definition of the substituents, lower alkyl, lower alkoxy, lower alkenyl and halogen have the same meanings as defined above for each group.

Examples of the pharmacologically acceptable salt of compound (I) include pharmacologically acceptable acid addition salts, for example, hydrochloride, hydrobromide, sulfate, phosphate and the like. Examples thereof include organic acid salts such as inorganic acid salts, acetates, methanesulfonates, oxalates, acetates, malonates, succinates, maleates, fumarates, tartaric acid and citric acid. Next, a method for producing compound (I) will be described. Process 1: Compound (IA) in which Z is CH and X is a single bond and n = 0. Compound (IA) can be produced from compound (II) according to the following reaction step.

[0010]

[Chemical 3]

(Wherein R ¹ , R ² , R ³ and a have the same meanings as described above) The compound (IA) is obtained by converting the compound (II) into a suitable Lewis acid catalyst such as boron trifluoride. It can be obtained by reacting in the presence of an inert solvent such as dichloromethane, chloroform or diethyl ether at room temperature for 1 to 24 hours. Production Method 2: Compound (IB) in which Z is CH, X is a single bond, and n is an integer of 1 to 10. Compound (IB) can be produced from compound (III) according to the following reaction step. it can.

[0012]

[Chemical 4]

(In the formula, n ¹ represents an integer of ¹ to 10, R ¹ ,
R ² , R ³ and a have the same meanings as described above.) The compound (IV) is obtained by converting the compound (III) into an alcohol such as ethanol in the presence of a catalyst such as palladium-carbon, Raney nickel and platinum dioxide under a hydrogen gas atmosphere. It can be obtained by reacting in an inert solvent such as a solvent at room temperature to the boiling point of the solvent used for 1 to 24 hours.

Then, the compound (IB) is converted into the compound (I-B).
V) in the presence of an oxidizing agent such as pyridinium dichromate, pyridinium chlorochromate and manganese dioxide in an inert solvent such as dichloromethane, chloroform or tetrahydrofuran at 0 ° C to room temperature for 1 to 72 hours. You can Production Method 3: Compound (IC) in which Z and X are combined and C = CH Compound (IC) is compound (V) or compound (V).
It can be produced according to the following reaction step from I).

[0015]

[Chemical 5]

(Wherein R ¹ , R ² , R ³ , n and a have the same meanings as described above) The compound (IC) is obtained by reacting the compound (V) with a reducing agent such as diisobutylaluminum hydride. It can be obtained by reacting under an inert solvent such as diethyl ether or tetrahydrofuran at −30 ° C. to room temperature for 1 to 24 hours. Further, the compound (IC) is obtained by converting the compound (VI) into the presence of an oxidizing agent such as pyridinium dichromate, pyridinium chlorochromate or manganese dioxide in an inert solvent such as dichloromethane, chloroform or tetrahydrofuran at 0 ° C. to It can also be obtained by reacting at room temperature for 1 to 72 hours.

Next, the raw material compounds (II), (III),
The manufacturing method of (V) and (VI) will be described. Production Method 4: Compound (II) can be produced from compound (VII) according to the following reaction step.

[0018]

[Chemical 6]

(Wherein R ¹ , R ² , R ³ and a have the same meanings as described above) The compound (II) is a compound (VII) obtained by the method described in JP-A-1-319464 and an iodine compound. With trimethylsulfonium chloride in the presence of a base in an inert solvent at 0 ° C. to room temperature for 1 to 72 hours.
As the base, n-butyllithium, lithium diisopropylamide, sodium hydride, potassium hydride, tert
-Butoxy potassium, sodium amide, etc.
Sodium hydride is preferably used. As the inert solvent, diethyl ether, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, etc. may be used alone or in combination. The reaction is preferably carried out in a dry inert gas atmosphere such as nitrogen, argon or helium. Production method 5: Compound (VI) can be produced from compound (VII) according to the following reaction step.

