JPH06206819A - Peripheral circulation improving agent - Google Patents
Peripheral circulation improving agentInfo
- Publication number
- JPH06206819A JPH06206819A JP5263378A JP26337893A JPH06206819A JP H06206819 A JPH06206819 A JP H06206819A JP 5263378 A JP5263378 A JP 5263378A JP 26337893 A JP26337893 A JP 26337893A JP H06206819 A JPH06206819 A JP H06206819A
- Authority
- JP
- Japan
- Prior art keywords
- lower alkyl
- alkyl group
- peripheral circulation
- compound
- cis
- 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.)
- Granted
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、末梢循環改善剤に関す
る。さらにくわしくは、本発明は、末梢循環改善作用を
有し、慢性動脈閉塞症、レイノー病、バージャー病等の
治療及び／又は予防剤として有用な末梢循環改善剤に関
する。TECHNICAL FIELD The present invention relates to a peripheral circulation improving agent. More specifically, the present invention relates to a peripheral circulation improving agent having a peripheral circulation improving action and useful as a therapeutic and / or preventive agent for chronic arterial occlusion, Raynaud's disease, Buerger's disease and the like.
【０００２】[0002]
【従来の技術】２−（４−低級アルキルフェニル）−３
−低級アルカノイルオキシ（又はヒドロキシ）−５−
（２−ジ低級アルキルアミノエチル）−８−低級アルキ
ル−２，３−ジヒドロ−１，５−ベンゾチアゼピン−４
（５Ｈ）−オン、２−（４−低級アルキルフェニル）−
３−低級アルカノイルオキシ（又はヒドロキシ）−５−
（２−モノ低級アルキルアミノエチル）−８−低級アル
キル−２，３−ジヒドロ−１，５−ベンゾチアゼピン−
４（５Ｈ）−オン等の１，５−ベンゾチアゼピン誘導体
が、降圧作用、脳・冠血管拡張作用、血小板凝集抑制作
用を有することは知られている（例えば、特公平２−２
８５９４号、特公平３−７４６６１号等）。2. Description of the Related Art 2- (4-lower alkylphenyl) -3
-Lower alkanoyloxy (or hydroxy) -5-
(2-Di-lower alkylaminoethyl) -8-lower alkyl-2,3-dihydro-1,5-benzothiazepine-4
(5H) -one, 2- (4-lower alkylphenyl)-
3-lower alkanoyloxy (or hydroxy) -5-
(2-Mono-lower alkylaminoethyl) -8-lower alkyl-2,3-dihydro-1,5-benzothiazepine-
It is known that 1,5-benzothiazepine derivatives such as 4 (5H) -one have antihypertensive action, cerebral / coronary vasodilator action, and platelet aggregation inhibitory action (for example, Japanese Patent Publication No. 2-2.
No. 8594, Japanese Examined Patent Publication No. 3-74661, etc.).
【０００３】[0003]
【発明が解決しようとする課題】本発明は、末梢循環改
善剤を提供するものである。DISCLOSURE OF THE INVENTION The present invention provides a peripheral circulation improving agent.
【０００４】[0004]
【課題を解決するための手段】本発明者らは、上記の如
き１，５−ベンゾチアゼピン誘導体の（−）−シス体が
特異的に末梢循環改善作用を有することを見出し、本発
明を完成した。The present inventors have found that the (-)-cis isomer of the 1,5-benzothiazepine derivative as described above specifically has a peripheral circulation improving action, and the present invention is as follows. completed.
