JPH0559064A - Tetrahydroxazepine derivative - Google Patents

Abstract

PURPOSE:To provide new compounds showing an anticonvulsant effect, a chronotropic action and a bronchus relaxation effect and useful as a medical drug. CONSTITUTION:Compounds of formula I (R is H, aminoloweralkyl in which amino may be substituted or phenylloweralkyl in which phenyl may have substituent), e.g. 2,2-dimethyl-5-oxo-2,3,4,5-tetrahydro-8trifluoromethylpyrid[3,2- f][1,4]oxazepine. The compound of formula I can be obtained by reacting 3,4- dihydro-2,2-dimethyl-7-trifluoromethyl-2H-pyrano[2,3-b]pyridin-4-one of formula II with hydrazoic acid in the presence of an acid catalyst (e.g. sulfuric acid) in an inert solvent (e.g. chloroform) at an ice-cooling temperature.

Description

【発明の詳細な説明】Detailed Description of the Invention

【０００１】[0001]

【産業上の利用分野】本発明は、抗痙攣作用、変時作
用、気管支弛緩作用を有し、医薬品として有用な次式
（１）INDUSTRIAL APPLICABILITY The present invention has an anticonvulsant action, a chronotropic action, and a bronchial relaxant action, and is useful as a drug, represented by the following formula (1).

【０００２】[0002]

【化２】 [Chemical 2]

【０００３】で表されるテトラヒドロオキサゼピン誘導
体に関する。The present invention relates to a tetrahydrooxazepine derivative represented by

【０００４】[0004]

【従来の技術及び発明が解決しようとする課題】従来、
２−メチル−４−オキソ−２，３，４，５−テトラヒド
ロ−１，５−ベンゾオキサゼピン誘導体が優れた酵素阻
害活性及び血管拡張作用を有することが知られている
〔Ａｒｃｈ．Ｐｈａｒｍ．，３２３，６０１（１９９
０）〕。従って、本発明は、更にテトラヒドロオキサゼ
ピンの新規な誘導体を製造し、その薬理効果を検討する
ことを目的とするものである。2. Description of the Related Art Conventionally, the problems to be solved by the invention
It is known that 2-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine derivative has excellent enzyme inhibitory activity and vasodilatory effect [Arch. Pharm. , 323 , 601 (199
0)]. Therefore, the present invention aims at further producing a novel derivative of tetrahydrooxazepine and studying its pharmacological effect.

【０００５】[0005]

【課題を解決するための手段】斯かる実情において、本
発明者は鋭意研究を行った結果、上記一般式（１）で表
わされるテトラヒドロオキサゼピン誘導体が優れた抗痙
攣作用、変時作用、気管支弛緩作用を有することを見出
し、本発明を完成した。Under the circumstances, as a result of intensive studies by the present inventors, the tetrahydrooxazepine derivative represented by the general formula (1) has excellent anticonvulsant action, chronotropic action, The present invention has been completed by finding that it has a bronchial relaxation effect.

【０００６】従って、本発明は、一般式（１）で表わさ
れる新規なテトラヒドロオキサゼピン誘導体を提供する
ものである。Therefore, the present invention provides a novel tetrahydrooxazepine derivative represented by the general formula (1).

【０００７】本発明化合物は、例えば次の反応式に従っ
て、３，４−ジヒドロ−２，２−ジメチル−７−トリフ
ルオロメチル−２Ｈ−ピラノ［２，３−ｂ］ピリジン−
４−オン類（２）にアジ化水素酸（３）を反応せしめて
化合物（１ａ）となし、更にこれにハロゲン化合物
（５）を反応させて化合物（１ｂ）とすることにより製
造される。The compound of the present invention is obtained, for example, according to the following reaction formula: 3,4-dihydro-2,2-dimethyl-7-trifluoromethyl-2H-pyrano [2,3-b] pyridine-
It is produced by reacting 4-ones (2) with hydrazoic acid (3) to form compound (1a), and further reacting halogen compound (5) with compound (1b).

