JPH0776208B2 - Piperidine derivatives and related derivatives - Google Patents

Description

Detailed Description of the Invention

[0001]

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

[0002]

2. Description of the Related Art Arrhythmias occur with heart diseases such as myocardial infarction and heart failure, and in severe cases, induce ventricular fibrillation and cause sudden death. Currently, various antiarrhythmic agents are on the market, but none of them are satisfactory in terms of both efficacy and safety.
For example, class I antiarrhythmic drugs in the Vaughan-Williams classification are not sufficiently effective in preventing ventricular fibrillation, and in terms of safety, myocardial suppression is likely to occur, and conduction arrhythmia Has been a problem. Other β-blockers and calcium antagonists are also used, but their safety is higher than that of class I antiarrhythmic agents, but their effects are uncertain. Meanwhile, class II
The antiarrhythmic drug of I (prolongs action potential duration) has no myocardial suppression due to its mechanism of action, and has little effect on suppressing cardiac conduction, so it induces less arrhythmia and also prevents ventricular fibrillation. Is also considered to be effective, and from this aspect, development of antiarrhythmic drugs classified into this class III is expected.

[0003]

OBJECT OF THE INVENTION It is an object of the present invention to provide a novel piperidine derivative, a derivative thereof and a pharmacologically acceptable salt thereof, and further to provide a process for producing the derivative or a salt thereof. Furthermore, it is to provide a medicine comprising a derivative or a salt thereof as an active ingredient.

[0004]

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

[0005]

[Chemical 35]

[In the formula, R ¹ represents a lower alkyl group or a tolyl group, R ² represents a hydrogen atom, a hydroxyl group, a lower alkoxy group or a lower alkyl group, and R ³ represents a hydrogen atom, a lower alkyl group, a lower group. It means an alkenyl group or a cycloalkylalkyl group. X is a group represented by the formula -CO-, a group represented by the formula -CH _2- , or

[0007]

[Chemical 36]

G means an integer of 1 or 2 and h means an integer of 2 or 3. Y is a hydrogen atom, a lower alkyl group,
A lower alkenyl group, a cyano group, a group represented by the formula -CH ₂ COOR (wherein R represents a hydrogen atom or a lower alkyl group),
Cycloalkylalkyl group,

[0009]

[Chemical 37]

A group represented by the formula (wherein m represents an integer of 2 or 3), or a formula-AB (wherein A is a formula- (CH ₂ ) _n- (wherein n is
Means an integer of 1 to 5), a group having 1 to 5 carbon atoms
1 or 2 constituting the linear alkylene group of 5
A divalent group obtained by removing one hydrogen atom from each carbon atom at both ends of a linear alkane in which a lower alkyl group, a phenyl group or a hydroxyl group is directly bonded to the above carbon atoms, a linear alkylene group having 2 to 5 carbon atoms. , A divalent group obtained by removing one hydrogen atom from each of the carbon atoms at both ends of a straight chain alkene having a double bond between any adjacent carbon atoms, a formula-(CH ₂ ) _k -S- ( In the formula, k means an integer of 2 to 5), or

[0011]

[Chemical 38]

[0012]

[Chemical Formula 39]

[0013]

[Chemical 40]

In the above definition, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ ,
The lower alkyl group found in R ⁷ , R ⁸ and A has 1 carbon atom.
6 straight or branched alkyl groups such as methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, 1-methylpropyl, tert-butyl,
n-pentyl, 1-ethylpropyl, isoamyl, n-
It means hexyl and the like, and the lower alkoxy group found in R ² means all lower alkoxy groups derived from the above lower alkyl groups. In the structural formula of the present invention, g means an integer of 1 to 2 and h means an integer of 2 to 3, and typical examples thereof include a piperidine ring, a pyrrolidine ring and a homopiperidine ring.

In the definition of A, in the straight-chain alkylene group having 1 to 5 carbon atoms, a straight-chain alkane in which a lower alkyl group, a phenyl group or a hydroxyl group is directly bonded to one or more carbon atoms constituting A divalent group obtained by removing one hydrogen atom from each carbon atom at both ends is specifically a lower alkyl group such as a methyl group at the terminal carbon or other carbon atom,
A phenyl group or a divalent group in which one hydrogen atom is removed from each carbon atom at both ends of a straight chain alkane to which a hydroxyl group is directly bonded, and preferred examples are

[0016]

[Chemical 41]

And the like. Carbon number 2
In the straight-chain alkylene groups of to 5, a divalent group obtained by removing one hydrogen atom from each carbon atom at both ends of a straight-chain alkene having a double bond between any adjacent carbon atoms is Includes, for example, a group represented by the formula -CH ₂ -CH = CH-, the formula -CH ₂ -CH
₂ means a group represented by -CH = CH-.

The pharmacologically acceptable salt is, specifically, an addition salt of an inorganic acid such as hydrochloride, sulfate, hydrobromide, perchlorate or hydroiodide, an oxalate salt, Mention may be made of addition salts of organic acids such as maleate, fumarate, succinate and methanesulfonate.

The object compound (I) of the present invention or a pharmacologically acceptable salt thereof has excellent antiarrhythmic activity and high safety, and is therefore useful as an antiarrhythmic agent.
Effectiveness can also be expected for arrhythmias ineffective with other drugs and intractable arrhythmias.

[0020] Although are various for production method of the production method the present compound (I), is as follows Stated representative methods.

[0021]

[Chemical 42]

[0022]

[Chemical 43]

When the production method B R ³ is a lower alkyl group, a lower alkenyl group or a cycloalkylalkyl group, the target substance can also be produced by the following method.

[0024]

[Chemical 44]

[0025]

[Chemical formula 45]

[0026]

[Chemical formula 46]

The group represented by can be obtained by the following method. Compound (IV) above
Is directly reduced without going through the third step to give the following compound
(XII) can be obtained. The reduction method is the same as the above-mentioned fourth step.

[0028]

[Chemical 47]

Production Method D In the formula (I), when X is a group represented by the formula --CH _2- , it can also be obtained by the following method.

[0030]

[Chemical 48]

Production Method E In Production Method A, the target substance can be obtained in the third step. When Y in the formula (I) is a group represented by the following formula, the methods listed below are used. Can also be manufactured.

[0032]

[Chemical 49]

[0033]

[Chemical 50]

[0034]

[Chemical 51]

First step The sulfone anilide derivative (II) obtained by a known method or a known method is prepared, for example, from carbon disulfide, dichloromethane, chloroform, dichloroethane, nitrobenzene,
Or other inert solvent, aluminum chloride, tin chloride,
In the presence of a Lewis acid such as zinc chloride, the general formula

[0036]

[Chemical 52]

(In the formula, g and h have the above-mentioned meanings, and R'means a lower alkyl group or a phenyl group.) A reactive acid such as an acid halide of carboxylic acid or carboxylic acid anhydride. By subjecting the derivative to a Friedel-Crafts reaction by a conventional method, the corresponding anilide derivative (III) is obtained.

Second Step This step is a step of hydrolyzing the acyl group of the compound (III) obtained in the first step, and is carried out, for example, in a dilute aqueous alkaline solution or a dilute aqueous mineral acid solution. As a preferred example, it is carried out under reflux in 2 to 6N hydrochloric acid or in 0.5 to 3N sodium hydroxide aqueous solution.

In the definition of the third step Y, when Y is other than a hydrogen atom, that is, Y ¹ , the compound (IV) produced in the second step and, for example, Z
-A-B,

[0040]

[Chemical 53]

(Wherein Z represents a halogen atom such as chlorine, bromine, iodine, etc., a leaving group such as methanesulfonyloxy group, p-toluenesulfonyloxy group, etc., and A, B, m have the above-mentioned meanings) The compound Z-Y ¹ (V) represented is condensed by a conventional method. To describe one of the preferred methods, N, N-dimethylformamide, dimethylsulfoxide, in the presence of a deoxidizing agent such as potassium carbonate or sodium carbonate and potassium iodide (provided that Z is iodine is not necessary), About 50 in a solvent such as acetonitrile, acetone, butanol, propanol, ethanol, methanol, etc.
The compound (VI) is obtained by reacting at a temperature of 120 ° C.