【０００５】即ち、本発明は、一般式〔Ｉ〕That is, the present invention has the general formula [I]
【０００６】[0006]
【化２】 [Chemical 2]
【０００７】（式中、Ｒ1 は低級アルキル基又は低級ア
ルコキシ基であり、Ｒ2 は水素原子又は低級アルカノイ
ル基であり、Ｒ3 は低級アルキル基であり、Ｒ4 は水素
原子又は低級アルキル基であり、Ｒ5 は水素原子、低級
アルキル基又はヒドロキシ低級アルキル基であり、Ａは
低級アルキレン基を表す）で示される（−）−シス−
１，５−ベンゾチアゼピン誘導体又はその薬理的に許容
し得る塩を有効成分としてなる末梢循環改善剤に関す
る。(In the formula, R 1 is a lower alkyl group or a lower alkoxy group, R 2 is a hydrogen atom or a lower alkanoyl group, R 3 is a lower alkyl group, and R 4 is a hydrogen atom or a lower alkyl group. And R 5 represents a hydrogen atom, a lower alkyl group or a hydroxy lower alkyl group, and A represents a lower alkylene group) (-)-cis-
The present invention relates to a peripheral circulation improving agent comprising a 1,5-benzothiazepine derivative or a pharmacologically acceptable salt thereof as an active ingredient.
【０００８】本発明の有効成分である（−）−シス−
１，５−ベンゾチアゼピン誘導体〔Ｉ〕及びその薬理的
に許容し得る塩は、優れた末梢循環改善作用を有し、か
つ安全性が高く、慢性動脈閉塞症（末梢動脈閉塞症）、
レイノー病、バージャー病等に対し優れた治療・予防効
果を奏する。(-)-Cis- which is the active ingredient of the present invention
The 1,5-benzothiazepine derivative [I] and a pharmacologically acceptable salt thereof have an excellent peripheral circulation improving effect and are highly safe, and have a chronic arterial occlusion (peripheral arterial occlusion),
It has excellent therapeutic / preventive effects on Raynaud's disease and Buerger's disease.
【０００９】上記（−）−シス−１，５−ベンゾチアゼ
ピン誘導体〔Ｉ〕のうち優れた治療効果を奏する化合物
としては、Ｒ1 が低級アルキル基であり、Ｒ2 が低級ア
ルカノイル基であり、Ｒ4 が低級アルキル基であり、Ｒ
5 が低級アルキル基である化合物があげられる。Among the above-mentioned (-)-cis-1,5-benzothiazepine derivative [I], R 1 is a lower alkyl group and R 2 is a lower alkanoyl group as a compound having an excellent therapeutic effect. , R 4 is a lower alkyl group, R
An example is a compound in which 5 is a lower alkyl group.
【００１０】また、本発明において、低級アルキル基、
低級アルキレン基及び低級アルコキシ基の好ましい例と
しては、炭素数１〜６、とりわけ炭素数１〜４のもの、
低級アルカノイル基としては、炭素数２〜６、とりわけ
炭素数２〜４のものがあげられる。Further, in the present invention, a lower alkyl group,
Preferred examples of the lower alkylene group and the lower alkoxy group are those having 1 to 6 carbon atoms, especially those having 1 to 4 carbon atoms,
Examples of the lower alkanoyl group include those having 2 to 6 carbon atoms, especially those having 2 to 4 carbon atoms.
【００１１】本発明の有効成分である（−）−シス−
１，５−ベンゾチアゼピン誘導体〔Ｉ〕は、遊離の形で
も又その薬理的に許容し得る塩の形でも医薬用途に用い
ることができる。薬理的に許容し得る塩としては、例え
ば、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、過塩素酸
塩、硫酸塩もしくはリン酸塩等の無機酸付加塩又はシュ
ウ酸塩、マレイン酸塩、フマル酸塩、酒石酸塩もしくは
メタンスルホン酸塩等の有機酸付加塩等があげられる。(-)-Cis- which is the active ingredient of the present invention
The 1,5-benzothiazepine derivative [I] can be used for medicinal use either in a free form or in the form of a pharmaceutically acceptable salt thereof. Examples of the pharmaceutically acceptable salt include, for example, inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate or phosphate, or oxalate, and maleate. Examples thereof include organic acid addition salts such as acid salts, fumarate salts, tartrate salts, and methanesulfonate salts.