【０００８】[0008]

【化３】 [Chemical 3]

【０００９】（式中、Ｒ′はアミノ基が置換されていて
もよいアミノ低級アルキル基又はフェニル基に置換基を
有していてもよいフェニル低級アルキル基を、Ｘはハロ
ゲン原子を示す）(In the formula, R'represents an amino lower alkyl group in which an amino group may be substituted or a phenyl lower alkyl group in which a phenyl group may have a substituent, and X represents a halogen atom).

【００１０】化合物（２）と（３）の反応は、クロロホ
ルム、ベンゼン等の不活性溶媒中、酸触媒の存在下に氷
冷下行なわれる。また、酸触媒とアジ化ナトリウムを用
いて、反応溶液中にアジ化水素酸（３）を発生させなが
ら行うこともできる。酸触媒としては硫酸、塩酸、三塩
化リン、トリクロル酢酸等を用いることができるが、ポ
リリン酸を用いて、触媒と溶媒をかねさせることもでき
る。The reaction between the compounds (2) and (3) is carried out in an inert solvent such as chloroform or benzene in the presence of an acid catalyst under ice cooling. It is also possible to use an acid catalyst and sodium azide while generating hydrazoic acid (3) in the reaction solution. As the acid catalyst, sulfuric acid, hydrochloric acid, phosphorus trichloride, trichloroacetic acid or the like can be used, but polyphosphoric acid can also be used to serve as the catalyst and the solvent.

【００１１】尚化合物（２）と（３）の反応において、
化合物（１ａ）と共に次式（６）In the reaction of the compounds (2) and (3),
Compound (1a) and the following formula (6)

【００１２】[0012]

【化４】 [Chemical 4]

【００１３】で表わされる２，２−ジメチル−４−オキ
ソ−２，３，４，５−テトラヒドロ−８−トリフルオロ
メチルピリド［２，３−ｂ］［１，５］オキサゼピンが
副生するが、両者は、例えばシリカゲルクロマトグラフ
ィー等によって容易に分離することができる。2,2-dimethyl-4-oxo-2,3,4,5-tetrahydro-8-trifluoromethylpyrido [2,3-b] [1,5] oxazepine represented by However, both can be easily separated by, for example, silica gel chromatography.

【００１４】化合物（１ａ）から（１ｂ）を得るには、
まず化合物（１ａ）に塩基を作用させて塩を形成させ、
次いでこれに化合物（５）を反応させるのが好ましい。
塩基としては、水素化ナトリウム、水素化リチウム、水
素化カリウム等の無機塩基、ｎ−ブチルリチウム、リチ
ウムジメチルアミド等の有機塩基が使用できる。化合物
（１ａ）と（５）の反応は、ジメチルホルムアミド、ジ
メチルアセトアミド、ジメチルスルホキシド、ヘキサメ
チルホスホリルアミド、ジオキサン等の溶媒中行うのが
好ましい。反応温度は室温〜１５０℃、特に１００℃付
近、反応時間は１〜２４時間が好ましい。尚この反応に
おいて、Ｒ′がアミノ低級アルキル基の場合には、この
アミノ基を適当な保護基で保護しておき、反応後、濃塩
酸、濃硫酸等の強酸、あるいは抱水ヒドラジン、水酸化
リチウム、水酸化ナトリウム等の塩基によって除去する
こともできる。To obtain (1b) from compounds (1a),
First, a base is allowed to act on the compound (1a) to form a salt,
Then, it is preferable to react this with the compound (5).
As the base, inorganic bases such as sodium hydride, lithium hydride and potassium hydride, and organic bases such as n-butyllithium and lithium dimethylamide can be used. The reaction of the compounds (1a) and (5) is preferably carried out in a solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphorylamide, dioxane and the like. The reaction temperature is preferably room temperature to 150 ° C., particularly around 100 ° C., and the reaction time is preferably 1 to 24 hours. In this reaction, when R'is an amino lower alkyl group, this amino group is protected with an appropriate protecting group, and after the reaction, a strong acid such as concentrated hydrochloric acid or concentrated sulfuric acid, or hydrazine hydrate or hydroxylation is used. It can also be removed with a base such as lithium or sodium hydroxide.

