JP2637989B2 - Piperidine derivative and arrhythmia therapeutic / prophylactic agent containing the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to a piperidine derivative having excellent action as a medicament, a pharmaceutically acceptable salt thereof, a method for producing the same, and a medicament containing the same.

2. Prior Art Arrhythmia occurs with heart diseases such as myocardial infarction and heart failure, and in severe cases, induces ventricular fibrillation to cause sudden death.

At present, various antiarrhythmic agents are on the market, but none are satisfactory in both efficacy and safety. For example, a class I antiarrhythmic agent in the Vaughan- / Williams classification is not sufficiently effective in preventing ventricular fibrillation, and is more susceptible to myocardial suppression in terms of safety, and furthermore, due to conduction inhibition. The induction of arrhythmias is a problem. Other β-blockers and calcium antagonists have also been used, but these have higher safety than class I antiarrhythmic drugs, but their effects are uncertain.

On the other hand, class III antiarrhythmic drugs (prolonging action potential duration) have no myocardial suppression due to their mechanism of action, and have a small inhibitory effect on intracardiac conduction. Therefore, development of an antiarrhythmic agent classified into this class III is expected.

An object of the present invention is to provide a novel piperidine derivative and a pharmaceutically acceptable salt thereof, and further to provide a method for producing the derivative or a salt thereof, and further provide a derivative thereof. Another object of the present invention is to provide a medicine containing a salt thereof as an active ingredient.

Structure and Effect of the Invention The object compound of the present invention is a piperidine derivative represented by the following general formula (I) and a pharmaceutically acceptable salt thereof.

[Wherein, R ¹ represents a lower alkyl group, X is a group represented by the formula -S-, A group represented by or a formula Means a group represented by

R ² is a hydrogen atom or a formula — (CH ₂ ) _n —Y (wherein n represents an integer of 1 to 5, and Y represents an aryl group or a substituted or unsubstituted pyridyl group). Group. In the definition of the compound of the present invention, the lower alkyl group found in R ¹ is a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, n-butyl, isopropyl, It means isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl, n-hexyl group, etc., most preferably a methyl group.

X is a group represented by the formula -S-, A group represented by or a formula Means a group represented by

In the definition of R ² , n means an integer of 1 to 5,
Preferred examples include a case where n = 1 or an integer of 2 is meant.

In the definition of Y, when the aryl group is preferably a phenyl group, the phenyl ring is preferably a lower alkyl group of 1 to 6 shown above, a lower alkoxy group derived from the lower alkyl group, or a halogen atom. It may be substituted. These phenyl group substituents may be substituted with 1 to 3 identical or different phenyl groups. Therefore, preferred examples are the case of a substituted or unsubstituted phenethyl group or benzyl group. Specifically, when Y is a pyridyl group, (Wherein, R ³ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a cyano group, a hydroxyl group, or a halogen atom). At this time, the most preferred examples, may be mentioned as R ² pyridylmethyl group, pyridylethyl group, or a pyridine ring methyl pyridylmethyl group substituted with a methyl group, and methyl pyridyl ethyl.

The pharmacologically acceptable salts specifically include addition salts of inorganic acids such as hydrochloride, sulfate, hydrobromide, perchlorate, hydroiodide, oxalate, and maleic acid Salts, addition salts of organic acids such as fumarate, succinate, methanesulfonate and the like can be mentioned.

The object compound (I) of the present invention or a pharmacologically acceptable salt thereof has excellent antiarrhythmic activity and high safety. Therefore, it is useful as an antiarrhythmic agent. It can also be expected to be effective against intractable arrhythmias.

Production Method There are various methods for producing the compound (I) of the present invention, and a typical method is as follows.

In the following, not only the final step for obtaining the target substance, but also methods for producing from the starting compound before that are listed for easy understanding.

When production method AX is a group represented by -S- Step 1 This step is a step of alkylsulfonylating the aniline derivative (II).

As usual, in the presence of a base such as pyridine and triethylamine, in an inert solvent such as DMF, acetonitrile, benzene, dichloromethane, chloroform, tetrahydrofuran, and dioxane, an alkylsulfonyl chloride such as an alkylsulfonylating agent and an alkylsulfonic acid anhydride are used. By reacting at 20 ° C. to room temperature, an alkylsulfonylanilide compound (III) is obtained.