【００１２】（−）−シス−１，５−ベンゾチアゼピン
誘導体〔Ｉ〕又はその薬理的に許容し得る塩の投与量
は、投与方法・患者の年令・体重・状態あるいは疾患の
程度等により異なるが、経口投与の場合は、通常１日当
たり約０．１〜３００ｍｇ／ｋｇ、とりわけ、１〜３０
ｍｇ／ｋｇ程度とするのが好ましく、非経口投与の場合
は、通常１日当たり約０．００１〜１０ｍｇ／ｋｇ、と
りわけ、０．０１〜０．３ｍｇ／ｋｇ程度とするのが好
ましい。The dose of the (-)-cis-1,5-benzothiazepine derivative [I] or a pharmacologically acceptable salt thereof is, for example, administration method, age of the patient, body weight, condition or degree of disease. When administered orally, it is usually about 0.1 to 300 mg / kg, especially 1 to 30 mg per day.
The amount is preferably about mg / kg, and in the case of parenteral administration, it is usually about 0.001 to 10 mg / kg per day, preferably about 0.01 to 0.3 mg / kg.
【００１３】（−）−シス−１，５−ベンゾチアゼピン
誘導体〔Ｉ〕又はその薬理的に許容し得る塩は、経口的
にも非経口的にも投与することができる。The (-)-cis-1,5-benzothiazepine derivative [I] or a pharmaceutically acceptable salt thereof can be administered orally or parenterally.
【００１４】経口投与する場合の剤形は、錠剤、顆粒
剤、カプセル剤、散剤の如き固形剤であってもよく、溶
液、懸濁液の如き液剤であってもよく、経口投与に適し
た医薬担体と共に医薬製剤として使用することができ
る。かかる医薬担体としては、例えば、結合剤（シロッ
プ、アラビアゴム、ゼラチン、ソルビット、トラガン
ト、ポリビニルピロリドン等）、賦形剤（乳糖、砂糖、
コーンスターチ、リン酸カリウム、ソルビット、グリシ
ン等）、滑沢剤（ステアリン酸マグネシウム、タルク、
ポリエチレングリコール、シリカ等）、崩壊剤（バレイ
ショデンプン等）又は湿潤剤（ラウリル硫酸ナトリウム
等）等慣用のものをいずれも使用できる。The dosage form for oral administration may be a solid preparation such as tablets, granules, capsules and powders, or a liquid preparation such as a solution or suspension, which is suitable for oral administration. It can be used as a pharmaceutical preparation together with a pharmaceutical carrier. Examples of such pharmaceutical carriers include binders (syrup, acacia, gelatin, sorbit, tragacanth, polyvinylpyrrolidone, etc.), excipients (lactose, sugar,
Corn starch, potassium phosphate, sorbit, glycine, etc., lubricants (magnesium stearate, talc,
Any conventional one such as polyethylene glycol, silica, etc., a disintegrating agent (potato starch, etc.) or a wetting agent (sodium lauryl sulfate, etc.) can be used.
【００１５】一方、非経口投与する場合の剤形は、例え
ば、注射用蒸留水、生理的食塩水、ブドウ糖水溶液等を
用いて、注射剤や点滴注射剤とするのが好ましい。On the other hand, the dosage form for parenteral administration is preferably an injection or drip injection using, for example, distilled water for injection, physiological saline, glucose aqueous solution or the like.
【００１６】本発明の有効成分である（−）−シス−
１，５−ベンゾチアゼピン誘導体〔Ｉ〕は、既知方法
（例えば、特公昭４７−８１３号、特公平２−２８５９
４号、特公平３−７４６６１号、特開平１−１８６８７
５号等に記載の方法）に従って製造することができる。(-)-Cis- which is the active ingredient of the present invention
The 1,5-benzothiazepine derivative [I] can be prepared by a known method (for example, JP-B-47-813 and JP-B-2-2859).
No. 4, Japanese Patent Publication No. 3-74661, JP-A No. 1-18687.
No. 5, etc.).
