JPH0655674B2 - antiarrhythmic drugs - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION TECHNICAL FIELD The present invention relates to [I] an antiarrhythmic agent containing a benzoxepino[3,4-b]pyridine derivative or a pharmacologically acceptable acid addition salt thereof as an active ingredient.

BACKGROUND ART Various compounds have been known as [1] benzoxepinopyridine derivatives and [1] benzthiepinopyridine derivatives. For example, Japanese Patent Application Laid-Open No. 49-117496 and Chem. Pharm. Bull., Vol. 29, p. 3515 (1981) disclose compounds of the formula: (wherein A and B are different from each other and represent -CH- or nitrogen, X' represents oxygen or sulfur, and ^Ra represents hydrogen or lower alkyl)
0, JP-A-60-89419, USP 4,547,496 and EP 129,879 A2 disclose a compound of the formula: [wherein R ^b is hydrogen, alkyl, halogenated alkyl,
represents alkoxy or halogen, X' represents oxygen or sulfur, and R ^c is (wherein Y′ represents amino, substituted amino, a heterocyclic group or a substituted heterocyclic group; N′ represents hydrogen, alkyl or acyl; and n′ represents an integer of 1 to 3), or (wherein m' represents 0, 1 or 2, and Z' has the same meaning as above). JP-A-60-78985 discloses a compound of the formula: (wherein R ^c , X′, Y′ and m′ are as defined above, and R ^d represents hydrogen or alkyl).

However, it has not been reported that [1] benzoxepinopyridine derivatives or [1] benzthiepinopyridine derivatives have antiarrhythmic effects. Among known compounds with antiarrhythmic effects, there are no compounds with a skeleton similar to the above derivatives. As a compound with a pyridine skeleton and antiarrhythmic effects, Pirmenol, represented by the following formula, is known.
is known (US Patent No. 4,112,103).

DISCLOSURE OF THE INVENTION The pharmaceutical composition of the present invention having excellent antiarrhythmic activity is a compound represented by the following formula (I): [1] benzoxepino[3,4-
b) A compound containing a pyridine derivative or a pharmacologically acceptable acid addition salt thereof as an active ingredient.

wherein: a) R ¹ is lower alkoxy, halogenated lower alkyl,
Halogenated lower alkoxy, hydroxy, lower alkylamino, di-lower alkylamino, cycloalkylamino, lower alkanoylamino, carboxyamino or lower alkoxycarbonylamino, R ² is hydrogen, R ³ is (wherein Y represents amino, lower alkylamino, di-lower alkylamino, cycloalkylamino, a nitrogen-containing heterocyclic group or a lower alkyl-substituted nitrogen-containing heterocyclic group; Z represents hydrogen, a lower alkyl or a lower alkanoyl; n represents 1,
2 or 3.) or (Wherein, W represents hydrogen or lower alkyl, and m is 0, 1
or 2), and ^R4 represents hydrogen; b) ^R1 is lower alkoxy or halogenated lower alkyl, ^R2 is hydrogen, ^R3 is _-NHCOCH2Y (wherein Y is as defined above), and ^R4 represents hydrogen; c) ^R1 and ^R2 are both lower alkoxy, and ^R3 is (wherein n, Y, and Z are as defined above). (wherein m and W are as defined above) or -X-
( _CH2 ) _n -Y (wherein n and Y are as defined above, and X represents oxygen or sulfur), and ^R4 represents hydrogen, or d) ^R1 represents hydrogen, lower alkyl, halogen, halogenated lower alkyl, lower alkoxy, halogenated lower alkoxy, hydroxyl, lower alkylamino, di-lower alkylamino, cycloalkylamino, lower alkanoylamino, carboxyamino, or lower alkoxycarbonylamino, ^R2 represents hydrogen, ^R3 and ^R4 represent ^R3
represents -X-( _CH2 ) _n -Y (wherein n, X and Y are as defined above), and ^R4 represents hydrogen, or ^R3
and ^R4 together represent =CH( _CH2 ) _nY (wherein n and Y are as defined above), or ^R3 is -
(CH ₂ ) _n+1 -Y (wherein n and Y are as defined above), and R ⁴ represents cyano or carbamoyl. (Hereinafter referred to as Compound I. The same applies to compounds having other formula numbers.) In the definitions of various groups in formula (I), lower alkyl represents a group having 1 carbon atom.
-6 linear or branched alkyl, e.g., methyl;
The lower alkoxy includes straight or branched alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, etc. The halogenated lower alkyl includes 1 to 6 carbon atoms.
The lower alkylamino includes linear or branched alkyl halides having 1 to 3 carbon atoms substituted with up to three of the same or different halogens, such as fluorine, chlorine, bromine, etc., such as trifluoromethyl.
The di-lower alkylamino includes amino substituted with the same or different straight-chain or branched alkyl groups having 1 to 6 carbon atoms, such as methylamino, ethylamino, isopropylamino, etc. The di-lower alkylamino includes amino substituted with the same or different straight-chain or branched alkyl groups having 1 to 6 carbon atoms, such as dimethylamino, diethylamino, diisopropylamino, etc. The cycloalkylamino includes cycloalkylamino having 5 to 7 carbon atoms, such as cyclopentylamino, cyclohexylamino, etc.
The halogenated lower alkoxy includes alkoxy having 1 to 6 carbon atoms substituted with 1 to 3 of the same or different halogens, such as fluorine, chlorine, bromine, etc., such as trifluoromethoxy, 2,2,2-trifluoroethoxy, etc. The lower alkoxycarbonylamino includes straight-chain or branched alkoxycarbonylamino having 2 to 7 carbon atoms, such as methoxycarbonylamino, ethoxycarbonylamino, etc.

