WO1996005174A1 - Novel amine derivative, process for producing the same, and use thereof as antiarrhythmic - Google Patents

Abstract

A novel amine derivative represented by general formula (I) and a salt thereof, both being useful as an antiarrhythmic, wherein (a) represents (b) or (c); A represents -NR8-(CH2)a-(5- or 6-membered nitrogenous heterocycle)- or a 6-membered nitrogenous heterocycle, wherein R8 represents lower alkyl or hydroxylated lower alkyl, and a represents 0 or 1; D represents -(CH2)m-, -(CH2)m-O-, -CO- or -SO2-; R1 and R2 represent each independently hydrogen, halogen, lower alkoxy or lower alkylsulfonylamino; R3 represents lower alkyl; R4, R5, R6 and R7 represent each independently hydrogen or lower alkylsulfonylamino; R represents nitro or lower alkylsulfonylamino; X represents hydrogen or halogen; and m and n represent each an integer of 0 to 3.

Description

 Specification

 Novel amine derivative, its production method and use as antiarrhythmic agent

Technical field

 The present invention relates to amine derivatives useful as antiarrhythmic agents. More specifically, the present invention relates to an amine derivative represented by the following general formula (I) and a salt thereof, which can be usefully used as an antiarrhythmic agent having a blocking effect on a potassium channel.

HI (C) (I)

In the above formula,

Is the general formula

Or

Represents a group of

A is a general formula

-lJ CH ₂ ) _a

 R8 group or nitrogen-containing 6-membered hetero ring

Wherein, R _e represents a lower alkyl group or a hydroxy lower alkyl group, a is 0 or 1,

〇_

Is a 5- or 6-membered nitrogen-containing heterocycle,

D is the formula - (CH _{2) m} -, one (CH ₂₎ ™ -0-, -CO- or single S0 ₂ - shows a group,

And R ₂ each independently represent a hydrogen atom, a halogen atom, a lower alkoxy group or a lower alkylsulfonylamino group,

R ₃ represents a lower alkyl group, R ₄ , R ₅ , _Re and R ₇ each independently represent a hydrogen atom or a lower alkylsulfonylamino group;

 R represents a nitro group or a lower alkylsulfonylamino group,

X represents a hydrogen atom or a halogen atom,

m and n each represent an integer of 0 to 3.

 The present invention includes a method for producing the amide derivative of the above general formula (I) and a salt thereof, and uses thereof as an antiarrhythmic agent.

Background art

 Potassium channels, one of the mechanisms that regulate systemic physiology, are distributed in whole body cell lines, including monocytes, myocardium, and so on. Are used for the treatment of various cardiovascular diseases, and are used, for example, as antidiabetic agents, antiarrhythmic agents and the like. Numerous compounds are known in the prior art for such a potassium channel blocker. C For example, glibenclamide, an oral antidiabetic agent that blocks the potassium channel present in the cells of the tendon, is It has been reported that it blocks the ATP-dependent potassium channel of the kidney ^ one cell and thereby induces the release of insulin, thereby exerting a hypoglycemic effect, which is based on the sulfonylprea structure. It is considered to be a common mechanism of action for oral diabetes therapeutics possessed by the skeleton. References [Europe an Jou rna l o f Phar rma c o l ogy, 141, 243-251 (1987); B r i t i sh h J o u n a l o f

Pharmacolgy, 93, 61-68 (1988) 1, it is known that 4-position substituted benzoic acid derivatives exert the same effect. Compounds that block myocardial potassium channels, on the other hand, exhibit antiarrhythmic activity and are classified by the Baugan-Williams classification [see: Anti—Arrhythhmic Action, EM Vaughan "Willli ams, Ac ademi". c P ress, 1980] According to the substance, it is classified as a class III antiarrhythmic agent. As an example of such a compound, a compound represented by the following general formula (A) has recently been proposed as an antiarrhythmic agent in European Patent Publication No. 0503411 or the like.

In the above equation,

R iH, N0 ₂ , CN. No, Rogen, C, 1 C <alkyl, CF ₃ , OCF ₃ , OH. CH ₂ OH, COOH, CHO, NH-CHO, NH ₂ , CO—NH ₂ , tetrazine-5 - I ^{le, R 4 - 0-, R -0} -CH 2 -, R 4 - 0- CO-, R 4 - CO-, R 4 - NH - CO -, R 4 - CO - NH -, R 4 - S 0 ₂ - NH - and is,

R ² is hydrogen, nitro, halogen, d—C <alkyl or R ⁴ —0—,

R ³

_{-N (R5) - (CH 9} 2) ½ - N (R 5) - (CH 2) M -CH (0R O) 7

R ⁴ is d—C ₄ alkyl or phenyl, including the residue R ² , R ⁵ and R ⁶ are hydrogen or the residue R ⁴ ,

R ⁷ represents residue R ¹

n is 0 or 1, m is 1 or 2,

However, if R ³

Then n is 1.

 However, the prior art potassium channel-blocking antiarrhythmic agents and the like which have been identified so far, including the above compounds, are not always satisfactory in their action, and those exhibiting a certain activity have serious side effects. There is also a problem in that there is an urgent need for the development of a powerful antiarrhythmic drug that has an excellent potassium channel blocking action and has few side effects.

Accordingly, the present inventors have searched various compound species for their ability to block the potassium channel and thereby their usefulness as an antiarrhythmic agent. As a result, the present inventors have identified a specific novel compound of the general formula (I) as defined above. Amine derivatives and their salts have few side effects and are strong It has been confirmed that a strong lithium channel blocking action is exhibited, and the present invention has been completed.

Disclosure of the invention

 Accordingly, the present invention relates to a novel amine derivative of the general formula (I) and a salt thereof.

HI (CH ₂ ) (I)

In the above formula,

Is the general formula

Or CT / 95/01134

Represents a group of

A is a general formula

Or a nitrogen atom-containing 6-membered hetero ring, wherein R ₈ represents a lower alkyl group or a hydroxy lower alkyl group,

a is 0 or 1;

〇-

Is a 5- or 6-membered nitrogen-containing heterocycle,

D is formula one (CH _{2) m} -, one (CH _{2) m} -. 0- shows an CO- or SO ₂ groups,

And R ₂ each independently represent a hydrogen atom, a halogen atom, a lower alkoxy group or a lower alkylsulfonylamino group; R 3 represents a lower alkyl group,

R ₄ , R ₅ , _Re and R ₇ each independently represent a hydrogen atom or a lower alkylsulfonylamino group;

 R represents a two-terminal group or a lower alkylsulfonylamino group,

X represents a hydrogen atom or a halogen atom,

m and π represent an integer of 0 to 3.

BEST MODE FOR CARRYING OUT THE INVENTION

 In the expression of various substituents in the present invention, the following meanings are given unless otherwise limited.

 A 5- or 6-membered heterocyclic ring containing a nitrogen atom is a group of a saturated or unsaturated 5- or 6-membered ring containing at least one nitrogen atom as a heteroatom and optionally containing an oxygen atom and a zeo atom. Means, for example, a pyrrolidinyl group, a pyrrolyl group, a pyrrolinyl group, an imidazolyl group, an imidazolidinyl group, a vilazolyl group, a vilazolidinyl group, a vilazolinyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, an isoxoxazolyl group, a piperidinyl group, a piperidinyl group, a piperidinyl group. Pyridyl group, bilaridinyl group, pyrimidinyl group, pyridazinyl group, triazinyl group, thiadianyl group, morpholinyl group and the like. Desirable are a pyrrolidinyl group, a biperidinyl group, a piperazinyl group and the like.

 The halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group and the like.

The lower alkoxy group refers to a chained or branched alkoxy group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as a methoxy group, an ethoxyquin group, and n-propoxy group. Examples thereof include i-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy and t-butoxy.

 A hydroxy lower alkyl group is a group in which any hydrogen atom of a lower alkyl group is substituted with at least one hydroxyl group. For example, a hydroxymethyl group, a 1-hydroxyshethyl group, a 2-hydroquinethyl group, , 2-dihydroxyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1,2-dihydroxypropyl, 2,3-dihydroxypropyl, 1 , 2, 3-trihydroxypropyl group and the like.