【００１７】例えば、一般式〔ＩＩ〕For example, the general formula [II]
【００１８】[0018]
【化３】 [Chemical 3]
【００１９】（式中、Ｒ51は水素原子、低級アルキル基
又は保護基を有するヒドロキシ低級アルキル基であり、
他の記号は前記と同一意味を表す）で示される化合物と
一般式〔ＩＩＩ〕(In the formula, R 51 is a hydrogen atom, a lower alkyl group or a hydroxy lower alkyl group having a protecting group,
Other symbols represent the same meaning as described above) and a compound represented by the general formula [III]
【００２０】[0020]
【化４】 [Chemical 4]
【００２１】（式中、Ｘはハロゲン原子であり、他の記
号は前記と同一意味を表す）で示される化合物を、塩基
（例えば、炭酸アルカリ金属等）の存在下で反応させた
後、要すれば、一般式〔ＩＶ〕(Wherein X is a halogen atom and other symbols have the same meanings as described above), the compound is reacted in the presence of a base (eg, alkali metal carbonate), Then, the general formula [IV]
【００２２】[0022]
【化５】 [Chemical 5]
【００２３】（式中、Ｒ21は低級アルカノイル基を表
す）で示される化合物の酸無水物を、脱酸剤（例えば、
有機アミン等）の存在下で反応させ、さらにＲ51が保護
基を有するヒドロキシ低級アルキル基である場合には当
該保護基を常法により除去することにより製造すること
ができる。The acid anhydride of the compound represented by the formula (wherein R 21 represents a lower alkanoyl group) is treated with a deoxidizing agent (eg,
It can be produced by reacting in the presence of an organic amine or the like), and when R 51 is a hydroxy lower alkyl group having a protecting group, the protecting group is removed by a conventional method.
【００２４】実験例１ （検体化合物）下記第１表記載の化合物を、検体化合物
として用いた。Experimental Example 1 (Sample Compound) The compounds shown in Table 1 below were used as sample compounds.
【００２５】[0025]
【表１】 [Table 1]
【００２６】（方法）成犬（１群１匹）に、麻酔及び人
工呼吸下、検体化合物を１０、３０、１００、３００μ
ｇ／ｋｇ体重となるように６０分間隔で順次静脈内投与
し、経時的に大腿動脈血流量を測定した。大腿動脈血流
量の測定は、大腿動脈に装着したフロープローブ（ｆｌ
ｏｗ ｐｒｏｂｅ）を介し、電磁血流計（日本光電製、
ＭＦＶ−２１００）を用いて行った。大腿動脈血流増加
量は、検体化合物投与前の血流量を基準値（ベースライ
ン）とし、各投与量の検体化合物を投与してから６０分
後の血流量から基準値を差し引いた値として求めた。(Method) Adult dogs (1 dog per group) were anesthetized and artificially ventilated with 10, 30, 100, 300 μ of the test compound.
The femoral artery blood flow was measured over time by sequential intravenous administration at 60 minute intervals so that the body weight was g / kg. The blood flow of the femoral artery is measured by a flow probe (fl attached to the femoral artery.
ow probe), an electromagnetic blood flow meter (manufactured by Nihon Kohden,
MFV-2100). The amount of increase in femoral artery blood flow was determined as the value obtained by subtracting the reference value from the blood flow 60 minutes after the administration of each dose of the sample compound, with the blood flow rate before administration of the sample compound as the reference value (baseline). It was
【００２７】（結果）各検体化合物の大腿動脈血流増加
量を下記第２表に示す。(Results) The femoral artery blood flow increase of each test compound is shown in Table 2 below.
【００２８】[0028]
【表２】 [Table 2]
【００２９】実験例２ （方法）実験例１と同様にして、成犬（１群４匹）に、
検体化合物Ａを１００μｇ／ｋｇ体重となるよう静脈内
投与し、投与３０、６０、１２０、１８０、２４０、３
００分後の大腿動脈血流量を測定し、検体化合物投与前
の血流量に対する増加量を求めた。Experimental Example 2 (Method) In the same manner as in Experimental Example 1, to adult dogs (4 dogs in one group),
The test compound A was intravenously administered at 100 μg / kg body weight, and the dose was 30, 60, 120, 180, 240, 3
The femoral artery blood flow after 00 minutes was measured and the increase in blood flow before administration of the test compound was determined.