The nitrogen-containing heterocyclic group is a 5-8-membered monocyclic or condensed bicyclic heterocyclic group having only 1 to 3 nitrogen atoms as heteroatoms, and a 5-8-membered monocyclic or condensed bicyclic heterocyclic group having 1 to 3 nitrogen atoms and one oxygen or sulfur atom as heteroatoms, such as pyrrolidino, pyrrolidinyl, piperidino, piperidyl, piperazino, piperazinyl, homopiperazino, homopiperazinyl, pyridyl,
The lower alkyl-substituted nitrogen-containing heterocyclic group includes pyrrolyl, quinuclidinyl, imidazolyl, morpholino, etc.
"Lower alkanoyl" includes the same nitrogen-containing heterocyclic groups as above substituted with up to three identical or different straight-chain or branched alkyl groups having 1 to 6 carbon atoms (e.g., methyl, ethyl, isopropyl, etc.), such as 1-ethyl-2-pyrrolidinyl, 4-methyl-1-piperazinyl, 2,6-dimethylpiperidino, etc. "Lower alkanoyl" includes straight-chain or branched alkanoyl groups having 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, etc. "Halogen" means fluorine, chlorine, bromine, or iodine. "Lower alkanoylamino" includes straight-chain or branched alkanoylamino groups having 1 to 6 carbon atoms, such as formylamino, acetylamino, etc.

Pharmacologically acceptable acid addition salts of Compound I include acid addition salts with pharmacologically acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc., and acid addition salts with pharmacologically acceptable organic acids such as acetic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, methanesulfonic acid, toluenesulfonic acid, aspartic acid, glutamic acid, etc.

The results of acute toxicity tests and antiarrhythmic activity tests of representative Compound I are shown below.

Acute toxicity test: Groups of five dd strain male mice weighing 20±1 g were used, and the test compound was administered orally (po: 0.3 mg/g) or intraperitoneally (ip:
The animals were administered a dose of 0.1 mg/g. Seven days after administration, the mortality was observed and the MLD (minimum lethal dose) was calculated. The results are shown in Table 1.

Antiarrhythmic effect test The antiarrhythmic effect was examined in a chloroform-induced arrhythmia test in mice.

dd mice weighing 18 to 22 g were fasted for 4 to 5 hours and then subjected to the method of Block [Life Science, 28 , 2623 (1999)].
The antiarrhythmic effect was evaluated according to the method described in 81). After oral administration of the test compound (100 mg/kg), the mice were placed in a chloroform atmosphere, and after respiratory arrest, the mice were removed and immediately electrocardiograms were recorded using the standard limb lead method. The effect was judged to be effective if the heart rate remained below 720 beats/min for 30 seconds or more.

If the test compound was judged to be effective in two or more of the three cases, the test compound was deemed to be effective. The results are shown in Table 1.

Among compounds I, the compound represented by formula (I-1) (wherein Z, Y and n are as defined in formula (I), and R ¹ ' is lower alkoxy), particularly compounds in which R ¹ ' is bonded to the 7-position, exhibit excellent separation between antiarrhythmic activity and toxicity and side effects, and are extremely excellent as antiarrhythmic agents. For example, 1.
The results of the antiarrhythmic effect, acute toxicity and typical side effects of the fumarate salt are shown in Table 2.
When 500 mg/kg of benzodiazepine was orally administered to male rats (strain, male), no central effects such as central excitation, central depression or muscle relaxation were observed.

In Table 2, 1 and 4 are experiments on antiarrhythmic action, and 3 (anticholinergic action) and 5 are experiments on side effects. The smaller the value of 1 relative to 3, and the smaller the value of 4 relative to 5, the better the separation of side effects.

