WO1998013364A1

WO1998013364A1 - 2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinoline derivatives or medicinal compositions thereof

Info

Publication number: WO1998013364A1
Application number: PCT/JP1997/003378
Authority: WO
Inventors: Toshihiro Watanabe; Akio Kakefuda; Noriyuki Masuda
Original assignee: Yamanouchi Pharmaceutical Co., Ltd.
Priority date: 1996-09-25
Filing date: 1997-09-24
Publication date: 1998-04-02
Also published as: AU4319797A

Abstract

2-(3-Piperidyl)-1,2,3,4-tetrahydroisoquinoline derivatives represented by general formula (I) or their salts and medicinal compositions containing these derivatives or salts thereof together with pharmaceutically acceptable carriers, wherein R?1 and R2¿ are the same or different and each represents hydrogen, halogeno, hydroxy, lower alkyl, halogenated lower alkyl, (lower alkyl)-O-, nitro, cyano, amino, oxopyrrolidinyl, (lower alkyl)-O-CO-NH-, (lower alkyl)-CO-NH- or (lower alkyl)-SO¿2?-NH-, or R?1 and R2¿ may together form -O-(lower alkylene)-O-; R?3 and R4¿ represent each hydrogen, or R?3 and R4¿ may together form oxo; X represents a single bond, oxygen or sulfur; A represents lower alkylene; and the ring B represents an optionally substituted hydrocarbon ring or an optionally substituted heterocycle which may be bonded to a benzene ring. These compounds have a current If inhibitory effect and are useful as heart rate depressants in the prevention or treatment of, in particular, ischemic cardiac diseases such as angina pectoris (thoracic angina pectoris) and myocardial infarction and circulatory diseases such as congestive heart failure and irregular pulse (supraventricular irregular pulse, etc.).

Description

Specification

2- (3-piperidyl) -1,2,3,4-tetrahydroisoquinoline derivative

Or its pharmaceutical composition

The present invention relates to a pharmaceutical, particularly a novel 2- (3-piperidyl) 1-1,2,3,4-tetrahydroisoquinoline derivative or a salt thereof having an If current-inhibiting action, and a pharmaceutically acceptable derivative thereof. It relates to a pharmaceutical composition containing an acceptable carrier. Background art

As drugs having heart rate lowering effect, and drugs that act conventionally to neurotransmitter receptors and Ionchiyane Le is known adenosine receptor agonists in the former, M ₂ muscarinic receptor agonists and ^ adrenergic A typical example is a receptor antagonist, and the latter is a calcium channel inhibitor. Such heart rate-lowering drugs may be used for various clinical symptoms resulting from an imbalance between the supply and demand of oxygen in the heart muscle, for example, angina, ischemic heart disease such as myocardial infarction, or arrhythmia, heart failure. It has been confirmed that it is useful as a preventive and therapeutic agent for cardiovascular diseases such as cardiovascular diseases. However, these drugs have an inhibitory effect on atrioventricular conduction and cardiac contractile function as well as a heart rate lowering effect, or a blood pressure lowering effect, and sometimes exert an effect leading to complete cardiac arrest. Because of this, there was concern that it would be used especially in patients with impaired cardiac function.

On the other hand, it is known that electrical excitement occurs spontaneously in cells such as the sinoatrial node, which has a physiological pacemaker activity in the heart, and the atrioventricular node, the His bundle, and the Purkinje fibers, which constitute the stimulation conduction system. In cells with cardiac pacemaker activity, there is no selectivity in cations such as sodium and potassium ions. Its existence was confirmed and named If current (current If). (D rancesco D. et al. J. Physiol. 377: 61 -88, 1986, Irisawa H, et al. Physiol. Rev. 73 :. 197 - 227,1993; DiFracesco D. , Ann Rev. Physiol, 55: 455-472, 1993) 0 heart this current in, contribute to the formation of diastolic depolarization of the cells having a pacemaker one activity, It is thought to be a current that regulates heart rate.

Therefore, the effect of lowering the heart rate by suppressing the If current that defines the slope of diastolic depolarization is expected. In fact, a new tie that inhibits the If current and produces a heart rate lowering effect Drugs have recently been reported. Such If current inhibitors can selectively reduce heart rate without inhibiting atrioventricular conduction and cardiac contractile function, and also reduce myocardial oxygen consumption. Therefore, inhibitors of If current are distinguished from the activities of conventional receptor agonists and calcium channel blockers in that they have no inhibitory action on atrioventricular conduction and cardiac contractile function, or no cardiac arrest action. Therefore, if current inhibitors are expected to be prophylactic and therapeutic agents for ischemic heart disease (eg, angina pectoris, myocardial infarction, etc.) and cardiovascular diseases (arrhythmia, heart failure, etc.) with few side effects. Furthermore, it is also useful in controlling an excessively increased heart rate and maintaining a constant heart rate during an operation using anesthesia.

