JPH04334371A - Benzazepinopiridazine compound and synthetic intermediate thereof - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

0001

FIELD OF THE INVENTION The present invention relates to new and pharmaceutically useful benzazepinopyridazine compounds and synthetic intermediates thereof.

[Prior Art] Currently, diazepine compounds such as diazepam and clotiazepam are frequently used as anxiolytics, but benzodiazepine compounds in particular have muscle relaxing effects in addition to anxiolytic effects, causing light-headedness and other symptoms. ,There's a problem. In addition, in recent years, it has been discovered that benzodiazepine receptors exist in the central nervous system, and compounds that have a non-benzodiazepine skeleton and have affinity for these receptors are considered promising as more selective anxiolytics. It is becoming more and more common. In addition, compounds that show high affinity for the same receptor but have the opposite effect to benzodiazepine compounds have been developed as anti-dementia drugs. One of the compounds with such activity is pyridazino[4,3-d][1]
Benzazepine derivatives are known (Japanese Patent Application Laid-open No. 2-22
9193).

OBJECTS OF THE INVENTION The object of the present invention is to provide benzazepinopyridazine compounds useful as anxiolytics, amnesia therapeutics, etc., and synthetic intermediates thereof.

0002

[Means for Solving the Problems] The present invention provides the general formula

[C6
] (In the formula, R1 is a hydrogen atom, C1-4 alkyl, aryl, or halogen on the aromatic ring, trifluoromethyl,
aryl having 1 to 3 substituents selected from hydroxy, amino, nitro, cyano, C1-4 alkyl, C1-4 alkoxy and acylamino, R2 is a hydrogen atom, C1-4 alkyl, aryl-C1-4 alkyl or Aryl-C1-4 having 1 to 3 substituents selected from halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C1-4 alkyl, C1-4 alkoxy and acylamino on the aromatic ring
In the alkyl, R3 and R4 may be the same or different, and each is a hydrogen atom, halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C1-4
It represents alkyl, C1-4 alkoxy, acyl or acylamino, and the bond between the 4-position and the 4a-position represents a single bond or a double bond. ) or a pharmaceutically acceptable salt thereof, and its synthetic intermediate, the general formula

embedded image (In the above formula, R5 represents C1-4 alkyl, R6 represents a hydrogen atom or C1-4 alkyl, and the other symbols are as described above.)

[0003] In each definition of the above general formula and in this specification, C1-4 alkyl refers to alkyl having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tertiary butyl. Aryl refers to phenyl, naphthyl, etc. Halogen refers to fluorine, chlorine, bromine, and iodine. C1-4 Alkoxy refers to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, etc. having 1 to 1 carbon atoms.
Indicates 4 alkoxy. Acylamino refers to acetylamino, propionylamino, butyrylamino, pivaloylamino, and the like. Aryl-C1-4 alkyl means benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-
Indicates phenylpropyl, naphthylmethyl, etc. Acyl refers to acetyl, propionyl, butyryl, pivaloyl, etc. Furthermore, aryl having 1 to 3 substituents selected from halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C1-4 alkyl, C1-4 alkoxy, and acylamino on the aromatic ring means 2-chlorophenyl, 3 -chlorophenyl, 4-chlorophenyl, 3,
4-dichlorophenyl, 4-bromophenyl, 4-fluorophenyl, 3-trifluoromethylphenyl, 4-
Hydroxyphenyl, 4-aminophenyl, 4-cyanophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-acetylaminophenyl, 4-propionylaminophenyl, etc. When the compound of general formula (I) has one asymmetric carbon atom, racemic mixtures and individual optical isomers may exist, and when it has two or more asymmetric carbon atoms, individual optical isomers may exist. diastereomers or mixtures thereof. The present invention includes all these mixtures and individual isomers. Also included are stereoisomers. Pharmaceutically acceptable salts of the compound of general formula (I) include acid addition salts with inorganic or organic acids (hydrochloride, hydrobromide, sulfate, maleate, fumarate, tartrate, etc.) ) or quaternary ammonium salts.