Fourth to Sixth Steps In this step, the compound (VI) obtained in the third step is appropriately reduced by a conventional method to obtain the compounds (VII) and (VIII). Moreover, if the compound (IV) is directly reduced, Y =
It is also possible to obtain the compound (XIV) described below which is H 2.

(A ) Fourth step This is a step of reducing the compound (VI) obtained in the third step.
The reduction method is a conventional method, for example, compound (VI) in a solvent such as methanol, ethanol, 2-propanol, dimethylformamide, dimethyl sulfoxide, etc., at about -10 ℃.
By treatment with sodium borohydride, lithium borohydride, etc. at room temperature, the alcohol derivative (VII), which is one of the target substances of the present invention, can be obtained.

( B) Fifth step Aryl ketone body (VI) and 2 or more equivalents of trialkylsilane, preferably triethylsilane, are reacted in a large excess of trifluoroacetic acid at room temperature to 100 ° C. for several hours to several days. Then, the compound (VIII) is obtained. As the solvent, dichloroethane, carbon tetrachloride, chloroform, dichloromethane, acetonitrile and the like can be used.

( C) Sixth step The alcohol compound (VII) obtained in the fourth step is treated in the presence of an acid,
Compound (VIII) is preferably obtained by treating briefly in 20% sulfuric acid-acetic acid and subjecting the resulting dehydrated product to catalytic hydrogenation.
Can be obtained.

Seventh Step This step is a step such as N-alkylation of the compound (VI) ′ in the case of R ³ ═H in the formula (I). According to a conventional method, for example, compound (VI) 'is represented by (IX) in the presence of a base in a solvent such as dimethylformamide, dimethylsulfoxide, lower alkyl alcohol such as methanol, ethanol and propanol, and acetone. Compound (X), which is one of the target substances, is obtained by reacting with an alkyl halide at a reaction temperature of about 50 to 120 ° C. In this case, examples of the base include potassium carbonate, sodium carbonate, sodium bicarbonate, sodium ethoxide, sodium methoxide, sodium hydride and the like. If R ″ · Hal (IX) is used at 2 molar equivalents or more, when Y is H in formula (I), dialkylation, dilower alkenylation, or dicycloalkylalkylation is possible. The N-alkylation can be performed by the same treatment in the eighth step in the production method B.
The obtained compound (X) is reduced by the same method as described in steps 4 to 6 to obtain the compound (VI) which is one of the target substances.
I) 'and (VIII)' can be obtained.

In each of the ninth to eleventh steps , each reaction can be carried out in the same manner as in the above-mentioned fifth step (reduction), second step (hydrolysis) and third step.

Twelfth step This step is a step of converting secondary amine (XV) to Mannich.
In this step, the tertiary amine (XX) is synthesized by the reaction. Usually, compounds with active hydrogen, such as furans,
Using a pyrrole or a nitrogen-containing heterocyclic compound having a methyl group, a condensation reaction is caused by the action of formaldehyde or paraformaldehyde with an amine. As the reaction solvent, water, alcohol, etc. are preferably used, and the reaction is preferably carried out at room temperature to 100 ° C. under acidic conditions such as acetic acid and hydrochloric acid.

Thirteenth step In this step, the secondary amine (XV) is added to Mannich.
It is a step of alkylating by reaction. Basically, it can be synthesized by the same operation as in the 12th step, but as shown in this step, even if the secondary amine (XV) is not in the free form but in the form of the hydrochloride, it is one of the target compounds. Compound (XXIV) can be synthesized. The piperidine derivative produced by the above method can be converted into a pharmaceutically acceptable salt, if necessary, by a conventional method.

Next, representative compounds of the present invention will be listed, but the purpose thereof is to facilitate understanding of the present invention, and it is said that the present invention is not limited thereto. There is no end. The compounds are shown in free form.

1. 4- (4-methylsulfonylaminobenzoyl) piperidine 2.4- (4-methylsulfonylaminobenzoyl)-
1- [2- (2-thienyl) ethyl] piperidine 3. 4- (4-methylsulfonylaminobenzoyl)-
1- (2-Tenyl) piperidine 4.1- [6,7-dihydro-5H-7-cyclopenta (b)
Pyridinyl] methyl-4- (4-methylsulfonylaminobenzoyl) piperidine 5.4- (4-Methylsulfonylaminobenzoyl)-
1- (1-naphthyl) methylpiperidine 6. 4- (4-methylsulfonylaminobenzoyl)-
1- [2- (4-Methyl-5-thiazolyl) ethyl] piperidine 7. 1- (5-Methyl-2-furanyl) methyl-4-
(4-Methylsulfonylaminobenzoyl) piperidine 8. 1- (N-methyl-2-pyrrolyl) methyl-4-
(4-Methylsulfonylaminobenzoyl) piperidine 9. 1- [3- (1-imidazolyl) propyl] -4-
(4-Methylsulfonylaminobenzoyl) piperidine 10. 4- (4-Methylsulfonylaminobenzoyl)-
1- [2- (3-pyridazinyl) ethyl] piperidine 11. 4- (4-methylsulfonylaminobenzoyl)-
1- [2- (4-pyrimidinyl) -3-propenyl] piperidine 12. 4- (4-methylsulfonylaminobenzoyl)-
1-[(2-pyrazinyl) methyl] piperidine 13.4- (4-methylsulfonylaminobenzoyl)-
1- [2- (2-pyrazinyl) ethyl] piperidine 14.1- [2- (1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile-5-yl) -2-oxoethyl] -4- (4-Methylsulfonylaminobenzoyl) piperidine 15.4- (4-Methylsulfonylaminobenzoyl)-
1-[(6-uracil) methyl] piperidine 16.1- [2- (3-indolyl) ethyl] -4- (4
-Methylsulfonylaminobenzoyl) piperidine 17. 4- (4-methylsulfonylaminobenzoyl)-
1- (2-phthalimidoethyl) piperidine 18.4- (4-methylsulfonylaminobenzoyl)-
1-[(2-quinolyl) methyl] piperidine 19. 4- (4-methylsulfonylaminobenzoyl)-
1-[(3-quinolyl) methyl] piperidine 20. 1-[(2-imidazo [1,2-a] pyridyl) methyl]
-4- (4-Methylsulfonylaminobenzoyl) piperidine 21.1- [2- (2-imidazo [1,2-a] pyridyl) ethyl] -4- (4-methylsulfonylaminobenzoyl) piperidine 22.1- (6-imidazo [1,2-a] pyridylmethyl)-
4- (4-Methylsulfonylaminobenzoyl) piperidine 23. 1- [2- (3-imidazo [1,2-a] pyridyl)-
2-oxoethyl] -4- (4-methylsulfonylaminobenzoyl) piperidine 24.1-[(2-benzimidazolyl) methyl] -4-
(4-Methylsulfonylaminobenzoyl) piperidine 25. 4- (4-Methylsulfonylaminobenzoyl)-
1- [2- (2-quinoxalinyl) ethyl] piperidine 26. 4- (4-methylsulfonylaminobenzoyl)-
1- [2- (7-Theophyllinyl) ethyl] piperidine 27. 1- (9-fluorenyl) -4- (4-methylsulfonylaminobenzoyl) piperidine 28.1-ethyl-4- (4-methylsulfonylaminobenzoyl) Piperidine 29.1-n-Butyl-4- (4-methylsulfonylaminobenzoyl) piperidine 30.1-Cyclohexylmethyl-4- (4-methylsulfonylaminobenzoyl) piperidine 31.1- (2-Methyl-2-propenyl) ) -4- (4-
Methylsulfonylaminobenzoyl) piperidine 32.1-[(ethoxycarbonyl) methyl] -4- (4
-Methylsulfonylaminobenzoyl) piperidine 33.4- (4-methylsulfonylaminobenzoyl)-
1- (5,6,7,8-tetrahydro-8-quinolyl) methylpiperidine 34. 4- (4-methylsulfonylaminobenzoyl)-
1- [2- (3-Quinazolinedionyl) ethyl] piperidine 35.1 1-Cyano-4- (4-methylsulfonylaminobenzoyl) piperidine 36.1-Cyanomethyl-4- (4-methylsulfonylaminobenzoyl) piperidine 37 .1- (3-Cyanopropyl) -4- (4-methylsulfonylaminobenzoyl) piperidine 38.1- [2- (N ', N'-diethylamino) ethyl] -4
-(4-Methylsulfonylaminobenzoyl) piperidine 39. 4- (4-Methylsulfonylaminobenzoyl)-
1- [2- (1-pyrrolidinyl) ethyl] piperidine 40. 4- (4-methylsulfonylaminobenzoyl)-
1- [2- (1-piperidinyl) ethyl] piperidine 41. 4- (4-methylsulfonylaminobenzoyl)-
1- [2- (4-morpholinyl) ethyl] piperidine 42. 4- (4-methylsulfonylaminobenzoyl)-
1- [3- (1-Piperidinyl) propyl] piperidine 43. 1-ethyl-4- [4- (N-ethylmethylsulfonylamino) benzoyl] piperidine 44.1-n-butyl-4- [4- (N -N-Butylmethylsulfonylamino) benzoyl] piperidine 45.1-cyclohexylmethyl-4- [4- (N-cyclohexylmethylmethylsulfonylamino) benzoyl] piperidine 46.1- (2-methyl-3-propenyl) -4 -{4-
[N- (2-methyl-3-propenyl) methylsulfonylamino] benzoyl} piperidine 47. 1- [2- (6-methyl-2-pyridyl) ethyl]
-4- (4-Methylsulfonylaminophenyl) hydroxymethylpiperidine 48. 4- (4-Methylsulfonylaminophenyl) hydroxymethyl-1- [3- (4-pyridyl) propyl]
Piperidine The piperidine derivative obtained by the present invention has the property of not affecting the conduction velocity of the myocardium, prolonging the refractory period by specifically prolonging the action potential, and suppressing arrhythmia. -Located as a Class III antiarrhythmic agent in the Williams classification.