The lower alkylsulfonylamino group means an alkylsulfonylamino group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as methylsulfonylamino group, ethylsulfonylamino group, and n-propylsulfonyl. amino groups, i one Puropirusu Ruhoniruamino group, n- butylsulfonyl § amino group, i over butylsulfonyl amino group, s- heptyl sulfonyl § amino group, t one-heptyl sulfonyl § amino _Q that group, and the like

As described above, the compound of the general formula (I) according to the present invention has a strong power channel blocking action as an antiarrhythmic agent belonging to class III, and has a sustained action potential in cardiac muscle and conductive tissue. Prolong the period, thus increasing refractory to extra stimuli (pr ema turest imu li). They have effects on atria, ventricles and conductive tissue both in vitro and in vivo, and are therefore useful in the prevention and treatment of various types of ventricular and supraventricular arrhythmias, including atrial and ventricular fibrillation. is there. These compounds do not alter the rate at which the impulse is conducted and therefore have less tendency to promote or exacerbate arrhythmias than other currently used antiarrhythmic drugs (mostly Class I). In addition, there are few occurrences of neural side effects. Also, some of these compounds have some positive inotropic activity and are particularly useful in patients with impaired cardiac pump function. Desirable compounds of the general formula (I) of the present invention include:

〇- is a general formula

Or

Represents a group of

A is the general formula ( ^CH 2) a

Ro Group showed heterocycles or nitrogen atom one or two to six-membered saturated containing the, wherein R ₈ is Ci one C _e-lower alkyl group or a hydroxy-C, shows an C _e-lower alkyl group, a is 0 Or 1;

〇

Is a 5- or 6-membered heterocycle containing one nitrogen atom,

D is formula chromatography (CH _{2) m} -, one (CH _{2) m} - indicates the group, - 0-, One CO- or - S0 ₂

And R ₂ are each independently a hydrogen atom, a halogen atom, Ci one C _e-lower alkoxy group or a C! A C _β lower alkylsulfonylamino group;

RaiiCj-C _{6 represents} lower alkyl,

R "R ₅ , R _e and R ₇ each independently represent a hydrogen atom or d-C ₆ lower alkylsulfonylamino group,

R is nitro port groups or C, shows an C _e lower alkylsulfonyl § amino group,

X represents a hydrogen atom or a Hagen atom,

m and n are compounds each representing an integer of 0 to 2.

 Among the above desirable compounds, particularly desirable compounds of the general formula (I) are

〇

Is the general formula

Or

Represents a group of

A is the general formula Byeon ^(CH 2) _a O-

R 8

Or a piperidino group or a piperazino group, wherein R ₈ represents a methyl group, an ethyl group or a hydroquinethyl group, a is 0 or 1, and

〇

Is a 3-piperidinyl group or a 2-pyrrolidinyl group; D represents a group of the general formula — (CH ₂ ) _m —,-(CH ₂ ) _m — 0—, —CO— or —S 0 ₂ —,

R! And R ₂ each independently represent a hydrogen atom, a chlorine atom, a methoxy group or a methylsulfonylamino group,

R ₃ represents a methyl group,

R ₄ , R ₅ , R ₆ and R ₇ each independently represent a hydrogen atom or a methylsulfonylamino group,

 R represents a two-terminal group or a methylsulfonylamino group,

X represents a hydrogen atom, a chlorine atom or a fluorine atom,

m and n are compounds showing an integer of 0 to 2.

 The compound of the general formula (I) according to the present invention can further form a pharmaceutically acceptable salt. Such pharmaceutically acceptable salts include acids which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, Inorganic acids such as iodide hydrous acid, etc., and organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid or trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, etc. And acid addition salts formed with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid. Specific examples of such salts include hydrochloride, hydrobromide, hydroiodide, sulfate or hydrogensulfate, phosphate or hydrogenphosphate, acetate, maleate, fumarate Acid salt, lactate, tartrate, citrate, gluconate, benzoate, methanesulfonate, benzenesulfonate or p-toluenesulfonate.

The present invention further includes a process for producing the novel amine derivative of the above general formula (I) and a salt thereof. According to the method of the present invention, the amine derivative of the general formula (I) and a salt thereof are (A) a compound of the following general formula (II) or a salt thereof with a compound of the following general formula (III) or Reacting with a salt thereof to produce a compound of the general formula (Ia) or a salt thereof,

 (B) reacting a compound of the following general formula (IV) or a salt thereof with a compound of the following general formula (V) or a salt thereof to produce a compound of the following general formula (Ib) or a salt thereof: It can be manufactured by a method.

 The above method according to the present invention can be represented by the following reaction scheme.

Method

(ID (III)

(la) Method B

 (IV) (V)

(lb) In the above reaction scheme.

0-

Is the general formula

Or

Represents a group of

 Het represents a nitrogen atom-containing 6-membered hetero ring,

R ₈ represents a lower alkyl group or a hydroxy lower alkyl group, a is 0 or 1,

0- Is a 5- or 6-membered nitrogen-containing heterocycle,

D represents a group of the general formula — (CH ₂ ) _m —, one (CH ₂ ) _m — 0—, one CO— or one S0 ₂ —,

Rt and R ₂ each independently represent a halogen atom, a lower alkoxy group or a lower alkyl sulfonylamino group,

R ₃ represents a lower alkyl group,

R ₄ , R ₅ , _Re and R ₇ each independently represent a hydrogen atom or a lower alkylsulfonylamino group;

 R represents a nitro group or a lower alkylsulfonylamino group,

X represents a hydrogen atom or a halogen atom,

m and n each represent an integer of 0 to 3,

 L is a reactive leaving group, for example, a halogen atom such as a chlorine atom, a bromine atom, an iodine atom, an alkanesulfonyloxy group such as a methanesulfonyloxy group, a benzenesulfonyloxy group or a toluenesulfonyloxy group; Group.

 Hereinafter, each of the methods A and B for producing the compound of the general formula (I) according to the present invention will be described more specifically.

Method A

According to the method A of the present invention, a compound of the general formula (Π) or a salt thereof is reacted with a compound of the general formula (III) or a salt thereof, and A is represented by the general formula- ^(CH 2) _a J ~

The compound of the general formula (I), ie, the compound of the general formula (la) or a salt thereof can be produced. The reaction of Method A can be desirably performed in an organic solvent, generally in the presence or absence of a water-soluble base. The organic solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and is preferably an alcohol solvent such as methanol or ethanol, a halogenated hydrocarbon solvent such as chloroform, methylene chloride, or the like. The reaction can be carried out using dimethyl sulfoxide, dimethylformamide, acetone or the like. This reaction can be further carried out in the presence of an acid acceptor, particularly when the reactive leaving group L is a halogen atom, that is, a chlorine atom, a bromine atom or an iodine atom, and the reaction is carried out in the presence of an acid acceptor. It may be advantageous. When the reaction is carried out in the presence of a water-soluble base, examples of the water-soluble base include pyridine, triethylamine, potassium carbonate, potassium bicarbonate, potassium iodide, sodium methoxide, 1,8-diazabicyclo [5.4. [0] Usual water-soluble bases such as Ndeco 7-ene (DBU) can be desirably used.

 Although the reaction of the method A can be carried out in a relatively wide temperature range, it is generally carried out at room temperature to elevated temperature, preferably at the flow temperature of the solvent used or at a temperature of 50 to 150 ° C. The reaction is generally carried out for 0.5 to 24 hours, preferably for 1 to 15 hours. After the reaction is completed, the reaction product can be separated and purified by a post-treatment method common in the art, if necessary, for example, a method such as column chromatography or recrystallization.

Method B

 According to the method B of the present invention, a compound of the general formula (IV) or a salt thereof is reacted with a compound of the general formula (V) or a salt thereof, and A is a nitrogen-containing 6-membered heterocyclic ring such as piperidino or piperazino. A compound of the general formula (I) representing a group, that is, a compound of the general formula (lb) or a salt thereof can be produced.

The reaction of this method B is carried out under substantially the same reaction conditions as in the above method A. After the reaction is completed, the reaction product can be separated and purified by a post-treatment method common in the art, if necessary, for example, a method such as column chromatography or recrystallization.