[0020]

[Chemical 7]

(In the formula, R ⁴ represents lower alkyl, lower alkenyl or substituted or unsubstituted aralkyl, and Hal
Represents chlorine, bromine or iodine, and R ¹ , R ² , R ³ , n and a have the same meanings as defined above, wherein lower alkyl, lower alkenyl and substituted or unsubstituted aralkyl are each of the groups described above. Is synonymous with the definition of.

The compound (X) can be obtained by reacting the compound (VII) with the compound (VIII) or the compound (IX) in the presence of a base in an inert solvent. As the base, n-butyllithium, lithium diisopropylamide, sodium hydride, potassium hydride, tert-
Examples include butoxypotassium and sodium amide.
As the inert solvent, diethyl ether, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, etc. may be used alone or in combination. The reaction is nitrogen,
It is preferably carried out under an atmosphere of a dry inert gas such as argon or helium, and usually completed at -78 to 30 ° C for 1 to 24 hours.

Then, the compound (VI) is converted into the compound (X).
In the presence of a reducing agent such as diisobutylaluminum hydride in an inert solvent such as diethyl ether, tetrahydrofuran or dichloromethane at -30 ° C to room temperature for 1 to 24 hours. Production method 6: Compound (III) can be produced from compound (VII) according to the production method 5. Production Method 7: Compound (V) can be produced from compound (X) according to the following reaction step.

[0024]

[Chemical 8]

(In the formula, R ¹ , R ² , R ³ , R ⁴ , n and a have the same meanings as described above.) The compound (XI) is the compound (X) in an amount of 1 equivalent to an excess amount of sodium hydroxide. , In the presence of a base such as potassium hydroxide or the like, in a lower alcohol such as methanol or ethanol or a mixed solvent thereof with water, at room temperature to the boiling point of the solvent used.
It can be obtained by hydrolysis for 48 hours.

Then, the compound (V) is obtained by mixing the compound (XI) with 1 to 5 equivalents of a halogenating agent such as thionyl chloride or phosphorus oxychloride in an inert solvent such as dichloromethane or chloroform, if necessary, such as pyridine. In the presence of a base, or using a base as a solvent, at room temperature to the boiling point of the solvent used, which is 1 to 48.
After reacting for 1 hour, it can be obtained by reacting with 1 equivalent to an excess amount of methoxymethylamine at 0 ° C. to the boiling point of the solvent used for 1 to 10 hours.

The intermediates and target compounds in each of the above-mentioned production methods are purified by a method commonly used in synthetic organic chemistry, for example, extraction with ethyl acetate, methylene chloride, chloroform, etc., washing, filtration, drying, concentration, recrystallization, various methods. It can be isolated and purified by subjecting it to chromatography and the like. Compound (I-
With respect to stereochemistry, C) has geometrical isomers of E-form and Z-form, and a mixture thereof is usually provided in the above-mentioned production method. Isolation and purification of them can be performed by a method usually used in synthetic organic chemistry, for example, various chromatography, recrystallization and the like. If desired, the E and Z isomers can be isomerized with each other. For example, the isomerization can be carried out by treating for 1 to 24 hours under reflux of acetic acid in the presence of a suitable acid catalyst such as p-toluenesulfonic acid. Be converted. Some compound (I) may have stereoisomers such as optical isomers in addition to the above E and Z isomers, but the present invention includes all possible isomers including these isomers. And mixtures thereof.

When it is desired to obtain a salt of compound (I), when compound (I) can be obtained in the form of a salt, it can be purified as it is. When it is obtained in a free form, it can be used in a suitable solvent. It may be dissolved or suspended, added with an acid to form a salt, and isolated and purified. The compound (I) and a pharmaceutically acceptable salt thereof may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention.

Representative examples of the compound (I) obtained by the present invention are shown in Table 1.