Specific experimental examples are shown below to explain the effects of the compounds of the present invention. Pharmacological experiment example Experimental example 1 Action potential extension action in isolated guinea pig myocardium The right ventricular papillary muscle of Hartley guinea pig (male 300 to 400 g) was excised and fixed with a pin on the bottom of an acrylic thermostat, 37
Perfusion with Tyrode's solution at 0 ° C. 95% for Tyrode solution
A mixed gas of oxygen and 5% carbon dioxide was saturated. The papillary muscles were electrically stimulated and driven under the stimulation conditions of 1 Hz, 1 msec and maximum stimulation. The action potential was recorded using a glass microelectrode filled with 3 M KCl to measure the action potential duration (APD ₉₀ ), and the maximum rise rate (V _max ) was measured using a differentiator. 10 ^-6 M and 10 ^-5 M of each test compound in ^Tyrode's solution
Was dissolved at a concentration of 3 and perfused. After observing the action of the test compound at a concentration of 10 ^-6 M for 10 minutes, the concentration was switched to a concentration of 10 ^-5 M and the observation was performed for another 10 minutes. The results are shown in Table 1.

The test compounds in Table 1 are as follows: As a control compound, sotalol, which is currently used as a β-blocker and is also said to have an action of prolonging the duration of myocardial action potential, was selected. Compound A: 4- (4-Methylsulfonylaminobenzoyl) -1- (2-quinolylmethyl) piperidine dihydrochloride Compound B: 4- (4-Methylsulfonylaminobenzoyl) -1- (3-quinolylmethyl) piperidine.2 Hydrochloride Compound C: 1- [2- (3-imidazo [1,2-a] pyridyl) -2-oxoethyl] -4- (4-methylsulfonylaminobenzoyl) piperidine dihydrochloride Compound D: 1- ( 1-imidazo [1,2-a] pyridylmethyl) -4- (4-methylsulfonylaminobenzoyl)
Piperidine dihydrochloride Compound E: 1-ethyl-4- (4-methylsulfonylaminobenzoyl) piperidine hydrochloride Compound F: 1- (6-imidazo [1,2-a] pyridylmethyl) -4- (4 -Methylsulfonylaminobenzoyl)
Piperidine dihydrochloride

[0054]

[Table 1]

[0055] using the QT _c prolongation enflurane anesthesia Zakken in Experimental Example 2 anesthesia dog, heart surface electrocardiogram of the QT _c
The effect on was investigated. A thoracotomy was performed from the fifth intercostal space, and the pericardium was opened to expose the left ventricle. A monopolar electrode fixed to an acrylic plate was sutured and fixed to the dominant region of the left anterior descending coronary artery. Using this electrode, the electrocardiogram of the surface of the left ventricle was recorded on an electrocardiograph (manufactured by Nihon Kohden, ECG-6403). The test compound was intravenously injected through a catheter inserted into the forearm vein. Test Compound A 31% at a dose of 0.1 mg / kg, observed extension of 56% of QT _c administration of 0.3 mg / kg, test compound B 0.
7% for administration of 1 mg / kg, 13% for administration of 0.3 mg / kg, 1.0 mg / kg
21% with test compound E and 7 mg with test compound E at 0.1 mg / kg
%, 0.3% / kg administration resulted in 14% QT _c prolongation.
The control compound sotalol was administered at a dose of 1.0 mg / kg.
% Extension was recognized.

Experimental Example 3 Acute toxicity test A male ddy mouse (body weight 20 to 30 g) was used to perform an acute toxicity test by intravenous administration. The LD ₅₀ value was calculated by the up and down method (common ratio 2). In the test, compound B,
C, D and sotalol were dissolved in physiological saline at a ratio of 16 mg / ml to prepare stock solutions. The stock solution had a dose corresponding to 160 mg / kg when a volume of 0.1 ml / 10 g body weight was administered, and other doses were administered by dose conversion of this stock solution. Compound A was dissolved in 20% polyethylene glycol at a rate of 8 mg / ml to prepare a stock solution. The administration was performed using a 1 ml tuberculin syringe (1/5 intravenous injection needle) in the tail vein, and the life / death determination time was 30 minutes after administration. The results are shown in Table 2.

[0057]

[Table 2]

From the above Experimental Examples 1 and 2, it is clear that the compound of the present invention has properties as a class III antiarrhythmic agent and is superior to sotalol selected as a control compound. Therefore, the compound of the present invention is expected to be effective for treating / preventing all types of arrhythmias such as ventricular arrhythmia and atrial (supraventricular) arrhythmia. It can be advantageously used for controlling recurrent arrhythmia in humans and preventing sudden death due to ventricular fibrillation.

When the compound of the present invention is used as an antiarrhythmic agent, it is administered orally or parenterally (intramuscularly or subcutaneously). The dose varies depending on the difference in disease, the degree of symptoms, the age, health condition, weight of the patient, the type of concurrent treatment, the frequency of treatment, the nature of the desired effect, etc., but is not particularly limited, Orally, about 1 mg to 100 mg, preferably about 5 mg to 50 mg, more preferably about 5 mg to 15 mg is administered once a day or more times. In the case of injection, it is about 0.01 mg.
/ kg to 1 mg / kg, preferably about 0.03 mg / kg to 0.1 mg / kg.

Examples of dosage forms include powders, fine granules,
Granules, tablets, capsules, suppositories, injections and the like can be mentioned. In the case of formulation, it is produced by a conventional method using a usual formulation carrier. That is, when preparing an oral solid preparation,
Excipients and, if necessary, binders, disintegrating agents, lubricants, coloring agents, flavoring agents, etc. are added to the main drug, and then tablets, coated tablets, granules, powders, capsules, etc. are prepared by a conventional method. To do.

Examples of the excipient include lactose, corn starch, sucrose, glucose, sorbit, crystalline cellulose,
Silicon dioxide, etc., as the binder, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose,
Hydroxypropyl starch, polyvinylpyrrolidone and the like, disintegrants such as starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin, pectin and the like, and lubricants such as stearin. Magnesium acid, talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc., those that are allowed to be added to the drug as a colorant, as the flavoring agent, cocoa powder, peppermint, aromatic acid, peppermint oil, Borneolum, cinnamon powder, etc. are used. Of course, these tablets and granules may be sugar-coated, gelatin-coated, or any other suitable coating, if necessary. When preparing an injectable drug, pH should be
A regulator, a buffer, a stabilizer, a solubilizer, etc. are added, and an intravenous injection is prepared by a conventional method.