 As described above, the amide derivative of the general formula (I) and the pharmaceutically acceptable salt thereof according to the present invention have a strong potassium channel blocking action, and are used as a useful antiarrhythmic agent for beds. be able to. When these compounds are to be used clinically, they can be formulated and used in preparations common in the pharmaceutical field. Therefore, the present invention further provides an antiarrhythmic agent composition comprising as a active ingredient a novel amine derivative of the general formula (I) or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions according to the invention may furthermore be prepared in the customary pharmaceutical field using customary pharmaceutically acceptable carriers by customary methods, such as tablets, capsules, troches, solutions, suspensions and the like. Suspensions and other preparations for oral administration, solutions for injection or suspensions, or dry powders for immediate use that are reconstituted with distilled water for injection at the time of injection It can be formulated into an injection.

 Carriers used for such purposes are conventional in the pharmaceutical field, for example, in the case of formulations for oral administration, binders, lubricants, disintegrants, excipients, solubilizers, dispersants Agents, stabilizing agents, suspending agents, dyes, fragrances, etc. In the case of injections, there are preservatives, soothing agents, solubilizing agents, stabilizing agents, isotonic agents, etc. The pharmaceutical preparation thus produced can be administered orally or parenterally, for example, intravenously, intramuscularly or subcutaneously.

 When the amamine derivative of the general formula (I) according to the present invention is administered for the purpose of treating and preventing arrhythmia, the administration dose can be varied depending on the patient's condition, body weight, age and the like. 1) to 60 mg per kg) is divided into 1 to 3 divided doses.

【Example】 The present invention will be more specifically described by the following examples and experimental examples, but the present invention is not limited thereto.

Example 1 (Optical activity) Production of 1-3- [N- (3,4-dimethoxyfunetyl) -1-N-methylamino] -1- (4-nitrobenzyl) piperidine dihydrochloride (1) (±) —3—Hydroxypiperidine (10.1 g, 99.9 mmol) is dissolved in 400 ml of acetone, and (1 S) — (+) — 30.2 g (130 mmol) of 10-camphorsulfonic acid is dissolved in acetone. It was mixed with a solution dissolved in 40 Om1, stirred at room temperature for 14 hours, and stored in a refrigerator for about 12 days. The generated桔晶by濂過dissolved in 4N- H ₂ S0 ₄ 25ml after drying in vacuo. The crystals were dissolved 4N- the H ₂ S0 ₄ solution and extracted 5 times with black port Holm 1 Om 1, 4N one H ₂ S0 ₄ aqueous solution basified with 50% sodium hydroxide aqueous solution at 0 to 5 ° C After adjustment, extraction was carried out five times with 1 Oml of black-mouthed form. All the extracted form-form layers are combined, dried over anhydrous magnesium sulfate and concentrated to give an oily residue, which is crystallized from a small amount of getyl ether to give the desired compound (R) —3-H 1.681 g of droxycipiperidine were obtained (melting point: 80-85 ° C.).

(2) 1.5 g (14.9 mimol) of (R) -3 -hydroxypiperidine prepared in (1) above, 3.2 g (14.9 mimol) of 4,12 trobenzylbutamide ) And potassium carbonate (2.66 g, 14.9 mmol) were heated in methanol 2 Om 1 for 2 hours at reflux. Then the solvent was evaporated from the reaction mixture, the residue was diluted with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate and evaporated, and the residue was purified by column chromatography on silica gel using n-hexane (25%) in ethyl acetate as eluent. The fractions containing the product were combined and evaporated to give 3 g of the desired compound (R) -3-Hydroquine-111 (4-nitrobenzyl) piperidine in the form of a roll. _{'H-NMR (CDC 1 3} ) δ 8. 18 (d, 2H), 7. 5 (d. 2H)

3.8 (s, 1H), 3.55 (s, 2H), 2.6-2.15 (m, 5 H), 1.85- 1.45 (m, 4H)

 (3) (R) — 3-hydroxy-11- (412-trobenzyl) piperidine (g: 4.3 mimol) and 0.59 ml of triethylamine prepared in (2) above

To a mixture of (4.3 mmol) and 20 ml of methylene chloride, 0.39 ml (5.2 mmol) of methanesulfonyl chloride was gradually added, and the mixture was stirred at room temperature for 3 hours. Thereafter, the solvent was removed from the reaction mixture by evaporation, and the residue was diluted with a saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The organic extract was dried over magnesium sulfate and evaporated to give 0.91 g of the desired compound (R) -3-methanesulfonyloxie1-1 (4-nitrotrobenzyl) piperidine.

 (4) 0.91 g (2.89 millimoles) of (R) —3-methanesulfonyloxy 1-1 (4-nitrobenzyl) piperidine produced in (3) above in methanol 1 Om After dissolving in 1, 1.6 ml (8.67 mmol) of 2- (3,4-dimethoxyphenyl) -N-methylethylamine was added at room temperature. After the reaction mixture was stirred at room temperature for 24 hours, the solvent was evaporated and the residue was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. After drying the organic extract over anhydrous magnesium sulphate and evaporating, the residue is subjected to column chromatography on silica gel using ethyl acetate containing n-hexane (25%) as eluent. Refined. The fractions containing the desired product were combined and evaporated and the residue was dissolved in 10 ml of methanol. HC 1 gas was added to the solution, the product was converted to the hydrochloride, and evaporated under reduced pressure to give the title compound (optically active) 1-3- [N- (3,4-dimethoxyphenethyl) -1 N-methylamino] There was obtained 0.85 g of 4- (4-nitrobenzyl) piperidine dihydrochloride.

[a] 9. Melting point: 77-79 ° C (dihydrochloride form)

-NMR (CD ₃ OD): δ 8.05 (d, J = 8.6 Hz, 2H, ArH) .7.5 (d, J = 8.4 Hz, 2H, ArH), 6. 65 (m, J = 8. 0Hz , 3H, A r H), 4. 25 (d, J = 14. 1Hz, 1 H, A r CH 2), 3. 78 (s, 3 H, OCH 3) , 3.75 (s.3H, O

CH ₃ ), 3.25 (d.J = 14.OH z, 1 H, Ar CH ₂ ), 2.8 (m, 1 H, N (CH ₃ ) CH), 2.7-2.3 ( m, 8H, Piberidine H + NCH ₂ CH ₂ ), 2.25 (s, 3H, N-CH ₃ ), 2.15—1.8 (m, 2H, piperidine alternate), 1.65 ( m, 2H, Piberidine Day)

IR (KB r, cm " ¹ ): 1530, 1360 (N = 0)

MS: 414 (MH +)

 Example 2 Production of 2- [N- (3,4 dimethoxybenzyl) -1-N-methylamino] methyl-11- (4-upperoxyl) pidinidine hydrochloride

 (1) Dissolve 100 g (0.060 mol) of 3,4-dimethoxybenzyl alcohol in 200 ml of benzene, add 21.2 g (0.179 mol) of thionyl chloride dropwise over 10 minutes, and add dimethylformamide. After addition of 2 drops, the mixture was refluxed for 5 hours. Thereafter, the reaction mixture was washed with water, a saturated aqueous solution of sodium bicarbonate and saturated saline, and then dried over anhydrous magnesium sulfate. The residue was distilled under reduced pressure to obtain 10.4 g of the target compound 3,4-dimethoxybenzyl chloride as a pale yellow substance.

 'H-NMR (CDC "): δ 6.95-6, 77 (m. 3H, Ar H), 4.56 (s, 2H. -CH ^ C 1). 3.89 (s. 3H, Cj O-), 3.87 (s, 3H, CH3O-)

(2) 3.4-Dimethoxybenzyl chloride produced in (1) above 3.0 g (0.016 mol) was dissolved in 100 ml of dioxane, 10 Om1 of 40% methylamine Z water was added, and the mixture was stirred at room temperature for 0.5 hour. Thereafter, the reaction mixture was distilled under reduced pressure to remove dioxane, and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to give the target compound N- (3,4-dimethoxybenzyl) methylamine 2.80 as a pale yellow oil. g was obtained.

_{'H-NMR (CDC 1 3} ):. Δ 6. 88-6 80 (m, 3H, A r H), 3 • 88 (s, 3H, CH3O-), 3. 86 (s, 3H, CH 3 0-), 3.69 (s, 2H. One CH ₂ NH—), 2.45 (s, 3H, one CH ₂ N)

 (3) 3-Hydroxypiperidine hydrochloride 19.1 (0.139 mol) and 10.0 g (0.463 mol) of 12-trobenzyl bromide were dissolved in 300 ml of methanol, After adding 25.6 g (0.185 mol) of potassium, the mixture was allowed to flow slowly for about 30 minutes. The reaction mixture was filtered to remove potassium carbonate, and the methanol was distilled off under reduced pressure to remove it. Then, a saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract is washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to give the target compound, 3-hydroxy (11-nitrobenzyl) piperidine, in the form of a pale yellow foil 10. 7 g were obtained.