【００３０】（結果）検体化合物Ａの投与各時間後の大
腿動脈血流量及び血流増加量を下記第３表に示す。(Results) The femoral artery blood flow and the blood flow increase after each hour of administration of the test compound A are shown in Table 3 below.
【００３１】[0031]
【表３】 [Table 3]
【００３２】実験例３ （検体化合物）第１表に記載の化合物Ａ、Ｂ、Ｃ、Ｅ及
びＦを検体化合物として用いた。Experimental Example 3 (Sample compounds) Compounds A, B, C, E and F shown in Table 1 were used as sample compounds.
【００３３】（方法）成犬（１群５匹）に、麻酔及び人
工呼吸下、検体化合物を１０、３０、１００、３００μ
ｇ／ｋｇ体重となるように６０分間隔で順次静脈内投与
し、経時的に大腿動脈血流量を測定した。大腿動脈血流
量の測定は、大腿動脈に装着したフロープローブ（ｆｌ
ｏｗ ｐｒｏｂｅ）を介し、電磁血流計（日本光電製、
ＭＦＶ−２１００）を用いて行った。大腿動脈血流増加
量は、検体化合物投与前の血流量を基準値（ベースライ
ン）とし、各投与量の検体化合物を投与してから６０分
間における血流量の最大値から基準値を差し引いた値と
して求めた。(Method) Adult dogs (5 animals per group) were anesthetized and artificially respired with 10, 30, 100, 300 μ of the test compound.
The femoral artery blood flow was measured over time by sequential intravenous administration at 60 minute intervals so that the body weight was g / kg. The blood flow of the femoral artery is measured by a flow probe (fl attached to the femoral artery.
ow probe), an electromagnetic blood flow meter (manufactured by Nihon Kohden,
MFV-2100). The amount of increase in femoral artery blood flow is the value obtained by subtracting the reference value from the maximum value of blood flow 60 minutes after the administration of each dose of the sample compound, with the amount of blood flow before administration of the sample compound as the reference value (baseline). Sought as.
【００３４】（結果）各検体化合物の大腿動脈血流増加
量を下記第４表に示す。(Results) The femoral artery blood flow increase of each test compound is shown in Table 4 below.
【００３５】[0035]
【表４】 [Table 4]
【００３６】製造例 （１）（−）−シス−２−（４−メチルフェニル）−３
−ヒドロキシ−８−トリチルオキシメチル−２，３−ジ
ヒドロ−１，５−ベンゾチアゼピン−４（５Ｈ）−オン
２．４８ｇ、２−（ジメチルアミノ）エチルクロリド・
塩酸塩０．７５ｇ、炭酸カリウム１．７０ｇ及びアセト
ン５０ｍｌの混合物を、攪拌しながら一晩還流する。冷
却後、不溶物をろ去し、ろ液を減圧濃縮する。残査を酢
酸エチルとｎ−ヘキサンの混液より再結晶することによ
り、（−）−シス−２−（４−メチルフェニル）−３−
ヒドロキシ−５−〔２−（ジメチルアミノ）エチル〕−
８−トリチルオキシメチル−２，３−ジヒドロ−１，５
−ベンゾチアゼピン−４（５Ｈ）−オン２．５９ｇを得
る。Production Example (1) (-)-cis-2- (4-methylphenyl) -3
-Hydroxy-8-trityloxymethyl-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one 2.48 g, 2- (dimethylamino) ethyl chloride.