In addition, not only cells having pacemaker activity but also intrinsic cardiomyocytes that do not usually have pacemaker activity, that is, atrial and ventricular myocytes, have this property of If current (there is no selectivity in permeability to cations). (Hangang Yu, Circ. Res. 72: 232-236, 1993). In certain disease states such as myocardial infarction or hypertension, intrinsic myocardial cells also spontaneously generate electrical excitation, and when action potentials are recorded from these cells, the membrane potential is determined during electrical diastole after the action potential is repolarized. Diastolic depolarization, which gradually depolarizes, is observed. Increased I-flow was confirmed in these conditions, and if current contributed to the formation of this diastolic depolarization, which is expected to be the cause of abnormal autoactivity (Elisabetta, C. et al. ., Circulation. 94: 1674-1681, 1996; Elisabetta, C. et al., Circulation. 95: 568-571, 1997). Therefore, if current inhibitors are thought to be useful in suppressing abnormal automatic hyperactivity in these conditions.

It is known that Zatebradine, which is known as a compound having a heart rate lowering effect, is based on the action of inhibiting If current. However, it has been reported that Zatebradme causes visual impairment with a heart rate lowering effect (William H. Frishman, J. Am. Coll. Cardiol, 26: 305-312, 1995; Stephen P. Glasser et al. al., The American Journal of Cardiology, 79: 1401-1405, 1997). It is known that a current (Ih current) having properties similar to the If current exists in photoreceptors (Shaul Hestrin, J. Physiol. 39 319-333, 1987). At the same time, it is expected that such visual impairment will occur because it also inhibits the Ih current.

In the study of If current inhibitors, the ability to separate from the Ih current inhibitory action is an issue.

As other compounds having a heart rate lowering effect, 1,3,4,5-ditrahydro-2H-3-benzazepin-12-one derivatives represented by the following general formula have been reported (Japanese Unexamined Patent Publication No. No. 138491; EP224794).

[Wherein A is one CH2-CH2-, one CH-CH-, etc., B is methylene, carbonyl or thiocarbonyl,

E is a straight-chain alkylene having 1 to 3 carbon atoms and optionally substituted with alkyl having 1 to 3 carbon atoms,

m is a number of 1, 2, 3, 4 or 5 and n is a number of 0, 1 or 2, but n + m must be 3, 4 or 5. Refer to the above publication for other symbols]

Further, as a compound having a heart rate lowering effect, a derivative such as a substituted lower alkyl 1,2,3,4-tetrahydroisoquinoline represented by the following general formula has been reported (Japanese Patent Application Laid-Open No. 1-45381). EP292840).

[Where A represents one CH2—, one CH2—CH2—, one CH = CH—

B is one CH2-, one CH2-CH2-, one CO- or one CH2-C〇,

m represents the number 1, 2, 3, 4, 5 or 6, n represents the number 0, 1, 2 or 3, but n + m must represent 3, 4, 5 or 6. Refer to the above publication for other symbols]

Further, as a compound having an anti-tachycardia action or a vasodilator action, an amino acid amide derivative represented by the following general formula has been reported (JP-A-2-138172).

(Where z is

F. Is an integer of 2 to 5, m is an integer of 2 to 4, n is an integer of 0 to 4, and other symbols are described in the above publication. Disclosure of the invention

The present inventors have conducted intensive studies on the above-mentioned agents that suppress the If current, and as a result, a series of compounds represented by the following general formula (I) suppresses the If current and has a heart rate lowering effect in the heart. The inventors have found that the present invention has been completed and completed the present invention.

That is, the present invention relates to a 2- (3-piperidyl) -1,2,3,4-dihydrohydroquinoline derivative represented by the following general formula (I) or a salt thereof.

(The symbols in the formula have the following meanings.

R ', R ^2: the same or different and represent a hydrogen atom, a halogen atom, hydroxy, lower alkyl, halogeno-lower alkyl, lower alkyl - 0-, nitro, Shiano, Ami's O Kiso pyrrolidinylmethyl, lower alkyl -0- CO - NH -, lower alkyl - CO-NH- or lower alkyl - S02-NH - group, or R 'and became R ² guard member - 0 - form 0-group, - lower alkylene

R ³ , R ⁴ : each form a hydrogen atom or an oxo group in which R ³ and R ⁴ are

X: bond, oxygen atom or sulfur atom,

A: lower alkylene group,

Ring B: an optionally substituted hydrocarbon ring group or an optionally substituted heterocyclic group which may be condensed with benzene, and so on)

Particularly preferred compounds of the compound (I) of the present invention include a 2- (3-piperidyl) -1,2,3,4-tetrahydroisoquinoline derivative in which R ³ and R ⁴ form an integrated oxo group or Its salt;

2- (3-piperidyl) -1,2,3,4-tetrahydroisoquinoline derivative or a salt thereof, wherein R ³ and R ⁴ are each a hydrogen atom;

Ring B is a halogen atom, hydroxy, lower alkyl, halogeno lower alkyl, lower alkyl-O-, nitro, cyano, aminooxopyrrolidinyl, lower alkyl-O-CO-NH-, lower alkyl-CO-NH- Lower alkyl-S02-NH- and -0-lower alkylene-0-phenyl optionally substituted with 1 to 3 substituents, phenyl, naphthyl, indanyl, 1,2,3,4-亍 Trahydronaphthyl, furyl, phenyl, pyridyl, 2,3-dihydro-3-oxobenzofuranyl or 2,3-dihydrid 2- (3-piperidyl) -1,2,1-H-indolyl group 3,4-tetrahydroisoquinoline derivative or a salt thereof; 2- (3-piperidyl) -1,2,3,4-pentahydroisoquinoline derivative or salt thereof wherein A is an ethylene or propylene group and X is an oxygen atom;

R ′ and R ² are lower alkyl-0-groups, and ring B is phenyl optionally substituted with one or two substituents selected from lower alkyl-0-, methylenedioxy and ethylenedioxy groups. there 2 - (3-piperidyl) -1, 2,3, ⁴ - tetrahydroisoquinoline derivative or a salt thereof;

R ', R ² force << a methoxy group and phenyl which is optionally substituted on ring B with one or two substituents selected from methoxy, ethoxy, methylenedioxy and ethylenedioxy groups. 3-piperidyl) -1,2,3,4-ditrahydroisoquinoline derivative or a salt thereof.