[0062]

EXAMPLES Examples of the present invention will be given below, but it goes without saying that the present invention is not limited thereto. The final step for producing the target compound of the present invention will be described as an example, and the starting materials used when carrying out the example will be described as reference examples prior to the examples.

Reference Example 1 (±) -N-benzoyl-nipecotic acid

[0064]

[Chemical 54]

20.0 g (155 mmol) of (±) -nipecotic acid was dissolved in 33 ml of 20% aqueous sodium hydroxide solution, and 23.84 g of benzoyl chloride was added dropwise at a rate such that the reaction temperature did not exceed 20 ° C. Then, 60 ml of 20% aqueous sodium hydroxide solution is added dropwise, the mixture is stirred at 0 ° C. for 1 hour, and then acidified by adding concentrated hydrochloric acid, and the mixture is extracted with dichloromethane. The organic layer is washed with water and saturated brine, dried over magnesium sulfate and concentrated. Recrystallization of the residual solid from ethanol gives 18.0 g (40% yield) of the title compound as white crystals.

Melting point (° C.); 187 to 188 ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 1.3 to 2.2 (4 H, m), 2.2 to
4.4 (5H, m), 7.42 (5H, s), 12.0 to 12.6 (1H, br) (±) -In place of nipecotic acid, (±) -β-proline was similarly treated as a raw material to give the following compound: Obtained. (±) -N-benzoyl-β-proline

[0067]

[Chemical 55]

Melting point (° C.); 111-113 ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 2.18 (2H, qlike, J = 7 Hz),
2.8 to 3.3 (1H, m), 3.35 to 4.00 (4H, m), 7.36 (5H, m) Reference Example 2 (±) -N-benzoyl-nipecotic acid chloride

[0069]

[Chemical 56]

10.0 g (42.9 mmol) of (±) -N-benzoyl-nipecotic acid obtained in Reference Example 1 was added to thionyl chloride.
Dissolve in 15 ml, add a few drops of dimethylformamide, and stir at room temperature for 2 hours. Distilling off excess thionyl chloride under reduced pressure gives the title compound as a colorless oil almost quantitatively.

The following compounds were obtained by the same treatment using (±) -N-benzoyl-β-proline as a raw material instead of (±) -N-benzoyl-nipecotic acid. (±) -N-benzoyl-β-proline chloride

[0072]

[Chemical 57]

The acid chloride obtained in Reference Example 2 is used in the next reaction (Reference Example 3) as a crude product without purification.

Reference Example 3 1-Acetyl-4- (4-methylsulfonylaminoben)
Zoyl) piperidine

[0075]

[Chemical 58]

Aluminum chloride 14.40 g (0.108 mol) was suspended in methylene chloride 25 ml, 1-acetylisonipecotic acid chloride 5.50 g (0.029 mol) and methanesulfonanilide 5.00 g (0.029 mol) were added with stirring, Reflux for 2 hours. After cooling, the reaction mixture is poured into 100 ml of ice water and stirred vigorously. The precipitated crystals are collected by filtration and dried to give the title compound (7.22 g).

Melting point (° C.); 210 to 211.5 ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 1.20 to 2.00 (4H, m) 2.00 (3H,
s), 2.60 to 4.00 (4H, m), 3.10 (3H, s), 4.36 (1H, br), 7.28
(2H, d, J = 8Hz), 7.98 (2H, d, J = 8Hz), 10.34 (1H, s, D ₂ O exch
ange) Hereinafter, instead of methanesulfonanilide, ethanesulfonanilide, 3-methoxymethanesulfonanilide,
With paratoluene sulfone anilide, or 1-
Similar to Reference Example 3 using (±) -N-benzoyl-nipecotic acid chloride and (±) -N-benzoyl-β-proline acid chloride synthesized in Reference Example 2 instead of acetylisonipecotic acid chloride. To give the following compound. * 1-acetyl-4- (4-ethylsulfonylamino)
Nzoyl) piperidine

[0078]

[Chemical 59]

¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.35 (3 H, t, J = 7 H
z), 1.5 to 2.10 (4H, m), 2.11 (3H, s), 2.65 to 3.70 (3H,
m), 3.16 (2H, q, J = 7Hz), 3.88 (1H, br d, J = 12Hz), 4.51 (1
H, br d, J = 12Hz), 7.28 (2H, d, J = 8Hz), 7.83 (2H, d, J = 8Hz),
8.60 (1H, br s, D ₂ O exchange) ・1-Acetyl-4- (2-hydroxy-4-methyls)
Rufonylaminobenzoyl) piperidine

[0080]

[Chemical 60]

¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.2 to 2.0 (4 H,
m), 1.99 (3H, s), 3.10 (3H, s), 4.16 (1H, br d, J = 13Hz),
6.62 ~ 6.80 (2H, m), 7.90 (1H, d, J = 8Hz), 10.34 (1H, s, D ₂ O
exchange), 13.22 (1H, s, D ₂ O exchange) ・1-acetyl-4- (2-methoxy-4-methylsulfur)
Honylaminobenzoyl) piperidine

[0082]

[Chemical formula 61]

¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 1.2 to 2.0
(4H, m), 2.00 (3H, s), 3.12
(3H, s), 3.88 (3H, s), 6.86 (1
H, dd, J = 8,2 Hz), 6.96 (1H, d,
J = 2Hz), 7.57 (1H, d, J = 8Hz),
10.34 (1H, s, D ₂ O exchange) 1-Acetyl-4- (4-paratoluenesulphonyl )
Minobenzoyl) piperidine

[0084]

[Chemical formula 62]

¹ H-NMR (90 MHz, CDC
l ₃ ) δ; 1.4 to 2.0 (4H, m), 2.14 (3H, s), 2.37 (3H, s),
2.5 to 3.6 (3H, m), 3.92 (1H, br d, J = 14Hz), 4.57 (1H, br d,
J = 14Hz), 7.23 (4H, d, J = 8Hz), 7.75 (2H, d, J = 8Hz), 7.83 (2
H, d, J = 8Hz), 8.80 (1H, br) ・(±) -1-benzoyl-3- (4-methylsulfoni
Luminobenzoyl) piperidine

[0086]

[Chemical formula 63]

¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 1.5 to 2.2 (4
H, m), 3.00 (3H, s), 7.24 (2H, m), 7.42 (5H, s), 7.88 (2
H, m) etc. (±) -1-benzoyl-3- (4-methylsulfoni)
Luminobenzoyl) pyrrolidine

[0088]

[Chemical 64]

¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.9 to 3.0 (3 H,
m), 3.01 (3H, s), 3.4 to 4.2 (4H, m), 7.34 (7H, m), 7.84 (2
H, m) Reference Example 4 1-Acetyl-4- [4- (N-methylmethylsulfoni
Lumino) benzoyl] piperidine

[0090]

[Chemical 65]

0.29 g of sodium hydride (1
2.0 mmol) in 30 ml of dimethylformamide,
1-Acetyl-4- (4-methylsulfonylaminobenzoyl) piperidine (3.24 g, 10.0 mmol) was added, and the temperature was 60 ° C.
Stir for 20 minutes. Methyl iodide 1.7 g (1
(2.0 mmol), and the mixture is stirred at 60 ° C. for 1 hour, 100 ml of chloroform is added, and the mixture is washed with water and saturated brine. The chloroform layer is concentrated, the residual oil is subjected to column chromatography (chloroform: methanol = 99: 1), and the target fraction is concentrated to obtain 2.0 g of the title compound.