The compound of the present invention can be synthesized by the following production method. Production method 1 The compound of general formula (I) is mixed with a suitable solvent (
methanol, ethanol, propanol, butanol,
benzene, toluene, chloroform, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, etc.), the compound of general formula (IV) is substituted with general formula R1 -NHN.
It can be produced by reacting with a hydrazine derivative represented by H2 (VI) (wherein R1 has the same meaning as above) or a hydrate or acid addition salt thereof. Preferably, the reaction can be carried out by reacting the compound of the general formula (IV) with the hydrazine derivative of the general formula (VI) or its hydrate or acid addition salt in a solvent such as ethanol at around the boiling point for 1 to 10-odd hours. Alternatively, in a solvent such as ethanol, a compound of general formula (IV) is mixed with general formula (
VI) The compound produced by reacting with the hydrazine derivative, its hydrate, or acid addition salt near the boiling point for 1 to 10-odd hours is reacted in a solvent such as acetic acid for 1 to 10-odd hours near the boiling point. It can be manufactured by Production method 2 The compound of general formula (I) is mixed with a suitable solvent (
methanol, ethanol, propanol, butanol,
It can be produced by reacting a compound of general formula (V) with a hydrazine derivative of general formula (VI) or its hydrate or acid addition salt in a mixture of benzene, toluene, chloroform, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, etc.). Preferably, the compound of the general formula (V) is reacted with the hydrazine derivative of the general formula (VI) or its hydrate or acid addition salt in a solvent such as ethanol at around the boiling point for 1 to 10-odd hours. or a hydrazine derivative of general formula (VI) or a hydrate thereof, a compound of general formula (V) in a solvent such as ethanol,
A compound produced by reacting with an acid addition salt near the boiling point for 1 to 10-odd hours can be produced by reacting it in a solvent such as acetic acid for 1 to 10-odd hours near the boiling point.

Production method 3 When the bond between the 4-position and the 4a-position in general formula (I) is a double bond, a compound in which the bonding site is a single bond is treated with bromine in a mixed solvent of acetic acid and chloroform. [Journal of Medicinal Chemistry (J.Med.Chem.) Vol. 14, 26]
2 pages (1971)] can be synthesized. The reaction proceeds suitably when 1 to 1.5 times the molar amount of bromine is added dropwise at 20 to 60°C in a mixed solvent of acetic acid and chloroform. Also,
The general formula (I
) is a compound whose binding site is a single bond, sodium-m-nitrobenzenesulfonate (Bachm
It can also be synthesized by reacting the ann method (UK Patent No. 1,168,291).

Compounds of general formulas (II), (III), (IV) and (V) can be synthesized by the following method. Production method 4 A base (triethylamine, pyridine, 1,8-diazabicyclo[5.4.0
] undec-7-ene, potassium carbonate, sodium hydroxide, sodium hydrogen carbonate, etc.), the general formula

[chemical 8
] (In the formula, X1 represents halogen, R7 represents C1-4 alkyl, and the other symbols have the same meanings as above.) The compound represented by the general formula R2 NHCH2 CH2 CN (V
III) (wherein R2 has the same meaning as above) is reacted to obtain a general formula

A compound represented by the formula (wherein each symbol has the same meaning as above) in a suitable solvent (benzene, toluene, chloroform, methylene chloride, dimethylformamide, tetrahydrofuran, dioxane, etc.) that does not inhibit the reaction, The general formula (I
Compound I) is obtained. In addition, the compound of general formula (II) has the general formula

embedded image There are tautomers represented by (wherein each symbol has the same meaning as above). In the present invention, the general formula (
It shall be represented by the compound II).

Production method 5 A compound of the general formula (IX) is prepared by converting the compound of the general formula (IX) into a compound of the general formula R5 OH (X) (where R
5 represents C1-4 alkyl. ) by treatment with an acid (sulfuric acid, p-toluenesulfonic acid, etc.) in a solution of an alcohol represented by the general formula

Formula 11 An ester compound represented by (in the formula, each symbol has the same meaning as above) is used, and this compound is mixed with a suitable solvent that does not inhibit the reaction (benzene, toluene, chloroform, methylene chloride, dimethylformamide, tetrahydrofuran, -
The compound of general formula (III) is obtained by carrying out the reaction at 5°C to 0°C for 30 minutes to several hours. In addition, the compound of the general formula (III) has the general formula

embedded image There are tautomers represented by (wherein each symbol has the same meaning as above). In the present invention, the general formula (
It shall be represented by the compound III). Also, the general formula (
The compound of general formula (III) is a compound of general formula (II)
It can also be obtained by treatment with an acid (sulfuric acid, p-toluenesulfonic acid, etc.) in an alcohol solution of X).