 ! H-NMR (CDC 13): δ 8.18 (d, J = 8.7 Hz, 2H, A r H). 7.49 (d, J = 8.7 H z. 2H. A r H) .

3.82 (b s, 1H, Ν), 3.59

 HO H

(s. 2H.> N-CH ₂ -^)-N0 ₂ ), 2.55--2.15 (m, 5H, resin),] 90-1.50 (m. 3H, piperidine and)

 (4) 10.4 g (0.044 mol) of 3-hydroquinone-1-1 (4-nitrobenzyl) piperidine and 13.4 g (0.132 mol) of triethylamine prepared in (3) above were treated with methylene. The solution was dissolved in 300 ml of chloride and the temperature was lowered to 0 to 5 ° C. Methanesulfonyl chloride 5.1 ml at 0-5 ° C

(0.066 mol) was added dropwise over 10 minutes, the temperature was raised to room temperature, and the mixture was stirred for 30 minutes. Thereafter, the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate, water and saturated saline, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to give the target compound 3-methanesulfonyloxyl as a yellow oil. There were obtained 12.8 g of benzyl) piperidine.

_{'H-NMR (CDC 1 3} ): δ 8. 19 (d, 2H), 7. 50 (d, 2H), 4. 78 (m, 1H), 3. 63 (dd, 2H), 3. 01 (s, 3H). 2.91 (d, 1H), 2.52 (bs, 1 H), 2.43 (m, 1 H), 2.19 (m. 1H). 2.01 (bs, 1 H), 1.80 (bs, 1H), 1.63 (m, 2H)

(5) 3-Methanesulfonyloxy 11- (412-port benzyl) piperidine 31 Omg (0.99 millimol) produced in (4) above and N-methane produced in (2) above 536 mg (2.96 mmol) of (3,4-dimethoxybenzyl) methylamine was dissolved in 30 ml of methanol, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was distilled under reduced pressure to remove methanol, the residue was added with a saturated sodium bicarbonate solution, extracted with ethyl acetate, and the extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. Let dry. After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography on silica gel using ethyl acetate as eluent, and purified to obtain 50 mg of the target compound as a pale yellow free base This is then chlorinated with HC1 gas to give the title compound 2— [N— (3.4-dimethyl There was obtained 53 mg of [cibenzyl)-[1-N-methylamino] methyl-11- (4-nitrobenzyl) pyrrolidine dihydrochloride.

Melting point: 64 ° C (decomposition)

^J H-NMR (CDsOD): δ 8.25 (d, J = 8.7 Hz 2H. A r H), 7.78 (d, J = 8.7 Hz, 2 H, A r H), 7 13 (s. 1 H, Ar H), 7.01 -6. 90 (m, 2H, Ar H) 4.46 (s, 2H,

-CH ₂ O N0 ₂ ) .4.35 (bs, 2H, -CH ₂ "^ ~ OCH ₃ ). 3.81 (s, 1 H, pyrrolidine), ^0CH

3.42 (m, 2H, -C).

3. 77 (s, 3H, CH3O- ), 3. 75 (s, 3H, CH 3 0 -), 3. 01 (m, 1H, pyrrolidine Dan), 2. 70 (s, 3H , - CH 2 one N (CH ₃ ) CH ₂ —), 2.26-1.87 (m, 5H, pyrrolidine H)

IR (KB r, cm " ¹ ): 1540, 1260 (one N0 ₂ )

MS: 400 (MH ⁺ )

 Example 3 Production of 2- [N- (3,4-dimethoxyphenethyl) -1-N-methylamino] methyl-11- (4-nitrobenzyl) pyrrolidine dihydrochloride

6.0 g (0.019 mol) of 3-methanesulfonyloxy- (4-nitrobenzyl) piperidine prepared in (4) of Example 2 and 2- (3,4-dimethyl) Toxiphenyl) 1-N-methylethylamine 11.18 g (0.057 mol) was dissolved in 200 ml of methanol and stirred at room temperature for 24 hours. The methanol was removed by distillation under reduced pressure, ethyl acetate was added, and the mixture was washed with water, a saturated aqueous solution of sodium bicarbonate and saturated saline, and dried over anhydrous magnesium sulfate. Depressurized residue The residue was distilled under reduced pressure to remove ethyl acetate, and purified by column chromatography on silica gel using ethyl acetate containing methanol (10%) as an eluent to give the title compound 1 in the free base state. .52 to give salt with 11: 1 gas to form the title compound in the solid state 2— [N— (3,4-Dimethoxyphenethyl) -1-N—methylamino] methyl-1- (4-12-trobenzyl) pyrrolidine dihydrochloride 1.5 g were obtained.

Melting point: 94-97 ° C

 Ή-NMR (CD3OD): δ 8.37 (d, J = 8.7 Hz, 2H, ArH), 7.97 (d, J = 8.8 Hz, 2H, ArH),

7. 01 -6. 85 (m, 3H, A r H), 4. 63 (b s. 2H, -CH 2 -Q-N0 2), 4. 11-3. 91

(m, 2H. -CH ₂ ), 3.87 (s, 3H,

CH ₃ 0-), 3.83 (s, 3H, CHg 0-),

 H ゥ CO

3. 54 (m, 4H, CH 3 0 "¾H¾CH2N rather),

3. 10 (m, 3H, pyrrolidine), 3.00 (s, 3Η, — CH ₂ N (CH ₃ ) one CH ₂ —), 2. 32-2.00 (m, 4H, pyrrolidine H)

IR (KB r, cm_ Ri: 1520, 1350 (-N0 ₂₎

MS: 413 (M ⁺ )

Example 4 Production of 3- [N- (4-Methanesulfonamidophenethyl) -1-N-methylamino 1-112 (412-trobenzyl) _piperidinedihydrochloride (1) 6.86 g (0.05 mol) of 4-aminophenylethyl alcohol was dissolved in 100 ml of pyridine and cooled in an ice water bath. To this, 15.5 ml (0.2 mol) of methanesulfonyl chloride was added dropwise, and the mixture was stirred at room temperature for 2.5 hours. 20 ml of methanol was added dropwise to the reaction mixture and evaporated under reduced pressure. A saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted three times with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the residue was added 230 ml of chloroform and further concentrated. The resulting solid was mixed with getyl ether, and the mixture was stirred. The resulting solid was dried by drying, to obtain 12.6 g of the target compound 4-methansulfonamide dophenethyl methyl sulfonate.

_{»H-NMR (CDC 1 3} ): δ 9. 20 (. B s 1H), 7. 25 (. D 2H), 7. 18 (d, 2H), 4. 39 (t, 2H), 3. 01 (t. 2H). 2.92 (s. 6H)

 (2) 1.47 g (5 mimol) of the 4-monomethanesulfonamidophenethylmethanesulfonate produced in the above (1) was added to a 40% methylamine Z methanol solution (6 Oml) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, 30 ml of ethanol was added, and the mixture was stirred to remove generated solids by filtration, and the base solution was concentrated under reduced pressure. Ether was added to the residue, stirred, filtered, and dried over anhydrous magnesium sulfate to obtain 0.98 g of the target compound 2- (4-methanesulfonamidophenyl) -1-N-methylethylamine in a solid state. Obtained.

'H-NMR (CD ₃ OD): <57.22 (s, 4H), 2.97 (s. 3H), 2.84 (s. 4H), 2.46 (s, 3H)

(3) 3-Methanesulfonyloxy-1- (4-nitrobenzyl) piperidine 0.5 g (1.6 mimol) and 2- (4-methanesulfonamide) produced in (2) above 0.34 g (l. 5 mimol) of 1 N-methylethylamine was attracted to a mixed solvent of 1 Om1 of methanol and 1 Om1 of formaldehyde. This reaction mixture The mixture was heated at a flowing temperature for 6 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a 15: 1 mixture of chloroform and methanol as eluent. The fractions containing the desired product were combined and evaporated under reduced pressure. The residue was dissolved in 10 ml of methanol, hydrogen chloride was added to chlorinate the solvent, and the solvent was evaporated under reduced pressure. Add isopropyl alcohol to form a solid, evaporate under reduced pressure, add ethyl ether, stir and evaporate to give the title compound in the solid state 3- [N- (4-Methanesulfonamide phenethyl) -N-methylamino] 0.11 g of (111-benzyl) biperidine dihydrochloride was obtained.