[0030]

[Table 1]

Next, the pharmacological action of compound (I) will be specifically described with reference to experimental examples. Experimental Example 1 Endothelin A receptor binding experiment Method by Ihara et al. [Journal of Cardiovasular Pharmacol
ogy, 17 ( 7), s119-121 (1991)] with some improvements. The bovine carotid artery was placed in a polytron homogenizer (Kinemati) in ice-cold sodium bicarbonate buffer (PH8.3).
It was crushed using a ca. The suspension was centrifuged at 12,500 xg for 10 minutes, and the supernatant was again centrifuged at 100,000 xg for 60 minutes.
Final precipitate protein concentration 250 mg protein
50 mM tris-hydroxymethylaminomethane hydrochloric acid (Tris-HCl) buffer solution (PH7.6) was added and suspended to a concentration of / ml. This tissue suspension 400 [mu] l, was Shimegio with ^{125 I [125 I] Tyr 13} -Endothelin-1 ([125 I] ET-1 NEN Inc.;
Specific activity 81.4 TBq / mmol; final concentration 60 pM) 50 μl and test drug solution 50 μl were added and reacted at 37 ° C. for 2 hours. After the reaction was completed, the cells were rapidly filtered on glass fiber filter paper (GF / B, manufactured by Whatman) using Cell Harvester (manufactured by Brandel), and immediately washed twice with ice-cooled Tris-HCl buffer. The radioactivity on the glass fiber was measured by a gamma counter (Packard
(Manufactured by the company). The value of the inhibition rate of the test compound for endothelin A receptor binding was determined by the following formula.

[0032]

[Equation 1]

(Note) The total amount of binding is the amount of [ ¹²⁵ I] ET-1 binding radioactivity in the absence of the test compound. The non-specific binding amount is the amount of [ ¹²⁵ I] ET-1 binding radioactivity in the presence of 100 nM Endothelin-1. The amount of binding in the presence of a drug is the amount of [ ¹²⁵ I] ET-1 binding radioactivity in the presence of various concentrations of a test compound.
The receptor binding constant (Ki value) was calculated by the Cheng-Prusoff equation.

The results are shown in Table 2.

[0035]

[Table 2]

Compound (I) or a pharmaceutically acceptable salt thereof is, for example, tablets, capsules, injections, drops,
It can be prepared in a commonly applied dosage form such as a suppository and administered orally or by parenteral administration such as intramuscular injection, intravenous injection, intraarterial injection, infusion or rectal administration. Conventionally known methods are applied to the formulation of such dosage forms for oral or parenteral administration, for example, various excipients, lubricants, binders, disintegrating agents, suspending agents, It may contain an isotonicity agent, an emulsifier and the like.

The carrier for the formulation used is, for example,
Water, distilled water for injection, physiological saline, glucose, sucrose, mannitol, lactose, starch, cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, alginic acid, talc, sodium citrate, calcium carbonate, calcium hydrogen phosphate, stearin. Examples thereof include magnesium acid salt, urea, silicone resin, sorbitan fatty acid ester, glyceric acid ester and the like.

The dose and frequency of administration vary depending on the administration form, age, weight and symptoms of the patient, but usually 0.05
-5g / 60kg / day is suitable, 0.01-5mg / k for infusion
It is preferable that the dose per g / min is within the range of the oral dose per day. Hereinafter, embodiments of the present invention will be described with reference to Examples and Reference Examples.

[0039]

【Example】

Example 1 11-formyl-6-methyl-5,11-dihydropyrido [4,3-
c] [1] Benzazepine-5 (6H) -one (Compound 1) 5-oxo-6-methyl-5,11-dihydropyrido [4,3-c] [1] benzazepine-obtained in Reference Example 1 11 (6H) -spiro
780 mg (3.28 mmol) of -2'-oxirane (Compound 6) was dissolved in 20 ml of dichloromethane, 2 ml of boron trifluoride ether solution was added thereto, and the mixture was stirred at room temperature for 2 hours under a nitrogen stream. After the reaction was completed, 50 ml of saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. By subjecting the residue to silica gel column chromatography (elution solvent; hexane / ethyl acetate = 1/2), 510 mg (65%) of Compound 1 was obtained as a colorless crystalline substance.
%)Obtained.