In view of their pharmacological effects, Compound I and its pharmacologically acceptable acid salts can be used in various pharmaceutical forms for administration purposes. The pharmaceutical compositions of the present invention can be prepared by uniformly mixing an effective amount of a specific compound, either in the form of a free or acid addition salt, as the active ingredient with a pharmacologically acceptable carrier. This carrier can take a wide variety of forms depending on the preparation form desired for administration. These pharmaceutical compositions are preferably in a unit dosage form suitable for oral or injectable administration. Any useful pharmacologically acceptable carrier can be used to prepare compositions in oral dosage form. For example, oral liquid preparations such as suspensions and syrups can be prepared using 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, preservatives such as alkyl parahydroxybenzoates, and flavors such as strawberry flavor and peppermint. Powders, pills, capsules, and tablets can be prepared using lactose, glucose, sucrose,
They can be prepared using excipients such as mannitol, disintegrating agents such as starch and sodium alginate, lubricants such as magnesium stearate and talc, binders such as polyvinyl alcohol, hydroxypropyl cellulose and gelatin, surfactants such as fatty acid esters, plasticizers such as glycerin, etc. Tablets and capsules are the most useful unit oral dosage forms because they are easy to administer. When preparing tablets and capsules, solid pharmaceutical carriers are used.

Injectable solutions can also be prepared using a carrier consisting of distilled water, saline, glucose solution, or a mixture of saline and glucose solution.

The oral dose of Compound I or its salt is 150-800 mg.
The preferred dose is 100 mg/person (about 60 kg)/day, administered about three times a day, and parenterally administered at a dose of 150 to 600 mg/person (about 60 kg) as needed.

Administration of Compound I can prevent and treat arrhythmias, particularly sinoatrial arrhythmia, sinus tachycardia, supraventricular arrhythmia, ventricular arrhythmia and the like.

Next, a production example of Compound I will be described.

Compound I has the formula The compound II represented by the formula (I) (wherein R ¹ and R ² are as defined in formula (I)) can be used as a starting material to prepare the compound II by the method described below.

The compound II can be prepared, for example, by the method disclosed in Japanese Patent Application Laid-Open No. 49-117496 or Chem.
M. Pharm. Bull. 29 , 3515 (1981) or the methods shown in Compound Preparation Examples 33 and 35.

Manufacturing Method A wherein R ⁵ is hydrogen, lower alkyl, halogen, halogenated lower alkyl, lower alkoxy, halogenated lower alkoxy, lower alkylamino, di-lower alkylamino, cycloalkylamino, lower alkanoylamino,
In the carboxyamino or lower alkoxycarbonylamino, R ⁶ represents hydrogen, or R ⁵ and R ⁶ both represent lower alkoxy.

^R7 is (wherein n and Y are as defined in formula (I), and Z′ represents hydrogen or lower alkyl.) (wherein W and m are as defined in formula (I)) or -X-( _CH2 ) _n -Y (wherein X, Y and n
(I) has the same meaning as in formula (I). Compound II is dissolved in an alcohol solvent such as methanol or ethanol, and if necessary, tetrahydrofuran is further added. Compound III is obtained by reacting Compound III with 0.5 to 1 equivalent of a reducing agent such as sodium borohydride at 0°C to room temperature for 1 to 6 hours. Compound III is dissolved in methylene chloride for 1 to 6 hours.
The reaction is carried out with 2 equivalents of a halogenating agent, such as thionyl chloride, at room temperature for 1 to 6 hours under ice-cooling to obtain a chlorinated compound, which is then reacted in methylene chloride with 1 to 5 equivalents of a compound represented by the formula R ⁷ —H(IV) and, if necessary, in the presence of 1 to 5 equivalents of a base such as pyridine or triethylamine under ice-cooling to room temperature for 1 to 6 hours.
The reaction is carried out for about 6 hours to obtain Compound I-I. A production example of Compound III is shown in Compound Production Example 36.

Manufacturing method B (wherein ^R5 and ^R6 are as defined in formula (II), and Y and n are as defined in formula (I).) Compound III is chlorinated with thionyl chloride or the like in the same manner as in Process A, and then reacted with an excess amount of ammonia solution, e.g., methylene chloride solution, under ice-cooling to room temperature for 1 to 6 hours to obtain Compound V. Compound V and 1 to 2 equivalents of Cl-
Compound I-2 is obtained by reacting ( _CH2 ) _n -Y (Compound VI) (wherein n and Y are as defined in Formula (I)) or its hydrochloride in the presence of 1 to 5 equivalents of a base such as triethylamine and a catalytic amount of potassium iodide or sodium iodide, if necessary, in an inert solvent such as toluene or acetonitrile at a suitable temperature between room temperature and the boiling point of the solvent used for 4 to 20 hours. A production example of Compound V is shown in Compound Production Example 24.

Manufacturing method C wherein R ⁸ is hydrogen, lower alkyl, halogen, halogenated lower alkyl, lower alkoxy, halogenated lower alkoxy, lower alkylamino, di-lower alkylamino, cycloalkylamino, lower alkanoylamino,
carboxyamino or lower alkoxycarbonylamino, and Y and n have the same meanings as in formula (I).

Compound III' and 1 to 2 equivalents of compound (VII) or an acid addition salt thereof are reacted in the presence of 1 to 2 equivalents of trifluoroacetic anhydride relative to compound III in a solvent such as carbon tetrachloride, chloroform, 1,2-
The reaction is carried out in an inert organic solvent such as dichloroethane or 1,1,2,2-tetrachloroethane at a suitable temperature between room temperature and the boiling point of the solvent used for 4 to 20 hours to obtain compound 1-3.