Melting point:> 133 ° C (decomposition)

_{^{! H-NMR (CD 3 OD}} ): δ 8. 11 (.. D 5 = 8 7Hz, 2H, A r H) (7. 76 (d, J = 8. 7Hz, 2H, A r H), 7 .12 (d, J = 8.5 Hz, 2H, ArH), 7.03 (d, J = 8.5 Hz, 2H, ArH), 4.74 (d, J = 11.8 Hz, 1 H, N-CH ₂ -A r), 4.23 (d, J = l 1.8 Hz, 1H, N-CH ₂ -A r), 4.0

3 (bs, 1H, piperidine), 3.74 (bs, 1H, piperidine H), 3.54 (bs, 1H, piperidine and), 3.24 (bs, 3H , Ar CH ₂ CH ₂ N + piperidine. 2, 92 (t, J = 8.3 Hz, 2H, Ar CH ₂ CH ₂ N), 2.84 (s, 3H, NCH ₃ ). 2. 7 5 (s. 3H, S0 ₂ CH ₃ ), 2.42 (b s. 1H, piperidine)

, 1.91-2.01 (m, 4 H, piperidine H)

 I R (KB r.cnr: 3440 (NH), 1160 (S = 0)

^{MS: 447 (M + + 1} )

Example 5 (Optical activity) Production of 1-3- [N- (3,4-Dimethoxyphenethyl) -1-N-ethylamino] 1-12- (412nitrobenzyl) piperidine dihydrochloride (1) 5 g (27.5 mimol) of 3,4-dimethyphenethyl alcohol and 7.66 ml (55 mimol) of triethylamine are added to 5 Om 1 of methylene chloride and then added to this mixture. At 0 ° C., 3.18 ml (41.3 mmol) of methanesulfonyl chloride was gradually added, and the mixture was stirred at room temperature for 3 hours. Thereafter, the solvent was evaporated, and the residue was diluted with a saturated aqueous solution of sodium bicarbonate and extracted with a black hole form. The organic extract was dried over sodium sulfate and evaporated to obtain 6.6 g of the target compound 3,4 dimethoxyphenethyl methyl sulfonate.

... JH - NMR (CDC 1 3): 5 6. 8 (m, 3H), 4. 4 (. T 2H), 3 85 (s, 6H) 3. 0 (t, 2H) 2. 9 ( s, 3H)

 (2) 5 g (19.3 mimol) of 3.4-dimethoxyfunetyl methanesulfonate prepared in (1) above and 3.26 ml (57.9 mimol) of 70% ethylamine were added to methanol 5 Heated at flowing temperature in Om1 for 6 hours. After that, the remaining solvent was evaporated and concentrated under reduced pressure to remove residual water, thereby obtaining a crude target compound N- (3,4-dimethoxyx-ethyl) ethylamine. The product was used in the next step reaction without further purification.

(3) Dissolve 1.22 g (4.3 mimol) of (R) — 3-methanesulfonyloxy 11- (4-nitrobenzyl) piperidine in 15 ml of methanol, and add the above solution (2) at room temperature. 2.66 g (12.9 mimol) of N- (3,4-dimethoxyphenethyl) ethylamine prepared in the above was added. After stirring the reaction mixture at room temperature for 24 hours, the solvent was evaporated and the residue was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate and evaporated, and the residue was chromatographed on a silica gel using ethyl acetate containing n-hexane (25%) as eluent. And purified. The fractions containing the desired product are combined and evaporated, the residue is dissolved in 1 Oml of methanol, HC1 gas is added to form the hydrochloride salt and evaporated to give the title compound as a foam. (Optical activity) 1.3- [N- (3.4 dimethoxyphenethyl) -1-N-ethylamino] 111 (4-nitrobenzyl) piperidine dihydrochloride 0.23 g was obtained.

_{'H-NMR (CDC 1 3} ): δ 8. 2 (bs, 2H, A r H), 7. 95 (. Bs, 2H A r H), 6. 7 (m, 3H, A r H), 3. 7-3.95 (m, 8H, OCH ₃ X2 + A r -CH) .2.0-3.45 (m, 12H

, Ar— CH + Ar— CH ₂ -CH ₂ -N (CH ₂ CH ₃ ) CH + Piberidine H). 1.35-1.65 (m, 7H, CH ₂ -N (CH ₂ CH ₃ ) One CH ₂ + peridine

 I R (KB r, cm_ re: 1358, 1522 (N = 0)

MS: 428 (MH +)

 Example 6 (Optical activity) Production of 1-3- [N- (2-amino-4,5-dimethoxyfuhethyl) -1-N-methylamino] 111- (412-nitrobenzyl) piperidine dihydrochloride

 (1) Dissolve 2.74 g (0.011 mol) of 2- (4.5-dimethoxy-2-nitrophenyl) -N-methylethylamine in a mixed solvent of 100 ml of ethyl acetate and 100 ml of methanol. To this, 0.685 g of 10% PdZC was gradually added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The mixture was passed through celite, and the solvent was distilled off under reduced pressure to obtain 2.39 g of the target compound 21- (2-amino-4.5-dimethylethoxy) -1-N-methylethylamine as a yellow oil. Obtained. The obtained compound was used for the next step reaction without further purification.

(2) 2- (2-amino-4,5-dimethoxyphenyl) -N-methylethylamine prepared from (1) above 2.0 g (9.51 mimol) and (S) -3 1.93 g (2.95 mmol) of 1-methanesulfonyloxy-1- (4-nitrobenzyl) piperidine was dissolved in 50 ml of methanol and stirred at room temperature for 3 hours. Later the methanol was distilled off under reduced pressure. Alkaliized with saturated aqueous sodium bicarbonate and extracted three times with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. Ethyl acetate was removed by distillation under reduced pressure, and the residue was purified by column chromatography on silica gel using chloroform (7%) containing chloroform as eluent. The title compound (optically active) 13- [N- (2-amino-4,5 dimethoxyphenethyl) -1-N-methylamino] 1- (4- (12-trobenzyl)) piperidine dihydrochloride 16 Omg (Yield: 12.7%).

'H-NMR (CD ₃ OD): δ 8.21 (d, J = 8.7 Hz, 2H, ArH), 7.86 (d, J = 8.7 Hz, 2H, ArH), 7 . 02 (s,

1H, ArH), 6.85 (s, 1H, ArH). 4.90 (d, J = l 2.9Hz,

1H, -CH ₂ --N0 ₂ ), 4.37 (d, J = 12.9 Hz,

4.18 (bs, 1H, piperidine H), 3.92 (d. 1H, piperidine), 3.80 (s, 3H, CH3O-), 3.75 (s, 3H, CH3O) -), 3.59-3.11 (m, 6H, piperidine

H + <H CH N <), 2.95 (s, 3 H, N-CH3),

2.55 (m. 1H, piperidine), 2.19-1.88 (m, 4H, piperidine)

IR (KB r, cm ' ¹ ): 3400 (-NH ₂ ), 1620, 1290 (-NO ₂ ) MS: 429 (MH ⁺ ) [Example 7]

 The following compounds and the like can be produced by the methods described in Examples 1 to 6 above.