Particularly preferred compounds are 6,7-dimethoxy-2- {1- [3- (3,4-methylenedioxyphenoxy) propyl] -3-piperidyl 1,2,3,4-tetrahydroisoquinoline or Its salt,

6,7-dimethoxy-2- {1- [3_ (3,4-methylenedioxyphenoxy) probild 3-piperidyl} -1, 2,3,4- 亍 trahydroisoquinolin-K2H) -one or Its salt,

6-ethoxy-7-methoxy-2- 2- {1- [3- (3,4-methylenedioxyphenoxy) propyl] -3-piberidyl} -1,2,3,4-tetrahydroisoquinoline -1 (2H) -one or a salt thereof,

6,7-dimethoxy-2- { ^1- [3- (3,4-dimethoxyphenoxy) propyl;!-3-piperidyl}-1, 2,3,4-tetrahydroisoquinoline-1 (2H) -On or its salt,

6,7-dimethoxy-2- {tri [3- (4-methoxyphenoxy) propyl] -3-piperidyl H, 2,3,4-tetrahydridoisoquinolin-1 (2H) -one or a salt thereof,

6,7-dimethoxy - 2 - {1 - [3- (4-methoxycarbonyl phenoxyethanol) propyl] - 3 - piperidyl} - 1, 2, ^3, 4 - dihydroisoquinoline - 1 (2H> - one or a salt,

6,7-dimethoxy-2-(1- (3- (4-ethoxyphenoxy) propyl) 3-piperidyl H, 2,3,4- 亍 trachid isoquinoline-K2H) -one or a salt thereof,

2-Π- [3- (3,4-dimethoxyphenoxy) propylto 3-piperidyl 6-ethoxy-7-methoxy-1,2,2,3,4- 亍 trahydroisoquinolin-1 (2H) -one or a mixture thereof Salt.

Also, a pharmaceutical composition containing a 2- (3-piperidyl) -1,2,3,4-tetrahydroisoquinoline derivative of the compound (I) of the present invention or a salt thereof, and particularly a pharmaceutically acceptable carrier, The present invention relates to a pharmaceutical composition which is a current inhibitor, and more particularly to a pharmaceutical composition which is a heart rate lowering agent.

Hereinafter, the compound (I) of the present invention will be described in detail.

The compound (I) of the present invention has a structural feature in that the nitrogen atom of the 1,2,3,4-tetrahydroisoquinoline ring and the carbon atom at the 3-position of the piperidine ring are directly bonded. However, the structure differs from the patent application compound described in the background art particularly in the above point. In the definition of the general formula of the present invention, the term “lower” means a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified.

Accordingly, specific examples of the “lower alkyl group” in the present specification include, for example, a methyl group, an ethyl group, and a linear or branched propyl, butyl, pentyl and hexyl group. It is preferably an alkyl having 1 to 4 carbon atoms, and particularly preferably a methyl, ethyl, propyl and isopropyl group.

The “lower alkylene group” is a divalent group obtained by removing any hydrogen atom from the above “lower alkyl group”, preferably an alkylene group having 1 to 4 carbon atoms, and particularly preferably methylene and ethylene. , Propylene and butylene groups. Here, the lower alkylene represented by the group A in the general formula is preferably an ethylene or propylene group.

The hydrocarbon ring group of the “optionally substituted hydrocarbon ring group” is a saturated or unsaturated, monocyclic or condensed hydrocarbon ring group, preferably a aryl group or a cycloalkyl group. .

The “aryl group” is an aryl group having 6 to 14 carbon atoms, specifically, phenyl, dolyl, xylyl, biphenyl, naphthyl, indenyl, anthryl and phenanthryl groups. And dihydro, trihydro, and tetrahydro forms in which a hydrogen atom has been added to any carbon atom of the thiol group. Preferable is phenyl, naphthyl or 1,2,3,4-ditrahydronaphthyl group, particularly preferred is phenyl or 1,2,3,4-tetrahydronaphthyl group.

As the "cycloalkyl group", a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl group having 3 to 8 carbon atoms are preferable.

The `` heterocyclic group which may be substituted and which may be condensed with a benzene ring '' `` the heterocyclic group which may be condensed with a benzene ring '' means that a benzene ring is condensed with the heterocyclic group described below. It is a cyclic group or an uncondensed heterocyclic group.