Manufacturing Method D [wherein R ⁸ , Y and n are as defined in formula (III′) and formula (I)] First, 1 to 5 equivalents of compound (II′) are added to compound (II′). (Compound VIII) (wherein n and Y are as defined above) or its acid addition salt is maintained in an organic solvent such as ether, tetrahydrofuran, 1,2-dimethoxyethane, dimethyl sulfoxide or dimethylformamide in the presence of 2 equivalents of a base, such as sodium hydride or n-butyllithium, relative to Compound VIII at a suitable temperature between 0°C and room temperature for 1 to 5 hours to produce an ylide represented by the formula _Ph3P =CH( _CH2 ) _n -Y (wherein n and Y are as defined above).

Then, 1 equivalent of compound (II') was added to the imide reaction solution.
The reaction is carried out at a suitable temperature between 8° C. and room temperature for 2 to 12 hours to give Compound 1-4 and Compound 1-5.
These compounds can be isolated by subjecting them to silica gel column chromatography or recrystallization.

Manufacturing Method E (wherein R ⁹ represents alkoxy, halogenated lower alkoxy or halogenated lower alkyl; R ¹⁰ and R
¹¹ are equal to or different from each other and represent hydrogen, lower alkyl, or cycloalkyl; represents a heterocycle or a lower alkyl-substituted heterocycle contained in the aforementioned Y. Compound V' obtained by Production Method B is reacted with 1 to 1.5 equivalents of α-chloroacetyl chloride, if necessary in the presence of 1 to 2 equivalents of a base such as pyridine or triethylamine, in an organic solvent such as methylene chloride or ethyl ether at ice-cooling to room temperature for 1 to 3 hours to obtain Compound IV.

Compound IV is reacted with 1 to 5 equivalents of compound X in an organic solvent such as toluene or acetonitrile, optionally in the presence of a catalytic amount of sodium iodide or potassium iodide, at a suitable temperature between room temperature and the boiling point of the solvent used for 1 to 6 hours to obtain compound I-6.

Manufacturing method F [wherein R ⁸ , Y and n are as defined in formula (III') and formula (I), respectively.] Compound III' is chlorinated with thionyl chloride or the like in the same manner as in Preparation Method A, and then reacted with 1 to 3 equivalents of a cyanide such as sodium cyanide, potassium cyanide, copper cyanide or silver cyanide in an organic solvent such as acetonitrile or dimethylformamide at an appropriate temperature between room temperature and the boiling point of the solvent used for 1 to 3 hours to obtain Compound XI. Compound XI and 1.5 equivalents of a base, for example, sodium hydride or sodium amide, are dissolved in toluene,
The anion is generated by reacting in an organic solvent such as tetrahydrofuran or dimethylformamide at a suitable temperature between room temperature and the boiling point of the solvent for 1 to 3 hours, and then 1 to 2 equivalents of compound XII are added and the reaction is continued at a suitable temperature between room temperature and the boiling point of the solvent for 3 to 10 hours to obtain compound 1-7. Compound 1-7 is hydrolyzed by heating in an acidic or basic condition, for example, in a mineral acid such as concentrated sulfuric acid or concentrated hydrochloric acid, to obtain compound I-8.

Manufacturing method G [In the formula, ^R3 and ^R4 are defined as in formula (I).] Compound I-9 obtained by the above-mentioned Production Methods A to F is reacted with 1 to 3 equivalents of a boron halide, such as boron trichloride, boron tribromide, or boron triiodide, in an organic solvent such as methylene chloride at an appropriate temperature between −78° C. and room temperature for 2 to 12 hours, and then water is added for hydrolysis to obtain compound I-10.

Compound I thus obtained by Processes A to G is obtained as a free base in the form of crystals or oil, and if necessary, can be purified to a higher purity by column chromatography or recrystallization.

A pharmacologically acceptable acid addition salt of Compound I can be easily prepared by reacting Compound I with an acid in a conventional manner.

The names of representative compounds I are shown in Table 3, and their structures are shown in Table 4-1.
Table 4-2 and Table 4-3 show the physicochemical properties of representative Compound I or its acid addition salts in Table 5.

EXAMPLES Next, examples of the present invention and examples of compound production will be described.

Example 1. Tablets Tablets of the following composition were prepared by a conventional method.

Compound 1-1.5 fumarate salt 20 mg Lactose 60 mg Potato starch 30 mg Polyvinyl alcohol 2 mg Magnesium stearate 1 mg Dye (trace amount) Example 2: Powder A powder was prepared using the following composition by a standard method.

Compound 4 trihydrochloride monohydrate 20 mg Lactose 280 mg Example 3 Injection Compound 8 trihydrochloride monohydrate (100 mg) was dissolved in distilled water for injection to make up a total volume of 20 ml, and an injection was prepared by the usual method.

