JPH0373545B2 - - Google Patents
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- Publication number
- JPH0373545B2 JPH0373545B2 JP13492283A JP13492283A JPH0373545B2 JP H0373545 B2 JPH0373545 B2 JP H0373545B2 JP 13492283 A JP13492283 A JP 13492283A JP 13492283 A JP13492283 A JP 13492283A JP H0373545 B2 JPH0373545 B2 JP H0373545B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- general formula
- lower alkyl
- benzothiazepine
- alkyl group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Description
【発明の詳細な説明】
本発明は新規ベンゾチアゼンピン誘導体及びそ
の製法に関し、更に詳しくは一般式
（但し、R1及びR2は低級アルキル基を表わ
す。）で示されるベンゾチアゼピン誘導体及びそ
の製法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel benzothiazenpine derivative and a method for producing the same, and more particularly, to a novel benzothiazenpine derivative and a method for producing the same. (However, R 1 and R 2 represent lower alkyl groups.) The present invention relates to a benzothiazepine derivative represented by the following formula and a method for producing the same.
本発明の化合物（）は新規化合物であり、血
小板凝集抑制作用を有する化合物例えば３−低級
アルカノイルオキシ−５−〔２−（ジメチルアミ
ノ）エチル〕−２−（４−低級アルコキシフエニ
ル）−１，５−ベンゾチアゼピン−４（5H）−オン
の合成中間体として有用な化合物である。 The compound () of the present invention is a new compound, and is a compound having an inhibitory effect on platelet aggregation. For example, 3-lower alkanoyloxy-5-[2-(dimethylamino)ethyl]-2-(4-lower alkoxyphenyl)-1 , 5-benzothiazepin-4(5H)-one is a useful compound as a synthetic intermediate.
本発明は化合物としては、一般式（）におい
て、例えばR1がメチル基、エチル基、プロピル
基、ブチル基の如き低級アルキル基であり、R2
がメチル基、エチル基、プロピル基、ブチル基の
如き低級アルキル基である化合物が挙げられる。
これらのうち、とくに好ましい化合物としては一
般式（）において、R1がメチル基であり、R2
がメチル基である化合物が挙げられる。 The present invention provides a compound in which, in the general formula (), for example, R 1 is a lower alkyl group such as a methyl group, ethyl group, propyl group, or butyl group, and R 2
Examples include compounds in which is a lower alkyl group such as a methyl group, ethyl group, propyl group, or butyl group.
Among these, particularly preferred compounds are those in the general formula () in which R 1 is a methyl group and R 2
Examples include compounds where is a methyl group.
本発明によれば、化合物（）は一般式
（但し、R1は前記と同一意味を有する。）で示
されるベンゾチアゼピン誘導体と一般式
R2COOH （）
（但し、R2は前記と同一意味を有する。）で示
されるカルボン酸の反応性誘導体とを一般式
（R3）2SO （）
（但し、R3は低級アルキル基を表わす。）で示
されるスルホキシド化合物の存在下に反応させる
ことにより製することができる。 According to the invention, the compound () has the general formula (However, R 1 has the same meaning as above.) Reaction of a benzothiazepine derivative represented by the general formula R 2 COOH () (However, R 2 has the same meaning as above) It can be produced by reacting a sulfoxide compound with a sulfoxide compound represented by the general formula (R 3 ) 2 SO ( ) (wherein R 3 represents a lower alkyl group).
以下、本発明の反応を詳細に説明する。 Hereinafter, the reaction of the present invention will be explained in detail.
化合物（）と化合物（）の反応性誘導体と
の反応は適当な溶媒又は無溶媒中化合物（）の
存在下に容易に実施することができる。本反応に
用いられる化合物（）の反応性誘導体として
は、例えば化合物（）の酸無水物（例えば、無
水酢酸、プロピオン酸無水物、酪酸無水物、吉草
酸無水物）が好適に挙げられ、とくに無水酢酸が
好ましい。化合物（）としては、例えばジメチ
ルスルホキシドがとくに好適に挙げられる。溶媒
としては、例えばジメチルスルホキシド、ベンゼ
ン、トルエン、ジオキサン、テトラヒドロフラン
等を好適に使用することができる。本反応は０℃
〜６℃、好ましくは室温付近で実施するのが適当
である。 The reaction between compound () and a reactive derivative of compound () can be easily carried out in the presence of compound () in an appropriate solvent or in the absence of a solvent. Preferred examples of the reactive derivatives of compound () used in this reaction include acid anhydrides of compound () (e.g., acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride), particularly Acetic anhydride is preferred. As the compound (), for example, dimethyl sulfoxide is particularly preferably mentioned. As the solvent, for example, dimethyl sulfoxide, benzene, toluene, dioxane, tetrahydrofuran, etc. can be suitably used. This reaction is at 0℃
It is appropriate to carry out the reaction at a temperature of ~6°C, preferably around room temperature.