Production method 6 A compound of the general formula (III) is prepared by converting the compound of the general formula (III) into a compound of the general formula CH2
COOR6 a (XII) (wherein, X2
represents a halogen such as chlorine or bromine, and R6 a is C1
-4 Indicates alkyl. ) by reacting the compound represented by C1-4 with the compound near the boiling point of the solvent.
Compounds of general formula (IV) and (V) which are alkyl are prepared. Preferably, R6 is obtained by reacting the compound of general formula (III) with a compound of general formula (XII) such as methyl bromoacetate for 2 hours in a solvent such as tetrahydrofurafne in the presence of sodium hydride near the boiling point of the solvent. Compounds of general formula (IV) and (V) which are C1-4 alkyl are obtained. Also, R6 is C1-4
R
A compound of general formula (IV) in which 6 is hydrogen is obtained, and by further refluxing for 3 to 5 hours, a compound of general formula (V) in which R6 is hydrogen is obtained.

Production method 7 The compound of general formula (XI) in production method 5 is prepared by adding a base (triethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate, sodium hydroxide, sodium hydrogen carbonate, etc.), the compound of general formula (VII) is reacted with general formula R2 NHCH2 CH2 COOR5
It can also be synthesized by reacting a compound represented by (XIII) (wherein each symbol has the same meaning as above).

Production method 8 General formula obtained by adding concentrated hydrochloric acid to a compound of general formula (II) or (III) in an acetic acid solution and refluxing for several hours.

[Chemical formula 13] (wherein, each symbol has the same meaning as above) is subjected to a Mannich reaction using formaldehyde and dimethylamine hydrochloride to obtain the general formula

embedded image By adding methyl iodide to the compound represented by (wherein each symbol has the same meaning as above) or an acid addition salt thereof in acetone and keeping it at room temperature for 2 to 5 hours, the
grade ammonium salt, and add potassium cyanide or sodium cyanide to this in water-containing methanol for 30~
After reacting at 50°C for 4 to 10 hours, the general formula

[Chemical formula 15] (In the formula, each symbol has the same meaning as above) is prepared as a cyano compound, and then the compound of general formula (XVI) is added to acetic acid and concentrated hydrochloric acid, and the mixture is heated under reflux for 2 to 5 hours. R6
Compounds of general formula (V) can be synthesized where is hydrogen. When the compound of the present invention has one asymmetric carbon atom, it is usually obtained as a racemic mixture, but this can be resolved into optical isomers by conventional methods, or using optical isomers as starting materials. It can also be manufactured by Furthermore, individual diastereomers when the compound has at least two asymmetric atoms can also be obtained by conventional methods. Moreover, stereoisomers can also be easily separated. The compound of the present invention or its isomer can be treated with an inorganic or organic acid in a conventional manner to form the above-mentioned acid addition salt, or can also be formed into a quaternary ammonium salt.

[0011]

[Action and Effect of the Invention] The general formula (I
) was found to exhibit high inhibitory activity against benzodiazepine receptors using tritium-labeled diazepam. Therefore, the compound of general formula (I) is useful as an anxiolytic drug, and as a neutralizing agent (antidote) for overdosing or poisoning of existing anxiolytic drugs such as diazepam, and also as a therapeutic agent for amnesia. is also useful. Furthermore, general formulas (II), (III), (IV) and (
The compound V) is important as a synthetic intermediate for the compound of general formula (I). When using the compound of the present invention as a medicine, it is mixed with appropriate pharmacologically acceptable excipients, carriers, diluents, etc., and prepared into tablets, capsules, granules, syrups, injections, suppositories, or It can be administered in the form of a powder, etc. For example, in the case of oral administration, the dosage is usually about 5 to 500 mg per day for an adult, and this can be administered once or in divided doses.