Compound Preparation Example 1. 6.00 g of 5-hydroxy-7-methoxy-5,11-dihydro[1]benzoxepino[3,4-b]pyridine obtained in Compound Preparation Example 336 was dissolved in 100 ml of methylene chloride, and 2.7 ml of thionyl chloride was added under ice cooling. The mixture was stirred for 30 minutes under ice cooling and then at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to dryness, and the residue was dissolved in 30 ml of methylene chloride. Under ice cooling, a solution of 14.50 g of N,N-dimethylethylenediamine in 120 ml of methylene chloride was added. The reaction mixture was stirred for 30 minutes under ice cooling and then at room temperature for 1 hour, after which 100 ml of methylene chloride was added. The mixture was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate:triethylamine=20:1) to give Compound 1.
7.21 g of crystals were obtained.

1.00 g of compound 1 and 0.51 g of fumaric acid in isopropanol
The salt was obtained by reacting with the compound 1, and recrystallization was carried out from isopropanol to obtain 1.07 g of the 1.5 fumarate salt of compound 1.

Compound Preparation Examples 2 to 20: In Compound Preparation Example 1, instead of the raw materials 5-hydroxy-7-methoxy-5,11-dihydro[1]benzoxepino[3,4-b]pyridine 6.00 g and N,N-diethylethylenediamine 14.50 g, the raw materials shown in Table 6 were used, and compounds 2 to 20 shown in Table 6 were obtained in the same manner as in Compound Preparation Example 1.

The resulting compounds 2 to 15, 18 and 19 were treated in the same manner as in Compound Preparation 1 or with hydrogen chloride in isopropanol to give the corresponding salts shown in Table 5.

Compound Preparation Example 21. 2.00 g of 5-amino-7-methoxy-5,11-dihydro[1]benzoxepino[3,4-b]pyridine, 2.60
g of 2-(2,6-dimethylpiperidino)ethyl chloride hydrochloride, 3.5 ml of triethylamine and a catalytic amount of sodium iodide were refluxed in 60 ml of toluene for 12 hours.
After cooling, the reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: triethylamine = 10:1) to give 2.1%.
1 g of compound 21 was obtained.

This was treated with a solution of hydrogen chloride in isopropanol to give the trihydrochloride 1/2 of compound 21.
The hydrate was obtained.

Compound Preparation Examples 22 and 23: 4.80 g of 5-amino-7-methoxy-5,11-dihydro[1]benzoxepino[3,4-b]pyridine and 6.0
Using 2-(2,5-dimethyl-1-piperidinyl)ethyl chloride hydrochloride (g), a reaction was carried out in the same manner as in Compound Preparation Example 21 to give a mixture of Compounds 22 and 23.
This was purified by silica gel chromatography (elution solvent n-
Hexane: ethyl acetate: triethylamine = 5:10:
1) and purified to obtain 2.79 g of Compound 22 and 1.51 g of Compound 23. Compounds 22 and 23 were converted into the corresponding hydrochlorides by the same method as in Compound Production Example 21.

Compound Preparation Example 24. 2.00 g of 5-hydroxy-7-methoxy-5,11-
Dihydro[1]benzoxepino[3,4-b]pyridine and 2.6 ml of trifluoroacetic anhydride were mixed in a nitrogen atmosphere at room temperature for 3 minutes.
After stirring for 10 minutes, 4.20 g of 2-diethylaminoethanethiol hydrochloride was added, and the mixture was stirred at 100°C for 12 hours.
After cooling, the reaction mixture was poured into ice water and neutralized with an aqueous solution of caustic soda. The aqueous layer was discarded, and the organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate:triethylamine=10:
5:1) to give 2.74 g of compound 24 as an oil.

The dihydrochloride of Compound 24 was obtained in the same manner as in Compound Preparation Example 21.

Compound Preparation Example 25: 5-amino-7-methoxy-5,11-dihydro[1]benzoxepino[3,4-
b) 2.00 g of pyridine and 1.2 ml of triethylamine were dissolved in 50 ml of ethyl ether, and 0.93 g of chloroacetyl chloride was added dropwise under ice cooling. The reaction solution was stirred under ice cooling for 1 hour, then ethyl acetate was added, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. 70 ml of toluene and 3.0 g of diethylamine were added to the residue and refluxed for 3 hours. Ethyl acetate was added to the reaction solution, and water,
The residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane: triethylamine = 10:5:1) to give compound 25 as an oil.
2.35 g was obtained.

The dihydrochloride of Compound 25 was obtained in the same manner as in Compound Preparation Example 21.

Compound Preparation Example 26: 3.00 g of 5-hydroxy-5,11-dihydro[1]benzoxepino[3,4-b]pyridine was suspended in 60 ml of methylene chloride, and 2.0 ml of thionyl chloride was added under ice-cooling. The mixture was then reacted for 30 minutes under ice-cooling and then for 1 hour at room temperature. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was added with 60 ml of acetonitrile and 4.69 g of silver cyanide and refluxed for 1.5 hours.
After the reaction was completed, the reaction mixture was filtered, ethyl acetate and water were added to the filtrate, and the mixture was shaken. The aqueous layer was discarded, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 4:1) to obtain 1.70 g of 5-cyano-5,11-dihydro[1]
Benzoxepino[3,4-b]pyridine was obtained.