 (1) 3— [N— (3,4-dimethoxyphenethyl) -1-N— (2-hydroxyethyl) amino] 111— (412-benzyl) piperidine dihydrochloride

Contact point: 93. 6—96. 1

'H-NMR (CDsOD): δ 8.33 (d, J = 8.7Hz. 2H, ArH), 7.93 (d, J = 8.7Hz, 2H, ArH), 6 . 99 (s. 1 H, A r H), 6. 91 (m, 2H. A r H), 4. 23 (m, 2H. N CH 2 CH 2 -OH), 4. 02 (t, J = 4.8 Hz, 2H, NCH ₂ C ₆

H ₄ ), 3.87 (s.3H, CH ₃ Q) .3.80 (s, 3H, CH ₃ Q). 3.49 (bs, 4H, CH ₂ CH ₂ N (CH ₂ CH ₂ OH) 3.25 (bs, 1H, pyridine), 3.08 (m, 2H, Ar CH ₂ CH ₂ N). 2.61 (bs, 1H, pyridine), 2. 12 (m, 3H, pyridine H), 1.35 (m, 3H, pyridine H), 0.9

7 (m, 1H, piperidine)

IR (KB r, cm " ¹ ): 3450 (OH), 1520 and 1350 (aromatic N = 0)

 MS: 444 (MH +)

 (2) 3- [N- (4-methanesulfonamidobenzyl) -1-N-methylamino] 111- (4-nitrobenzyl) piperidine dihydrochloride (foam)

_{JH-NMR (CDC 1 3)} :. Δ 8. 1 (. D, J = 8 6 H z, 2 H. A r H), 7. 4 (d, J = 8 3H z, 2H, A r H ), 7.18 (d, J = 8.7Hz, 2H, ArH), 7.0 (d, J = 8.3Hz, 2H, ArH), 4.25 (d, J = 13H z, 1 H, Ar CH ₂ ) .3.36 (s, 2H.A r CH ₂ ), 3.29 (d, J = 13 Hz, 1 H.A r CH ₂ ),

2.9 (s, 3H, SO2CH3), 2.81 (m, 1H, pyridine), 2.65 (m, 1 1, pyridine), 2.57 (m. 1 1, 2.32 (m, 1 ,, piperidine), 2.13 (s, 3H, N-CH ₃ ), 2.1 (m, 1Η, piperidine), 1 . 9 (m

, 1Η, piperidine Η), 1.65 (m, 3Η, piperidine H) I R (KB r, cm_: 1360, 1540 (N = 0)

MS: 433 (MH +)

 (3) 1— (4-Methanesulfonamidobenzyl) 1-41 (3,4-Dimethoxyphenethyl) piperazine dihydrochloride

Melting point:> 120 (decomposition)

^X H-NMR (DMSO-d ₆ ): δ 7.56 (d, J = 8.3 Hz, 2H, Ar H), 7.27 (d, J = 8.3 Hz, 2H, Ar H), 6.91 (m, 2H, Ar H), 6.79 (d, J = 8.2 Hz.1 H, Ar H), 4.22 (bs, 2H, NCH ₂ Ar), 3.77 (s, 3 H, OCH ₃ ),

3.74 (s, 3H. OCHs), 3.20—

3.64 (bs, 10H + H ₂ O, piperazine H + CH ₂ CH ₂ -N), 3.04 (s, 3H, S0 ₂ CH ₃ ), 2.97 (m, 2H, CH CH-N N)

I R (KB r, cm- r: 3430 (NH), 1160 (S = 0)

MS: 433 (M +)

(4) 4- (4-methanesulfonamidobenzoyl) 1-1-1 [2- (4-methyl-2-quinolyl) ethyl] piperidine Melting point: 135.5-137.5 ° C

• H-NMR (CD ₃ OD): δ 7.1-8.3 (m. 9H. Quinoline H + ArH), 3.0-3.5 (m, 1 OH. Piperidine and + . Kino Li down one _{CH 2 + S0 2 CH 3)} , 2. 3-2 9 (m, 5 H, quinoline one CH ₃ + CH ₂ CH ₂ - piperidine), 1. 7- 2. 1 (m , 4H, piperidine H)

I R (KB r, cm-ri: 3400 (NH), 1660 (C = 0)

MS: 169 (M ⁺ -282), 282 (M ⁺ -169)

 (5) 4- (4-Methanesulfonamidobenzoyl) 1-11 (6-Methanesulfonamide 4-methyl-2-quinolylmethyl) piperidine

Melting point:> 199.5 ° C (decomposition)

^ -NMR (DMSO-de): δ 10.18 (b s. 2H, SQ ₂ NHX2), 7.94 (m, 3H, quinoline H + Ar), 7.78 (s, 1 H) , Quinoline and), 7.58 (m, 1H, quinoline J |), 7.47 (s, 1Η, quinoline), 7.29 (m, 2H, ArH), 3. 70. (s. 2H, NCH ₂ -quinoline), 3.08 (m, 6H. SQ ₂ CH ₃ X2), 2.87 (m, 2H. Pyridine), 2.62 (s. 3Η) , Quinoline CH ₃ )> 2.23 (m, 2H, piperidine), 1.60-1.76 (m, 4H. Piperidine)

IR (KB r.cm ' ¹ ): 3270 (NH), 1150 (S = 0)

MS: 420 (M ⁺ -l 10), '341 (M +-189)

 (6) 3- [N- (3,4-dimethoxybenzyl) -1-N-methylamino] 111- (412-trifluorophenyl) biperidine dihydrochloride

_{'H-NMR (CDC 1 3} ):. Δ 8. 06 (d, 2 H, A r H), 7. 73 (s, 1 H. A r H), 6. 92 (d, 2H A r H ), 6. 48 (d. 2H , A r H), 4. 42 (s, 2 H, N- CH 2), 4. 0 (d. 1 H. Pi 3.91 (s. 6H, CH ₃ OX2), 3.49 (bs, 2H, peridine), 3.28 (bs, 2H. Peridine), 2.93 (s. bs, 3H, N-CH ₃ ), 2.16—2.36 (m. 4Η, bipyridine)

IR (KB r.cm- ¹ ): 1120, 1320 (S = 0)

 S: 386 (M + l)

(7) 3- [N- (3, 4 Jime Tokishifuenechiru) Single N- Mechiruamino] one 1 one (4 one methanesulfonate Ami Dobenjiru) piperidine dihydrochloride (foam) 'H-NMR (CDC 1 3 ): Δ 7.3 (d, 2H. J = 8.3 Hz, ArH), 7.15 (d, J = 8.4 Hz, 2H, ArH). 6.75 (m, 3

H, A r H), 4. 15 (d, J = 13H z, 1 H, A r one _{CH 2), 3. 86 (} s, 3H, OCH 3). 3. 84 (s, 3H, OCH 3 ), 3. 2 (d, J = 13H z, 1H, A r- CH 2), 2. 95 (s, 3H, S0 2 CH 3), 2. 0-2. 9 (m, 12H, A r CH ₂ CH ₂ N + NCH ₃ + piperidine, 1.65—1.9 (m, 4 H, piperidine)

 I R (KB r.cm- r: 1150.1340 (S = 0)

MS: 462 (MH ⁺ )

 (8) 1- (4-Methanesulfonamidobenzyl) -1- [N- (6-Methanesulfonamido-1-methyl-2-quinolylmethyl) -1-N-methylamino] piperidine

Melting point: 78-80

^{X H-NMR (CD3OD):} . Δ 7. 85 (. D J = 9H z, 1 H, keno Li emissions H) 7. 8 (.. D , J = 2 4Hz 1 H, keno Li down Dan), 7.55 (d, J = 2.1 Hz, 1H, quinoline and), 7.5 (d. 1H. Quinoline and), 6.85 (d, J = 8.8 Hz, 2H, A r H). 6.35 (d, J = 8. 9H z. 2H, A r H), 3. 69 (d, J = 6H z, 2H, keno Li Hmm _{CH 2), 2. 95 (m} . 5H, N-CH 3 + A r -CH ₂ ), 2.71 (s, 3H, SQ ₂ CH ₃ ), 2.65 (s, 3H. S 0 ₂ CH ₃ ). 2.47 (d, 1H, J = 2.9 Hz, piperidine Dan), 2. 35 (s. 3H , quinoline _{CH 3), 2. 3-1. 7} (m, 5Η, Piperi Jin且)

IR CKB r, cm ' ¹ ): 1160. 1340 (S = 0)

MS: 532 (MH ⁺ )

 (9) 3— [N— (3,4-dimethoxyphenethyl) 1-N-methylamino] 111 (412-trobenzyl) piperidine hydrochloride (foam)

_{Ή-NMR (CDC 1 3)} : δ 8. 25 (m, 2H, A r H), 7. 8 (m, 2H, A r H), 6. 7 (m, 3H, A r H), 3 79 (s, 3H, 0 CH ₃ ), 3.78 (s, 3H, OCH ₃ ) .2.9-3.65 (m, 12 H, Ar CH ₂ CH ₂ N + NCH ₃ + peak Lysine), 1.8-2. 5 (m, 4Η, piperidine and)

IR (KB r, cm " ¹ ): 1520, 1360 (N = 0), 1640 (C = 0) MS: 428 (MH ⁺ )

 [Embodiment 8]

 The following compounds and the like can be further produced by the methods described in Examples 1 to 6 above.