Specific examples of the ring group J in which a benzene ring is condensed to a heterocyclic group include quinolyl, isoquinolyl, quinazolinyl, quinolizinyl, quinoxalinyl, cinnolinyl, benzimidazolyl, imidazopyridyl, benzofuranyl and 1,2-benzoisoxyl. Means condensed heteroaryl groups such as sazolyl, benzoyloxazolyl, benzothiazolyl, oxazolopyridyl, isothiazolopyridyl, and benzochenyl, and 2,3-dihydro-1H-indole and 3-oxo-benzofuranyl. And the like. Preferably Among these groups 2,3-dihydro - a base Nzofuraniru group - ¹ H - indole, 3-year old Kiso.

As the “heterocyclic group”, a heteroatom consisting of an oxygen atom, a sulfur atom or a nitrogen atom is It means a heteroaryl group or a saturated heterocyclic group containing up to four, and the heteroaryl group is preferably a 5- or 6-membered group, furyl, chenyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, Examples include monocyclic heteroaryl groups such as isothiazolyl, isoxazolyl, pyridyl, pyrimidyl, pyridazinyl, virazyl, triazolyl and tetrazolyl groups, and bicyclic heteroaryl groups such as naphthyridinyl group. Preferred are furyl, phenyl and pyridyl groups.

The “saturated heterocyclic group” is preferably a 5- to 7-membered ring. Specific examples include a pyrrolidinyl, imidazolidinyl, virazolidinyl, piperidyl, piperazinyl, and morpholinyl group, and a piperidyl group is preferable.

The substituent of the `` hydrocarbon ring group which may be substituted '' and the `` heterocyclic group which may be S-substituted or optionally condensed '' is a group which can be usually substituted on these ring groups. Any may be used. Preferably, halogen atom, lower alkyl, lower alkenyl, lower alkynyl, hydroxy, mercapto, halogeno lower alkyl, lower alkyl-0-, lower alkyl-S-, lower alkyl-0-CO-, carboxy, sulfonyl, sulfinyl, Lower alkyl-SO ^2- , lower alkyl- S0-, lower alkyl-C0-, lower alkyl-GO-0-, levamoyl, lower alkyl-NH-CO-, di-lower alkyl-N-C0-, nitro, Lower alkyl-NH-, di-lower alkyl-N- and -0-lower alkylene-0- groups. These substituents may be substituted with one or more, preferably one to three.

The “lower alkenyl group” is a straight-chain or branched alkenyl group having 2 to 6 carbon atoms, specifically, vinyl, 1-probenyl, 2-propenyl (aryl), butyl Nyl, pentenyl and hexenyl groups.

"The lower alkynyl group J is a straight-chain or branched alkynyl group having 2 to 6 carbon atoms, and specific examples include ethynyl, propynyl, butynyl, pentynyl, and hexynyl groups.

"Halogen atom" means a fluorine atom, chlorine atom, bromine atom or iodine atom, and "halogeno lower alkyl group" means a group in which any hydrogen atom of the above lower alkyl group is substituted by a halogen atom. .

When X is a bond, it means that the groups A and B are directly bonded.

The compound (I) of the present invention has at least one asymmetric carbon atom, and there are optical isomers such as (R) -form and (S) -form, racemic forms, diastereomers and the like based on this. Further, depending on the type of the S-substituent, a geometric isomer or a tautomer exists. The present invention includes all separated or mixtures of these isomers. The compound (I) of the present invention may form a salt with an acid. Such salts include mineral acids with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc., formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid Acid addition salts with organic acids such as acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid and glutamic acid can be mentioned. Further, the present invention also includes hydrates of compound (I), solvates such as ethanol, and yarns;

(Manufacturing method)

The compound (I) of the present invention can be produced by applying various production methods. Hereinafter, a typical manufacturing method will be described.

No.

B ring

(In the ^{^{formula, R 1, R 2, R}} 3, R 4, A, B ring and X are as defined above. A 'represents a single bond or a carbon number C, and alkylene groups of ～〇 ^5. Z is This represents a leaving group or a halogen atom of hydroxy.) The production method of the compound of the present invention is based on the perhydroisoquinoline compound represented by the general formula (II) or any one of the methods A, B and C. This is a method for obtaining (I). The three cases, Method A, Method B, and Method C, are described below.

Method A

This reaction is a reaction using a base such as compound (III). This reaction is carried out without solvent or in a solvent. The compound (11) and the compound (III) are used in an equimolar amount to an excess molar amount of the compound (III), and the reaction temperature varies depending on the type of the reaction compound and is appropriately set. For some compounds, it may be advantageous to carry out the reaction in the presence of a base.

Solvents include solvents that are advantageous for the reaction and inert solvents. Examples of the inert solvent include pyridin, tetrahydrofuran, dioxane, ether, N, N-dimethylformamide, benzene, toluene, xylene, methylene chloride, dichloroethane, chloroform, ethyl acetate, and acetonitrile. Preferably it is acetonitrile.

Examples of the base include organic bases such as trimethylamine, triethylamine, pyridine, picoline, lutidine, dimethylaniline, and N-methylmorpholine, and inorganic bases such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, and potassium hydroxide. Is mentioned. Note that pyridin can also serve as a solvent.

Examples of the leaving group for hydroxy include mesyl, tosyl, and trifluoromethanesulfonyl group.

B method

This reaction is a reaction using a reductive amination reaction. This reaction is a method in which compound (IV) is appropriately dissolved in the above solvent, reacted with amine of compound (III), and the resulting Schiff base is isolated or not, and then the Schiff base is reduced. is there.