NMR (CDCl ₃ ) δ (ppm): 9.89 (1H, s), 8.96 (1
H, d, J = 5Hz), 8.77 (1H, s), 7.90 (1H, d J = 5Hz), 7.05-
7.80 (4H, m), 6.76 (1H, s), 3.86 (3H, s) .MS (m / z): 238 (M ⁺ ).

Example 2 11-formylmethylene-5,11-dihydropyrido [4,3-c]
[1] Benzazepine-5 (6H) -one (Compound 2) 11- (N, O-Dimethylhydroxyaminocarbonylmethylene) -5,11-dihydropyrido [4,3-
c] [1] Benzazepine-5 (6H) -one (Compound 11) 6.27g
(20.3 mmol) was dissolved in 400 ml of tetrahydrofuran, and 61 ml (61 mmol) of diisobutylaluminum hydride (1M toluene solution) was added thereto at -78 ° C under a nitrogen stream, and the mixture was stirred for 1 hour. After the reaction was completed, 500 ml of water was added and the mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; hexane / ethyl acetate = 1/2) to give Compound 2 as a colorless crystalline substance.
2.44 g (48%) was obtained.

NMR (CDCl ₃ ) δ (ppm): 9.64 (1H, d, J = 8Hz),
8.80 (1H, d, J = 5.5Hz), 8.64 (1H, broad s), 8.62 (1H,
s), 7.94 (1H, s), 7.94 (1H, d, J = 5.5Hz), 7.00-7.55 (4
H, m), 6.41 (1H, d J = 8Hz) .MS (m / z): 250 (M ⁺ ).

Example 3 11-Formylmethylene-6-methyl-5,11-dihydropyrido [4,3-c] [1] benzazepin-5 (6H) -one (Compound 3) Obtained by Reference Example 7 11 -(N, O-Dimethylhydroxyaminocarbonylmethylene) -6-methyl-5,11-dihydropyrido [4,3-c] [1] benzazepine-5 (6H) -one (Compound
12) In the same manner as in Example 2 except that 16.7 g (53.4 mmol) was used, 8.82 g (63%) of Compound 3 was obtained.

NMR (CDCl ₃ ) δ (ppm): 9.76, 9.71 (1H, each d, J = 8Hz), 8.72, 8.69 (1H, each dist d, J
= 5.8Hz), 8.51 (1H, broad s), 7.84, 7.83 (1H, each d, J = 5.8Hz), 7.10-7.52 (4H, m), 6.40, 6.39 (1H, each d, J = 8Hz) , 3.58 (3H, s) .MS (m / z): 264 (M ⁺ ).

Example 4 (E) -11-formylmethylene-9-methyl-5,11-dihydropyrido [4,3-c] [1] benzazepin-5 (6H) -one (Compound 4) and (Z ) -11-Formylmethylene-9-methyl-5,11
-Dihydropyrido [4,3-c] [1] benzazepine-5 (6H)-
On (Compound 5) 11-Hydroxyethylidene-9-obtained in Reference Example 8
Methyl-5,11-dihydropyrido [4,3-c] [1] benzazepine-5 (6H) -one (Compound 13) 3.58 g (13.5 mmol) was dissolved in 36 ml of dimethylformamide, and imidazole 3.67 g ( 53.9 mmol) and 6.1 g (40.5 mmol) of tert-butyldimethylsilyl chloride, and under a nitrogen stream,
The mixture was stirred at room temperature for 16 hours. After completion of the reaction, 200 ml of water was added and the mixture was extracted 3 times with toluene. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; hexane / ethyl acetate = 9/1) to give (E) -11 as a colorless oil.
-tert-Butyldimethylsilyloxyethylidene-9-methyldihydropyrido [4,3-c] [1] benzazepine-5 (6H)-
On 1.5g (29%), (Z) -11-tert-butyldimethylsilyloxyethylidene-9-methyldihydropyrido [4,3-c] [1]
Benzazepine-5 (6H) -one 1.95g (38%) and mixture 0.4g
(8%) was obtained.