 (1) 3— [N— (6-Methanesulfonamido 4-methyl-2-quinolinylmethyl) -1-N-methylamino] 111- (412-trophenyl) piperidine

Melting point: 88-90 ° C

 (2) 1— (3,4-dimethoxyphenethyl) 1-41 (4-1 methanesulfonamide phenethyl) piperazine

Melting point: 131- 132 ° C (3) 4- (4-methanesulfonamidobenzenesulfonyl) 1-1-1 (6-methansulfonamide 4-methyl-2-quinolyl) piperazine

 S: 554 (M + 1)

 (4) 3- [N- (3,4-dimethoxybenzyl) 1-N-methylamino] .111 (4-nitrobenzyl) piveridine dihydrochloride

 MS: 400 (MH +)

 (5) 2- [N- (3,4-dimethoxyphenethyl) -N-methylaminomethyl] 111- (4-Methanesulfonamidobenzyl) pyrrolidine dihydrochloride

Melting point: 113 ^e C (decomposition)

 (6) 2- [N- (3,4-dimethoxybenzyl) -1-N-methylaminomethyl] 111 (4-methanesulfonamidobenzyl) pyrrolidine dihydrochloride

MS: 448 (MH +)

 (7) 1- (2-chloro-4,2-trobenzyl) -1 (optically active) 1-3- [N- (3,4-Dimethoxyphenethyl) -1-N-methylamino] piperidine dihydrochloride MS: 449 (M + 1)

 (8) 1- (2-chloro-4-1 methanesulfonamidobenzyl) 1-3- [N- (3,4-dimethoxyphenethyl) -N-methylamino] biperidine dihydrochloride

MS: 497 (M + 1)

 (9) 1- [4- (3,4-Dimethoxyphenethyl) biperazino] 1-2- (4-Methanesulfonamidophenoxy) ethaneni hydrochloride

 MS: 463 (NT)

 (10) 3- [N- (3.4 dimethoxyphenethyl) 1 N-methylamino] 1 1 1 1 (4 12 tropofinyl) bidiridine dihydrochloride

 MS: 400 (NT)

(11) (S) — 3— [N— (3,4-dichlorophenethyl) -N-methyla Mino] 1 1 1 (4 12 trobenzyl) piperidine dihydrochloride

MS: 422 (M ⁺ )

 (12) 3- [N- (3,4-dichlorophenethyl) -1-N-methylamino] 111- (4-methanesulfonamidobenzyl) piperidine dihydrochloride

MS: 470 (M +)

 (13) 3- [N— (3,4-dimethoxyphenethyl) -1-N-methylamino] 111 (412-tropenetyl) piperidine dihydrochloride

 MS: 428 (M ++ 1)

 (14) 3— [N— (3,4-dimethoxybenzyl) 1 N-methylamino] 1 1— (412 tropenetyl) piperidine dihydrochloride

 MS: 414 (M ++ 1)

 (15) 3- [N- (3,4-dimethoxybenzyl) -1-N-methylaminomethyl] 111- (4-nitrobenzyl) piperidine dihydrochloride

 MS: 414 (M ++ 1)

 (16) 3- [N- (3,4-dimethoxyphenethyl) -N-methylamino] -111 (4-nitrobenzenesulfonyl) piperidine hydrochloride

_{'H-NMR (CDC 1 3} ):.. 5 ( as an organic base) 8. 37 (d, 2H) , 8 02 (d, 2H), 6. 75 (m, 3H), 3. 88 (s 6H ), 3.69 (bs.1H), 3.45 (bs, 1H). 3.10 (m.1H). 2.70 (m, 5H), 2.40 (m, 4H). 1. 85 (m, 2H)

. 1. 66 (m. 2H)

 (17) 3- (4-Methanesulfonamide phenoxymethyl) 1-1-1 (4-methyl-2-quinolylmethyl) piperidine

Melting point: 73_75 ° C

(18) 1— (6-Methanesulfonamide 4-methyl-2-quinolylmethyl) —3— (4-Methanesulfonamidophenoxymethyl) piperidine

MS: 533 (M + 1)

 (19) 1-1 (3,4-diethoxyphenyl) 1-41 (4-1 methanesulfonamide phenyl) piperazine

Melting point: 132. 5-133. 9 ° C

 (20) 4- (2-Fluoro-4-1 methanesulfonamidobenzoyl) 1-11

 [2- (4-Methyl-2-quinolyl) ethyl] piperidine

Melting point: 160—161 ° C

 (21) 1- [4- (3,4-dimethoxyphenyl) 1-1-piperazinyl] 1 2- (4-methanesulfonamide phenoxy) ethane

Melting point: 100-102 ° C

 (22) 1- [4- (3,4-dimethoxybenzyl) 1-1-piperazinyl] 1-2- (4-methanesulfonamidophenoxy) ethaneni hydrochloride

MS: 450 (M + 1)

Experimental example 1

Efficient refractory period (ER P c) prolongation using contractile force in papillary muscles isolated from guinea pigs

And isolated right ventricular papillary muscle of male guinea pigs weighing 400-600 g, the temperature is maintained at 3 4 ° C, a gas mixture (95%: 5% = 0 2: C0 2) Kureppu Sue Ringer solution saturated with the _c one side which is Konshide the organ bath (organbath) containing the ligated to the transducer (tr an s duc er), the other side gave an initial tension of 0. 5 g is fixed. The isolated papillary muscle was subjected to electrical stimulation (frequency: 1 Hz, vibration width: 4 msec, voltage: low value xl. 5), and was stabilized for at least 2 hours while washing at 15 minute intervals. An early stimulation (ex trast imu lus, frequency: 1 Hz, vibration width: 4 ms ec, voltage: 閩 value xl. 5) is applied to the stabilized isolated papillary muscle, and the contraction force is applied. The effective refractory period (ERP c) was measured. During the experiment at 3 Hz, only the frequency was changed under the same conditions as at 1 Hz, and the experiment was performed in the same manner. Each experiment compound was dissolved in a concentration of 10- ² M with 100% dimethyl sulfoxide (DMSO), was used by diluting with Kure' Pusu Ringer's solution. 10- ^beta concentration Micromax: was measured ERP c of up to 1 hour after administration of the experimental compound (final DMSO concentration 0.1%). Data for overnight was shown as the percentage change (%) after drug administration compared to before drug administration. The experimental results are shown in Tables 1 and 2. Table 1. ERP c elongation rate of compounds in the present invention

 Compound number Concentration (M)

(Example) H z ^10β

 Example 1 3 127.9 + 1.15

 Example 2 3 127.2 + 2.20

 Example 3 3 126.1 + 3.08

 Example 4 3 130.0 + 2.84

 Example 5 3 137.9 + 2.18

Example 6 3 133.4 + 2.34

O

40 Table 2. Rate of change of ERP c of compounds in the present invention

 (Mean ± standard error)

Note) * E— 4031 = 4 '— [[1- [2- (6-methyl-12-pyridyl) ethyl] -14-piperidyl] carbonyl] methanesulfonylanilide

 From the above experimental results, the compound of the present invention exhibits a 3HzZ1Hz ratio that is several times higher than that of the E-4031 compound already developed as an antiarrhythmic agent. It shows that it is an excellent antiarrhythmic agent that has improved the proarrhythmic effect due to reverse 'youth dependency'.

 Experimental example 2

Action potential extension (APD ₉₀ ) for papillary muscles isolated from guinea pigs

The right ventricular papillary muscle of a male guinea pig weighing 400-600 g is removed and Was fixed to an organ bus made by the company. In organ bath, the temperature is 34 ° mixed-gas (95%: 5% = 0 2: CO 2) which is maintained at C and the Kuretsubusu one ringer first solution saturated with flowed harbor. After applying electrical stimulation (frequency: 1 Hz or 3 Hz, oscillation width: 2 ms ec, voltage: 閎 value x 1.5) to the fixed isolated papillary muscle and stabilizing for about 2 hours, 3M KC The action potential duration (APD ₉₀ ) was measured using a glass microelectrode (20-30ΜΩ) charged with one solution. Each experiment compounds, was dissolved in 100% dimethylsulfoxide (DMS O), concentration of 1 0_ ^beta Micromax in Kure' Pusu Ringer's solution: was used diluted to (final DMS O concentration 0.1%). The effect of prolonging the action potential duration observed for about 1 hour after drug administration was shown as a change rate (%) compared to that before drug administration. The experimental results are shown in Tables 3 and 4.