IR (KBr): 2900, 2250, 1490, 1450 ¹ H-NMR (CDCl ₃ ): 5.12 and 5.80 (q, 2
H, AB type), 5.31 (s, 1H), 6.89-7.56
(m, 5H), 7.85 (dd, 1H), 8.39 (dd, H) 5-cyano-5,11-dihydro [1] obtained above
1.50 g of benzoxepino[3,4-b]pyridine and 0.31 g of sodium amide were heated in 25 ml of toluene at 100°C for 1 hour, and then 1.7 g of 3-(N,N-diisopropylamino)propyl chloride (1.66 g) was added and refluxed for 7 hours. After cooling, 20 ml of water was added and the mixture was extracted with ethyl acetate.
After washing with saturated saline, it was dried over anhydrous sodium sulfate,
After filtration, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate: triethylamine = 10:2:1).
15 g of compound 26 was obtained.

Compound Preparation Example 27. 1.25 g of Compound 26 obtained in Compound Preparation Example 26 was heated and stirred in 3.6 ml of concentrated sulfuric acid at 90-95°C for 2 hours. After cooling, the mixture was poured onto ice, made basic with aqueous caustic soda, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to yield 0.96 g of Compound 27 hemihydrate as crystals.

Compound Preparation Example 28.2.18 Compound 1 was dissolved in 60 ml of methylene chloride.
A solution of 1.2 ml of boron tribromide dissolved in 12 ml of methylene chloride was added dropwise at -60°C. After the addition, the temperature was gradually raised and the mixture was stirred at room temperature overnight. The reaction mixture was extracted with water, and then an aqueous solution of caustic soda was added to adjust the pH to 9. Methylene chloride was added and the mixture was stirred. The resulting crystals were filtered and dried to obtain 1.00 g of compound 28.

The trihydrochloride of Compound 28 was obtained in the same manner as in Compound Preparation Example 21.

Compound Preparation Examples 29 and 30. 45.0 g of 3-diethylaminopropyltriphenylphosphonium bromide hydrobromide was dissolved in 30 mL of tetrahydrofuran.
The mixture was suspended in 100 ml of water, and 116 ml of 1.5 M n-butyllithium was added dropwise under ice cooling.

After the dropwise addition, the mixture was stirred at room temperature for 2.5 hours.
A solution of 10.0 g of methoxy-5,11-dihydro[1]benzoxepino[3,4-b]pyridine in 160 ml of tetrahydrofuran was added dropwise under ice cooling. The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. Ethyl acetate was added to the residue, which was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate:triethylamine=10:5:1) to give 4.73 g of compound 29 and 5.21 g of compound 30.

Compounds 29 and 30 were treated in the same manner as in Compound Preparation Example 21 to give the respective trihydrochloride 1/3 hydrates.

Compound Preparation Examples 31 and 32: Using 6.33 g of 5-oxo-5,11-dihydro[1]benzoxepino[3,4-b]pyridine and 32.6 g of 3-diethylaminopropyltriphenylphosphonium bromide hydrobromide, 3.17 g of Compound 31 and 2.80 g of Compound 32 (containing a small amount of Compound 31) were obtained in the same manner as in Compound Preparation Examples 29 and 30.

In the same manner as in Compound Preparation Example 21, the dihydrochloride of Compound 31 and the dihydrochloride 2/3 hydrate of Compound 32 (containing 12% of Compound 31) were obtained.

Compound Preparation Example 33.4 g of 5-oxo-5,11-dihydro[1]benzoxepino[3,4-b]pyridine was dissolved in 30 ml of concentrated sulfuric acid, and a mixture of 2 g of concentrated nitric acid and 1 ml of concentrated sulfuric acid was added dropwise at -30°C. After the addition, the temperature was gradually raised to room temperature, and the reaction solution was poured into ice water, after which an aqueous caustic solution was added to make it basic. The crystals were filtered off, washed with ether, and then dried.
4.2 g of 7-nitro-5-oxo-5,11-dihydro[1]benzoxepino[3,4-b]pyridine were obtained.

Melting point: 205-207°C (decomposition) IR (KBr tablet): 1660, 1610, 1580, 1518, 1340
1080cm ^{-1 1} H-NMR (DMOS-d ₆ ): 5.58 (s, 2H),
7.42 (d, 1H), 7.67 (dd, 1H), 8.25 (dd,
1H), 8.43 (dd, 1H), 8.84 (dd, 1H), 8.
90(d,1H) 4.0 g of the obtained 7-nitro-5-oxo-5,11-dihydro[1]benzoxepino[3,4-b]pyridine
The residue was dissolved in water and then basified with an aqueous sodium hydroxide solution. The resulting crystals were filtered and dried to give 3.1 g of 7-amino-5-
Oxo-5,11-dihydro[1]benzoxepino[3,4-b]pyridine was obtained.