In the reaction, compound (IV) and compound (II) are used in an amount corresponding to the reaction or in a slightly excessive amount, preferably in the presence of an acid catalyst such as p-toluenesulfonic acid, adipic acid, oxalic acid, pyridine hydrochloride, and diacid. Depending on the reaction conditions, the reaction may be performed by adding a hygroscopic agent such as potassium hydroxide or molecular sieves, or by using a Dean-Stark trap (azeotropic dehydrator) to remove the generated water. Is advantageous. Although the reaction temperature varies depending on the type of the reaction compound, it is usually preferable to set it at room temperature, or at an azeotropic or reflux temperature depending on the reaction.

The reduction of the resulting Schiff base is carried out by adding a metal hydride complex (sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, etc.) Or by adding a reducing agent such as borane.

C method

This reaction is a reaction in which the compound (II) is reacted with a carboxylic acid represented by the general formula (V) or a derivative thereof, and further, a reduction reaction is used. This reaction is carried out without a solvent or in the solvent described above, using an equimolar amount of the compound (11) or the compound (V) or an excess amount of the compound (V) to obtain a compound (VI). ) Is carried out by a conventional reduction reaction. The reaction temperature varies depending on the type of reaction compound. And it is set appropriately.

Examples of the reactive derivative of compound (V) include acid halides such as acid chloride and acid bromide; acid azides; active esters with N-hydroxybenzotriazole (HOB), P-ditrophenyl ゃ N-hydroxysuccinimide and the like. Symmetric acid anhydrides; mixed acid anhydrides with alkyl carbonic acid, p-toluenesulfonic acid, and the like.

When reacting the compound (V) in the free carboxylic acid, hexyl Cal positive imide dicyclohexyl, 1 Echiru 3- ⁽³ - dimethyl § amino propyl) carbodiimide, 1, ¹ 'single carbonyldiimidazole imidazole, N, N' It is advantageous to carry out the reaction in the presence of a condensing agent such as bis (2-oxo-1-oxazolidinyl) phosphinic chloride, diphenylphosphoryl azide (DPPA).

The above reduction reaction is carried out in the above inert solvent under cooling to room temperature, at room temperature to heating (reflux), using a reducing agent such as the metal hydride complex of the above-mentioned Method B or borane.

Second manufacturing method

A (B 琛

Reductive amination

(VII) No (la)

(In the formula, R ¹ , R ² , A, B rings and X have the above-mentioned meanings.)

This production method is a method for obtaining a compound (la) of the present invention by a reductive amination reaction of a tetrahydroisoquinoline compound represented by the general formula (VII) with a oxopiperidine compound represented by the general formula (VIII). The reductive amination reaction is the same as in the first method B, and the conditions such as the reaction solvent and the reaction temperature are the same as those in the first method B.

Third manufacturing method

(In the formula, R ′, R ² , A, B rings, X and Z have the above-mentioned meanings. R ′ represents an acyl-protecting group, specifically, a lower alkyl or benzyl group, and Ra represents ^a hydroxy group. And specifically a lower alkyl group.)

Method A

This production method comprises reacting compound (IX) with compound (X), further obtaining a compound of the present invention (lb) by a cyclization reaction, and optionally performing a reduction reaction to obtain a compound of the present invention (ia). It is.

The reaction is carried out in the above-mentioned inert solvent under cooling to room temperature, at room temperature to heating (reflux), using an equimolar amount of each of compound (IX) and compound (X) or an excess mole of compound (X). In some cases, it is advantageous to carry out the reaction in the presence of the base described in the first production method, if desired. The cyclization reaction is performed in the above inert solvent in the presence of an acid. Acids used in this reaction include polyphosphoric acid (PPA), phosphorus oxychloride (POCI ₃ ), anhydrous J-fluoroacetic acid-dimethylaminopyridine (J. Chem. Soc. Ghem. Commum. 2551-2553 (1995)). And the like.

The reduction reaction to be carried out as desired is the same as in the first production method C, and the conditions such as the reaction solvent and the reaction temperature are the same as in the above production method. B method

In the present production method, the compound (XII) is reacted with the compound (XIII), and the compound (lb) of the present invention is further obtained by 1) cyclization reaction and 2) reduction reaction. This is a method for obtaining compound (la).

The acylation reaction and the optional reduction reaction are performed in the same manner as in the third production method A, and the conditions such as the reaction solvent and the reaction temperature are also the same as those in the above production method. The cyclization reaction is performed in the above-mentioned inert solvent in the presence of hydrochloric acid, a mixed solution of acetic acid-monohydrochloric acid, a mixed solution of acetic acid-monosulfuric acid, trifluoroacetic acid and the like.

4th manufacturing method

(Wherein, R ¹ , R ² , R ³ R ⁴ , A, A ′, a ring and X have the above-mentioned meanings. Υ represents a hydroxy or mercapto group.)

In this production method, the compound represented by the general formula (XVI) is obtained by a reductive amination reaction using the compound (II) and the aldehyde of the compound (XV), and further represented by the compound (XVI) and the general formula (XVII) This is a method for obtaining the compound (I) of the present invention by reacting with an alcohol or a thiol compound.

The reductive amination reaction is the same as in the first production method, and the conditions such as the reaction solvent and the reaction temperature are the same as those in the above production method.

The reaction of the compound (XVI) with the compound (XVII) is carried out in the above-mentioned inert solvent under cooling to room temperature, at room temperature to heating (reflux), and the compound (XVI) and the compound (XVI I) are each equimolar to the compound. (XVII) using an excess molar amount, and if desired, i) the base described in the first production method, or Π) an interlayer transfer catalyst (for example, a quaternary ammonium salt crown such as tetrabutylammonium bromide). It may be advantageous to carry out the reaction in the presence of alcohols.

(Production method of raw material compounds) (a)

1) Reductive amination R

2) Remove lOT protection WiH fiN, `` H

(vii) (xviii) (Ha)

(Wherein R ¹ and R ² have the meanings given above. R ″ ′ represents an amino protecting group.)

This production method is a method of condensing compound (VII) and compound (XVIII) with oxopiperidine according to a conventional method to obtain a raw material compound (lla).

The synthesis of the starting compound Ola) is the same as in the reductive amination reaction of the first production method B. This reaction is carried out without solvent or in the above-mentioned solvents, using equimolar amounts of compound (Vll) and compound (XVIII) and an excess mole of compound (XVIII). The conditions such as the reaction solvent and the reaction temperature are the same as those in the first production method B.

Examples of R ′ ″ include a protecting group for an acyl-based amino group and a protecting group for an aralkyl-based amino group.Examples of the protecting group for the acyl-based amino group include lower alkanol groups such as formyl, acetyl, and propionyl groups, methoxycarbonyl, and ethoxy. Lower alkoxycarbonyl groups such as carbonyl and BOC groups, lower alkanesulfonyl groups such as methanesulfonyl and ethanesulfonyl groups, and aliphatic acyls such as methoxyacetyl, methoxypropionyl, benzoyl, benzyloxycarbonyl, and p-nitrobenzyloxycarbonyl groups. Examples of the group include a heterocyclic lower alkanol group such as a ceryl acetyl, thiazolyl acetyl, and perazolyl acetyl group, and a heterocyclic acyl group such as an azolyl glyoxyloyl and a cyenyl glyoxyloyl group. Aralkyl-based protecting groups for the amino group include benzyl, _P -nitrobenzyl, benzhydryl, and trityl groups.

(b)

(Wherein the rings AX and B have the above-mentioned meanings.)

In this production method, compound (XX) is obtained from 3 piberidinol of compound (XIX) by using any of the first production method A, method B or method C described above, and further subjected to an oxidation reaction to give the starting compound (VIII). There is a way to get

The reaction for synthesizing compound (XX) from compound (XIX) is the same as in the first method A, method B, and method C, and the conditions such as the reaction solvent and the reaction temperature are the same as those in the above method. or. Oxidation reaction Commonly used oxidizing agents (for example, organic peracids such as m-chloroperbenzoic acid, pyridinum dichromate (PCC), pyridinium dichromate (PDC), inorganic peracids such as sodium periodate, and peroxidation It can be carried out by using chromic acid oxidation using hydrogen, 03 pyridine, CuCrOs, or the like, or dimethyl sulfoxide (DMS〇) oxidation. The reaction temperature varies depending on the type of the reaction compound and is set as appropriate.

(c) i)

Ring

Η)

Reductive amination (XXII)

(Wherein, R ¹ , R ² , R ", A, a ring and X have the above-mentioned meanings.)

This production method comprises: i) a method of reacting an amine represented by the compound (XXI) with an oxopiperazine compound of the compound (VIII) and performing reductive amination to obtain a starting compound (IX); ) Is reacted with an oxopiperazine compound of the compound (XVIII) to perform reductive amination to obtain the compound (XXII).

The reductive amination reaction is the same as in the first production method B, and the conditions such as the reaction solvent and the reaction temperature are the same as in the first production method B.

(d) i)

ϋ)

o R "OR ^A

, OR ^A

H, NCH, H (XVIII)

IMH "

OR 'N

(XXIV)

(XXIII) Reductive amination

(Wherein, R 1, R ″, A, B rings and X have the above-mentioned meanings.)

This production method comprises: i) a method of reacting an amamine represented by the compound (XXIII) with a oxopiperazine compound of the compound (VIII) to carry out reductive amination to obtain a starting compound (XII); and Π) a compound (XXIII) Indicated by In this method, a compound (XXIV) is obtained by reacting a benzoamine with an oxopiperazine compound of the compound (XVIII) to perform reductive amination.

The reductive amination reaction is the same as in the first method B, and the conditions such as the reaction solvent and the reaction temperature are the same as those in the first method B.

(e)

Method A Method B

(Wherein, R ¹ , R ² , R ^a , R,, R "and Z have the above-mentioned meanings.)

Method A In this production method, an amine of compound (XXII) is reacted with a carboxylic acid derivative of compound (X) to carry out carbamoylation, followed by a compound represented by the general formula (XXV), 1) cyclization reaction, 2 ) This is a method in which the raw material compound (lib) is deprotected to obtain the raw material compound (Ha) by further performing a reduction reaction. A series of reactions such as the acylation reaction, the subsequent cyclization reaction, and the deprotection are the same as in the third production method A, and the conditions such as the reaction solvent and the reaction temperature are the same as those in the third production method A.

Method B In this production method, an amide of compound (XXIV) is reacted with a carboxylic acid derivative of compound (XXVI) to carry out acylation, and through a compound represented by the general formula (XXVII), 1) cyclization reaction, 2) reduction Reaction 3) This is a method in which the starting compound (lib) is obtained by deprotection and the starting compound (lla) is obtained by further performing a reduction reaction. A series of reactions such as the acylation reaction, the subsequent cyclization reaction, and the deprotection are the same as in the third production method B, and the conditions such as the reaction solvent and the reaction temperature are the same as those in the third production method B.

The reaction product obtained by each of the above production methods is isolated and purified as various solvates such as a free compound, a salt thereof or a hydrate. Salt can be produced by subjecting it to the usual salt-forming treatment.

Isolation and purification are performed by applying ordinary chemical operations such as extraction, shrinkage, distillation, crystallization, filtration, recrystallization, and various types of chromatography.

The various isomers can be isolated by a conventional method utilizing physical differences between the isomers, and the optical isomers can be separated by a general racemic resolution method, for example, fractional crystallization or chromatography. The optical isomer can also be synthesized from an appropriate optically active starting compound.

As the fractional crystallization, fractional crystallization using an optically active organic acid such as a tartaric acid derivative, a mandelic acid derivative, and a camphorsulfonic acid derivative is suitably performed. As the solvent, a solvent capable of performing optical resolution efficiently is appropriately selected. Industrial applicability

The compound of the present invention has an activity of inhibiting If current, selectively lowers the heart rate, and exhibits a strong and specific activity of reducing myocardial oxygen consumption, thereby inhibiting angina pectoris and myocardial infarction. It is useful as a therapeutic agent for the prevention and treatment of cardiovascular diseases such as ischemic heart disease, depressive heart failure and arrhythmia. The compounds of the present invention are particularly useful for the prevention or treatment of various clinical conditions arising between the supply and consumption of myocardial oxygen, such as thoracic angina, myocardial infarction and associated arrhythmias, and for the treatment of arrhythmias, especially supraventricular arrhythmias. Highly useful for prevention or treatment.

In addition, the compound of the present invention is expected to have an effect of reducing vascular hemodynamic compression and thereby reducing complications of sclerosis, particularly coronary sclerosis. Further, the compound of the present invention is an agent which suppresses an excessively elevated heart rate and is useful also in controlling the heart rate to a constant state during general surgery.

Since the compound of the present invention directly acts on the If current in the above-mentioned heart rate lowering action, it has been confirmed that the selectivity of the heart rate lowering action for visual impairment which does not suppress the atrioventricular conduction or the cardiac contractile function is high. I have.

Furthermore, it is known that, in addition to the If current, an ion current contributing to the formation of an action potential in the heart includes a current passing through a Na channel, a K channel, and a Ca channel. Inhibits the If current other than the If current present in the heart Since no significant inhibitory effect is shown at the dose, it is expected that there are few side effects due to current inhibition other than If current. Therefore, the compound of the present invention is useful as a heart rate-lowering agent having few side effects for the prevention and treatment of the above-mentioned various diseases.

The compound of the present invention is useful as an inhibitor of abnormal automatic hyperactivity caused by If current in certain disease states such as myocardial infarction or hypertension.

The pharmacological effects of the compounds of the present invention were confirmed by the following test methods.

(Test method)

1. If current inhibition test

After stunning a male Hartree type 1 guinea pig weighing about 200 to 350 g by capping, the heart was promptly removed while exsanguinating the carotid artery. The heart was transferred into Tyrode's solution in which a gas mixture of 95% oxygen + 5% carbon dioxide was sufficiently ventilated, and the sinoatrial node (pacemaker) site (about 3 x 5 mm) was cut out. The excised sinoatrial node was treated with a collagenase (manufactured by Yakult) (1.5 mg / ml) in a Ca ²⁺ -free Tyrode solution at 37 ° C. for 30 minutes. Then, it was left still at 4 ° C for 1 hour or more in K + rich solution ("KB recovery solution"). The treated sinoatrial node was minced with an injection needle and pipetting was performed to obtain isolated cardiomyocytes.

Kuden / J 〖shibiki Z

The isolated myocardium thus obtained was scattered in a dedicated chamber, and patch-clamping (whole cell mode) was applied to spindle-shaped cells undergoing spontaneous contraction. The holding potential was set at −40 mV, and an If current was induced by sequentially applying a hyperpolarizing pulse (1 second) from this potential to −10, −20, −30, ■, −80 mV. Because the If current force was the largest due to the -80 mV hyperpolarizing pulse, the drug efficacy was evaluated by evaluating the effect of the test compound on the If® current induced by the -80 mV pulse.

The perfusion of the extracellular fluid (Tyrode solution) containing the test compound was started, an If current was induced by a hyperpolarizing pulse of -80 mV at 5-second intervals, and recording was performed until the 100th pulse (about 8 minutes). It was confirmed that the action of the drug reached saturation after 90 pulses or more. The inhibitory effect of the test compound on If current was measured by measuring the If current obtained before perfusion of the drug solution and after 90 pulses, respectively, and comparing them with the concentration (IC ₅ ) of 50% that inhibits the If current.

Result: _{5 for the} example compound of the present invention. Values were 10- ⁹ M ~ 10- ⁵ M.

