JP2584454B2 - 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 pharmacologically 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, is more likely to inhibit myocardium in terms of safety, and has arrhythmia due to conduction inhibition. Triggering 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. Or to resist a drug 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, R ² is a hydrogen atom,
A halogen atom, a lower alkyl group, a lower alkoxy group or a hydroxyl group] In the definition of the general formula (I), the lower alkyl group found in R ¹ and R ² is a straight or branched chain having 1 to 6 carbon atoms. Alkyl groups such as methyl, ethyl, n-propyl, n
- butyl, isopropyl, isobutyl, 1-methylpropyl, tert- butyl, means n- pentyl, 1-ethylpropyl, isoamyl, and n- hexyl group, further R ²
The lower alkoxy group found in the above means all lower alkoxy groups derived from the above lower alkyl group, the most preferred groups are methyl group, ethyl group,
A methoxy group and an ethoxy group.

Further, the halogen atom found in R ² means a chlorine atom, a bromine atom, an iodine atom, a fluorine atom and the like.

Pharmaceutically acceptable salts specifically include addition salts of inorganic acids such as hydrochloride, sulfate, hydrobromide, perchlorate, hydroiodide hydrochloride, oxalate, maleate , Fumarate, succinate, methanesulfonate and the like.

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.

First Step This step is a step of reducing a known ketone derivative (II) to obtain a corresponding alcohol derivative (III).

According to a conventional method, for example, using a reducing agent such as sodium borohydride or sodium cyanoborohydride, in a solvent such as methanol, ethanol or propanol, -20.
The compound (III) can be obtained by reacting at a temperature of from C to room temperature.

Second step In this step, the halogenated compound (III) such as the bromo compound obtained in the first step is aminoalkylated by reacting it with a piperidine derivative (IV) obtained by a known method or a known method. This is the step of obtaining (I).

According to a conventional method, for example, a compound (IV) is converted to a lower alkyl alcohol such as dimethylformamide, dimethyl sulfoxide, methanol, ethanol, or propanol;
Reaction with the halogenated compound represented by formula (III) at a reaction temperature of about 50 to 120 ° C. in a solvent such as acetone in the presence of a base gives compound (I) as a target substance. In this case, examples of the base include potassium carbonate, sodium carbonate, sodium bicarbonate, sodium ethoxide, sodium methoxide, and sodium hydride.

The piperidine derivative obtained by the present invention does not affect the conduction velocity of the myocardium, has a property of prolonging the refractory period by specifically prolonging the action potential and suppressing arrhythmia, It is a class III antiarrhythmic agent in the Williams classification.

Hereinafter, specific experimental examples will be 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% oxygen and 5% carbon dioxide was saturated. The papillary muscle was electrically stimulated under the stimulation conditions of 1 Hz, 1 msec. 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: Compound of Example 1 N- [4- [2-hydroxy-1- [4- (4-fluorobenzoyl) piperidyl} ethyl] phenyl] methanesulfonamide hydrochloride Compound B: Compound of Example 4 N- [4- [2-hydroxy-1- {4- (4-chlorobenzoyl) piperidyl} ethyl] phenyl] methanesulfonamide The above examples have revealed that the compounds of the present invention have excellent antiarrhythmic activity.

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 0.01 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, excipients are added to the active ingredient, and if necessary, a binder, a disintegrant, a lubricant, a coloring agent,
After adding a flavoring agent and the like, tablets, coated tablets, granules, powders, capsules and the like are prepared in a usual manner.

As excipients, for example, lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose, silicon dioxide, etc., as binders, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, Hydroxypropyl cellulose, hydroxypropyl starch, polyvinylpyrrolidone, etc., as disintegrants, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin, pectin, etc., as lubricants For example, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oils and the like are those that are permitted to be added to pharmaceuticals as coloring agents, but as flavoring agents Include cocoa powder, menthol, aromatic acid, peppermint oil, borneol, cinnamon powder and the like are used. Of course, these tablets and granules may be sugar-coated, gelatin-coated and optionally coated as needed.

When preparing an injection, a pH adjusting agent, 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 Synthesis of N- [4- [2-hydroxy-1- [4- (4-fluorobenzoyl) piperidyl] ethyl] phenyl] methanesulfonamide hydrochloride (1) N- [4- (2-bromo) -1-hydroxyethyl) phenyl] methanesulfonamide N- [4- (2-bromoacetyl) phenyl] methanesulfonamide (20.0 g, 61.0 mmol) was added to methanol 240
suspended in 20 ml and cooled to -20 ° C, sodium borohydride
2.84 g are added in three portions at 5 minute intervals. The mixture is -20
After stirring at 2 ° C for 2 hours, concentrated hydrochloric acid was added dropwise to make it acidic,
Add 300 ml and 500 ml of chloroform and extract with chloroform. The residue solid obtained by concentrating the organic layer is recrystallized from ether to give 16.4 g (82% yield) of the title compound as white crystals.

Melting point (° C); 91-93 ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 2.96 (3H, s), 3.61 (2H, m), 4.75 (1H, q like, J = 7H)
z), 5.78 (1H, d, J = 5Hz), 7.15 (2H, d, J = 8Hz), 7.35
(2H, d, J = 8Hz), 9.70 (1H, brs) (2) N- [4- [2-hydroxy-1- [4- (4
-Fluorobenzoyl) piperidyl] ethyl] phenyl] methanesulfonamide hydrochloride 4- (4-fluorobenzoyl) piperidine hydrochloride
After stirring a solution of 4.00 g (16.4 mmol) and 11.3 g (81.9 mmol) of potassium carbonate in 100 ml of dimethylformamide for 30 minutes at room temperature, the N- [4- (2-bromo-1-hydroxyethyl) obtained in (1) was stirred. ) Phenyl) methanesulfonamide (4.82 g, 16.4 mmol) and potassium iodide 2.7
Add 2 g (16.4 mmol) and stir at 90 ° C. for 3 hours. The mixture is filtered, and the residue obtained by concentrating the filtrate is purified by silica gel column chromatography (chloroform: methanol = 97: 3). The desired fraction was concentrated, an excess hydrochloric acid-ethanol solution was added to the residue, and the residue was recrystallized from ethanol 2-propanol to give the title compound 2.
41 g are obtained as white crystals.

Melting point (° C.); 199-202 MASS; m / e 389 (M ⁺ −H ₂ O) Elemental analysis value: C N N as C ₂₁ H ₂₅ FN ₂ O ₄ S · HCl Theoretical value (%) 55.20 5.73 6.13 Actual measurement Value (%) 55.22 5.97 5.94 ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 1.70 to 2.40 (4H, m), 2.60 to 3.50 (8H, m), 3.04 (3H,
s), 7.10 to 7.70 (6H, m), 8.00 (2H, m) Examples 2 to 5 The appropriate compound (I
The compounds shown in Table I were obtained using V).

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Tadao Shoji 57-7 Hoyodai, Kusazaki-cho, Inashiki-gun, Ibaraki Pref. 2-1-1 Nishi, Toride-shi, Prefecture Toride Central 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, R ² is a hydrogen atom,
A halogen atom, a lower alkyl group, a lower alkoxy group or a hydroxyl group] and a pharmaceutically acceptable salt thereof. 2. The following general formula: Wherein R ¹ represents a lower alkyl group, R ² is a hydrogen atom,
A halogen atom, a lower alkyl group, a lower alkoxy group or a hydroxyl group] and a pharmacologically acceptable salt thereof as an active ingredient.