【００１５】[0015]

【作用】次に本発明化合物の薬理作用を示す。 １．抗痙攣作用 一群３匹のマウスに供試化合物を経口投与（mg／kg）
し、１時間後にメトラゾール（１００mg／kg）を静脈内
投与した。メトラゾール投与後３０分間に抗痙攣作用を
示した場合を２点／マウス、死亡した場合を１点／マウ
スとし、最大抑制値を９点（３×３）として評価した。
この結果を表１に示す。Next, the pharmacological action of the compound of the present invention will be shown. 1. Anticonvulsant effect Oral administration of test compound to 3 mice per group (mg / kg)
Then, 1 hour later, metrazole (100 mg / kg) was intravenously administered. The maximum inhibitory value was evaluated as 9 points (3 × 3) with 2 points / mouse showing anticonvulsive activity and 1 point / mouse showing death for 30 minutes after the administration of metrazol.
The results are shown in Table 1.

【００１６】[0016]

【表１】 [Table 1]

【００１７】２．変時作用 ３７℃の生理食塩水に浸した自発鼓動しているモルモッ
ト右心房に供試化合物を作用させた時の心拍数の変化率
を測定した。この結果を表２に示す。2. Chronotropic action The rate of change in heart rate when the test compound was allowed to act on the spontaneously beating guinea pig right atrium immersed in 37 ° C. physiological saline was measured. The results are shown in Table 2.

【００１８】[0018]

【表２】 [Table 2]

【００１９】３．気管支弛緩作用 ジグザグカットしたモルモット気管支を３７℃で生理食
塩水中に浸し、０．５ｇの負荷を与え自然収縮させた。
この気管支筋に、０．３μｇ／mlのエピネフリンを作用
させた時に誘起される弛緩を最大として、供試化合物の
弛緩率を測定した。この結果を表３に示す。3. Broncho-relaxation action The zigzag-cut guinea pig bronchus was immersed in physiological saline at 37 ° C., and 0.5 g of a load was applied to cause spontaneous contraction.
The relaxation rate of the test compound was measured by maximizing the relaxation induced when 0.3 μg / ml of epinephrine was applied to the bronchial muscle. The results are shown in Table 3.

【００２０】[0020]

【表３】 [Table 3]

【００２１】[0021]

【発明の効果】本発明化合物は、優れた抗痙攣作用、変
時作用及び気管支弛緩作用を有し、医薬品として有用で
ある。INDUSTRIAL APPLICABILITY The compound of the present invention has excellent anticonvulsant action, chronotropic action and bronchial relaxant action, and is useful as a drug.

【００２２】[0022]

【実施例】次に実施例を挙げて説明する。EXAMPLES Next, examples will be described.

