JPH0425266B2 - - Google Patents
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- Publication number
- JPH0425266B2 JPH0425266B2 JP58134924A JP13492483A JPH0425266B2 JP H0425266 B2 JPH0425266 B2 JP H0425266B2 JP 58134924 A JP58134924 A JP 58134924A JP 13492483 A JP13492483 A JP 13492483A JP H0425266 B2 JPH0425266 B2 JP H0425266B2
- Authority
- JP
- Japan
- Prior art keywords
- methoxyphenyl
- benzothiazepine
- ethyl
- compound
- dimethylamino
- 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 - Lifetime
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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２−（４−メトキシフエニル）−１，５
−ベンゾチアゼピン−３，４（2H，5H）−ジオン
に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention provides 2-(4-methoxyphenyl)-1,5
-Relating to benzothiazepine-3,4(2H,5H)-dione.
上記本発明の化合物は新規化合物であつて、血
小板凝集抑制作用を有する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−４
（5H）−オンの合成中間体として有用な化合物で
ある。 The above-mentioned compound of the present invention is a new compound, and has 3-acetoxy-5-
[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-1,5-benzothiazepine-4
This compound is useful as a synthetic intermediate for (5H)-one.
本発明のジオン型化合物（）は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（特公昭45−9383号）をジメチルスルホキシド
−無水酢酸を用いて酸化し、ついで得られる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）−オンを弱塩基
で加水分解することにより製することができる。 The dione type compound () of the present invention is 3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (Japanese Patent Publication No. 45-9383 ) is oxidized using dimethyl sulfoxide-acetic anhydride, then the resulting 3-
Acetoxy-2-(4-methoxyphenyl)-1,
It can be produced by hydrolyzing 5-benzothiazepin-4(5H)-one with a weak base.
第一工程の酸化反応は、適当な溶媒（例えばベ
ンゼン）中、室温で撹拌することにより実施でき
る。 The oxidation reaction in the first step can be carried out by stirring at room temperature in a suitable solvent (eg, benzene).
続く第二工程の加水分解反応は、適当な溶媒
（例えばメタノール）中、弱塩基（例えばアンモ
ニア水）を加温下に作用させることにより実施で
きる。 The subsequent hydrolysis reaction in the second step can be carried out by reacting a weak base (for example, aqueous ammonia) with a suitable solvent (for example, methanol) under heating.
かくして得られた化合物（）は、これを水素
化ナトリウムの存在下に適当な溶媒（例えばジメ
チルスルホキシド）中、２−（ジメチルアミノ）
エチルハライドと反応させて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−３，４（2H，5H）
−ジオンとし、次いで該化合物を適当な溶媒（例
えばベンゼン）中、塩基（例えばトリエチルアミ
ン）の存在下に無水酢酸と反応させることによ
り、優れた血小板凝集抑制作用を有する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−４（5H）−オン（）に導くことがで
きる。 The compound (2) thus obtained is prepared by diluting it into 2-(dimethylamino) in a suitable solvent (e.g. dimethyl sulfoxide) in the presence of sodium hydride.
5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl) by reacting with ethyl halide
-1,5-Benzothiazepine-3,4(2H,5H)
-dione and then reacting the compound with acetic anhydride in a suitable solvent (e.g. benzene) in the presence of a base (e.g. triethylamine), 3-acetoxy-5-[2 -(dimethylamino)ethyl]-
2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one ().
この化合物（）は要すれば常法により薬理的
に許容し得る酸付加塩に変換することができる。
かかる薬理的に許容し得る酸付加塩としては例え
ば塩酸塩、臭化水素酸塩、硫酸塩、過塩素酸塩、
硝酸塩の如き無機酸付加塩、シユウ酸塩、酢酸
塩、コハク酸塩、マレイン酸塩の如き有機酸付加
塩があげられる。 This compound () can be converted into a pharmacologically acceptable acid addition salt by a conventional method, if necessary.