1.3 g (3.4 mmol) of the (E) body obtained above
And 1.75 g (4.6 mmol) of the (Z) compound were dissolved in 130 ml and 170 ml of methanol, and 0.5 ml and 0.7 ml of 4N hydrochloric acid were added thereto, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate was added to each, and the solvent was evaporated under reduced pressure. The residue was extracted with chloroform, the solvent was evaporated under reduced pressure, and the crude products were respectively obtained as (E) -11-hydroxyethylidene-9-methyldihydropyrido [4,3-c] [1] benzazepine-5. (6H)
-ON 0.9 g (99%) and (Z) -11-hydroxyethylidene-9
-Methyldihydropyrido [4,3-c] [1] benzazepine-5
Obtained 1.20 g (98%) of (6H) -one.

161 mg (0.61 mmol) of (E) form and 150 mg (0.56 mmol) of (Z) form obtained above were dissolved in a mixed solvent of 200 ml of dichloromethane and 100 ml of tetrahydrofuran, respectively, and 500 mg of manganese dioxide was added thereto. The mixture was stirred at room temperature for 5 hours under a nitrogen stream. After the reaction was completed, the inorganic substances were filtered and the solvent was distilled off under reduced pressure. By subjecting the residue to silica gel column chromatography (elution solvent; dichloromethane / methanol = 99/1), 141 mg (88%) of compound 4 and compound 5 as colorless crystals were obtained.
Was obtained in 130 mg (87%).

Compound 4: NMR (CDCl ₃ ) δ (ppm): 9.72 (1H, d, J = 9Hz), 9.48 (1H, bro
ad s), 8.84 (1H, d, J = 5.8Hz), 8.68 (1H, s), 7.95 (1H,
d, J = 5.8Hz), 6.99-7.25 (3H, m), 6.40 (1H, d, J = 9Hz),
2.35 (3H, s) .MS (m / z): 264 (M ⁺ ).

Compound 5: NMR (CDCl ₃ ) δ (ppm): 9.74 (1H, d, J = 7.5Hz), 9.44 (1H, b
road s), 8.78 (1H, broad s), 8.65 (1H, broad s), 7.9
1 (1H, broad s), 7.03-7.30 (3H, m), 6.38 (1H, d, J = 7.
5Hz), 2.34 (3H, s) .MS (m / z): 264 (M ⁺ ).

Reference Example 1 5-oxo-6-methyl-5,11-dihydropyrido [4,3-c] [1]
Benzazepine-11 (6H) -spiro-2'-oxirane (Compound 6) 6-methyl-5,11-dihydropyrido [4,3-c] [1] benzazepine-5,11 (6H) -dione 1 g (4.5 mmol) was dissolved in 50 ml of dimethyl sulfoxide, and sodium hydride 54
0 mg (13.5 mmol, 60% oily) and trimethylsulfonium iodide 2.75 g (13.5 mmol) were added, and under a nitrogen stream,
The mixture was stirred at room temperature for 18 hours. After the reaction is complete, add 200 ml of water,
It was extracted twice with toluene. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give 780 mg (74%) of Compound 6 as a colorless crystalline substance.

NMR (CDCl ₃ ) δ (ppm): 8.70 (1H, s), 8.60 (1
H, d, J = 5.4Hz), 7.63 (1H, d, J = 5.4Hz), 7.13-7.60 (4
H, m), 3.62 (3H, s), 3.10 (2H, s). MS (m / z): 238 (M ⁺ ).