【００２３】実施例１ ２，２−ジメチル−５−オキソ−２，３，４，５−テト
ラヒドロ−８−トリフルオロメチルピリド［３，２−
ｆ］［１，４］オキサゼピンの製造：クロロホルム６０
０mlに３，４−ジヒドロ−２，２−ジメチル−７−トリ
フルオロメチル−２Ｈ−ピラノ［２，３−ｂ］ピリジン
−４−オン５．１ｇ（２０．８mmol）を溶解し、氷冷し
た。この中に濃硫酸３０mlを加え、次いでアジ化ナトリ
ウム８．７ｇ（純度９０％，１２０．５mmol）を粉末で
２時間を要して添加した。終了後、氷冷下１時間攪拌
し、さらに氷浴を除去し、室温にて一晩攪拌した。反応
液を氷水中に注ぎ込み、炭酸カリウム粉末で中和後、有
機層を分液し、水洗した後、無水硫酸マグネシウムで乾
燥した。次いで溶媒を減圧留去して得た残渣をシリカゲ
ルクロマトグラフィー（溶媒；ｎ−ヘキサン／酢酸エチ
ル）にて分離精製し、標記化合物を得た。 収量２．２ｇ（収率４１％） mp. 163.0℃ UV λ_max ^EtOH nm: 276.0(ε 4500), 221.6(ε 740
0), 205.2(ε11500) IR ν_max ^KBr cm^-1： 3180, 3050, 1665, 1590, 157
0, 1240, 1170, 1130,1090¹ H-NMR(50MHz, CDCl₃ ) δ: 1.52(6H,s), 3.32(2H,d,J=
6Hz),7.47(1H,d,J=8Hz), 8.36(1H,d,J=8Hz),8.19〜8.58
(1H,bs)Example 1 2,2-Dimethyl-5-oxo-2,3,4,5-tetrahydro-8-trifluoromethylpyrido [3,2-
f] [1,4] Oxazepine production: chloroform 60
3,4-dihydro-2,2-dimethyl-7-trifluoromethyl-2H-pyrano [2,3-b] pyridin-4-one (5.1 g, 20.8 mmol) was dissolved in 0 ml and cooled with ice. .. To this was added 30 ml of concentrated sulfuric acid, and then 8.7 g of sodium azide (purity 90%, 120.5 mmol) was added as a powder over 2 hours. After the completion, the mixture was stirred under ice cooling for 1 hour, the ice bath was removed, and the mixture was stirred at room temperature overnight. The reaction solution was poured into ice water, neutralized with potassium carbonate powder, the organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure and the obtained residue was separated and purified by silica gel chromatography (solvent; n-hexane / ethyl acetate) to obtain the title compound. Yield 2.2 g (41% yield) mp. 163.0 ° C UV λ _max ^EtOH nm: 276.0 (ε 4500), 221.6 (ε 740)
0), 205.2 (ε11500) IR ν _max ^KBr cm ^-1 : 3180, 3050, 1665, 1590, 157
0, 1240, 1170, 1130, 1090 ¹ H-NMR (50MHz, CDCl ₃ ) δ: 1.52 (6H, s), 3.32 (2H, d, J =
6Hz), 7.47 (1H, d, J = 8Hz), 8.36 (1H, d, J = 8Hz), 8.19 ~ 8.58
(1H, bs)