A mixture of 0.75 g of hydrochloride salt, 1.70 g of potassium carbonate and 50 ml of acetone is refluxed with stirring overnight. After cooling, the insoluble matter is removed by filtration, and the filtrate is concentrated under reduced pressure. By recrystallizing the residue from a mixed solution of ethyl acetate and n-hexane, (-)-cis-2- (4-methylphenyl) -3-
Hydroxy-5- [2- (dimethylamino) ethyl]-
8-Trityloxymethyl-2,3-dihydro-1,5
2.59 g of benzothiazepin-4 (5H) -one are obtained.
【００３７】ｍ．ｐ．１１０−１１４℃ 〔α〕D 20−８３．７°（ｃ＝０．２５１、メタノー
ル） （２）上記（１）で得た化合物２．４６ｇ、無水酢酸９
ｍｌ及びピリジン２５ｍｌの混合物を室温で一晩攪拌す
る。反応混合物を氷水中に注加し、酢酸エチルで抽出す
る。抽出液を洗浄、乾燥後、減圧濃縮することにより、
（−）−シス−２−（４−メチルフェニル）−３−アセ
トキシ−５−〔２−（ジメチルアミノ）エチル〕−８−
トリチルオキシメチル−２，３−ジヒドロ−１，５−ベ
ンゾチアゼピン−４（５Ｈ）−オン２．７２ｇを油状物
として得る。M. p. 110-114 ° C. [α] D 20 -83.7 ° (c = 0.251 , methanol) (2) Compound obtained in the above (1) 2.46 g, acetic anhydride 9
A mixture of ml and 25 ml of pyridine is stirred overnight at room temperature. The reaction mixture is poured into ice water and extracted with ethyl acetate. After washing and drying the extract, by concentrating under reduced pressure,
(-)-Cis-2- (4-methylphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-
2.72 g of trityloxymethyl-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one are obtained as an oil.
【００３８】 ＩＲliquidνmax （ｃｍ-1）：１７４５，１６８０ （３）上記（２）で得た化合物２．０ｇをトリフルオロ
酢酸２０ｍｌに溶解し、室温で３時間攪拌した後、減圧
濃縮する。残査に炭酸水素ナトリウム飽和水溶液２００
ｍｌ及びジエチルエーテル１００ｍｌを加え、室温で３
０分間攪拌する。IR liquid ν max (cm −1 ): 1745, 1680 (3) 2.0 g of the compound obtained in (2) above is dissolved in 20 ml of trifluoroacetic acid, stirred at room temperature for 3 hours, and then concentrated under reduced pressure. . Residue is saturated sodium bicarbonate 200
ml and 100 ml of diethyl ether, and add 3 at room temperature.
Stir for 0 minutes.
【００３９】反応混合物を酢酸エチル抽出し、抽出液を
減圧濃縮して（−）−シス−２−（４−メチルフェニ
ル）−３−アセトキシ−５−〔２−（ジメチルアミノ）
エチル〕−８−ヒドロキシメチル−２，３−ジヒドロ−
１，５−ベンゾチアゼピン−４（５Ｈ）−オンを粗生成
物として得る。The reaction mixture was extracted with ethyl acetate and the extract was concentrated under reduced pressure to give (-)-cis-2- (4-methylphenyl) -3-acetoxy-5- [2- (dimethylamino).
Ethyl] -8-hydroxymethyl-2,3-dihydro-
1,5-Benzothiazepin-4 (5H) -one is obtained as a crude product.
【００４０】本品をシュウ酸で処理し、エタノール−エ
ーテル混液より再結晶することにより、（−）−シス−
２−（４−メチルフェニル）−３−アセトキシ−５−
〔２−（ジメチルアミノ）エチル〕−８−ヒドロキシメ
チル−２，３−ジヒドロ−１，５−ベンゾチアゼピン−
４（５Ｈ）−オン・シュウ酸塩９６６ｍｇを得る。This product was treated with oxalic acid and recrystallized from an ethanol-ether mixture to give (-)-cis-
2- (4-methylphenyl) -3-acetoxy-5-
[2- (Dimethylamino) ethyl] -8-hydroxymethyl-2,3-dihydro-1,5-benzothiazepine-
966 mg of 4 (5H) -one oxalate are obtained.