Melting point: 149-151.5°C IR (KBr tablet): 3400, 3330, 1650, 1618, 1490
1320 cm ^{-1 1} H-NMR (CDCl ₃ +DMSO-d ₆ ): 4.78
(br s, 2H), 5.19 (s, 2H), 6.84 (d, 2H)
H), 7.23-7.59 (m, 2H), 8.22 (dd, 1H),
8.62 (dd, 1H) Obtained 7-amino-5-oxo-5,11-dihydro[1]benzoxepino[3,4-b]pyridine 2.6
g of the product was dissolved in a mixed solvent of 80 ml of ethanol and 30 ml of tetrahydrofuran, and the solution was added with 0.5 ml of sodium borohydride at room temperature.
The reaction mixture was poured into water, and the crystals were filtered off and dried to give 2.0 g of 7-amino-5-hydroxy-5,11-dihydro[1]benzoxepino[3,4-b]pyridine.

Melting point 176-178°C IR (KBr): 3380, 1580, 1500, 1200, 1050 cm ^{-1 1} H-NMR (DMSO-d ₆ + CDCl ₃ ): 4.51
(bs, 2H), 4.94 and 5.23 (q, 2H, ABty
pe), 5.73-6.89 (m, 5H), 7.10 (dd, 1
2.0 g of the resulting 7-amino-5-hydroxy-5,11-dihydro[1]benzoxepino[3,4-b]pyridine was dissolved in 70 ml of methanol, and the solution was made weakly acidic by adding hydrochloric acid. Then, 2.7 g of sodium cyanoborohydride was added to the solution.
Then, a 35% aqueous formaldehyde solution was added,
The reaction mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure, and then water was added, followed by addition of an aqueous solution of caustic soda to make the mixture basic.
The mixture was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain crude crystals, which were recrystallized from isopropanol to give 1.7 g of 7-dimethylamino-5-hydroxy-5,11-dihydro[1]benzoxepino[3,4-b]pyridine.
obtained.

Melting point: 154-157°C IR (KBr): 3150, 1615, 1580, 1510, 1220, 1050
cm ^{-1 1} H-NMR (DMSO-d ₆ + CDCl ₃ ): 2.80
(s + 6H), 5.03 and 5.26 (q, 2H,, AB t
yqe), 5.89 (bs, 1H), 6.14 (s1H), 6.33
-7.26 (m, 4H), 7.94 (dd, 1H), 8.22 (d
d, 1H) Compound Preparation Example 34. 5.0 g of 5-hydroxy-7-methoxy-5,11-
Dihydro[1]benzoxepino[3,4-b]pyridine was dissolved in 120 ml of methylene chloride, and 1.6 ml of thionyl chloride was added under ice-cooling. The mixture was stirred for 30 minutes under ice-cooling and then for 1 hour at room temperature. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was dissolved in 100 ml of methylene chloride. This was added dropwise to 300 ml of methylene chloride saturated with ammonia gas under ice-cooling. The reaction mixture was stirred for 1 hour at room temperature, and then insoluble matter was filtered off. The filtrate was washed with water, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure to give an oily 5-amino-7-methoxy-5,
4.9 g of 11-dihydro[1]benzoxepino[3,4-b]pyridine were obtained.

IR (liquid film): 3370, 1580, 1500, 1210, 1040 cm ^{-1 1} H-NMR (CDCl ₃ ): 2.33 (s, 2H), 3.72
(s, 3H), 4.86 (s, 1H), 5.07 and 5.39
(q, 2H, AB type), 6.577 (m, 4H),
7.67 (dd, 1H), 8.36 (dd, 1H) Compound Preparation Example 35. 2-(4-Methoxyphenoxy)methylpyridine-3-
100.0 g of carboxylic acid was suspended in 1.5 g of 1,1,2,2-tetrachloroethane, and 136 ml of trifluoroacetic anhydride was added at room temperature and stirred for 40 minutes. 38 ml of boron trifluoride ethyl ether complex was added, and the mixture was stirred for 100 to 11 minutes.
The mixture was stirred at 0°C for 4 hours. After cooling, the mixture was poured onto ice and an aqueous solution of sodium hydroxide was added to make the aqueous layer basic. After shaking, the aqueous layer was discarded and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=
2:1) to give 67.0 g of 7-methoxy-5-oxo-5,11-dihydro[1]benzoxepino[3,4
-b] Pyridine was obtained as crystals.