【００２４】実施例２ ２，２−ジメチル−５−オキソ−４−（４−メトキシベ
ンジル）−２，３，４，５−テトラヒドロ−８−トリフ
ルオロメチルピリド［３，２−ｆ］［１，４］オキサゼ
ピンの製造：無水ジメチルホルムアミド３０mlに２，２
−ジメチル−５−オキソ−２，３，４，５−テトラヒド
ロ−８−トリフルオロメチルピリド［３，２−ｆ］
［１，４］オキサゼピン２．０ｇ（７．７mmol）を溶解
し、この中に水素化ナトリウム０．４６ｇ（純度６０
％，１１．５mmol）を加え、室温で１時間攪拌した。次
いでｐ−メトキシベンジルクロライド１．３ｇ（８．５
mmol）を加え、室温で２時間攪拌後、さらに８０〜９０
℃にて１．５時間加熱攪拌した。放冷後、反応液を水中
に注ぎ込み、塩化メチレンで抽出した。抽出後は水洗後
無水硫酸マグネシウムで乾燥し、減圧下溶媒を留去して
粘稠油状物３．４ｇを得た。この油状物をシリカゲルク
ロマトグラフィー（溶媒；ｎ−ヘキサン／酢酸エチル）
にて精製し、標記化合物を２．７ｇ（収率９１％）得
た。 樹脂状物 UV λ_max ^EtOH nm: 276.0(ε 7600), 225.6(ε1780
0), 204.8(ε19600) IR ν_max ^neat cm^-1： 1625, 1615, 1595, 1515, 124
5, 1180, 1130¹ H-NMR(60MHz, CDCl₃ ) δ: 1.42(6H,s), 3.27(2H,s),
3.77(3H,s),4.78(2H,s), 6.79(2H,d,J=8Hz),7.19(2H,d,
J=8Hz), 7.46(1H,d,J=8Hz),8.39(1H,d,J=8Hz)Example 2 2,2-Dimethyl-5-oxo-4- (4-methoxybenzyl) -2,3,4,5-tetrahydro-8-trifluoromethylpyrido [3,2-f] [ Preparation of 1,4] oxazepine: 2,2 in 30 ml of anhydrous dimethylformamide
-Dimethyl-5-oxo-2,3,4,5-tetrahydro-8-trifluoromethylpyrido [3,2-f]
2.0 g (7.7 mmol) of [1,4] oxazepine was dissolved, and 0.46 g of sodium hydride (purity 60
%, 11.5 mmol) was added and the mixture was stirred at room temperature for 1 hour. Then 1.3 g of p-methoxybenzyl chloride (8.5
mmol), and the mixture is stirred at room temperature for 2 hours, and further 80 to 90
The mixture was heated and stirred at ℃ for 1.5 hours. After allowing to cool, the reaction solution was poured into water and extracted with methylene chloride. After extraction, the extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 3.4 g of a viscous oil. Silica gel chromatography of this oil (solvent; n-hexane / ethyl acetate)
The product was purified by the method described above to obtain 2.7 g (yield 91%) of the title compound. Resinous substance UV λ _max ^EtOH nm: 276.0 (ε 7600), 225.6 (ε 1780
0), 204.8 (ε19600) IR ν _max ^neat cm ^-1 : 1625, 1615, 1595, 1515, 124
5, 1180, 1130 ¹ H-NMR (60MHz, CDCl ₃ ) δ: 1.42 (6H, s), 3.27 (2H, s),
3.77 (3H, s), 4.78 (2H, s), 6.79 (2H, d, J = 8Hz), 7.19 (2H, d,
J = 8Hz), 7.46 (1H, d, J = 8Hz), 8.39 (1H, d, J = 8Hz)