Table 3. APD ₉ D elongation rate of compounds in the present invention

Table 4. Rate of change of APD ₉ Q of the compound of the present invention

 (Mean ± standard error)

Note) * Ε— 4031 = 4 '— [[1- [2- (6-methyl-2-pyridyl) ethyl 114-piperidyl] carbonyl] methanesulfonylanilide Industrial applicability

 From the above experimental results, the compound of the present invention exhibits a 3% / 1% ratio which is several times higher than that of the E-4031 compound which has been already developed as an antiarrhythmic agent. It can be seen that this is an excellent antiarrhythmic drug that has improved the 7 roalismic effect due to a certain reverse use dependency (reverseused ep end en cy).

Claims

The scope of the claims

General formula (I)

In the above formula,

0- is a general formula

Or

Represents a group of

A is a general formula-( ^CH2 ) aO-

Or a 6-membered heterocyclic ring containing a nitrogen atom, wherein R ₈ represents a lower alkyl group or a hydroxy lower alkyl group, a is 0 or 1, and

Is a 5- or 6-membered heterocyclic ring containing a nitrogen atom,

D is formula one (CH ₂₎ ™ -. One (CH _{2) m} - indicates the group, - 0-, One CO- or - S0 ₂

And R ₂ each independently represent a hydrogen atom, a halogen atom, a lower alkoxy group or a lower alkylsulfonylamino group,

R ₃ represents a lower alkyl group,

R ₄ > R ₅ , _Re and R ₇ each independently represent a hydrogen atom or a lower alkylsulfonylamino group,

 R represents a nitro group or a lower alkylsulfonylamino group,

 X represents a hydrogen atom or a halogen atom,

m and n each represent an integer of 0 to 3) or a salt thereof.

 2.

A is a general formula Byon ^(c ¾) _a-

A group of ^R 8 or a 6-membered saturated heterocyclic ring containing 1 to 2 nitrogen atoms, wherein R ₈ is a lower alkyl group having 1 to 6 carbon atoms or a hydroxy lower alkyl group having 1 to 6 carbon atoms. A is 0 or 1;

0-

Is a 5- or 6-membered heterocycle containing one nitrogen atom,

And R ₂ are each independently a hydrogen atom, a halogen atom, a lower alkoxy group having 1 to 6 carbon atoms or a lower alkylsulfonylamino group having 1 to 6 carbon atoms,

R ₃ is a lower alkyl group having 1 to 6 carbon atoms,

R ₄ , R ₅ , R _e and R ₇ are each independently a hydrogen atom or a lower alkylsulfonylamino group having 1 to 6 carbon atoms,

 The compound or a salt thereof according to claim 1, wherein R is a ditoxyl group or a lower alkylsulfonylamino group having 1 to 6 carbon atoms, and m and n are integers of 0 to 2.

 3.

A is a general formula

^R 8 Wherein R ₈ is a methyl group, an ethyl group or a hydroquinethyl group, a is 0 or 1, and

Is a 3-piridinyl group or a 2-pyrrolidinyl group,

And R ₂ are each independently a hydrogen atom, a halogen atom or a methylsulfonylamino group;

R ₃ is a methyl group,

R ₄ , R ₅ , R _e and R ₇ are each independently a hydrogen atom or a methylsulfonylamino group;

 R is a nitro group or a methylsulfonylamino group,

2. The compound according to claim 1, wherein m and n are integers of 0 to 2, or a salt thereof.

 Four.

0-

Is the general formula

And

 And R 2 is a lower alkoxy group;

4. The compound according to claim 1, wherein R is a nitro group or a lower alkylsulfonylamino group, or a salt thereof.

 Five.

5. The compound according to claim 4, wherein R ₂ is a methoxy group, R is a nitro group, and X is a hydrogen atom, or a salt thereof.

 6. Hi

Is the general formula

And

Is a hydrogen atom, R ₂ is a lower alkylsulfonylamino group,

4. The compound according to claim 1, wherein R is a nitro group or a lower alkylsulfonylamino group, or a salt thereof.

 7.

7. The compound according to claim 6, wherein R ₂ is a methylsulfonylamino group, R is a nitro group, and X is a hydrogen atom, or a salt thereof.

8. The compound according to claim 1, which is 8.3_ [N- (4-methanesulfonamidophenethyl) -1-N-methylamino] 111 (412trobenzyl) piperidine or a salt thereof.

 9. The compound according to claim 1, wherein the compound is 2- [N- (3,4-dimethoxyphenethyl-N-methylamino) methyl-1- (412-trobenzyl) pyrrolidine or a salt thereof.

 10. (A) reacting a compound of general formula (II) or a salt thereof with a compound of general formula (III) or a salt thereof to produce a compound of general formula (la) or a salt thereof,

(B) reacting a compound of the following general formula (IV) or a salt thereof with a compound of the following general formula (V) or a salt thereof to produce a compound of the following general formula (Ib) or a salt thereof: A method for producing a compound of the general formula (I) and a salt thereof.

(la)

(In the above formula,

o- is a general formula

Or

Represents a group of

A is a general formula

Or a nitrogen atom-containing 6-membered heterocyclic ring, wherein R ₈ represents a lower alkyl group or a hydroxy lower alkyl group, and a is 0 or 1,

0-

Is a 5- or 6-membered heterocyclic ring containing a nitrogen atom,

D represents a group of the general formula-(CH ₂ ) π,-, one (CH ₂ ) „-0-, —CO— or one S 0 ₂ —,

And R ₂ each independently represent a hydrogen atom, a halogen atom, a lower alkoxy group or a lower alkylsulfonylamino group, R ₃ represents a lower alkyl group,

R ₄ , R ₅ , R _e and R ₇ each independently represent a hydrogen atom or a lower alkylsulfonylamino group;

 R represents a nitro group or a lower alkylsulfonylamino group,

X represents a hydrogen atom or a halogen atom,

m and n represent an integer of 0 to 3. .

L represents a reactive leaving group,

 Het represents a nitrogen-containing 6-membered hetero ring. )

 11. A compound of the general formula (II) characterized by reacting a compound of the following formula (II) or a salt thereof with a compound of the following formula (III) or a salt thereof to produce a compound of the formula (Ia) or a salt thereof A method for producing the compound (I) and a salt thereof.

Q- (CH2) _n -N (la)

 (In the above formula,

o- is a general formula

Or

Represents a group of

R ₈ represents a lower alkyl group or a hydroxy lower alkyl group,

a is 0 or 1;

0-

Is a 5- or 6-membered nitrogen-containing heterocycle,

D is formula chromatography (CH _{2) m} -, one (CH _{2) m} -. Indicates the group, - 0- one CO- or one S0 ₂

And R ₂ each independently represent a halogen atom, a lower alkoxy group or a lower alkyl sulfonylamino group,

R ₃ represents a lower alkyl group,

R ₄ , R ₅ , R _e and R ₇ each independently represent a hydrogen atom or a lower alkylsulfonylamino group;

 R represents a nitro group or a lower alkylsulfonylamino group,

X represents a hydrogen atom or a halogen atom,

m and n each represent an integer of 0 to 3,

L represents a reactive leaving group. )

12. A compound of the following general formula (IV) or a salt thereof is reacted with a compound of the following general formula (V) or a salt thereof to produce a compound of the following general formula (Ib) or a salt thereof: A method for producing a compound of the general formula (I) and a salt thereof.

(In the above formula,

〇 is a general formula

Or

Represents a group of

Het represents a nitrogen atom-containing 6-membered hetero ring,

D formula one (CH ₂₎ are "- one (CH _{2) m} -. Indicates the group, - 0- one CO- or one S0 ₂

And R ₂ each independently represent a halogen atom, a lower alkoxy group or a lower alkyl sulfonylamino group,

R ₃ represents a lower alkyl group,

R "R ₅ , R _e and R ₇ each independently represent a hydrogen atom or a lower alkylsulfonylamino group;

 R represents a nitro group or a lower alkylsulfonylamino group,

X represents a hydrogen atom or a halogen atom,

m and n each represent an integer of 0 to 3,

L represents a reactive leaving group. )

 13. An antiarrhythmic agent composition comprising, as an active ingredient, the compound according to any one of claims 1 to 9 or a salt thereof together with a pharmaceutically acceptable carrier.