Second step This step is a step of reductively cleaving the SS bond of the alkylsulfonylanilide derivative (III) obtained in the first step.

As usual, it can be obtained by reduction with a metal such as zinc or tin and an acid, reduction with lithium aluminum hydride, sodium borohydride, or reduction in triphenylphosphine and aqueous alcohol or aqueous dioxane.
Preferably triphenylphosphine, acidic aqueous methanol in the presence of EDTA, aqueous methanol in the presence of 1N-HCl,
The thiol derivative (IV) can be obtained by reacting at 0 ° C. to reflux temperature in aqueous dioxane.

Third Step The present invention is a step of coupling the thiol derivative (IV) obtained in the second step with the piperidine derivative (V).

For example, piperidine derivative (V) in an inert solvent such as DMF, DMSO, acetonitrile, benzene, dioxane, and tetrahydrofuran in the presence of a base such as sodium hydrogen carbonate, potassium carbonate, pyridine, and triethylamine.
And an alkylation reaction at room temperature to 100 ° C. to give the corresponding sulfide derivative (VI).

Fourth step This step is the sulfide derivative (VI) obtained in the third step
Is a step of hydrolyzing the amide group of

For example, the reaction is performed in a dilute alkaline aqueous solution or a dilute mineral acid aqueous solution. Preferred examples include, in 2-6N hydrochloric acid,
Alternatively, the amine derivative (VII) is obtained by hydrolysis in a 0.5 to 3N aqueous sodium hydroxide solution at room temperature to reflux temperature.

Fifth Step (1) In the formula (I), N-alkylation of the compound (VII) when n = 0 and Y = H, the compound (VII) produced in the fourth step and the compound (VII)
I) is subjected to a condensation reaction by a conventional method.

One of the preferred methods is as follows: N, N-dimethylformamide, dimethylsulfoxide in the presence of a deoxidizing agent such as potassium carbonate or sodium carbonate and potassium iodide (but not necessary when Z is iodine). The reaction is performed at a temperature of about 50 to 120 ° C. in a solvent such as side, acetonitrile, acetone, butanol, propanol, ethanol, and 6 ethanol to obtain compound (IX).

(2) In the definition of R ² , n is 2 and Y is a formula (In the formula, R ³ has the above-mentioned meaning), it can also be produced by the following method.

That is, the above-mentioned reaction formula is specifically shown as follows to facilitate understanding.

That is, unsubstituted or substituted vinylpyridine (X),
The compound (free base) obtained in the fourth step (VI)
I) or a pharmacologically acceptable acid addition salt thereof in a lower alkyl alcohol such as methanol, ethanol or propanol alone or in a mixed solvent with water at room temperature to about
The reaction is performed at a temperature of 100 ° C. to obtain a compound (XI) which is one of the target substances. In this case, when a free base is used as a starting material, it is preferable to use an acidic catalyst such as acetic acid or hydrochloric acid or an alkali metal catalyst such as sodium.

Manufacturing method B X is the formula Method (1) Method (2) Sixth Step This step is the sulfide derivative (IX) obtained in the fifth step
Is a step of oxidizing to obtain a sulfoxide derivative (XII).

The oxidation may be carried out in a conventional manner. For example, compound (IX) may be dissolved in a solution of methanol, ethanol, 2-propanol, water or the like in the presence of excess mineral acid such as hydrochloric acid in the presence of sodium periodate, hydrogen peroxide or peroxide. It is oxidized with an oxidizing agent such as acetic acid or m-chloroperbenzoic acid. The reaction is preferably performed in water-containing methanol at 0 ° C. to room temperature in the presence of excess hydrochloric acid.

Seventh step This step is the sulfide derivative (VI) obtained in the third step
Is a step of oxidizing to obtain a sulfoxide derivative (XIII).

For example, the target substance (XII
I) can be obtained, but in this case no excess acid is required.

Eighth step This is a step of hydrolyzing the compound (XIII) obtained in the seventh step. For example, the compound (XIV) which is one of the target substances of the present invention can be obtained by a method similar to the fourth step. .

Ninth step This is a step of alkylating the compound (XIV) obtained in the eighth step. For example, the compound (XII) which is one of the target substances of the present invention can be obtained by a method similar to the fifth step. .

Manufacturing method C X is the formula For a group represented by Tenth step This is a step of oxidizing the sulfide derivative (VI) obtained in the third step to obtain a sulfone derivative (XV).

For example, using a peracid such as hydrogen peroxide, peracetic acid, or m-chlorobenzoic acid, or an oxidizing agent such as sodium periodate, in a solvent such as methanol, ethanol, propanol, dichloromethane, or chloroform at room temperature to reflux temperature. Let me know. The reaction is preferably carried out in chloroform or dichloromethane at 0 ° C. to room temperature in the presence of 2 equivalents or more of m-chlorobenzoic acid.

Eleventh Step This step is a step of hydrolyzing the sialic group of the sulfone derivative (XV) obtained in the tenth step to obtain an amine derivative (XVI).

For example, the target substance (XV
I) can be obtained.

Twelfth Step This step is a step of N-alkylating the amine derivative (XVI) obtained in the eleventh step. For example, a compound ( XVII) can be obtained.

The piperidine derivative obtained by the present invention has the property of prolonging the refractory period by specifically elongating the action potential without inhibiting the conduction velocity of the heart muscle, thereby suppressing arrhythmia, -Located in the class III mineral arrhythmia in the Williams classification.

Hereinafter, experimental examples will be specifically described to explain the effects of the compounds of the present invention.

Pharmacological experiment example Experimental example 1 Action potential elongation action in isolated guinea pig myocardium The right ventricular papillary muscle of a Hartley guinea pig (male 300 to 400 g) was extracted and fixed to the bottom of an acrylic thermostat with a pin.
Perfused with Tyrode's solution at 37 ° C. 95 for Tyrodes liquid
A mixed gas of 5% oxygen and 5% oxygen gas was saturated. The papillary muscle was electrically stimulated and driven under the stimulation conditions of 1 Hz, 1 msec, and maximum stimulation. Using a glass microelectrode filled with 3MKcl to record the action potential and measure the action potential duration (APD ₉₀ )
The maximum rise speed (V _max ) was measured using a differentiator. Each test compound was dissolved in Tyrode's solution at a concentration of 10 ⁻⁶ M and 10 ⁻⁵ M and perfused.

After observing the effect of the test compound at a concentration of 10 ⁻⁶ M for 10 minutes, the concentration was switched to 10 ⁻⁵ M, and observation was performed for another 10 minutes.

 Table 1 shows the results.

 Test compounds in Table 1 are as follows.

As a control compound, sotalol, which is currently used as a β-blocker and has an action to extend the duration of myocardial action potential, was selected.

Compound A: 4- (4-methylsulfonylaminophenylthio) -1- [2- (3-pyridyl) ethyl] piperidine Compound B: 4- (4-methylsulfonylaminophenylsulfinyl) -1- [2- (3-pyridyl) ethyl] piperidine The above experimental examples revealed that the compound of the present invention has an excellent antiarrhythmic effect.

Separately, an acute toxicity test was conducted on a representative compound of the compound of the present invention (the above compounds (A, B), and a male ddy mouse (body weight)
20-30 g), and performed by intravenous administration,
In each case, the LD ₅₀ value was 180 to 400 mg / kg.

Therefore, the compound of the present invention is expected to be effective as a class III antiarrhythmic agent for the treatment and prevention of all types of arrhythmias such as ventricular arrhythmias and atrial (supraventricular) arrhythmias. It can be used advantageously to control recurrent arrhythmias in humans and to prevent sudden death from ventricular fibrillation.

When the compound of the present invention is used as an antiarrhythmic agent,
It is administered orally or parenterally (intramuscularly, subcutaneously intravenously). Dosage may vary depending on disease, severity of symptoms,
It depends on the patient's age, health condition, body weight, type of simultaneous treatment, if any, type of treatment, nature of desired effect, etc., and is not particularly limited.
g to 100 mg, preferably about 5 mg to 50 mg, more preferably about 5 mg
About 15 mg is administered once or more times a day. In the case of an injection, about 00.1 mg / kg to 1 mg / kg,
Preferably it is about 0.03 mg / kg to 0.1 mg / kg.

Examples of the dosage form include powders, fine granules, granules, tablets, capsules, suppositories, injections and the like. At the time of formulation, it is manufactured by an ordinary method using a usual formulation carrier.

That is, when preparing a solid preparation for oral use, an excipient and, if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent and a flavoring agent are added to the main drug, and then tablets and coated by a conventional method. Tablets, granules, powders, capsules, etc.

As an excipient, for example, lactose, corn starch, sucrose, glucose, sorbite, crystalline cellulose, silicon dioxide, and the like, as a binder, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, Hydroxypropyl cellulose, hydroxypropyl starch, polyvinylpyrrolidone and the like, as disintegrants, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogencarbonate, calcium citrate, dextrin, pectin, etc., lubricants As, for example, magnesium stearate, talc,
Polyethylene glycol, silica, hydrogenated vegetable oils, etc. are permitted to be added to pharmaceuticals as coloring agents, but as flavoring agents, cocoa powder, peppermint brain, aromatic acid, peppermint oil, dragon brain, cinnamon powder, etc. Is used. Of course, these tablets and granules may be sugar-coated, gelatin-coated and optionally coated as needed.

When preparing an injection, a pH adjuster, a buffer, a stabilizing agent, a solubilizing agent, and the like are added to the main drug, if necessary, to give an intravenous injection according to a conventional method.

Next, examples of the present invention will be described. Needless to say, the present invention is not limited to these examples.

Example 1 (1) Synthesis of N-benzoyl-4-hydroxypiperidine To a solution of 4-hydroxypiperidine (50.0 g, 495 mmol) and pyridine (260 ml) in dichloromethane (260 ml), a solution of benzoyl chloride (73.1 g, 520 mmol) in dichloromethane (70 ml) is added dropwise at 0 to 15 ° C. The mixture was stirred at room temperature for 3 hours,
The precipitated white crystals (pyridine / hydrochloride) are filtered off. The filtrate is concentrated, and the residual oil is purified by silica gel column chromatography (CHCl ₃ : CH ₃ OH = 95: 5) to obtain 79.8 g (yield 79%) of the title compound. ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.20 to 2,05 (4H, m), 2.80 to 4.30 (4H, m), 3,82 (1H, sep
tet like, J = 4Hz), 7.24 (5H, s) (2) Synthesis of N-benzoyl-4-piperidine-methanesulfonate 79.8 g (389 mmol) of N-benzoyl-4-hydroxypiperidine obtained in (1), 47.2 of triethylamine
-10 ° C in a solution of g (467 mmol) in 600 ml of dichloromethane
53.7 g of methylsulfonyl chloride (4
(67 mmol) in 30 ml of dichloromethane are added dropwise. After stirring the mixture at room temperature for 3 hours, it is washed with water and saturated saline. By concentrating the organic layer, 102.2 g of the title compound was obtained.
(98% yield) is obtained as a colorless oil. ^{1 H-NMR (90MHz, CDCl} 3) δ; 1.60~2.20 (4H, m), 3.02 (3H, s), 3.20~4.00 (4H,
m), 4.91 (1H, m), 7.33 (5H, s) (3) Synthesis of N-benzoyl-4-bromo-piperidine To a solution of 34.5 g (112 mmol) of N-benzoyl-4-piperidine methanesulfonate obtained in (2) in 100 ml of dimethylformamide (DMF), 13.8 g of lithium bromide was added.
(159 mmol) in 150 ml of dimethylformamide are added and stirred at 90 ° C. for 6 hours. The mixture is concentrated, water is added to the residue and extracted with ethyl acetate. The organic layer is concentrated, and the residue is purified by silica gel column chromatography to give 16.5 g (yield 50%) of the title compound as a light brown oil. ^{1 H-NMR (90MHz, CDCl} 3) δ; 1.80~2.36 (4H, m), 3.28~4.20 (4H, m), 4.41 (1H,
m), 7.36 (5H, s) (4) Synthesis of 4-methanesulfonylaminophenyl disulfide To a solution of 20.0 g (80.7 mmol) of 4-aminophenyl disulfide and 40 ml of pyridine in 160 ml of chloroform, a solution of 22.8 g (199 mmol) of methylsulfonyl chloride in 40 ml of chloroform is added dropwise at -10 ° C to 0 ° C. Mixture at 0 ° C
After stirring for 2 hours, add 80 ml of water and stir vigorously. The precipitated crystals are collected by filtration as pale red crystals to give the title compound.
32.2 g (yield 995) are obtained.

Melting point (° C); 211-212 ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 2.98 (6H, s), 7.10 (4H, d, J = 8 Hz), 7.40 (4H, d, J = 8H)
z) (5) Synthesis of 4-methylsulfonylaminothiophenol 41.0 g (102 mmol) of 4-methanesulfonylaminophenyl disulfide obtained in (4), 3.83 g (13.1 mmol) of ethylenediaminetetraacetic acid (EDTA), 1N hydrochloric acid 2
52.9 g (203 mmol) of triphenylphosphine is added to a mixed solution of 400 ml of 0 ml of dioxane and 400 ml of water, and the mixture is stirred at room temperature for 12 hours. The mixture was extracted with ethyl acetate and the organic layer was extracted with 1
The pH is adjusted to about 11 by adding a normal aqueous sodium hydroxide solution, and the mixture is extracted with water. After washing the aqueous layer with a small amount of ether, 1N hydrochloric acid is added at 0 ° C. to adjust the pH to about 3. The precipitated white crystals are collected by filtration to give 40.7 g (yield 99%) of the title compound.

Mp ^{(℃); 181~182 1 H-} NMR (90MHz, DMSO-d 6) δ; 2.98 (3H, s), 7.09 (2H, d, J = 8Hz), 7,39 (2H, d, J = 8H
z) (6) Synthesis of N-bezoyl-4- (4-methylsulfonylaminophenylthio) piperidine 5.60 g (27.6 mmol) of 4-methylsulfonylaminothiophenol obtained in (5), 7.61 g of potassium carbonate
(55.2 mmol) in 100 ml of dimethylformamide
After stirring at room temperature for 0 minutes, 7.40 g (27,6 mmol) of N-benzoyl-4-bromopiperidine obtained in (3) and 9.22 g (55.2 mmol) of potassium iodide were added, and the mixture was added at 90 ° C.
And stir for 1 hour and 30 minutes. The mixture is filtered, and the residue obtained by concentrating the filtrate is purified by silica gel column chromatography (CHCl ₃ : CH ₃ OH = 98: 2). Concentration of the desired fraction gives 8.80 g (80% yield) of the title compound as white crystals.

Melting point (° C); 184-185 ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.40-2,10 (4H, m), 2.99 (3H, s), 2.90-4.10 (5H,
m), 7.22 (2H, d, J = 8 Hz), 7.36 (5H, s), 7.36 (2H, d, J
= 8Hz) (7) Synthesis of 4- (4-methylsulfonylaminophenylthio) piperidine hydrochloride 8.60 g of N-benzoyl-4- (4-methylsulfonylaminophenylthio) piperidine obtained in (6) (21,
5 mmol) of 88 ml of 1N aqueous sodium hydroxide solution
Reflux for hours. After cooling the reaction solution, 120 ml of 1N hydrochloric acid was added to make the solution acidic, whereby white crystals were precipitated. The crystals were collected by filtration and washed with ethanol to give the title compound (6.11 g, yield 8).
8%).

MASS; (FAB) 287 (MH ⁺ ) Elemental analysis; CHN Theoretical (%) 44.69 5.94 8.69 Actual (%) 44.69 5.76 8.67 ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 1.60-2.20 (4H, m), 2.70 ~ 3.50 (5H, m), 3.00 (3H,
s), 7.17 (2H, d, J = 8 Hz), 7.40 (2H, d, J = 8 Hz), 9.40
(2H, br) (8) Synthesis of 4- (4-methylsulfonylaminophenylthio) -1- [2- (3-pyridyl) ethyl] piperidine A solution of 4- (4-methylsulfonylaminophenylthio) piperidine hydrochloride (4.00 g, 12.4 mmol) obtained in (7) and sodium hydrogencarbonate 4.17 g (49.6 mmol) in 40 ml of dimethylformamide was stirred at 85 ° C. for 40 minutes. After that, 4.12 g (24.8 mmol) of potassium iodide and 2.43 g (13.6 mmol) of 2- (3-pyridyl) ethyl chloride hydrochloride obtained by a conventional method are further added, and the mixture is stirred at 85 ° C for 1 hour and 30 minutes. The reaction mixture is collected by filtration, and the residue obtained by concentrating the filtrate is purified by silica gel column chromatography (CHCl ₃ : CH ₃ OH: NH ₄ OH = 97: 3: 0.3). The residue solid obtained by concentrating the desired fraction is recrystallized from ethyl acetate to give 1.82 g (yield 38%) of the title compound as white crystals.

Melting point (° C); 126-129 MASS; m / e (EI) 391 (M ⁺ ), 299 (base), 97 Elemental analysis; C ₁₉ H ₂₅ N ₃ O ₂ S ₂ .0.5H ₂ O as CH N Theoretical value (%) 56.97 6.54 10.49 Actual value (%) 56.97 6.40 10.40 ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.50 to 2.40 (4H, m), 2.40 to 3.20 (5H.m), 3.03 (3H ,
s), 7.08 to 7.24 (3H, m), 7.40 (2H, d, J = 8 Hz), 7.52 (1
H, brd, J = 8Hz), 8.44 (2H, m) Example 21 1- [2- (3,4-dimethoxyphenyl) ethyl] -4
-(4-methylsulfonylaminophenylthio) piperidine According to the methods (1) to (8) of Example 1, 2- (3-
Pyridyl) ethyl chloride instead of hydrochloride 3,4-
The same treatment was performed using dimethoxyphenethyl chloride to obtain the title compound.

Melting point (° C.); 104-106 MASS; (FD) 450 (M ⁺ ), 372,203 Elemental analysis; CH N as C ₂₂ H ₃₀ N ₂ O ₄ S ₂ Theoretical value (%) 55.64 6.71 6.22 Actual value (%) 58.87 6.69 6.16 ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.50 to 2.30 (4H, m), 2.40 to 3.20 (9H, m), 3.01 (3H,
s), 3.84 (6H, s), 6.74 (3H, m), 7,13 (2H, d, J = 8Hz),
7.40 (2H, d, J = 8 Hz) Example 3 4- (4-methylsulfonylaminophenylsulfinyl) -1- [2- (3-pyridyl) ethyl] piperidine 0.50 g (1.28 mmol) of 4- (4-methylsulfonylaminophenylthio) -1- [2- (3-pyridyl) ethyl] piperidine obtained in Example 1 and 0.33 g (1.53 mmol) of sodium periodate were used. 1N hydrochloric acid aqueous solution 5ml
And 5 ml of methanol are stirred at room temperature for 1 hour.
The pH is adjusted to about 7 by adding about 5 ml of 1N sodium hydroxide, and extracted with chloroform. The organic layer is concentrated and the residue is purified by silica gel column chromatography (CHCl ₃ :
_{CH 3 OH: NH 4 OH =} 95: 5: 0.5). Concentrate the desired fraction and recrystallize the residual solid with ethyl acetate to give the title compound.
0.34 g (64% yield) is obtained.

Melting point (° C.); 158 to 159 MASS; m / e (FAB) 408 (MH ⁺ ), 392 Elemental analysis; C N as C ₁₉ H ₂₅ N ₃ O ₂ S ₂ Theoretical value (%) 56.00 6.18 10.31 Actual measurement Value (%) 55.98 6.18 10.27 ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.56 to 2.30 (6H, m), 2.40 to 3.20 (7H, m), 3.07 (3H,
s), 7.40 (1H, dd, J = 8 Hz, 5 Hz), 7.30 to 7.68 (5H, m), 8.
44 (2H, m) Example 4 1- [2- (3,4-dimethoxyphenyl) ethyl] -4
-(4-methylsulfonylaminophenylsulfinyl) piperidine According to the method of Example 3, the same treatment was carried out using 1- [2- (3,4-dimethoxyphenyl) ethyl] -4- (4-methylsulfonylaminophenylthio) piperidine,
The title compound was obtained.

Melting point (° C.); 128-130 MASS; m / e (FAB) 467 (MH ⁺ ), 451,248 Elemental analysis; CH N as C ₂₂ H ₃₀ N ₂ O ₅ S ₂ Theoretical value (%) 56.63 6.48 6.00 Actual measurement Value (%) 56.75 6.46 5.98 ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.58 to 2.30 (6H, m), 2.45 to 3.20 (7H, m), 3.07 (3H,
s), 3.84 (6H, s), 6.72 (3H, m), 7.34 (2H, d, J = 8Hz),
7.58 (2H, d, J = 8 Hz) Example 5 4- (4-methylsulfonylaminophenylsulfonyl) piperidine.hydrochloride (1) 1-benzoyl-4- (4-methylsulfonylaminophenylsulfonyl) piperidine 7.00 g of 1-benzoyl-4- (4-methylsulfonylaminophenylthio) piperidine obtained by the method of Example 1- (6) ( (17.5 mmol) in 100 ml of dichloromethane was added 8.18 g (40.3 mmol) of metachloroperbenzoic acid little by little, and the mixture was stirred at room temperature for 1 hour. 20 ml of a 10% aqueous solution of sodium thiosulfate is added and stirred. The precipitated crystals are collected by filtration and washed with water to give the title compound as white crystals.

(2) 4- (4-methylsulfonylaminophenylsulfonyl) pipenidine hydrochloride Example 1 was prepared using 1-benzoyl-4- (4-methylsulfonylaminophenylsulfonyl) piperidine obtained in (1). The title compound was obtained as white crystals by treating in the same manner as in the method shown in (7).

Melting point (° C.); about 273 (decomposition) MASS; m / e (FAB) 319 (MH ⁺ ), 277,201 (base) Elemental analysis value; C H N theoretical value as C ₁₂ H ₁₈ N ₂ O ₄ S ₂ .CH1 (%) 40.65 5.40 7.90 Actual value (%) 40.62 5.27 7.86 ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 1.40 to 2.20 (4H, m), 2.60 to 3.70 (5H, m), 3.18 (3H,
s), 7.42 (2H, d, J = 8 Hz), 7.76 (2H, d, J = 8 Hz), 9.70
(2H, br) Example 6 1- [2- (6-Methyl-2-pyridyl) ethyl] -4
-(4-methylsulfonylaminophenylsulfonyl)
Piperidine 0.60 g of 4-4 (4-methylsulfonylaminophenylsulfonyl) piperidine.hydrochloride obtained in Example 5
(1.86 mmol), 6-methyl-2-vinylpyridine 0.
44 g (3.72 mmol) and 0.31 g of sodium acetate are suspended in 10 ml of methanol-water (1: 1) and refluxed for 2 hours. After filtration of the reaction solution, the residue obtained by concentrating the filtrate is extracted with dichloromethane and washed with water. When the organic layer is concentrated, white crystals precipitate. The crystals are collected by filtration and recrystallized from ethyl acetate to give 0.52 g (64% yield) of the title compound.

Melting point (° C.); 199-200 MASS; m / e (FAB) 438 (MH ⁺ ), 360, 311,277 Elemental analysis; C N N theoretical as C ₂₀ H ₂₇ N ₃ O ₄ S ₂ .0.5H ₂ (%) 53.79 6.32 9.41 Observed value (%) 53.79 5.95 9.33 ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 1.40 to 2.40 (6H, m), 2.40 to 3.50 (7H, m), 2.40 (3H,
s), 3.16 (3H, s), 7.03 (2H, d, J = 7 Hz), 7.40 (2H, d, J
= 8Hz), 7.54 (1H, t, J = 7Hz), 7.78 (2H, d, J = 8Hz) Example 7 1- [2- (2-chloro-4.5-dimethoxyphenyl)
Ethyl] -4- (4-methylsulfonylaminophenylsulfonyl) piperidine 0.54 g (1.20 mmol) of 1- [2- (3,4-dimethoxyphenyl) ethyl] -4- (4-methylsulfonylaminophenylthio) piperidine obtained in Example 2, 8
0.61 g (3.0 mmol) of metachloroperbenzoic acid is added to a mixture of 0.85 ml of normal hydrochloric acid ethanol and 15 ml of ethanol, and the mixture is stirred at room temperature for 1 hour. Sodium thiosulfate 10% aqueous solution
After adding 5 ml, the mixture is made alkaline by adding an aqueous solution of sodium hydrogen carbonate, and extracted with dichloromethane. The organic layer is concentrated, and the residue is purified by silica gel column chromatography. The desired fraction was concentrated, and the residue solid was recrystallized from ethyl acetate to give the title compound (0.34 g, yield 5).
5%) as white crystals.

Melting point (° C); 162-164 MASS; m / e (FD) 518 (MH ⁺ ) (FAB) 520 (12), 519 (46), 518 (28) 517 (M ⁺ , base) Elemental analysis; C _{22 H 29 ClN 2 O 6 S} 2 as C H N theoretical value (%) 51.10 5.65 5.42 Found ^{(%) 50.75 5.68 5.07 1 H} -NMR (90MHz, CDCl 3 -CD 3 OD) δ; 1.60~2.40 (6H , m), 2.40 ~ 4.20 (7H, m), 3.08 (3H,
s), 3.80 (6H, s), 6.66 (1H, s), 6.77 (1H, s), 7.32 (2
H, d, J = 8 Hz), 7.74 (2H, d, J = 8 Hz) Examples 8 to 9 According to the method described in Example 1- (8), 4- (4-methylsulfonylaminophenylthio) piperidine · hydrochloric acid. The same treatment was carried out using 4- (4-methylsulfonylaminophenylsulfonyl) piperidine.hydrochloride instead of the salt to obtain the following compound.

Example 8 4- (4-methylsulfonylaminophenylsulfonyl) -1- [2- (3-pyridyl) ethyl] piperidine Melting point (° C.); 169-171 MASS; m / e (FAB) 424 (MH ⁺ ), 311,277,201 (base) Elemental analysis; CH N as C ₁₉ H ₂₅ N ₃ O ₄ S ₂ Theoretical value (%) 53.88 5.95 9.92 Actual value (%) 53.93 5.79 9.87 ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 1.40 to 2.20 (4H, m), 2.40 to 3.40 (9H, m), 3.15 (3H,
s), 7.28 (1H, m), 7.38 (2H, d, J = 8 Hz), 7.61 (1H, dt, J
= 7Hz, 1Hz), 7.77 (2H, d, J = 8Hz), 8.37 (2H, m) Example 9 1- [2- (3,4-dimethoxyphenylinyl) ethyl]-
4- (4-methylsulfonylaminophenylsulfonyl) piperidine Melting point (° C.); 151-152 MASS; m / e (FAB) 483 (MH ⁺ ), 405,331,246 Elemental analysis; C N H as C ₂₂ H ₃₀ N ₃ O ₆ S ₂ Theoretical value (%) 54.75 6.27 5.80 Actual measurement Value (%) 54.78 6.22 5.77 ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 1.30 to 2.10 (4H, m), 2.20 to 3.30 (9H, m), 3.14 (3H,
s), 3.69 (6H, s), 6.57 to 6.79 (3H, m), 7.38 (2H, d, J =
8Hz), 7.77 (2H, d, J = 8Hz)

Continued on the front page (72) Inventor Tadao Shoji 57-7 Hoyodai, Kashizaki-cho, Inashiki-gun, Ibaraki Pref. Nishi 2-chome No. 1 Toride Chuo Town E-601 (72) Inventor Kenichi Nomoto 110-8 Arakawa-oki, Tsuchiura-shi, Ibaraki

Claims (2)

(57) [Claims] 1. The following general formula: [Wherein, R ¹ represents a lower alkyl group, X is a group represented by the formula -S-, A group represented by or a formula Means a group represented by R ² is a hydrogen atom or a formula — (CH ₂ ) _n —Y (where n is 1
And Y is an aryl group or a substituted or unsubstituted pyridyl group. ) Means a group represented by. ] The piperidine derivative represented by these, and its pharmacologically acceptable salt. 2. The following general formula: [Wherein, R ¹ represents a lower alkyl group, X is a group represented by the formula -S-, A group represented by or a formula Means a group represented by R ² is a hydrogen atom or a formula — (CH ₂ ) _n —Y (where n is 1
And Y is an aryl group or a substituted or unsubstituted pyridyl group. ) Means a group represented by. ] A therapeutic or prophylactic agent for arrhythmia, comprising a piperidine derivative represented by the following formula and a pharmacologically acceptable salt thereof as an active ingredient.