【００２５】実施例３ ４−〔２−（Ｎ，Ｎ−ジメチルアミノ）エチル〕−２，
２−ジメチル−５−オキソ−２，３，４，５−テトラヒ
ドロ−８−トリフルオロメチルピリド［３，２−ｆ］
［１，４］オキサゼピン塩酸塩の製造：ジメチルホルム
アミド５０ml中に２，２−ジメチル−５−オキソ−２，
３，４，５−テトラヒドロ−８−トリフルオロメチルピ
リド［３，２−ｆ］［１，４］オキサゼピン２．０ｇ
（７．７mmol）を溶解し、この中に水素化ナトリウム
０．４６ｇ（純度６０％，１１．５mmol）を加え、室温
で１時間攪拌した。次いで２−ジメチルアミノエチルク
ロライド０．９ｇ（８．５mmol）を加え、１１０℃にて
１時間加熱攪拌した。放冷後、反応液を水中に注ぎ込
み、塩化メチレンで抽出した。抽出液は水洗後無水硫酸
マグネシウムで乾燥し、減圧下溶媒を留去し赤褐色油状
物２．６ｇを得た。この油状物をシリカゲルクロマトグ
ラフィー（溶媒；クロロホルム／メタノール）にて精製
し、標記化合物のフリー塩基を１．８ｇ（収率６９％）
得た。 粘稠油状物 IR ν_max ^neat cm^-1： 1645, 1595, 1580, 1175, 113
0, 960¹ H-NMR(60MHz, CDCl₃ ) δ: 1.51(6H,s), 2.27(6H,s),
2.53(2H,t,J=7Hz), 3.43(2H,s),3.73(2H,t,J=7Hz), 7.4
8(1H,d,J=8Hz),8.32(1H,d,J=8Hz) 標記化合物のフリー塩基１．６ｇをアセトン２０mlに溶
解し、濃塩酸１mlを加え減圧濃縮して油状残渣を得た。
この残渣にエーテルを加え結晶化させた後、結晶をろ取
乾燥して標記化合物塩酸塩を１．５ｇ得た。 mp. 148.6℃（分解） UV λ_max ^EtOH nm: 276.8(ε4800), 204.8(ε12800) IR ν_max ^KBr cm^-1： 3550, 3410, 2640, 2475, 163
5, 1600, 1575, 1250,1170, 1145, 955¹ H-NMR(60MHz, MeOH-d₄) δ:1.50(6H,s), 3.03(6H,s),
3.47(2H,t,J=6Hz), 3.62(2H,s),4.10(2H,t,J=6Hz),7.64
(1H,d,J=8Hz),8.40(1H,d,J=8Hz)Example 3 4- [2- (N, N-dimethylamino) ethyl] -2,
2-Dimethyl-5-oxo-2,3,4,5-tetrahydro-8-trifluoromethylpyrido [3,2-f]
Preparation of [1,4] oxazepine hydrochloride: 2,2-dimethyl-5-oxo-2, in 50 ml of dimethylformamide
2.0 g of 3,4,5-tetrahydro-8-trifluoromethylpyrido [3,2-f] [1,4] oxazepine
(7.7 mmol) was dissolved, 0.46 g of sodium hydride (purity 60%, 11.5 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. Next, 0.9 g (8.5 mmol) of 2-dimethylaminoethyl chloride was added, and the mixture was heated with stirring at 110 ° C. for 1 hour. After allowing to cool, the reaction solution was poured into water and extracted with methylene chloride. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a reddish brown oily substance (2.6 g). This oily substance was purified by silica gel chromatography (solvent; chloroform / methanol) to give 1.8 g of the free base of the title compound (yield 69%).
Obtained. Viscous oil IR ν _max ^neat cm ^-1 : 1645, 1595, 1580, 1175, 113
0, 960 ¹ H-NMR (60MHz, CDCl ₃ ) δ: 1.51 (6H, s), 2.27 (6H, s),
2.53 (2H, t, J = 7Hz), 3.43 (2H, s), 3.73 (2H, t, J = 7Hz), 7.4
8 (1H, d, J = 8Hz), 8.32 (1H, d, J = 8Hz) 1.6 g of the free base of the title compound was dissolved in 20 ml of acetone, 1 ml of concentrated hydrochloric acid was added and concentrated under reduced pressure to obtain an oily residue. ..
Ether was added to this residue for crystallization, and the crystals were collected by filtration and dried to obtain 1.5 g of the title compound hydrochloride. mp. 148.6 ℃ (decomposition) UV λ _max ^EtOH nm: 276.8 (ε4800), 204.8 (ε12800) IR ν _max ^KBr cm ⁻¹ : 3550, 3410, 2640, 2475, 163
5, 1600, 1575, 1250, 1170, 1145, 955 ¹ H-NMR (60MHz, MeOH-d ₄ ) δ: 1.50 (6H, s), 3.03 (6H, s),
3.47 (2H, t, J = 6Hz), 3.62 (2H, s), 4.10 (2H, t, J = 6Hz), 7.64
(1H, d, J = 8Hz), 8.40 (1H, d, J = 8Hz)