Such pharmacologically acceptable acid addition salts include, for example, hydrochloride, hydrobromide, sulfate, perchlorate,
Examples include inorganic acid addition salts such as nitrates, and organic acid addition salts such as oxalates, acetates, succinates, and maleates.
化合物（）は前記の如く血小板凝集抑制作用
を有する為、抗血栓剤として有用であり、例えば
末梢動脈血栓症、肺塞栓症、冠動脈閉塞症、心筋
梗塞症、脳梗塞症、一過性脳虚血などの各種血栓
症の予防、治療に有用である。 Compound () has the effect of inhibiting platelet aggregation as described above, and is therefore useful as an antithrombotic agent, such as peripheral arterial thrombosis, pulmonary embolism, coronary artery occlusion, myocardial infarction, cerebral infarction, and transient cerebral ischemia. It is useful for the prevention and treatment of various thromboses such as blood clots.
化合物（）は経口的にも非経口的にも投与す
ることができ、また適当な医薬担体と混合して用
いることもできる。医薬担体としては、例えば乳
糖、マンニツトなどの糖類、デンプン類、結晶セ
ルロース、クエン酸カルシウム、第２リン酸カル
シウム、ゼラチン、デキストリン、メチルセルロ
ース、カルボキシメチルセルロースナトリウム、
ヒドロキシプロピルセルロース、ポリビニールピ
ロリドン、ステアリン酸及びそのマグネシウム塩
もしくはカルシウム塩、タルク等が挙げられる。
また、投与剤型としては、錠剤、散剤、カプセル
剤の如き固形剤であつてもよく、また溶液、懸濁
液の如き液剤であつてもよい。更に非経口的に投
与する場合には、注射剤として用いることもでき
る。 Compound () can be administered orally or parenterally, and can also be used in combination with a suitable pharmaceutical carrier. Examples of pharmaceutical carriers include saccharides such as lactose and mannite, starches, crystalline cellulose, calcium citrate, dibasic calcium phosphate, gelatin, dextrin, methylcellulose, sodium carboxymethylcellulose,
Examples include hydroxypropyl cellulose, polyvinyl pyrrolidone, stearic acid and its magnesium salt or calcium salt, talc, and the like.
Further, the dosage form may be a solid dosage form such as a tablet, powder, or capsule, or a liquid dosage form such as a solution or suspension. Furthermore, when administered parenterally, it can also be used as an injection.
以下、本発明を実施例、製造例及び実験例によ
り更に詳細に説明する。 Hereinafter, the present invention will be explained in more detail with reference to Examples, Production Examples, and Experimental Examples.
実施例
(1) 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（シス体）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の混液に溶解し室温で90時間撹拌する。反
応混合物を氷水中に注加し酢酸エチルエステルで
抽出し、抽出液を水洗、乾燥する。溶媒を減圧下
に留去したのち得られる残査にエーテルを加えて
ろ取することにより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。Example (1) 24 g of 3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (cis form) was dissolved in acetic anhydride.
80ml, dimethyl sulfoxide 150ml and benzene
Dissolve in 400 ml of mixed solution and stir at room temperature for 90 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate, and the extract was washed with water and dried. After the solvent was distilled off under reduced pressure, ether was added to the resulting residue and filtered to obtain 3-acetoxy-2-(4-
19 g of methoxyphenyl)-1,5-benzothiazepine-4(5H)-one are obtained.
m.p. 196〜200℃（分解）
本品をエタノールより再結晶することにより
m.p.202〜204℃（分解）のプリズム晶となる。 mp 196-200℃ (decomposition) By recrystallizing this product from ethanol
It becomes a prismatic crystal with a temperature of mp202-204℃ (decomposition).