0012

EXAMPLES The present invention will be explained in detail below using reference examples and examples, but the present invention is not limited by these in any way. Reference Example 1 67 ml of 2-cyanoethyl-methylamine and 167 ml of triethylamine were added to 600 ml of chloroform under ice cooling.
was added, and 159 g of 2-methoxycarbonylbenzoyl chloride was added dropwise while stirring. After the dropwise addition, the ice bath was removed and the mixture was stirred at room temperature for 1.5 hours. Thereafter, the reaction solution was poured into ice water, the organic layer was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off, and 2-(N-(2-
140 g of an oily substance of cyanoethyl)-N-methylcarbamoyl)benzoic acid methyl ester were obtained. Reference Example 2 70 g of 2-(N-(2-cyanoethyl)-N-methylcarbamoyl)benzoic acid methyl ester was added to 58 g of methanol.
The solution was dissolved in 0 ml and stirred under ice cooling. Add this to 78ml of concentrated sulfuric acid.
was added dropwise, and the mixture was heated under reflux for 3.5 hours. The reaction solution was poured into ice water, and the product was extracted with chloroform, washed with saturated aqueous sodium bicarbonate, dried, and then the solvent was distilled off. The obtained residue was crystallized by adding isopropyl ether, and recrystallized from a mixed solvent of isopropyl ether:ethanol = 5:1 to obtain methyl 2-(N-(2-methoxycarbonylethyl)-N-methylcarbamoyl)benzoate. 55 g of ester, melting point 80-82 DEG C., were obtained. Reference Example 3 23 g of 3-methylaminopropionic acid methyl ester and 40 ml of triethylamine in 300 ml of chloroform
32 g of 2-methoxycarbonylbenzoyl chloride was added to the solution under ice cooling and stirring, and after stirring at room temperature for 30 minutes, the mixture was heated under reflux for 2 hours. After cooling, water was added to the reaction solution, and the mixture was extracted with chloroform. After washing with water, drying over anhydrous magnesium sulfate, and distilling off the chloroform under reduced pressure, 26 g of 2-(N-(2-methoxycarbonylethyl)-N-methylcarbamoyl)benzoic acid methyl ester was obtained as a pale yellow oil. Ta.

Example 1 To a solution of 5.0 g of 2-(N-(2-cyanoethyl)-N-methylcarbamoyl)benzoic acid methyl ester in 80 ml of N,N-dimethylformamide was added 1 portion of sodium hydride with stirring under ice cooling. .0 g was added, the reaction was carried out for 45 minutes at room temperature, and the reaction solution was poured into ice. After acidifying with dilute hydrochloric acid, the mixture was extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and ethyl acetate was distilled off under reduced pressure. When the obtained crystals are recrystallized from ethanol, the melting point is 203-206
2-Methyl-1,5-dioxo- as white crystals at °C.
0.8 g of 2,3,4,5-tetrahydro-1H-2-benzazepine-4-nitrile was obtained. Example 2 3.2 g of sodium hydride was mixed with 20 g of dimethylformamide.
0 ml of 2-(
A solution of 20 g of N-(2-methoxycarbonylethyl)-N-methylcarbamoyl)benzoic acid methyl ester in 70 ml of dimethylformamide was added dropwise. After completion of dripping, 0
The mixture was stirred at ℃ for 1 hour. 5 ml of acetic acid was added to the reaction mixture, stirred at room temperature for 10 minutes, and then poured into ice water. The product was extracted with ethyl acetate, and the aqueous layer was made acidic with concentrated hydrochloric acid, and then the product was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated to give 2-methyl-1,5-dioxo-2,3
,4,5-tetrahydro-1H-2-benzazepine-
12 g of 4-carboxylic acid methyl ester, melting point 148-1
50°C was obtained. Example 3 15 g of 2-methyl-1,5-dioxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-carboxylic acid methyl ester was added to 300 ml of tetrahydrofuran.
It was dissolved in After adding 3.1 g of sodium hydride little by little to this, the mixture was stirred at room temperature for 30 minutes. After cooling on ice, 11.2 g of methyl bromoacetate was added dropwise, and then 2 g of methyl bromoacetate was added dropwise.
Refluxed for an hour. The reaction solution was poured into ice and made acidic with concentrated hydrochloric acid, and then the product was extracted with ethyl acetate. The organic layer was dried and filtered, and the solvent was distilled off. The residue was crystallized by adding isopropyl ether to give 18 g of 4-methoxycarbonyl-2-methyl-1,5-dioxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid ethyl ester, melting point 116. ~118°C was obtained.

Example 4 4-Methoxycarbonyl-2-methyl-1,5-dioxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid methyl ester 1.0 g of acetic acid 20
ml solution was added with 20 ml of concentrated hydrochloric acid, and the mixture was heated under reflux for 2.5 hours. After cooling, water was added to the reaction solution, extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the resulting crystals are recrystallized from a mixed solvent of ethanol and isopropyl ether, resulting in a melting point of 168~
0.1 g of 2-methyl-1,5-dioxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid was obtained as white crystals at 171°C. Example 5 2-benzyl-4-methoxycarbonyl-1,5-dioxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid methyl ester was dissolved in acetic acid,
By adding concentrated hydrochloric acid and refluxing, 2-benzyl-
4-methoxycarbonyl-1,5-dioxo-2,3,
4,5-tetrahydro-1H-2-benzazepine-4
- Acetic acid was obtained. Example 6 A solution of 1.0 g of 2-methyl-1,5-dioxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-carboxylic acid methyl ester in 10 ml of acetic acid was added with 1 part of concentrated hydrochloric acid.
0 ml was added, and the mixture was heated under reflux for 2.5 hours. After cooling, water was added to the reaction solution, neutralized with potassium carbonate, and extracted with ethyl acetate. After washing with water, drying over anhydrous magnesium sulfate, ethyl acetate was distilled off under reduced pressure, and the resulting crystals were recrystallized from a mixed solvent of ethyl acetate and isopropyl ether to give 2- Methyl-
0.3 g of 2,3,4,5-tetrahydro-1H-2-benzazepine-1,5-dione was obtained.