【００２６】実施例４ ２−〔４−〔２，２−ジメチル−５−オキソ−２，３，
４，５−テトラヒドロ−８−トリフルオロメチルピリド
［３，２−ｆ］［１，４］オキサゼピン−４−イル〕ブ
チルカルバモイル〕安息香酸の製造：ジオキサン３０ml
中に、２，２−ジメチル−５−オキソ−２，３，４，５
−テトラヒドロ−８−トリフルオロメチルピリド［３，
２−ｆ］［１，４］オキサゼピン２．０ｇ（７．７mmo
l）を溶解し、この中に水素化リチウム０．１９ｇ（２
３．９mmol）を加え、室温で２０分攪拌した。次いでＮ
−（４−ブロモブチル）フタルイミド２．４ｇ（８．５
mmol）を加え、１３時間加熱還流した。放冷後反応液に
水を加え、酢酸エチルで抽出し有機層に可溶な成分を除
去した。水層は、３Ｎ塩酸水溶液にてpH１とした後クロ
ロホルムで抽出し、抽出後は水洗後無水硫酸マグネシウ
ムで乾燥した。次いで溶媒を減圧留去して得た泡状残渣
に塩化メチレンを加え、析出した無色粒状晶をろ取し、
標記化合物を２．０ｇ（収率５４％）得た。 mp. 164.6℃（分解） UV λ_max ^EtOH nm: 275.2(ε6700), 206.0(ε26100) IR ν_max ^KBr cm^-1： 3290, 2980, 2940, 2600, 1705,
1620, 1600,1580,1180, 1130¹ H-NMR(60MHz,DMSO-d₆ ) δ: 1.43(6H,s), 1.52〜1.85
(4H,m),3.31(2H,t,J=6Hz), 3.51(2H,s),3.66(2H,t,J=6H
z), 7.29〜7.95(4H,m),7.70(1H,t,J=8Hz), 8.37(1H,d,J
=8Hz),7.25〜7.60(2H,bs)Example 4 2- [4- [2,2-dimethyl-5-oxo-2,3,3]
Preparation of 4,5-tetrahydro-8-trifluoromethylpyrido [3,2-f] [1,4] oxazepin-4-yl] butylcarbamoyl] benzoic acid: 30 ml dioxane.
2,2-dimethyl-5-oxo-2,3,4,5
-Tetrahydro-8-trifluoromethylpyrido [3,
2-f] [1,4] Oxazepine 2.0 g (7.7 mmo
l) was dissolved, and 0.19 g (2
3.9 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. Then N
-(4-Bromobutyl) phthalimide 2.4 g (8.5
mmol) was added and the mixture was heated under reflux for 13 hours. After allowing to cool, water was added to the reaction solution, and the mixture was extracted with ethyl acetate to remove components soluble in the organic layer. The aqueous layer was adjusted to pH 1 with a 3N aqueous hydrochloric acid solution, extracted with chloroform, washed with water after extraction, and dried over anhydrous magnesium sulfate. Next, methylene chloride was added to the foamy residue obtained by distilling off the solvent under reduced pressure, and the precipitated colorless granular crystals were collected by filtration,
2.0 g (yield 54%) of the title compound was obtained. mp. 164.6 ℃ (decomposition) UV λ _max ^EtOH nm: 275.2 (ε6700), 206.0 (ε26100) IR ν _max ^KBr cm ⁻¹ : 3290, 2980, 2940, 2600, 1705,
1620, 1600, 1580, 1180, 1130 ¹ H-NMR (60MHz, DMSO-d ₆ ) δ: 1.43 (6H, s), 1.52 ~ 1.85
(4H, m), 3.31 (2H, t, J = 6Hz), 3.51 (2H, s), 3.66 (2H, t, J = 6H
z), 7.29 to 7.95 (4H, m), 7.70 (1H, t, J = 8Hz), 8.37 (1H, d, J
= 8Hz), 7.25 ~ 7.60 (2H, bs)