(2) 上記(1)で得られた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4.08ｇ、ジメチルホルムアミ
ド30ml、メタノール20ml及び濃アンモニア水16ml
の混合物を浴温70℃にて20分間撹拌する。反応混
合物を氷水中に注加し10％塩酸で酸性とし酢酸エ
チルエステルで抽出する。抽出液を水洗、乾燥し
たのち減圧下に溶媒を留去する。残査にエーテル
を加えて析出する結晶をろ取することにより２−
（４−メトキシフエニル）−１，５−ベンゾチアゼ
ピン−３，４（2H，5H）−ジオン2.4ｇを微黄色
結晶として得る。(2) 3-acetoxy-2-(4) obtained in (1) above
-methoxyphenyl)-1,5-benzothiazepine-4(5H)-one 4.08 g, dimethylformamide 30 ml, methanol 20 ml and concentrated ammonia water 16 ml
The mixture was stirred for 20 minutes at a bath temperature of 70°C. The reaction mixture was poured into ice water, acidified with 10% hydrochloric acid, and extracted with ethyl acetate. After washing the extract with water and drying, the solvent is distilled off under reduced pressure. By adding ether to the residue and filtering the precipitated crystals, 2-
2.4 g of (4-methoxyphenyl)-1,5-benzothiazepine-3,4(2H,5H)-dione are obtained as pale yellow crystals.
m.p. 162〜164℃
製造例
(1) 窒素気流中下、ジメチルスルホキシド30mlと
水素化ナトリウム（69％、油性）0.54ｇの混合物
を60〜70℃に加熱する。次いで、室温まで冷却
後、２−（４−メトキシフエニル）−１，５−ベン
ゾチアゼピン−３，４（2H，5H）−ジオン1.8ｇ
を加え1.5時間撹拌する。これに２−（ジメチルア
ミノ）エチルクロリド0.709ｇを加えて50〜60℃
で3.5時間加熱撹拌する。冷後反応混合物を氷水
中に注加し、10％塩酸で酸性とし酢酸エチルエス
テルで洗浄する。次いでこの酢酸エチル洗浄液を
更に10％塩酸で抽出する。塩酸水溶液をあわせて
アンモニアアルカリ性とした後エーテルで抽出す
る。抽出液を水洗、乾燥し溶媒を留去し、得られ
る油状物（1.51ｇ）をシユウ酸塩とした後、メタ
ノールより再結晶することにより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−３，４（2H，
5H）−ジオン・シユウ酸塩1.51ｇを無色針状晶と
して得る。 mp 162-164°C Production Example (1) Under a nitrogen stream, a mixture of 30 ml of dimethyl sulfoxide and 0.54 g of sodium hydride (69%, oily) is heated to 60-70°C. Then, after cooling to room temperature, 1.8 g of 2-(4-methoxyphenyl)-1,5-benzothiazepine-3,4(2H,5H)-dione
Add and stir for 1.5 hours. Add 0.709g of 2-(dimethylamino)ethyl chloride to this and heat at 50-60℃.
Heat and stir for 3.5 hours. After cooling, the reaction mixture was poured into ice water, acidified with 10% hydrochloric acid, and washed with ethyl acetate. Next, this ethyl acetate washing solution is further extracted with 10% hydrochloric acid. The mixture is made ammonia alkaline with an aqueous hydrochloric acid solution, and then extracted with ether. The extract was washed with water, dried, and the solvent was distilled off. The resulting oil (1.51 g) was converted into an oxalate salt, which was recrystallized from methanol to give 5-[2-(dimethylamino)ethyl]-2-. (4-methoxyphenyl)-1,5-benzothiazepine-3,4(2H,
1.51 g of 5H)-dione oxalate are obtained as colorless needles.