上記の如くして得られる化合物（）はジメチ
ルアミノエチルクロリドと縮合反応させることに
より、血小板凝集抑制作用を有する３−低級アル
カノイルオキシ−５−〔２−（ジメチルアミノ）エ
チル〕−２−（４−低級アルコキシフエニル）−１，
５−ベンゾチアゼピン−４（5H）−オン−に導く
ことができる。 The compound () obtained as described above is subjected to a condensation reaction with dimethylaminoethyl chloride to produce 3-lower alkanoyloxy-5-[2-(dimethylamino)ethyl]-2-(4), which has an inhibitory effect on platelet aggregation. -lower alkoxyphenyl)-1,
5-benzothiazepine-4(5H)-one-.
尚、本発明の原料化合物（）はChem.
Pharm.Bull.，26（９）2889−2893（1978）記載
の方法に準じて、一般式
（但し、R1は前記と同一意味を有する。）で示
されるグリシツド酸エステルをオルトニトロチオ
フエノールと反応させ、得られる化合物を還元
し、次いで閉環することにより製することができ
る。 In addition, the raw material compound () of the present invention is Chem.
According to the method described in Pharm.Bull., 26 (9) 2889-2893 (1978), the general formula (However, R 1 has the same meaning as above.) It can be produced by reacting the glycidic acid ester represented by (R 1 has the same meaning as above) with orthonitrothiophenol, reducing the resulting compound, and then ring-closing.
実施例
シス−３−ヒドロキシ−２−（４−メトキシフ
エニル）−２，３−ジヒドロ−１，５−ベンゾチ
アゼピン−４（5H）−オン24ｇを無水酢酸80ml、
ジメチルスルホキシド150ml及びベンゼン400mlの
混液に溶解し、該溶液を室温で90時間かく拌す
る。反応混合物を氷水に注加し、該混合物を酢酸
エチルで抽出する。抽出液を水で洗浄し、乾燥後
減圧下に溶媒を留去する。残査をエーテルで処理
することにより、３−アセトキシ−２−（４−メ
トキシフエニル）−１，５−ベンゾチアゼピン−
４（5H）−オン19ｇを得る。M.p.196〜200℃（分
解）本品をエタノールから再結晶することによ
り、M.p.202〜204℃（分解）を示すプリズム晶
を得る。Example 24 g of cis-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one was mixed with 80 ml of acetic anhydride,
Dissolve in a mixture of 150 ml of dimethyl sulfoxide and 400 ml of benzene, and stir the solution at room temperature for 90 hours. The reaction mixture is poured into ice water and the mixture is extracted with ethyl acetate. The extract is washed with water, dried, and the solvent is distilled off under reduced pressure. By treating the residue with ether, 3-acetoxy-2-(4-methoxyphenyl)-1,5-benzothiazepine-
19 g of 4(5H)-one are obtained. Mp196-200℃ (decomposition) By recrystallizing this product from ethanol, prismatic crystals exhibiting Mp202-204℃ (decomposition) are obtained.
参考例
３−アセトキシ−２−（４−ネトキシフエニル）
−１，５−ベンゾチアゼピン−４（5H）−オン５
ｇ、ジメチルアミノエチルクロリド・塩酸塩2.3
ｇ、粉末炭酸カリウム、4.45ｇ及びアセトン300
mlの混合物を20時間加熱還流する。不溶物をろ去
し、エタノールで洗浄する。ろ液と洗液を合せ減
圧下に溶媒を留去する。残査を酢酸エチルに溶解
し、該溶液を10％塩酸で抽出する。抽出液を炭酸
カリウムでアルカリ性とした後酢酸エチルで抽出
する。抽出液を水で洗浄し、乾燥後減圧下に溶媒
を留去する。残査（3.79ｇ）をシリカゲルクロマ
トグラフイー（溶媒、酢酸エチル：エタノール＝
25：２）で精製後、シユウ酸塩とし、該塩をエタ
ノールとエーテルとの混液から再結晶することに
より、３−アセトキシ−５−〔２−（ジメチルアミ
ノ）エチル〕−２−（４−メトキシフエニル）−１，
５−ベンゾチアゼンピン−４（5H）−オン・シヨ
ウ酸塩１，２ｇを無色針状晶として得る。Reference example 3-acetoxy-2-(4-netoxyphenyl)
-1,5-benzothiazepine-4(5H)-one 5
g, dimethylaminoethyl chloride hydrochloride 2.3
g, powdered potassium carbonate, 4.45 g and acetone 300
ml of the mixture is heated to reflux for 20 hours. Insoluble matter is filtered off and washed with ethanol. The filtrate and washing liquid are combined and the solvent is distilled off under reduced pressure. The residue is dissolved in ethyl acetate and the solution is extracted with 10% hydrochloric acid. The extract is made alkaline with potassium carbonate and then extracted with ethyl acetate. The extract is washed with water, dried, and the solvent is distilled off under reduced pressure. The residue (3.79 g) was subjected to silica gel chromatography (solvent, ethyl acetate:ethanol =
25:2), the oxalate salt is obtained, and the salt is recrystallized from a mixture of ethanol and ether to give 3-acetoxy-5-[2-(dimethylamino)ethyl]-2-(4- methoxyphenyl)-1,
1.2 g of 5-benzothiazepine-4(5H)-one siolate are obtained as colorless needles.