【００２７】実施例５ ４−（４−アミノブチル）−２，２−ジメチル−５−オ
キソ−２，３，４，５−テトラヒドロ−８−トリフルオ
ロメチルピリド［３，２−ｆ］［１，４］オキサゼピン
塩酸塩の製造：メタノール３００ml中に、２−〔４−
〔２，２−ジメチル−５−オキソ−２，３，４，５−テ
トラヒドロ−８−トリフルオロメチルピリド［３，２−
ｆ］［１，４］オキサゼピン−４−イル〕ブチルカルバ
モイル〕安息香酸１．５ｇ（３．１mmol）及び抱水ヒド
ラジン１２mlを溶解し、１５．５時間加熱還流した。放
冷後反応液に水を加え塩化メチレンで抽出した。抽出液
は水洗後無水硫酸マグネシウムで乾燥し、次いで溶媒を
減圧留去して標記化合物のフリー塩基を０．５ｇ（収率
５０％）得た。 粘稠油状物 IR ν_max ^neat cm^-1： 3360, 3290, 1645, 1595, 117
5, 1135¹ H-NMR(60MHz, CDCl₃ ) δ: 1.50(6H,s), 1.30〜3.03(8
H,m),3.33(2H,s), 3.62(2H,t,J=7Hz),7.44(1H,d,J=8H
z), 8.29(1H,d,J=8Hz) 標記化合物のフリー塩基０．５ｇをメタノール５０mlに
溶解し、濃塩酸１mlを加え減圧濃縮して油状残渣を得
た。この残渣にエーテルを加え結晶化させた後、結晶を
ろ取乾燥して標記化合物塩酸塩を０．５ｇ得た。 mp. 170.3℃（分解） UV λ_max ^EtOH nm: 274.8(ε 5500), 220.8(ε 760
0), 204.8(ε12600) IR ν_max ^KBr cm^-1： 2980, 2930, 1645, 1595, 117
5, 1130, 980, 960¹ H-NMR(60MHz, MeOH-d₄) : 1.49(6H,s), 1.32〜2.10(4
H,m),2.30〜3.22(2H,m), 3.54(2H,s),3.40〜3.85(2H,
m), 7.62(1H,d,J=8Hz),8.33(1H,d,J=8Hz)Example 5 4- (4-aminobutyl) -2,2-dimethyl-5-oxo-2,3,4,5-tetrahydro-8-trifluoromethylpyrido [3,2-f] [ Preparation of 1,4] oxazepine hydrochloride: 2- [4-
[2,2-Dimethyl-5-oxo-2,3,4,5-tetrahydro-8-trifluoromethylpyrido [3,2-
f] [1,4] Oxazepin-4-yl] butylcarbamoyl] benzoic acid (1.5 g, 3.1 mmol) and hydrazine hydrate (12 ml) were dissolved and the mixture was heated under reflux for 15.5 hours. After allowing to cool, water was added to the reaction solution and the mixture was extracted with methylene chloride. The extract was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 0.5 g (yield 50%) of the free base of the title compound. Viscous oil IR ν _max ^neat cm ^-1 : 3360, 3290, 1645, 1595, 117
5, 1135 ¹ H-NMR (60MHz, CDCl ₃ ) δ: 1.50 (6H, s), 1.30〜3.03 (8
H, m), 3.33 (2H, s), 3.62 (2H, t, J = 7Hz), 7.44 (1H, d, J = 8H
z), 8.29 (1H, d, J = 8Hz) 0.5 g of the free base of the title compound was dissolved in 50 ml of methanol, 1 ml of concentrated hydrochloric acid was added, and the mixture was concentrated under reduced pressure to obtain an oily residue. Ether was added to this residue for crystallization, and the crystals were collected by filtration and dried to obtain 0.5 g of the hydrochloride of the title compound. mp. 170.3 ℃ (decomposition) UV λ _max ^EtOH nm: 274.8 (ε 5500), 220.8 (ε 760
0), 204.8 (ε12600) IR ν _max ^KBr cm ^-1 : 2980, 2930, 1645, 1595, 117
5, 1130, 980, 960 ¹ H-NMR (60MHz, MeOH-d ₄ ): 1.49 (6H, s), 1.32 ~ 2.10 (4
H, m), 2.30 ~ 3.22 (2H, m), 3.54 (2H, s), 3.40 ~ 3.85 (2H,
m), 7.62 (1H, d, J = 8Hz), 8.33 (1H, d, J = 8Hz)

Claims (1)

【特許請求の範囲】[Claims] 【請求項１】 次の一般式（１） 【化１】 で表されるテトラヒドロオキサゼピン誘導体。1. The following general formula (1): A tetrahydrooxazepine derivative represented by: