JPH041178A - Piperidine derivative and antiarrhythmic medicine containing the same derivative - Google Patents

Abstract

NEW MATERIAL:4-(4-Fluorobenzoyl)-1-2-(N-phenylcarbamoylamino)ethyl-piperidine expressed by the formula. USE:An antiarrhythmic medicine. PREPARATION:6 N-Hydrochloric acid salt solution of 4-(4- fluorobenzoyl)-1-[2-(benzoylamino)ethyl] piperidine is heated and reacted. The reaction mixture is cooled at ambient temperature and then cleaned with an ether and a solvent is distilled from water layer. The resultant solid residue is dissolved in chloroform and N-methylmorpholine is added thereto. Chloroform solution of phenylisocyanate is dropwise added thereto at ambient temperature and stirred.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a novel piperidine derivative and an antiarrhythmic drug containing the same.

BACKGROUND OF THE INVENTION Arrhythmia is a deviation of the heart from its normal regular sinus rhythm, and its treatment is of clinical importance because its occurrence disrupts the regular movement of the heart. Conventionally, as antiarrhythmic drugs, Na channel inhibitors, β blockers, drugs that prolong action potential duration, Ca antagonists, and the like have been used. However, because these drugs are not effective against all arrhythmias and the safety margin is not sufficiently secured, drug therapy has not yet been established, and the development of new antiarrhythmic drugs is desired. was.

Problems to be Solved by the Invention It is necessary to develop an antiarrhythmic drug having a characteristic activity that can be manufactured easily and industrially at low cost.

Means for Solving the Problems As a result of intensive research to solve the above problems, the present inventors found that (4-(4-fluorobenzoyl)1-2-
We discovered that (N-phenylcarbamoylamino)ethylpiperidine exhibits a unique activity that combines excellent antiarrhythmic activity and serotonin antagonistic activity, and that the synthesis process is simple and that it can be easily produced industrially. The present invention has now been completed.

When using the antiarrhythmic drug of the present invention, the administration route is oral,
It may be administered parenterally. The dose is determined by the patient's age, weight, condition, and method of administration.
The daily dose is 1 μg to 5 g for oral administration and 0.01 gg to 1 g for parenteral administration. The novel piperidine derivatives of the present invention may be in conventional pharmaceutical forms, such as tablets, powders, capsules, solutions, dragees, or depots, and can be prepared according to conventional methods using conventional formulation auxiliaries. . For example, tablets may be prepared by combining the novel piperidine derivatives of the invention with known auxiliary substances, such as inert diluents (such as lactose, calcium carbonate or calcium phosphate), binders (such as gum arabic, cornstarch or gelatin), leavening agents (such as alginic acid, (corn starch or pre-gelatinized starch), sweeteners (e.g. sucrose, lactose or saccharin), flavoring agents (e.g. peppermint, redberry oil or cherry), humectants (e.g. magnesium stearate, talc or carboxymethyl cellulose). obtained by.

Examples) [Example 1 1-(4-fluorobenzoyl)-1-2-
Synthesis of (N-phenylcarbamoylamino)ethylpiperidine 4-(4-fluorobenzoyl)-1-(2-(benzoylamino)ethylpiperidine 4.50 g (12,7
A solution of 50 ml of 6N hydrochloride (1 mol) was heated to 100° C. and reacted for 5 hours. Ether 100m after cooling
/! The solution was washed four times with water, and the solvent was distilled off from the aqueous layer. The obtained solid residue was dissolved in 50 mf of chloroform, and 3.03 g (30.0+mol) of N-methylmorpholine was added. 2.38 g phenyl isocyanate (20
,0mmol) of chloroform 10m! The solution was added dropwise. After completion, stir for 1 hour, then add 50 mj of 5% aqueous sodium hydrogen carbonate solution! Washed twice with After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: chloroform:methanol = 40:1). The title compound was obtained by recrystallization from ethyl acetate, ether, and hexane.

Yield 4.33 g (11.7 mmol) Yield 92
% MS (m/z) 369 (M”)HNMRCT
MS/CDCl5, δ/pps+) 1.57-1.8
2 (5H, m) 2.38-2.48 (2H, m) 2.94 (2H, d, J=10Hz) 3.30
~3.45 (2H, m) 3.18 ~ 3.28 (2H, m) 6.88 (2H, t, J=8Hz) 6.06
(I H, t, J=6Hz) 7.21 (2H
, dd, J=6.6 Hz) 7.35 (2H,
dd, J=9.9 Hz) 7.40 (2H, d
, J-6Hz) 8.08 (2H, dd, J
= 10.81 (z) 8.63 (IH, s) Example 2 Evaluation of antiarrhythmic effect The test compound was intraperitoneally administered to three mice, and 30 minutes later, the mice were anesthetized with chloroform and the induced arrhythmia was measured.

Example 1 100 Example 1 50 Example 1 25 Lidocaine 25 0/3 1/3 2/3 2/3 Example 3 Evaluation of serotonin antagonism (SD male and female rats weighing around 300 g, 8-12 weeks old)
After the patient was beaten to death, the abdomen was opened and the thoracic aorta was removed.

This was cut into 2.5 cm pieces and kept warm at 37°C.
Suspend it in a Magnus tube containing 20mf of Linger solution9
Vent with 5% oxygen + 5% carbon dioxide. The specimens were connected to an isotropic transducer and recorded under Ig loading.

From the dose-response curve of serotonin to the test compound, pA
Two values were calculated.

Effects of the Invention From the above results, it is understood that the compound of the present invention has antiarrhythmic action and serotonin antagonistic action and can be used as a characteristic antiarrhythmic drug.

Claims (3)

[Claims] (1) Structural formula below ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ A piperidine derivative represented by (2) Structural formula below ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ An antiarrhythmic drug containing a piperidine derivative represented by: (3) The antiarrhythmic drug according to claim 2, wherein the piperidine derivative is in the form of a pharmaceutically acceptable salt.