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Optical isomer of 1,4-benzothiazepine-1-oxide derivative, and pharmaceutical composition prepared using same

A technology of optical isomers and pharmaceutical compositions, applied in the field of optical isomers of 1,4-benzothiazepine*-1-oxide derivatives and pharmaceutical compositions using it, can solve unavoidable proarrhythmic effect and other problems

Active Publication Date: 2017-05-31
AETAS PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in particular, the selective action on atrial arrhythmia such as atrial fibrillation has not been confirmed, but it has been confirmed to have a strong effect on the ventricle, and it is expected that the arrhythmogenic effect cannot be avoided if it is used for the treatment of atrial fibrillation
[0015] Thus, drugs that have been proposed as therapeutic drugs for atrial fibrillation or atrial arrhythmia include 1,4-benzothiazepine -1-Oxide derivatives, found to be highly effective against atrial fibrillation, but compared with the effectiveness against atrial fibrillation, the effect on the ventricle is often stronger, and there is a non-negligible proarrhythmia The problem of alignment

Method used

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  • Optical isomer of 1,4-benzothiazepine-1-oxide derivative, and pharmaceutical composition prepared using same
  • Optical isomer of 1,4-benzothiazepine-1-oxide derivative, and pharmaceutical composition prepared using same
  • Optical isomer of 1,4-benzothiazepine-1-oxide derivative, and pharmaceutical composition prepared using same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0130] Compound 4-[3-(4-benzylpiperidin-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4- represented by formula [Ia] Benzothiazepines - Manufacture of 1-oxide

[0131] In the reaction vessel, 30.0 g of 4-[3-(4-benzylpiperidin-1-yl)propionyl]-7-methoxy-2,3, 4,5-tetrahydro-1,4-benzothiazepine hydrochloride, adding solvent chloroform (CHCl 3 ) 800ml, stirred at room temperature to dissolve it. Next, the reaction container was immersed in an ice-water bath, and cooled until the temperature in the container reached 0 to 1°C. Here, while paying attention not to increase the reaction temperature, 14.0 g of m-chloroperbenzoic acid (mCPBA) was dissolved in chloroform (CHCl 3 ) The solution of 600ml was slowly dripped in with the dripping time of 110 minutes. After completion of the dropping, the mixture was stirred at 0°C to 1°C for about 20 minutes.

[0132] Next, 4.14g Na 2 SO 3 200ml of H 2 O solution was added dropwise at 0°C to 5°C over 1 minute, and stirred at 0°C to...

Embodiment 2

[0139] The first component and the second component of the optical isomers of the compound represented by the formula [IV] of the present invention are produced by separating and separately collecting the compound represented by the formula [Ia] produced in Example 1 under the following conditions .

[0140] Column: CHIRALPAK AD-H (manufactured by Daicel Corporation)

[0141] Size: inner diameter 0.46cm x length 25cm

[0142] Mobile phase: MeOH / MeCN / DEA=90 / 10 / 0.1(v / v)

[0143] Flow rate: 1.0mL / min

[0144] Temperature: 40°C

[0145] Detection wavelength: 245nm

[0146] Injection volume: 10μL

[0147] MeOH means methanol, MeCN means acetonitrile, and DEA means diethylamine.

[0148] Meanwhile, as an instrument, use:

[0149] Pump: LC-20AD (manufactured by Shimadzu Corporation)

[0150] Detector: SPD-20A (manufactured by Shimadzu Corporation)

[0151] Autosampler: SIL-20A (manufactured by Shimadzu Corporation)

[0152] From 10 g of the compound represented by the formula...

Embodiment 3

[0155] Determination of heartbeat, blood pressure, left ventricular systolic function (max dP / dt), left ventricular diastolic function (min dP / dt)

[0156] Test method: In this test, using rats under anesthesia, the hydrochloride of the optical isomer 1st component (A) and the optical isomer 2nd component (B) were administered continuously intravenously, respectively. Effects of medication on the circulatory system. Each group was performed with n=5. The first component (A) or the second component (B) was continuously administered at 0.1 mg / kg / min for 20 minutes, and heart rate, blood pressure, max dP / dt, and min dP / dt were measured. Measure the parameters of 0 minutes, 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, and 40 minutes of administration, so as to compare with the 0 minute value (previous value (control value)) The difference indicates. The measured values ​​are expressed as mean ± SD.

[0157] Test result: the resul...

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Abstract

The present invention provides: a novel compound which is characterized by being capable of increasing the number of heart beats or a blood pressure mildly to improve hemodynamics, and which is useful as a therapeutic or prophylactic agent for atrial fibrillation and heart failure; and a pharmaceutical composition which contains the compound. The present invention relates to: an optical isomer of a 1,4-benzothiazepine-1-oxide derivative represented by general formula [II] (wherein R represents a hydrogen atom or a hydroxy group; and * indicates the presence of an optical isomer) or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition which contains the optical isomer or a pharmaceutically acceptable salt thereof.

Description

technical field [0001] The present invention relates to 1,4-benzothiazepines represented by the general formula [I] of the present invention - Optical isomers of 1-oxide derivatives or pharmaceutically acceptable salts thereof, and pharmaceutical compositions using the same. Background technique [0002] Cardiac arrhythmias can be classified into bradycardia and tachycardia. Tachycardia arrhythmias are further classified into atrial and ventricular based on the site of occurrence. Among atrial tachycardia arrhythmias, there are atrial fibrillation, atrial flutter, supraventricular tachycardia, and atrial extrasystoles. Among ventricular tachycardia arrhythmias, there are ventricular fibrillation, ventricular flutter, ventricular tachycardia, and ventricular extrasystoles. [0003] Antiarrhythmic drugs are used in the treatment and prevention of such tachycardia arrhythmias. [0004] Currently, antiarrhythmic drugs are classified using the Vaughan-Williams classification...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/06A61K31/554A61P9/04A61P9/06A61P9/10
CPCA61K31/554C07D417/06A61P9/00A61P9/04A61P9/06A61P9/10C07B2200/07
Inventor 金子升
Owner AETAS PHARMA
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