Melting point: 79-80.5°C (isopropyl ether) IR (KBr tablet): 1643, 1610, 1489, 1300 cm ^{- 1} 1H-NMR ( _CDCl3 ): 3.78 (s, 3H), 5.24
(s, 2H), 6.93-7.70 (m, 4H), 8.25 (dd,
1H), 8.63 (dd, 1H) Compound Preparation Example _36. 7-Methoxy-5-oxo-5,11-dihydro[1]benzoxepino[3,4-
b) 10.0 g of pyridine was dissolved in a mixture of 200 ml of ethanol and 100 ml of tetrahydrofuran, and 1.0 g of sodium borohydride was added under ice cooling. After stirring at room temperature for 3 hours, the mixture was concentrated under reduced pressure. Ethyl acetate and water were added to the residue and the mixture was shaken. The aqueous layer was discarded, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The resulting crude crystals were recrystallized from toluene to give 5-hydroxy-7-methoxy-5,11-diol.
7.1 g of 1-dihydro[1]benzoxepino[3,4-b]pyridine was obtained as white crystals.

Melting point: 128-130.5°C IR (KBr tablet): 3150, 1590, 1490, 1435, 1200cm
^{-1 1} H-NMR (CDCl ₃ +DMSO-d ₆ ): 3.69
(s3H), 5.07 and 5.30 (q, 2H, AB type
e), 5.92 (d, 1H), 6.18 (d, 1H), 6.48-7.2
8 (m, 4H), 7.94 (dd, 1H), 8.22 (dd, 1
H) Compound Preparation Example 37. 1.00 g of 5-hydroxy-5,11-dihydro[1]benzoxepino[3,4-b]pyridine was suspended in 15 ml of methylene chloride, and 0.45 ml of thionyl chloride was added under ice cooling. The mixture was stirred for 30 minutes under ice cooling and then at room temperature for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was dissolved in 15 ml of N,N-dimethylformamide and added with 1.60 g of 2-diethylaminoethanethiol hydrochloride and 3.
20 g of potassium carbonate was added and stirred at room temperature for 6 hours. The reaction mixture was added to water and extracted with ethyl acetate.
The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane, ethyl acetate,
The mixture was purified with triethylamine (15:5:1) to obtain 0.74 g of oily compound 33.

Compound Preparation Example 38: In the same manner as in Compound Preparation Example 37, 2.00 g of 5-hydroxy-7-methyl-5,11-dihydro[1]benzoxepino[3,4-b]pyridine and 4.5 g of benzoxepino[3,4-b]pyridine were mixed together.
2.11 g of oily compound 34 was obtained from 0 g of 2-diethylaminoethanethiol hydrochloride.

──────────────────────────────────────────────────── Continued from the front page (56) References: JP 60-6690 (JP, A) JP 60-78985 (JP, A) JP 60-89419 (JP, A)

Claims (3)

[Claims] Claim 1: Formula (I) [wherein, a) R ¹ is lower alkoxy, halogenated lower alkyl,
Halogenated lower alkoxy, hydroxy, lower alkylamino, di-lower alkylamino, cycloalkylamino, lower alkanoylamino, carboxyamino or lower alkoxycarbonylamino, R ² is hydrogen, R ³ is (wherein Y represents amino, lower alkylamino, di-lower alkylamino, cycloalkylamino, a nitrogen-containing heterocyclic group or a lower alkyl-substituted nitrogen-containing heterocyclic group; Z represents hydrogen, a lower alkyl or a lower alkanoyl; and n represents 1, 2 or 3; or (wherein W represents hydrogen or lower alkyl, and m represents 0, 1, or 2), and ^R4 represents hydrogen; b) ^R1 represents lower alkoxy or halogenated lower alkyl, ^R2 represents hydrogen, ^R3 represents _-NHCOCH2Y (wherein Y is as defined above), and ^R4 represents hydrogen; c) ^R1 and ^R2 are both lower alkoxy, and ^R3 represents (wherein n, Y, and Z are as defined above). (wherein m and W are as defined above) or -X-
( _CH2 ) _n -Y (wherein n and Y are as defined above and X is oxygen or sulfur), and ^R4 represents hydrogen, or d) ^R1 represents hydrogen, lower alkyl, halogen, halogenated lower alkyl, lower alkoxy, halogenated lower alkoxy, hydroxy, lower alkylamino, di-lower alkylamino, cycloalkylamino, lower alkanoylamino, carboxyamino or lower alkoxycarbonylamino, ^R2 represents hydrogen, and ^R3 and ^R4 are such that ^R3 represents -X-( _CH2 ) _n -Y (wherein n, X and Y are as defined above) and ^R4 represents hydrogen, or ^R3 and ^R4 together represent =CH( _CH2 ) _nY (wherein n and Y are as defined above), or ^R3 is -
( _CH2 ) _n+1 -Y (wherein n and Y are as defined above), and ^R4 represents cyano or carbamoyl.
b) An antiarrhythmic agent containing a pyridine derivative or a pharmacologically acceptable acid addition salt thereof as an active ingredient. Claim 2 [1] A benzoxepino[3,4-b]pyridine derivative represented by formula (I-1) 2. The antiarrhythmic agent according to claim 1, characterized by being represented by the formula: wherein Z, Y and n are as defined in formula (I), and R ₁ ' represents lower alkoxy. 3. The antiarrhythmic agent according to claim 2, wherein R ₁ ' is bonded to the 7-position.