【００４１】ｍ．ｐ．１６８−１６９℃ 〔α〕D 20−８３．１°（ｃ＝０．２０１、メタノー
ル）M. p. 168-169 ° C. [α] D 20 -83.1 ° (c = 0.201 , methanol)
【００４２】[0042]
【発明の効果】本発明の有効成分である（−）−シス−
１，５−ベンゾチアゼピン誘導体〔Ｉ〕は、大腿動脈血
流量を顕著に増加させるという優れた末梢循環改善作用
を示し、さらに作用が長時間持続するという優れた特長
をも有する。(-)-Cis- which is the active ingredient of the present invention
The 1,5-benzothiazepine derivative [I] exhibits an excellent peripheral circulation improving action of significantly increasing femoral artery blood flow, and also has an excellent feature that the action lasts for a long time.
【００４３】加えて、（−）−シス−１，５−ベンゾチ
アゼピン誘導体〔Ｉ〕は、毒性が低く、高い安全性を有
する。例えば、マウスに、前記検体化合物Ａを１０００
ｍｇ／ｋｇ経口投与した場合、２日間経過しても死亡例
は観察されなかった。In addition, the (-)-cis-1,5-benzothiazepine derivative [I] has low toxicity and high safety. For example, the test compound A is added to a mouse at 1000
In the case of oral administration of mg / kg, no death was observed even after 2 days.
【００４４】従って、本発明の（−）−シス−１，５−
ベンゾチアゼピン誘導体〔Ｉ〕又はその薬理的に許容し
得る塩は、優れた末梢循環改善剤として有用であり、慢
性動脈閉塞症、レイノー病、バージャー病等の治療及び
／又は予防に効果的に用いることができる。Therefore, the (-)-cis-1,5-of the present invention is
The benzothiazepine derivative [I] or a pharmacologically acceptable salt thereof is useful as an excellent peripheral circulation improving agent, and is effective for the treatment and / or prevention of chronic arterial occlusion, Raynaud's disease, Buerger's disease and the like. Can be used.
Claims (4)
あり、Ｒ2 は水素原子又は低級アルカノイル基であり、
Ｒ3 は低級アルキル基であり、Ｒ4 は水素原子又は低級
アルキル基であり、Ｒ5 は水素原子、低級アルキル基又
はヒドロキシ低級アルキル基であり、Ａは低級アルキレ
ン基を表す）で示される（−）−シス−１，５−ベンゾ
チアゼピン誘導体又はその薬理的に許容し得る塩を有効
成分としてなる末梢循環改善剤。1. A compound represented by the general formula [I]: (In the formula, R 1 is a lower alkyl group or a lower alkoxy group, R 2 is a hydrogen atom or a lower alkanoyl group,
R 3 is a lower alkyl group, R 4 is a hydrogen atom or a lower alkyl group, R 5 is a hydrogen atom, a lower alkyl group or a hydroxy lower alkyl group, and A represents a lower alkylene group). -)-Cis-1,5-benzothiazepine derivative or a peripheral circulation improving agent comprising a pharmacologically acceptable salt thereof as an active ingredient.
級アルカノイル基であり、Ｒ4 が低級アルキル基であ
り、Ｒ5 が低級アルキル基である請求項１記載の末梢循
環改善剤。2. The peripheral circulation improving agent according to claim 1, wherein R 1 is a lower alkyl group, R 2 is a lower alkanoyl group, R 4 is a lower alkyl group, and R 5 is a lower alkyl group.
である請求項１又は２記載の末梢循環改善剤。3. The peripheral circulation improving agent according to claim 1, which is a therapeutic and / or preventive agent for chronic arterial occlusion.
／又は予防剤である請求項１又は２記載の末梢循環改善
剤。4. The agent for improving peripheral circulation according to claim 1, which is a therapeutic and / or preventive agent for Raynaud's disease or Buerger's disease.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5263378A JP2643798B2 (en) | 1992-10-23 | 1993-10-21 | Peripheral arterial blood flow enhancer |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28483492 | 1992-10-23 | ||
| JP4-284834 | 1992-10-23 | ||
| JP5263378A JP2643798B2 (en) | 1992-10-23 | 1993-10-21 | Peripheral arterial blood flow enhancer |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH06206819A true JPH06206819A (en) | 1994-07-26 |
| JP2643798B2 JP2643798B2 (en) | 1997-08-20 |
Family
ID=26545995
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5263378A Expired - Fee Related JP2643798B2 (en) | 1992-10-23 | 1993-10-21 | Peripheral arterial blood flow enhancer |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2643798B2 (en) |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60202871A (en) * | 1984-03-10 | 1985-10-14 | Tanabe Seiyaku Co Ltd | 1,5-benzothiazepine derivative and its preparation |
| JPS60226866A (en) * | 1984-04-10 | 1985-11-12 | Tanabe Seiyaku Co Ltd | 1,5-benzothiazepine derivative and its preparation |
| JPS60231669A (en) * | 1984-04-28 | 1985-11-18 | Tanabe Seiyaku Co Ltd | 1,5-benzothiazepine derivative and its preparation |
| JPS61293976A (en) * | 1985-06-20 | 1986-12-24 | イ−・ア−ル・スクイブ・アンド・サンズ・インコ−ポレイテツド | Benzthiazepine derivative |
| JPS62174019A (en) * | 1985-10-14 | 1987-07-30 | Tanabe Seiyaku Co Ltd | Platelet coagulation inhibitor |
| JPS63275572A (en) * | 1987-05-01 | 1988-11-14 | Tanabe Seiyaku Co Ltd | 1,5-benzothiazepine derivative |
| JPS649981A (en) * | 1987-06-29 | 1989-01-13 | Tanabe Seiyaku Co | 1,5-benzothiazepine derivative |
| JPS649982A (en) * | 1987-06-30 | 1989-01-13 | Tanabe Seiyaku Co | 1,5-benzothiazepine derivative |
| JPH01110679A (en) * | 1987-07-31 | 1989-04-27 | Tanabe Seiyaku Co Ltd | 1,5-benzothiazepine derivative |
-
1993
- 1993-10-21 JP JP5263378A patent/JP2643798B2/en not_active Expired - Fee Related
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60202871A (en) * | 1984-03-10 | 1985-10-14 | Tanabe Seiyaku Co Ltd | 1,5-benzothiazepine derivative and its preparation |
| JPS60226866A (en) * | 1984-04-10 | 1985-11-12 | Tanabe Seiyaku Co Ltd | 1,5-benzothiazepine derivative and its preparation |
| JPS60231669A (en) * | 1984-04-28 | 1985-11-18 | Tanabe Seiyaku Co Ltd | 1,5-benzothiazepine derivative and its preparation |
| JPS61293976A (en) * | 1985-06-20 | 1986-12-24 | イ−・ア−ル・スクイブ・アンド・サンズ・インコ−ポレイテツド | Benzthiazepine derivative |
| JPS62174019A (en) * | 1985-10-14 | 1987-07-30 | Tanabe Seiyaku Co Ltd | Platelet coagulation inhibitor |
| JPS63275572A (en) * | 1987-05-01 | 1988-11-14 | Tanabe Seiyaku Co Ltd | 1,5-benzothiazepine derivative |
| JPS649981A (en) * | 1987-06-29 | 1989-01-13 | Tanabe Seiyaku Co | 1,5-benzothiazepine derivative |
| JPS649982A (en) * | 1987-06-30 | 1989-01-13 | Tanabe Seiyaku Co | 1,5-benzothiazepine derivative |
| JPH01110679A (en) * | 1987-07-31 | 1989-04-27 | Tanabe Seiyaku Co Ltd | 1,5-benzothiazepine derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2643798B2 (en) | 1997-08-20 |
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