M.p.152〜156℃（分解）
実験例
血小板凝集抑制作用
（方法）
エーテル麻酔したSD系ラツト（体重：180−
230ｇ）の腹部大動脈より採血し、該血液９容を
3.8％（Ｗ／Ｖ）クエン酸三ナトリウム水溶液１
容と混和し、遠心分離（250×ｇ，５分間）によ
り、血小板けん濁血漿（PRP）を調製した。残
在血液をさらに遠心分離（1000×ｇ，10分間）し
血小板除去血漿（PPP）を調製した。PRPを血
小板数が８〜10×105／ｍm3となるようにPPPで
希釈した。希釈後のPRP250μに検体溶液25μ
を加え、該混合物（検体濃度：100μｇ／ml）を
凝集計（MODEL PAT−4A，N.K.K.社製）の
ガラスセルに注入し、37℃で２分間かく拌する。
コラーゲン溶液（ホルムセンらの方法〔ビオキミ
カ・エ・ビオフイジカ・アクタ．，186，254
（1969）〕により調製）25μを加えて血小板凝集
を起させ、凝集能をボーンらの方法〔ネイチヤ
ー．，194，927（1969）〕により測定し、下式によ
り血小板凝集抑制率を算出した。 Mp152-156℃ (decomposition) Experimental example Platelet aggregation inhibitory effect (method) SD rats anesthetized with ether (body weight: 180-
230g) was collected from the abdominal aorta, and 9 volumes of the blood were collected.
3.8% (W/V) trisodium citrate aqueous solution 1
Platelet-suspended plasma (PRP) was prepared by centrifuging (250×g, 5 minutes). The remaining blood was further centrifuged (1000×g, 10 minutes) to prepare platelet-free plasma (PPP). PRP was diluted with PPP to give a platelet count of 8 to 10×10 5 /mm 3 . Sample solution 25μ to PRP250μ after dilution
The mixture (specimen concentration: 100 μg/ml) is injected into a glass cell of an aggregometer (MODEL PAT-4A, manufactured by NKK), and stirred at 37° C. for 2 minutes.
Collagen solution (method of Holmsen et al. [Biochimica et Biofidica Acta., 186 , 254
(1969)] was added to induce platelet aggregation, and the aggregation ability was determined by the method of Born et al. [Nature. , 194 , 927 (1969)], and the platelet aggregation inhibition rate was calculated using the following formula.
抑制率＝〔１−検体添加時の凝集率／検体無添加時の
凝集率〕×100
（結果）
３−アセトキシ−５−〔２−（ジメチルアミノ）
エチル〕−２−（４−メトキシフエニル）−１，５
−ベンゾチアゼピン・シユウ酸塩の血小板凝集に
対する抑制率は62％であつた。 Suppression rate = [1-Agglutination rate when sample is added/Agglutination rate when sample is not added] x 100 (Result) 3-acetoxy-5-[2-(dimethylamino)
ethyl]-2-(4-methoxyphenyl)-1,5
-The inhibitory rate of benzothiazepine oxalate on platelet aggregation was 62%.
Claims (1)
す。）で示されるベンゾチアゼピン誘導体。 ２ 一般式 （但し、R1は低級アルキル基を表わす。）で示
されるベンゾチアゼピン誘導体と一般式 R2COOH （） （但し、R2は低級アルキル基を表わす。）で示
されるカルボン酸の反応性誘導体とを一般式 （R3）2SO （） （但し、R3は低級アルキル基を表わす。）で示
されるスルホキシド化合物の存在下に反応させる
ことを特徴とする一般式 （但し、R1及びR2は前記と同一意味を有す
る。）で示されるベンゾチアゼピン誘導体の製法。[Claims] 1. General formula (However, R 1 and R 2 represent lower alkyl groups.) A benzothiazepine derivative represented by: 2 General formula (However, R 1 represents a lower alkyl group.) benzothiazepine derivatives and reactive derivatives of carboxylic acids represented by the general formula R 2 COOH () (However, R 2 represents a lower alkyl group.) and is reacted in the presence of a sulfoxide compound represented by the general formula (R 3 ) 2 SO ( ) (wherein R 3 represents a lower alkyl group). (However, R 1 and R 2 have the same meanings as above.) A method for producing a benzothiazepine derivative.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13492283A JPS6025981A (en) | 1983-07-22 | 1983-07-22 | Benzothiazepine derivative and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13492283A JPS6025981A (en) | 1983-07-22 | 1983-07-22 | Benzothiazepine derivative and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6025981A JPS6025981A (en) | 1985-02-08 |
| JPH0373545B2 true JPH0373545B2 (en) | 1991-11-22 |
Family
ID=15139673
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13492283A Granted JPS6025981A (en) | 1983-07-22 | 1983-07-22 | Benzothiazepine derivative and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6025981A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09113003A (en) * | 1995-10-23 | 1997-05-02 | Sanyo Electric Co Ltd | Air conditioner |
-
1983
- 1983-07-22 JP JP13492283A patent/JPS6025981A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6025981A (en) | 1985-02-08 |
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