Example 7 7 g of 4-methoxycarbonyl-2-methyl-1,5-dioxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid methyl ester was added to 50 ml of acetic acid.
50 ml of concentrated hydrochloric acid was added and refluxed for 1 hour. The reaction solution was poured into ice, and the product was extracted with ethyl acetate. The organic layer was dried, filtered, and the solvent was distilled off. Isopropyl ether was added to the residue to crystallize it, and 4-methoxycarbonyl-2-methyl-1,5-dioxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid2.
9 g, melting point 186-189°C were obtained. Example 8 2.7 g of sodium hydride was mixed with 15 g of dimethylformamide.
5 ml and stirred at -3°C to 0°C for 2 hours.
A solution of 20 g of -(N-benzyl-N-(2-methoxycarbonylethyl)carbamoyl)benzoic acid in 31 ml of dimethylformamide was added dropwise at 0°C.
Stir for hours. After adding 5 ml of acetic acid to the reaction mixture and stirring at room temperature for 10 minutes, the mixture was poured into ice water and the product was extracted with ethyl acetate. Furthermore, the aqueous layer was made acidic with concentrated hydrochloric acid, and then the product was extracted with ethyl acetate. The organic layer was dried and filtered over anhydrous magnesium sulfate, and the solvent was distilled off to give 2-benzyl-1,5-dioxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-carboxylic acid methyl ester. 5.0 g, melting point 132-136°C was obtained. Example 9 7 g of 2-benzyl-1,5-dioxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-carboxylic acid methyl ester was added to 108 ml of tetrahydrofuran.
After adding 1.1 g of sodium hydride little by little, the mixture was stirred at room temperature for 30 minutes. This was cooled with ice, 4 g of methyl bromoacetate was added dropwise, and the mixture was refluxed for 2 hours after the dropwise addition. The reaction solution was poured into ice water and made acidic with concentrated hydrochloric acid, and then the product was extracted with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off. Isopropyl ether was added to the residue and crystallized to give 2-benzyl-4-methoxycarbonyl-1,5-dioxo-2,3,4,5
8.5 g of -tetrahydro-1H-2-benzazepine-4-acetic acid methyl ester were obtained.

Example 10 8.5 g of 2-benzyl-4-methoxycarbonyl-1,5-dioxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid methyl ester was mixed with 5 g of acetic acid.
4 ml of the solution was dissolved, 54 ml of concentrated hydrochloric acid was added thereto, and the mixture was refluxed for 40 minutes. The reaction solution was poured into ice, and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off to give 2-benzyl-1,5-dioxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid5. 2g was obtained. Example 11 1.9 g of 2-benzyl-4-methoxycarbonyl-1,5-dioxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid was dissolved in 50 ml of ethanol, and parachlorophenylhydrazine was dissolved. 0.55 g was added and refluxed for 18 hours. The reaction solution was concentrated, and 30 ml of acetic acid was added to the resulting residue, followed by refluxing for 3 hours. The reaction solution was concentrated, the residue was dissolved in chloroform, washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was crystallized from a mixed solvent of ethanol-hexane. This was recrystallized from ethanol and 6-benzyl-2-(4-chlorophenyl)-4,4a,5,6-tetrahydro-2H-pyridazino[4,3-d][2]benzazepine-3,7
0.8 g of -dione, melting point 199-202°C, was obtained. Example 12 2-Benzyl-1,5-dioxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid2.
0 g was dissolved in 100 ml of ethanol, 0.36 g of methylhydrazine was added thereto, and the mixture was refluxed for 14 hours. The reaction solution was concentrated and recrystallized from ethanol to give 6-benzyl-2-methyl-4,4a,5,6-tetrahydro-2H-pyridazino[4,3-d][2]benzazepine-3,7-dione. 1.4g was obtained. Melting point 185-188℃