m.p. 182〜183℃
(2) 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−３，４（2H，5H）−ジオン0.9ｇ、トリエ
チルアミン0.4ml、無水酢酸１ml及びベンゼン15
mlの混合物を室温で24時間撹拌する。次いで該反
応液を氷水中に注加して塩酸酸性としエーテルで
洗浄する。氷冷下にアンモニアアルカリ性としエ
ーテルで抽出する。抽出液を水洗、乾燥した後、
エーテルを留去することにより油状物0.98ｇを得
た。得られた油状物をシユウ酸塩とした後、エタ
ノールより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−ベンゾチアゼピ
ン−４（5H）−オン・シユウ酸塩0.80ｇを無色針
状晶として得た。 mp 182-183℃ (2) 5-[2-(dimethylamino)ethyl]-2-
(4-methoxyphenyl)-1,5-benzothiazepine-3,4(2H,5H)-dione 0.9 g, triethylamine 0.4 ml, acetic anhydride 1 ml and benzene 15
ml mixture is stirred at room temperature for 24 hours. Next, the reaction solution was poured into ice water, acidified with hydrochloric acid, and washed with ether. Make alkaline with ammonia under ice cooling and extract with ether. After washing the extract with water and drying it,
By distilling off the ether, 0.98 g of oil was obtained. The obtained oil was made into an oxalate salt and then recrystallized from ethanol to give 3-acetoxy-5-[2-(dimethylamino)ethyl]-2-(4
0.80 g of oxalate of -methoxyphenyl)-1,5-benzothiazepine-4(5H)-one was obtained as colorless needles.
m.p. 152〜156℃（分解）
実験例
血小板凝集抑制作用
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取した血液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
小板懸濁血漿（PRP）を調製した。残存血液を
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。
ついで希釈後のPRP20μと25μの検体化合物
溶液（最終濃度：100μｇ／ml）の混合物を凝集
計（MODEL PAT−4A，N.K.K.社製）のガラ
スセルに注入した。37℃で２分間撹拌した後、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）〕により調製したコ
ラーゲン溶液25μを加え血小板凝集をおこさ
せ、凝集能をボーンの方法〔ネイチヤー、194，
927（1969）〕により測定し検体化合物による血小
板凝集抑制率を算出した。その結果、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−４（5H）−オン（シユウ酸塩）は62％の
血小板凝集抑制率を示した。 mp 152-156℃ (decomposition) Experimental example Platelet aggregation inhibitory effect SD rats anesthetized with ether (body weight: 180-
9 volumes of blood collected from the abdominal aorta of 230 g (3.8 g)
Platelet suspended plasma (PRP) was prepared by mixing with 1 volume of % (W/V) trisodium citrate aqueous solution and 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 .
Then, a mixture of 20μ of diluted PRP and 25μ of the sample compound solution (final concentration: 100μg/ml) was injected into the glass cell of an aggregometer (MODEL PAT-4A, manufactured by NKK). After stirring at 37°C for 2 minutes, 25μ of a collagen solution prepared according to the method of Holmsen et al. [Biochimica Acta, 186 , 254 (1969)] was added to induce platelet aggregation, and the aggregation ability was measured using the method of Born [Biochimica Acta, 186, 254 (1969)]. Nature, 194 ,
927 (1969)], and the inhibition rate of platelet aggregation by the sample compound was calculated. As a result, 3-acetoxy-5-[2-(dimethylamino)ethyl]-2
-(4-Methoxyphenyl)-1,5-benzothiazepine-4(5H)-one (oxalate) showed a platelet aggregation inhibition rate of 62%.
Claims (1)
ゾチアゼピン−３，４（2H，5H）−ジオン。1 2-(4-methoxyphenyl)-1,5-benzothiazepine-3,4(2H,5H)-dione.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13492483A JPS6025983A (en) | 1983-07-22 | 1983-07-22 | Benzothiazepine derivative and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13492483A JPS6025983A (en) | 1983-07-22 | 1983-07-22 | Benzothiazepine derivative and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6025983A JPS6025983A (en) | 1985-02-08 |
| JPH0425266B2 true JPH0425266B2 (en) | 1992-04-30 |
Family
ID=15139721
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13492483A Granted JPS6025983A (en) | 1983-07-22 | 1983-07-22 | Benzothiazepine derivative and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6025983A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL121525A0 (en) * | 1996-08-26 | 1998-02-08 | Tanabe Seiyaku Co | Process for preparing optically active benzothiazepine compound and intermediate therefor |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59106477A (en) * | 1982-12-08 | 1984-06-20 | Hamari Yakuhin Kogyo Kk | Novel 1,5-benzothiazepin derivative and its preparation |
-
1983
- 1983-07-22 JP JP13492483A patent/JPS6025983A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6025983A (en) | 1985-02-08 |
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