[0092] melting point ^{(℃); 162 ~163 1 H} -NMR (90MHz, CDCl 3) δ; 1.5~2.1 (4H, m), 2.11 (3H,
s), 2.5 to 3.6 (3H, m), 2.95 (3H, s), 3.37 (3H, s), 3.92 (1
H, br d, J = 13Hz), 4.56 (1H, d, J = 13Hz), 7.50 (2H, d, J = 8H
z), 7.96 (2H, d, J = 8Hz) Reference Example 5 1-Acetyl-4-[(4-methylsulfonylaminophenyl)
[Ethyl) methyl] piperidine

[0093]

[Chemical formula 66]

1-Acetyl-4- (4-obtained in Reference Example 3
Methylsulfonylaminobenzoyl) piperidine 7.50 g
(23.1 mmol) was dissolved in 110 ml of dichloroethane, triethylsilane (11.0 ml) and trifluoroacetic acid (1
7.8 ml) and reflux for 50 hours. After cooling, add 20% aqueous sodium hydroxide to neutralize and extract with dichloromethane. The organic layer is washed with water and saturated brine, dried over magnesium sulfate and concentrated. The obtained residual oil was purified by silica gel column chromatography (chloroform: methanol = 98: 2) to give 3.30 g of the title compound (yield
46%) is obtained as white crystals.

Melting point (° C.); 145-146 ¹ H-NMR (90 MHz, CDCl ₃ ) δ; 1.4-2.0 (3 H, m), 2.08 (3 H,
s), 2.2 ~ 3.1 (4H, m), 3.00 (3H, s), 3.78 (1H, br d, J = 13H
z), 4.56 (1H, br d, J = 13Hz), 7.12 (4H, m) Elemental analysis value: C ₁₅ H ₂₂ N ₂ O ₃ S Theoretical value (%) C 58.04, H 7.14, N 9.02 Measured value (%) C 57.64, H 6.9
3, N 9.00 Example 1 4- (4-methylsulfonylaminobenzoyl) pipette
Lysine / hydrochloride

[0096]

[Chemical formula 67]

1-Acetyl-4- (4-methylsulfonylaminobenzoyl) piperidine 43.4 g (0.142 mol)
Is suspended in 1 liter of 3N-hydrochloric acid and refluxed with stirring for 3 hours. After completion of the reaction, the reaction solution was cooled, and the precipitated white crystals were collected by filtration, washed with water and dried to give 37.8 g of the title compound (yield 84
%) Is obtained.

Melting point (° C.);> 265 (decomposition) ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 1.6 to 2.1 (4 H, m), 3.12 (3
H, s), 7.33 (2H, d, J = 8Hz), 8.01 (2H, d, J = 8Hz), 8.8 ~ 9.5
(2H, br, D ₂ O exchange), 10.46 (1H, s, D ₂ O exchange) Elemental analysis value; C ₁₃ H ₁₈ N ₂ O ₃ S ・ HCl theoretical value (%) C 48.98, H 6.01, N 8.79 Measured value (%) C 48.64, H 5.77, N 8.65 The following compounds were obtained by the same treatment as in Example 1 using the compounds shown in the above-mentioned reference examples as raw materials.

Example 2 4- (4-Ethylsulfonylaminobenzoyl) piperi
Gin / hydrochloride

[0100]

[Chemical 68]

Melting point (° C.);> 220 (decomposition) ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 1.22 (3 H, t, 7 Hz), 1.62 to 2.
1 (4H, m), 2.8 ~ 3.9 (4H, m), 3.21 (3H, q, J = 7Hz), 7.34 (2H,
d, J = 8Hz), 8.01 (2H, d, J = 8Hz), 8.8 ~ 9.5 (2H, br), 10.38
(1H, s, D ₂ O exchange) Elemental analysis value; C ₁₄ H ₂₀ N ₂ O ₃ S ・ HCl theoretical value (%) C 50.52, H 6.06, N 8.42 Actual value (%) C 50.31, H 6.30, N 8.29 Example 3 4- (2-hydroxy-4-methylsulfonylamino)
Nzoyl) piperidine hydrochloride

[0102]

[Chemical 69]

Melting point (° C.);> 250 ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 1.6 to 2.1 (4H, m), 3.10 (3H,
s), 6.65 ~ 6.87 (2H, m), 7.89 (1H, d, J = 8Hz), 8.6 ~ 9.4 (2
H, br, D ₂ O exchange), 10.40 (1H, s, D ₂ O exchange), 12.05
(1H, s, D ₂ O exchange) Elemental analysis value; theoretical value as C ₁₃ H ₁₈ N ₂ O ₄ S ・ HCl (%) C 46.64, H 5.72, N 8.37 Measured value (%) C 46.71, H 5.97, N 8.30 Example 4 4- (2-Methoxy-4-methylsulfonylaminoben
Zoyl) piperidine hydrochloride

[0104]

[Chemical 70]

Melting point (° C.);> 220 (decomposition) ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 1.5 to 2.1 (4H, m), 3.12 (3H,
s), 3.88 (3H, s), 6.86 (1H, dd, J = 8,2Hz), 6.96 (1H, d, J = 2
Hz), 7.58 (1H, d, J = 8Hz), 9.0 (2H, br, D ₂ O exchange), 10.
32 (1H, s, D ₂ O exchange) Elemental analysis value; C ₁₄ H ₂₀ N ₂ 0 ₄ Theoretical value as SHCl (%) C 48.20, H 5.78, N 8.03 Actual value (%) C 48.32, H 5.93 , N 7.81 Similarly, in Example 1, instead of 1-acetyl-4- (4-methylsulfonylaminobenzoyl) piperidine, 1-acetyl-4- (4-paratoluenesulfonylaminobenzoyl) piperidine and 1-acetyl-4 were used.
The same procedure was performed using-(4-methylsulfonylaminobenzyl) piperidine as a raw material to obtain the following compound. Example 5 4- (4-paratoluenesulfonylaminobenzoyl)
Piperidine / hydrochloride

[0106]

[Chemical 71]

Melting point (° C.); 240-242 ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ: 1.6-2.1 (4H, m), 2.5-
3.8 (5H, m), 2.36 (3H, s), 7.24 (2H, d, J = 8Hz), 7.36 (2H,
d, J = 8Hz), 7.76 (2H, d, J = 8Hz), 7.90 (2H, d, J = 8Hz), 9.0
(2H, br), 10.97 (1H, s) Elemental analysis value; C ₁₉ H ₂₂ N ₂ O ₃ S ・ HCl ・ H ₂ O theoretical value (%) C 55.27, H 5.61, N 6.78 Measured value (%) C 55.25, H 5.68, N 6.85 Example 6 4- (4-Methylsulfonylaminobenzyl) piperidi
Hydrochloride

[0108]

[Chemical 72]

Melting point (° C.); 255-257¹ H-NMR (90MHz, DMSO-d₆) δ; 1.2 to 2.0 (5H, m), 2.94
(3H, s), 7.14 (4H, s), 9.0 (2H, br), 9.67 (1H, s) Elemental analysis value; C₁₃H₂₀N₂O₂S ・ HCl theoretical value (%) C 51.22, H 6.94, N 9.19 Actual value (%) C 51.26, H 6.86, N 9.16Example 7 (±) -3- (4-Methylsulfonylaminobenzoi
Le) piperidine / hydrochloride

[0110]

[Chemical formula 73]

(±) -1-benzoyl-obtained in Reference Example 3
5.70 g (14.8 mmol) of 3- (4-methylsulfonylaminobenzoyl) piperidine is dissolved in a mixed solution of 120 ml of 5N hydrochloric acid and 80 ml of methanol, and the mixture is refluxed for 8 hours. The reaction solution is concentrated and the residual solid is recrystallized from ethanol to give 2.61 g (yield 55%) of the title compound as white crystals.

Melting point (° C); 235-237¹ H-NMR (90MHz, DMSO-d₆) δ; 1.4 ~ 2.2 (4H, m), 2.6 ~
4.1 (5H, m), 3.11 (3H, s), 7.35 (2H, d, J = 8Hz), 7.98 (2H, d,
J = 8Hz), 8.0 to 8.5 (2H, br), 10.48 (1H, br s) Elemental analysis value; C₁₃H₁₈N₂O₃Theoretical value (%) as S.HCl C 48.98, H 6.01, N 8.79 Actual value (%) C 48.86, H 5.87, N 8.77Example 8 (±) -3- (4-Methylsulfonylaminobenzoi
Le) pyrrolidine / hydrochloride

[0113]

[Chemical 74]

Example using (±) -1-benzoyl-3- (4-methylsulfonylaminobenzoyl) pyrrolidine as a raw material instead of (±) -1-benzoyl-3- (4-methylsulfonylaminobenzoyl) piperidine Treatment as in 7 gave the title compound.

Melting point (° C.); 198-200 ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 1.7-2.5 (2H, m), 3.0-
3.8 (4H, m), 3.14 (3H, s), 4.20 (1H, qlike, J = 7Hz), 7.36 (2
H, d, J = 8Hz), 8.01 (2H, d, J = 8Hz), 9.5 (2H, br), 10.26 (1
H, s) Elemental _{analysis: C 12 H 16 N 2 O} 3 theoretical value as S · HCl (%) C 47.29 , H 5.62, N 9.19 Found (%) C 47.17, H 5.49 , N 9.11 Example 9 4 -[4- (N-methylmethylsulfonylamino) ben
Zoyl] piperidine hydrochloride

[0116]

[Chemical 75]

According to the method described in Example 1 using 1-acetyl-4- [4- (N-methylmethylsulfonylamino) benzoyl] piperidine (1.90 g) synthesized in Reference Example 4 as a starting material. 1.43 g (yield 90%) of the title compound was obtained.

Melting point (° C.); 254 to 255 ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 1.5 to 2.1 (4H, m), 3.04 (3H,
s), 3.32 (3H, s), 7.57 (2H, d, J = 8 Hz), 8.06 (2H, d, J = 8H
z), 8.8 to 9.6 (2H, br, D ₂ O exchange) Elemental analysis value; C ₁₄ H ₂₀ N ₂ SO ₃ · HCl theoretical value (%) C 50.50, H 6.37, N 8.42 Measured value (%) C 50.43, H 6.42, N 8.39 Example 10 1- {2- (2-imidazo [1,2-a] pyridyl) eth
Ru} -4- (4-methylsulfonylaminobenzoyl)
Piperidine

[0119]

[Chemical 76]

4- (4-Methylsulfonylaminobenzoyl) piperidine hydrochloride 1.02 g (3.2 mmol), sodium hydrogen carbonate 1.34 g and dimethylformamide 10 ml.
After stirring the mixture of 80 ° C. for 1 hour, 2- (2-chloroethyl) imidazo [1,2-a] pyridine hydrochloride 0.48
g and 0.53 g of potassium iodide are added, and the mixture is stirred at 80 ° C. for 2 hours. The mixture is filtered, the filtrate is concentrated, and the resulting solid residue is purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia = 190:
9: 1). The residual solid obtained by concentrating the target fraction was recrystallized from ethyl acetate to give the title compound (0.25 g)
(Yield 18%) is obtained.

Melting point (° C.); 190-191 ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 1.4-1.9 (4 H, m), 2.18 (2
H, m), 2.4 to 3.6 (7H, m), 3.10 (3H, s), 6.80 (1H, dt, J = 5,2
Hz), 7.04 to 7.34 (4H, m), 7.72 (1H, s), 7.95 (2H, d, J = 8H
z), 8.45 (1H, d, J = 7Hz) Elemental analysis value; theoretical value as C ₂₂ H ₂₆ N ₄ O ₃ S (%) C 61.95, H 6.14, N 13.14 Measured value (%) C 61.92, H 6.10 , N 12.92 example 11 1- [2- (3-imidazo [1, 2 -a] pyridinium Le) -1
-Oxoethyl] 4- (4-methylsulfonylaminobe
Nzoyl) piperidine dihydrochloride

[0122]

[Chemical 77]

I) 3-Acetyl-imidazo [1,2-a]
Dissolve 22.1 g of pyridine in 220 ml of acetic acid and use hydrogen bromide-acetic acid.
35.1 ml of 30% solution was added dropwise at 0 ° C, and then 28.6 g of bromine was added at 40 ° C.
Drop by. After stirring the mixture at 40 ° C. for 2 hours, the crystals that form are filtered off. Dissolve the crystals in 100 ml of water, add an excess of sodium hydrogen carbonate aqueous solution to make it alkaline,
Extract with ethyl acetate. The brown solid obtained by concentrating the organic layer was purified by silica gel column chromatography (eluted with ethyl acetate) to give 3-bromoacetyl-imidazo [1,2-a] pyridine (13.5 g, yield 40%) as yellow crystals. Obtained as.

Ii) 4- (4-methylsulfonylaminobenzoyl) piperidine hydrochloride 1.91 g (6.0 mmol), potassium carbonate 3.0 g and dimethylformamide.
40 ml of suspension are stirred at 80 ° C. for 1 hour. After cooling to room temperature, 1.99 g of 3-bromoacetyl-imidazo [1,2-a] pyridine synthesized in i) is added, and the mixture is stirred at room temperature for 6 hours. The reaction mixture is filtered, the filtrate is concentrated, and the resulting solid residue is purified by silica gel column chromatography (chloroform: methanol = 96: 4). The purified product was made into dihydrochloride with ethanolic hydrogen chloride, and methanol-
Recrystallization from acetone gave 1.75 g of the title compound (yield 58
%) Is obtained.

Melting point (° C.); 176 to 178 ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.95 to 2.10 (4H, m), 3.12
(3H, s), 3.33 (2H, m), 3.48 ~ 3.90 (3H, m), 4.96 (2H, s),
7.34 (2H, d, J = 8.8Hz), 7.51 (1H, t, J = 7.1Hz), 7.89 (1H, dd,
J = 7.8,7.3Hz), 8.02 (2H, d, J = 8.8Hz), 9.01 (1H, s), 9.54
(1H, d, J = 6.8Hz), 10.50 (1H, s, D ₂ O ex-change), 10.72 (1
H, br, D ₂ O exchange) Elemental analysis value: C ₂₂ H ₂₄ N ₄ O ₄ S ・ 2HCl ・ 1.2H ₂ O theoretical value (%) C 49.39, H 5.35, N 10.47 Actual value (%) C 49.46 , H 5.09, N 10.41 Example 12 4- (4-Methylsulfonylaminobenzoyl ) -1-
[2- (1-pyrrolidinyl) ethyl] pyridine ・ 2
Urate

[0126]

[Chemical 78]

10.0 g (31.4 mmol) of 4- (4-methylsulfonylaminobenzoyl) piperidine hydrochloride was suspended in 20 ml of an aqueous solution of 1.32 g of sodium hydroxide and stirred at room temperature for 1 hour. The resulting crystals are collected by filtration, washed with water and dried to give 8.28 g of 4- (4-methylsulfonylaminobenzoyl) piperidine (free form). 2.0 g of this crystal (7.0
9 mmol), Chloroethylpyrrolidine / hydrochloride 1.57
g, potassium iodide 2.35 g and dimethylformamide
40 ml of the mixture is stirred at 80 ° C. for 3 hours. The reaction mixture is filtered, and the solid residue obtained by concentrating the filtrate is purified by silica gel column chromatography (chloroform:
Methanol: ammonia water = 90: 9: 1). Purified product 0.
When 68 g of ethanol is added with 0.32 g of oxalic acid to give a dioxalate, and recrystallized from methanol-ethanol, 0.40 g of the title compound (yield 10%) is obtained.

Melting point: 214-216 ° C. ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ: 1.4-2.3 (8H, m), 2.4-3.6
(13H, m), 3.08 (3H, s), 7.21 (2H, d, J = 8.8Hz), 7.88 (2H, d,
J = 8Hz) Elemental analysis value: C ₁₉ H ₂₉ N ₃ O ₃ S ・ 2 (COOH) ₂ theoretical value (%) C 49.37, H 5.94, N 7.51 Actual value (%) C 49.40, H 5.85, N 7.37 Example 13 1- (5-Methyl-2-furanyl) methyl-4- (4-
Methylsulfonylaminobenzoyl) piperidine

[0129]

[Chemical 79]

4- (4-methylsulfonylaminobenzoyl) piperidine (free form) obtained in Example 12. 4.
1.88 ml of formalin and 1.07 g of methylfuran are added to a mixed solution of 43 g (15.7 mmol), 1.57 ml of glacial acetic acid and 10 ml of water, and the mixture is stirred at 90 ° C. for 2 hours. After cooling, add 20% aqueous sodium hydroxide to neutralize and extract with dichloromethane. The organic layer is washed with water and saturated brine, dried over magnesium sulfate and concentrated. The residual solid was recrystallized from ethanol-methanol to give 4.16 g of the title compound (yield
70%) is obtained.

Melting point (° C.); 181-182 ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 1.3-1.9 (4 H, m), 1.9-2.3
(2H, m), 2.23 (3H, d, J = 1Hz), 2.6 ~ 3.4 (3H, m), 3.10 (3H,
s), 3.43 (2H, s), 5.97 (1H, m), 6.13 (1H, d, J = 3Hz), 7.28
(2H, d, J = 8Hz), 7.94 (2H, d, J = 8Hz) Elemental analysis value; theoretical value (%) as C ₁₉ H ₂₄ N ₂ O ₄ S C 60.62, H 6.43, N 7.44 Measured value ( %) C 60.43, H 6.46, N 7.44 Example 14 4- (4-methylsulfonylaminobenzoyl) -1-
[2- (2-quinoxalinyl) ethyl] piperidine

[0132]

[Chemical 80]

5.0 g (15.7 mmol) of 4- (4-methylsulfonylaminobenzoyl) piperidine hydrochloride was suspended in 5 ml of ethanol, 2.49 g of 2-methylquinoxaline and 7.0 ml of formalin were added, and the mixture was stirred at 90 ° C. for 1 hour. .
After cooling, a 20% aqueous sodium hydroxide solution was added to the mixture to make it neutral, and the precipitated crystals were recrystallized from ethyl acetate to obtain 0.32 g (yield 5%) of the title compound.

Melting point (° C.); 156-157 ¹ H-NMR (90 MHz, DMSO-d ₆ ) δ; 1.4-2.0 (4 H, m), 2.0-2.4
(2H, m), 2.6 ~ 3.5 (7H, m), 3.13 (3H, s), 7.31 (2H, d, J = 8H
z), 7.73 to 8.15 (6H, m), 8.91 (1H, s) Elemental analysis value; theoretical value as C ₂₃ H ₂₆ N ₄ O ₃ S (%) C 62.99, H 5.98, N 12.78 Measured value (%) C 62.83, H 5.95, N 12.61 Examples 15-16 1-Ethyl-4- (4-methylsulfonylaminobenzo
Iyl) piperidine and 1-ethyl-4- [4- (N-
Ethylmethylsulfonylamino) benzoyl] piperidi
The

[0135]

[Chemical 81]

A suspension of 2.54 g (7.97 mmol) of 4- (4-methylsulfonylaminobenzoyl) piperidine hydrochloride, 5.0 g of potassium carbonate and 40 ml of dimethylformamide was stirred at 80 ° C. for 1 hour, and then ethyl iodide (1.3 g) was added. g
(8.3 mmol) is added and the mixture is stirred at 80 ° C for 12 hours. The mixture is filtered, the filtrate is concentrated, and the resulting solid residue is purified by silica gel column chromatography (chloroform: methanol: aqueous ammonia = 190: 9: 1). The residual solid obtained by concentrating each fraction is subjected to hydrochloric acid salification with ethanolic hydrochloric acid and recrystallized from methanol-ethyl acetate to obtain the title compound.

Example 15: 1-Ethyl-4- [4-
(N-ethylmethylsulfonylamino ) benzoyl] pi
Perijin hydrochloride: 0.23 g mp ^{(℃): 188 ~191 1 H} -NMR (90MHz, DMSO-d 6) δ; 1.04 (3H, t, J = 7Hz), 1.28 (3
H, t, J = 7Hz), 1.65 ~ 2.30 (4H, m), 2.60 ~ 3.95 (7H, m), 3.0
5 (3H, s), 3.78 (2H, q, J = 7 Hz), 7.57 (2H, d, J = 8Hz), 8.06
(2H, d, J = 8Hz) Elemental analysis value; theoretical value (%) as C ₁₇ H ₂₆ N ₂ O ₃ S.HCl C 54.45, N 7.27, N 7.47 Actual value (%) C 54.20, N 7 .0
9, N 7.24 (Example 16): 1-Ethyl-4- (4-methylsulfo)
Nylaminobenzoyl) piperidine hydrochloride : 1.70
g mp ^{(℃); 204 ~207 1 H} -NMR (90MHz, DMSO-d 6) δ; 1.27 (3H, t, J = 7Hz), 1.64~
2.23 (4H, m), 2.62 to 3.90 (7H, m), 3.13 (3H, s), 7.34 (2H,
d, J = 8Hz), 8.01 (2H, d, J = 8Hz), 10.42 (1H, br s) Elemental analysis value; Theoretical value (%) as C ₁₅ H ₂₂ N ₂ O ₃ S ・ HCl C 51.93, H 6.70, N 8.08 Measured value (%) C 51.76, H 6.57, N 7.86 Examples 17 to 54 Piperidine and pyrrolidine derivatives shown in Examples 1 to 9 according to the method of Examples 10 to 16 and appropriate halides. The compounds listed in Tables 3 to 11 were obtained using the above.

[0138]

[Table 3]

[0139]

[Table 4]

[0140]

[Table 5]

[0141]

[Table 6]

[0142]

[Table 7]

[0143]

[Table 8]

[0144]

[Table 9]

[0145]

[Table 10]

[0146]

[Table 11]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/50 31/505 31/52 31/535 C07D 211/28 211/32 401/06 207 209 211 405/06 211 409/06 211 417/06 211 471/04 108 A 473/08 (72) Inventor Tadao Shoji 57-7 Hoyodai, Kukizaki-cho, Inashiki-gun, Ibaraki Prefecture (72) Inventor Kaji Kaji, Sakura Village, Shinji-gun, Ibaraki Prefecture 2-15-3 Umezono (72) Kohei Sawada Inventor Kohei Sawada 1-2-1, Nishi Toride, Ibaraki Prefecture Toride Chuo Ton E-601 (72) Inventor Kenichi Nomoto 110-8 Oki Arakawa, Tsuchiura City, Ibaraki Prefecture

Claims (11)