Reference Example 2 11-Ethoxycarbonylmethylene-5,11-dihydropyride
[4,3-c] [1] Benzazepine-5 (6H) -one (Compound 7) 40.11 g (179 mmol) triethylphosphonoacetate
1000 ml of dry tetrahydrofuran was added, to this was added 7.16 g (179 mmol, 60% oily) of sodium hydride under nitrogen cooling in a nitrogen stream, and the mixture was stirred at room temperature for 1 hour. Then, 5,11-dihydropyrido [4,3-c] [1] benzazepine
-5 (6H) -one (21.12 g, 94.3 mmol) was added, and the mixture was stirred at room temperature for 2 hours.
Stir for hours. Add 2000 ml of water and adjust the pH with 4N hydrochloric acid.
It was adjusted to 4.5 and extracted with 2000 ml of chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. Compound 7 was obtained by subjecting the residue to silica gel column chromatography (elution solvent; hexane / ethyl acetate = 2/1).
26.37 g (95%) was obtained.

NMR (CDCl ₃ ) δ (ppm): 8.73, 8.64 (1H, d, J = 5Hz), 8.67, 8.65 (1H, s), 7.84
(1H, d, J = 5Hz), 7.50-7.05 (4H, m), 6.19, 6.18 (1H,
Each s), 4.11, 4.09 (2H, each q, J = 7Hz), 1.1
7, 1.12 (3H, each t, J = 7Hz) .MS (m / z): 294 (M ⁺ ).

Reference Example 3 11-Ethoxycarbonylmethylene-9-methyl-5,11-dihydropyrido [4,3-c] [1] benzazepine-5 (6H) -one (Compound 8) 9-methyl-5, Using 11-dihydropyrido [4,3-c] [1] benzazepine-5 (6H) -one 5.0 g (21 mmol), Reference Example 2
5.58g (86%) of compounds 8 were obtained similarly to the above.

NMR (CDCl ₃ ) δ (ppm): 8.70, 8.66 (1H, each s), 8.65, 8.60 (1H, each d, J = 5Hz), 7.83 (1
H, d, J = 5Hz), 7.26-7.03 (3H, m), 6.19, 6.16 (1H, each s), 4.11, 4.08 (1H, each q, J = 7.5Hz), 2.3
5, 2.32 (3H, each s), 1.16, 1.13 (3H, each
t, J = 7.5Hz) .MS (m / z): 308 (M ⁺ ).

Reference Example 4 11-Carboxymethylene-5,11-dihydropyrido [4,3-c]
[1] Benzazepine-5 (6H) -one (Compound 9) 3.0 g (10.2 mmol) of the compound 7 obtained in Reference Example 2 was dissolved in 100 ml of methanol, and 20 ml of 5N sodium hydroxide aqueous solution was added thereto. The mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluting solvent: chloroform / methanol = 98/2) to obtain 2.4 g (89%) of compound 9 as colorless crystals.

NMR (DMSO-d ₆ ) δ (ppm): 8.65, 8.58 (1H, each s), 8.58, 8.51 (1H, each d, J = 5Hz), 7.66,
7.62 (1H, each d, J = 5Hz), 7.00-7.50 (4H, m), 6.2
4, 6.16 (1H, each s). MS (m / z): 266 (M ⁺ ).

Reference Example 5 11-carboxymethylene-6-methyl-5,11-dihydropyrido [4,3-c] [1] benzazepine-5 (6H) -one (Compound 1
0) 6-Methyl-5,11-dihydropyrido [4,3-c] [1] benzazepine-5 (6H) -one 3.6 g (15.1 mmol) was used in the same manner as in Reference Example 2 and Reference Example 4. Thus, 2.9 g (68%) of Compound 10 was obtained.

NMR (DMSO-d ₆ ) δ (ppm): 8.52 (1H, s), 8.61,
8.51 (1H, each d, J = 5.5Hz), 7.73 (1H, d, J = 5.5H
z), 7.50-7.05 (4H, m), 6.21, 6.20 (1H, each s),
3.56,3.55 (3H, each s). MS (m / z): 280 (M ⁺ ).