[0017]
Example 13 The same procedure as in Example 12 was carried out by dissolving 2-methyl-1,5-dioxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid in butanol and using parachlorophenylhydrazine. By performing the reaction and treatment, 2-
(4-chlorophenyl)-6-methyl-4,4a,5,
6-tetrahydro-2H-pyridazino[4,3-d][
2] 0.7 g of benzazepine-3,7-dione, melting point 2
A temperature of 95-297°C was obtained. Example 14 2-(4-chlorophenyl)-4,4a,5,6-tetrahydro-6-methyl-2H-pyridazino[4,3-d
[2] Dissolve 0.95 g of benzazepine-3,7-dione in acetic acid:chloroform = 7:2 mixed solvent,
5 ml of bromine-acetic acid solution was added dropwise at <0>C. This is 60℃
After stirring for 15 minutes, the reaction solution was poured into ice water, and the product was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off. The product was recrystallized from ethanol to give 2-(4-chlorophenyl)
-5,6-dihydro-6-methyl-2H-pyridazino [
4,3-d][2] 0.75 g of white crystals of benzazepine-3,7-dione, melting point 213-215°C, were obtained. Example 15 4-Methoxycarbonyl-2-methyl-1,5-dioxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid was dissolved in butanol and treated with paramethoxyphenylhydrazine. 2-(4-methoxyphenyl) was obtained by carrying out the same reaction and treatment as in Example 11.
-6-methyl-4,4a,5,6-tetrahydro-2H
-pyridazino[4,3-d][2]benzazepine-3
, 7-dione, melting point 226-228°C.

Example 16 Using 2-benzyl-4-methoxycarbonyl-1,5-dioxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetic acid and hydrazine monohydrate,
The same reaction and treatment as in Example 11 were performed to obtain 6-benzyl-4,4a,5,6-tetrahydro-2H-pyridazino[4,3-d][2]benzazepine-3,7-
0.8 g of dione, melting point 212-215°C, was obtained.

The following compounds are obtained in the same manner as in the above examples. ◎ 2-(4-chlorophenyl)-10-fluoro-
6-Methyl-5,6-dihydro-2H-pyridazino[4
,3-d][2]Benzazepine-3,7-dione◎
2-(4-chlorophenyl)-10-methoxy-6-
Methyl-5,6-dihydro-2H-pyridazino[4,3
-d] [2] Benzazepine-3,7-dione◎ 6
-benzyl-2-(4-chlorophenyl)-10-nitro-5,6-dihydro-2H-pyridazino[4,3-d
] [2] Benzazepine-3,7-dione ◎ 6-benzyl-10-chloro-2-(4-chlorophenyl)-
5,6-dihydro-2H-pyridazino[4,3-d][
2] Benzazepine-3,7-dione◎ 2-(4-
chlorophenyl)-5,6-dihydro-2H-pyridazino[4,3-d][2]benzazepine-3,7-dione

Claims (5)

[Claims] Claim 1: General formula [Formula 1] (wherein R1 is a hydrogen atom, C1-4 alkyl, aryl, or a halogen on an aromatic ring, trifluoromethyl,
aryl having 1 to 3 substituents selected from hydroxy, amino, nitro, cyano, C1-4 alkyl, C1-4 alkoxy and acylamino, R2 is a hydrogen atom, C1-4 alkyl, aryl-C1-4 alkyl or Aryl-C1-4 having 1 to 3 substituents selected from halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C1-4 alkyl, C1-4 alkoxy and acylamino on the aromatic ring
In the alkyl, R3 and R4 may be the same or different, and each is a hydrogen atom, halogen, trifluoromethyl, hydroxy, amino, nitro, cyano, C1-4
It represents alkyl, C1-4 alkoxy, acyl or acylamino, and the bond between the 4-position and the 4a-position represents a single bond or a double bond. ) or a pharmaceutically acceptable salt thereof. 2. A benzazepine compound represented by the general formula: [Image Omitted] (wherein each symbol is as defined in claim 1). 3. A benzazepine compound represented by the general formula: [Image Omitted] (wherein R5 represents C1-4 alkyl, and the other symbols are as described in claim 1). [Claim 4] General formula [Image Omitted] (wherein R5 represents C1-4 alkyl, R6 represents a hydrogen atom or C1-4 alkyl, and the other symbols are as described in claim 1. ) A benzazepine compound represented by 5. A benzazepine compound represented by the general formula: [Image Omitted] (wherein R6 represents a hydrogen atom or C1-4 alkyl, and the other symbols are as described in claim 1).