[Claims] 1. A compound represented by the general formula (I): {In the formula, R ¹ represents a lower alkyl group or a tolyl group, and R ²
Means a hydrogen atom, a hydroxyl group, a lower alkoxy group or a lower alkyl group, and R ³ means a hydrogen atom, a lower alkyl group, a lower alkenyl group or a cycloalkylalkyl group. X is a group represented by the formula -CO-, a group represented by the formula -CH _2- ,
Or g means an integer of 1 or 2 and h means an integer of 2 or 3. Y is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a cyano group, a group represented by the formula —CH ₂ COOR (wherein R represents a hydrogen atom or a lower alkyl group), a cycloalkylalkyl group, and (Wherein m represents an integer of 2 or 3),
Or a group represented by the formula -AB (wherein A represents the formula-(CH ₂ ) _n- (wherein n represents an integer of 1 to 5) and a straight chain alkylene group having 1 to 5 carbon atoms, A divalent group obtained by removing one hydrogen atom from each carbon atom on both ends of a straight chain alkane in which a lower alkyl group, a phenyl group or a hydroxyl group is directly bonded to one or more carbon atoms, and a carbon number of 2 to 5 In the linear alkylene group of, a divalent group obtained by removing one hydrogen atom from each carbon atom at both ends of a linear alkene having a double bond between adjacent carbon atoms, a formula- (CH ₂ ). _k -S- (where k is 2-5
A group represented by the following), or [Chemical 5] [Chemical 6] A piperidine derivative represented by or a derivative thereof or a pharmacologically acceptable salt thereof. 2. X is a group represented by the formula —CO—.
The piperidine derivative described above, a derivative thereof, or a pharmaceutically acceptable salt thereof. 3. X is The piperidine derivative or a derivative thereof or a pharmaceutically acceptable salt thereof according to claim 1, which is a group represented by: 4. The piperidine derivative according to claim 1, wherein X is a group represented by the formula —CH ₂ —, a derivative thereof, or a pharmaceutically acceptable salt thereof. 5. A piperidine derivative or a derivative thereof or a pharmacological agent thereof according to claim 1, wherein A is a group represented by the formula:-(CH ₂ ) _n- (wherein n represents an integer of 1 to 5). Acceptable salt. 6. The piperidine derivative according to claim 1, wherein the compound is 4- (4-methylsulfonylaminobenzoyl) piperidine, a derivative thereof, or a pharmaceutically acceptable salt thereof. 7. A general formula: (In the formula, R ¹ represents a lower alkyl group or a tolyl group, and R ²
Represents a hydrogen atom, a hydroxyl group, a lower alkoxy group or a lower alkyl group, R ³ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, or a cycloalkylalkyl group,
R'means a lower alkyl group or a phenyl group. g is 1
Or, it means an integer of 2, and h means an integer of 2 or 3. ) Is hydrolyzed to give a compound represented by the general formula: (Wherein R ¹ , R ² , R ³ and g, h have the above-mentioned meanings) to obtain a sulfonamide derivative, and if necessary, to make it a pharmacologically acceptable salt piperidine A method for producing a derivative, a derivative thereof, or a pharmacologically acceptable salt thereof. 8. A general formula: (In the formula, R ¹ represents a lower alkyl group or a tolyl group, and R ²
Means a hydrogen atom, a hydroxyl group, a lower alkoxy group or a lower alkyl group, and R ³ means a hydrogen atom, a lower alkyl group, a lower alkenyl group or a cycloalkylalkyl group. g means an integer of 1 or 2 and h means an integer of 2 or 3. ) General formula Z-A-B [wherein A in the compound represented by the formula - (CH _{2) n} - (groups represented by n is an integer of 1 to 5 in the formula), 1 carbon atoms In the straight-chain alkylene group of 5, one hydrogen atom is removed from each carbon atom at both ends of a straight-chain alkane in which a lower alkyl group, a phenyl group or a hydroxyl group is directly bonded to one or more carbon atoms constituting the straight-chain alkylene group. In a divalent group, a linear alkylene group having 2 to 5 carbon atoms,
A divalent group obtained by removing one hydrogen atom from each carbon atom at both ends of a straight chain alkene having a double bond between any adjacent carbon atoms, a formula-(CH ₂ ) _k -S- (wherein k represents an integer of 2 to 5), or [Chemical 12] [Chemical 13] Z is a halogen atom, a methanesulfonyloxy group or p-
It means a toluenesulfonyloxy group. ] [Chemical 14] (Wherein Z has the above-mentioned meaning and m represents an integer of 2 or 3), and the compound represented by the general formula: (Wherein R ¹ , R ² , R ³ , g, h, A and B have the above meanings)
And a related derivative thereof, or (Wherein R ¹ , R ² , R ³ , g, h, and m have the above-mentioned meanings) to obtain a sulfonamide derivative, and if necessary, use this as a pharmacologically acceptable salt. A method for producing the above-mentioned piperidine derivative or a derivative thereof or a pharmaceutically acceptable salt thereof. 9. A general formula: {In the formula, R ¹ represents a lower alkyl group or a tolyl group, and R ²
Means a hydrogen atom, a hydroxyl group, a lower alkoxy group or a lower alkyl group, and R ³ means a hydrogen atom, a lower alkyl group, a lower alkenyl group or a cycloalkylalkyl group.
g means an integer of 1 or 2 and h means an integer of 2 or 3. Y is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a cyano group, a group represented by the formula —CH ₂ COOR (wherein R represents a hydrogen atom or a lower alkyl group), a cycloalkylalkyl group, (Wherein m represents an integer of 2 or 3),
Or formula -AB [wherein A has the formula - (CH _{2) n} - group (n in the formula is an integer of 1 to 5) are shown, in a straight-chain alkylene group having 1 to 5 carbon atoms, constitute A divalent group obtained by removing one hydrogen atom from each carbon atom on both ends of a straight chain alkane in which a lower alkyl group, a phenyl group or a hydroxyl group is directly bonded to one or more carbon atoms, and a carbon number of 2 to 5 In the linear alkylene group of, a divalent group obtained by removing one hydrogen atom from each carbon atom at both ends of a linear alkene having a double bond between adjacent carbon atoms, a formula- (CH ₂ ). _k -S- (where k is 2-5
A group represented by the following), or [Chemical 20] [Chemical 21] A compound represented by the general formula: (Wherein R ¹ , R ² , R ³ , g, h and Y have the above-mentioned meanings) to obtain a piperidine derivative or a derivative thereof, and if necessary, to make it a pharmacologically acceptable salt. A process for producing the piperidine derivative or a derivative thereof or a pharmaceutically acceptable salt thereof, which comprises: 10. A general formula: {In the formula, R ¹ represents a lower alkyl group or a tolyl group, and R ²
Means a hydrogen atom, a hydroxyl group, a lower alkoxy group or a lower alkyl group. g means an integer of 1 or 2 and h means 2
Or, it means an integer of 3. Y is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a cyano group, a formula-CH ₂ COOR (wherein R
Represents a hydrogen atom or a lower alkyl group), a cycloalkylalkyl group, (Wherein m represents an integer of 2 or 3),
Or a group represented by the formula -AB (wherein A represents the formula-(CH ₂ ) _n- (wherein n represents an integer of 1 to 5) and a straight chain alkylene group having 1 to 5 carbon atoms, A divalent group obtained by removing one hydrogen atom from each carbon atom on both ends of a straight chain alkane in which a lower alkyl group, a phenyl group or a hydroxyl group is directly bonded to one or more carbon atoms, and a carbon number of 2 to 5 In the linear alkylene group of, a divalent group obtained by removing one hydrogen atom from each carbon atom at both ends of a linear alkene having a double bond between adjacent carbon atoms, a formula- (CH ₂ ). _k -S- (where k is 2-5
A group represented by the following), or [Chemical formula 26] [Chemical 27] A compound represented by the formula: R ".Hal (wherein R is a lower alkyl group, a lower alkenyl group or a cycloalkylalkyl group, and Hal is a halogen atom), General formula (Wherein R ¹ , R ² , R ", g, h and Y have the above-mentioned meanings) to obtain a piperidine derivative or a derivative thereof, and, if necessary, to make it a pharmacologically acceptable salt. A process for producing the piperidine derivative or a derivative thereof or a pharmaceutically acceptable salt thereof, which comprises: 11. A compound represented by the general formula (I): {In the formula, R ¹ represents a lower alkyl group or a tolyl group, and R ²
Means a hydrogen atom, a hydroxyl group, a lower alkoxy group or a lower alkyl group, and R ³ means a hydrogen atom, a lower alkyl group, a lower alkenyl group or a cycloalkylalkyl group.
X is a group represented by the formula —CO—, a group represented by the formula —CH ₂ —, or Y is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a cyano group, a group represented by the formula —CH ₂ COOR (wherein R represents a hydrogen atom or a lower alkyl group), a cycloalkylalkyl group, and (Wherein m represents an integer of 2 or 3),
Or a group represented by the formula -AB (wherein A represents the formula-(CH ₂ ) _n- (wherein n represents an integer of 1 to 5) and a straight chain alkylene group having 1 to 5 carbon atoms, A divalent group obtained by removing one hydrogen atom from each carbon atom on both ends of a straight chain alkane in which a lower alkyl group, a phenyl group or a hydroxyl group is directly bonded to one or more carbon atoms, and a carbon number of 2 to 5 In the linear alkylene group of, a divalent group obtained by removing one hydrogen atom from each carbon atom at both ends of a linear alkene having a double bond between adjacent carbon atoms, a formula- (CH ₂ ). _k -S- (where k is 2-5
A group represented by the following), or [Chemical 33] [Chemical 34] An agent for treating / preventing arrhythmia, which comprises a piperidine derivative represented by the following formula or a derivative thereof or a pharmacologically acceptable salt thereof as an active ingredient.