Reference Example 6 11- (N, O-dimethylhydroxyaminocarbonylmethylene) -5,11-dihydropyrido [4,3-c] [1] benzazepine
-5 (6H) -one (Compound 11) 12.65 g (47.6 mmol) of Compound 9 obtained in Reference Example 4
Is dissolved in 350 ml of pyridine, and 10.3 ml of thionyl chloride is added to this.
(141 mmol) was added under ice-cooling stirring, and the mixture was stirred at room temperature for 1 hour. Then, N, O-dimethylhydroxylamine 11.04g
(181 mmol) was added, and the mixture was further stirred at room temperature for 1 hr.
After completion of the reaction, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. By subjecting the residue to silica gel column chromatography (elution solvent; chloroform / methanol = 99/1), 8.76 g (60%) of compound 11 was obtained as colorless crystals.
Obtained.

NMR (CDCl ₃ ) δ (ppm): 8.71, 8.63 (1H, each d, J = 5.5Hz), 8.64, 8.63 (1H, each s), 7.83,
7.79 (1H, each d, J = 5.5Hz), 7.50-7.00 (4H, m),
6.57, 6.54 (1H, each s), 3.69 (3H, s), 3.15 (3H,
s) .MS (m / z): 309 (M ⁺ ).

Reference Example 7 11- (N, O-dimethylhydroxyaminocarbonylmethylene) -6-methyl-5,11-dihydropyrido [4,3-c] [1] benzazepine-5 (6H) -one (compound 12) 15.52 g (55.4 mmol) of the compound 10 obtained in Reference Example 5
In the same manner as in Reference Example 6, using 14.05 g (79%) of Compound 12.
%) Obtained.

NMR (CDCl ₃ ) δ (ppm): 8.57 (1H, s), 8.56 (1
H, d, J = 5.5Hz), 7.68 (1H, d, J = 5.5Hz), 7.38-7.14 (4
H, m), 6.59 (1H, s), 3.67 (3H, s), 3.56 (3H, s), 3.14
(3H, s) .MS (m / z): 323 (M ⁺ ).

Reference Example 8 11-Hydroxyethylidene-9-methyl-5,11-dihydropyrido [4,3-c] [1] benzazepine-5 (6H) -one (Compound
13) 8.58 g (27.9 mmol) of the compound 8 obtained in Reference Example 3
200 ml of tetrahydrofuran and 200 m of dichloromethane
Dissolve it in a mixed solvent of l, and add it to a solution of diisobutylaluminum hydride (1.0 M in toluene) at -78 ° C under a nitrogen stream.
68 ml was added and stirred for 1 hour. After completion of the reaction, 300 ml of water was added and the mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent; chloroform / methanol = 99/1) to obtain 3.94 g (53%) of Compound 13 as a colorless crystalline substance.

NMR (CDCl ₃ + CD ₃ OD) δ (ppm): 8.66, 8.62 (1H,
D, J = 5.8Hz), 8.62, 8.56 (1H, each
s), 7.84, 7.82 (1H, each d, J = 5.8Hz), 7.25-6.95
(3H, m), 6.15, 6.07 (1H, each t, J = 6.0Hz), 4.2
7, 4.23 (2H, each d, J = 6.0Hz), 2.36 (3H, s). MS (m / z): 266 (M ⁺ ).

[0066]

According to the present invention, myocardial infarction, acute renal failure,
Provided is a benzazepinone derivative having an endothelin antagonism or a pharmacologically acceptable salt thereof, which is useful for the prevention and treatment of diseases involving endothelin such as bronchial asthma.

Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display location C07D 491/147 7019-4C

Claims (1)

[Claims] 1. Formula (I): (In the formula, Z represents CH, X represents a single bond, or Z and X
Together represent C = CH, R ¹ and R ² are the same or different and represent hydrogen, lower alkyl, lower alkenyl, hydroxy, lower alkoxy, lower alkylthio or halogen, or R ¹ and R ² are the same. Represents methylenedioxy, R ³ represents hydrogen, lower alkyl, lower alkenyl or substituted or unsubstituted aralkyl, and n is 0 to
Represents an integer of 10, and a represents N or N-oxide) or a pharmaceutically acceptable salt thereof.