.Heart rate lowering effect test

After stunning a male Hartley guinea pig weighing about 250 to 350 g by hitting the head, exsanguinating and lethal The heart was excised. Atrial specimens were prepared in Krebs-Henseleit solution sufficiently ventilated with 95% oxygen + 5% carbon dioxide. The sample is mounted on a stainless steel hook and suspended under a load tension of 0.5 g in a Magnus tube filled with Krebs-Henseleit solution sufficiently ventilated with 95% oxygen + 5% carbon dioxide gas, and the heart rate oscillates spontaneously. Was recorded. After suspending the sample and allowing it to stabilize for at least one hour, the test compound is cumulatively added to the Magnus tube at 30-minute intervals, and the portability action curve is determined from the value 30 minutes after the substance administration to determine the effect. Judged. Heart rate-lowering effect was compared by EC (concentration of substance) which reduced spontaneous heart rate by 30% before test substance administration.

Table A shows the results of this test.

Table A

3.Test for cardiac contractility

Male Hartley guinea pigs weighing about 250 to 350 _g were stunned by hitting the head, exsanguinated and sacrificed, and the heart was removed. Left atrial specimens were prepared in Krebs-Henseleit solution sufficiently ventilated with 95% oxygen + 5% carbon dioxide. The specimen was mounted on a stainless steel hook, suspended in a Magnus tube filled with Krebs-Henseleit solution sufficiently ventilated with 95% oxygen + 5% carbon dioxide under a load tension of 0.5 g, and subjected to transmural electrical stimulation (2 Hz, 2m _SeC , 1.5 times the Δ voltage). After a stabilization period of at least one hour, the test compound was added to the Magnus tube at intervals of 20 minutes, and changes in cardiac contraction were recorded 20 minutes after administration of the substance. The effect on cardiac contractility was compared with the contraction induced by this electrical stimulation by the inhibition rate of the test compound before administration of the test compound.

Result: The compound of the present invention did not show an inhibitory effect on cardiac contractility at a strain rate that shows a favorable heart rate lowering effect.

Pharmaceutical compositions containing one or more of the compounds of the present invention or salts thereof are prepared using ordinary pharmaceutically acceptable carriers. The pharmaceutical composition of the present invention may be administered orally or parenterally by injection, suppository, transdermal, inhalant or intravesical injection.

Dose symptoms, age of the administration subject, per day per adult human in the case 0.1 ₈ to 1 00 ₀ ^ Bruno about in § Li force normal oral administration in view of the sex and the like are appropriately determined depending on the individual case This should be given once or in 24 divided doses. When given intravenously due to symptoms, it is usually administered once or more than once a day in the range of 0.01 to 10 pounds per adult.

Pharmaceutical carriers include solid or liquid non-toxic pharmaceutical substances.

As the solid composition for oral administration according to the present invention, tablets, pills, capsules, powders, granules and the like are used. In such solid compositions, the one or more active substances comprise at least one inert diluent, for example, lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, agar. , Pectin, magnesium metasilicate, and magnesium aluminate. The composition may contain, in a conventional manner, an additive other than an inert diluent, such as a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose glycolate, a stabilizer such as lactose, A solubilizing agent such as glutamic acid or aspartic acid may be contained. If necessary, tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or a film of gastric or enteric substance.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents such as purified Includes water and ethanol. The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injections and physiological saline. Examples of non-aqueous solutions and suspensions include ethylene glycol, propylene glycol, polyethylene glycol, cocoa butter, vegetable oils such as olive oil and sesame oil, alcohols such as ethanol, gum arabic, polysorbate 80 (trade name). ). Such compositions may also contain additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (e.g., lactose), and solubilizers (e.g., glutamic acid, asnolaginic acid). May be included. These are sterilized by, for example, passing through a bacteria storage filter, blending a bactericide or irradiation. They also produce sterile solid compositions which may be sterile in water or sterile before injection. It can also be used by dissolving it in a solvent for spraying. BEST MODE FOR CARRYING OUT THE INVENTION

Next, the target compound and the production method of the present invention will be further described by way of examples, but the present invention should not be limited by these examples.

Reference example 1

By removing the benzyl group from 1.14 g of 2- (1-benzyl-3-piperidyl) -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline dihydrochloride, 6,7-dimethoxy-2 630 mg of-(3-piperidyl) -1,2,3,4-tetrahydroisoquinoline dihydrochloride was obtained as white crystals.

Reference example 2

A conventional addition reaction was carried out using 13.8 g of sesamol and 60 g of 1,3-dibromopropane to obtain 17.7 g of 1- (3-bromopropoxy) -3,4-methylenedioxybenzene as white crystals. .

In the same manner as in Reference Example 2, the compounds of Reference Examples 3 to 24 were obtained.

Reference Example 31- (3-bromopropoxy) -3,4-dimethoxybenzene

Reference Example 4 1- (3-bromopropoxy) -3,4,5-trimethoxybenzene

Reference Example 5 4- (3-bromopropoxy) isopropylbenzene

Reference Example 6 5- (3-bromopropoxy) indane

Reference Example 7 6- (3-bromopropoxy) -1,2,3,4-tetrahydronaphthalene

Reference Example 8 6- (3-Bromopropoxy) benzofuran-3-one

Reference Example 9 2- (3-bromopropoxy) naphthalene

Reference Example 10 2- (3-bromopropoxy) methoxybenzene

Reference Example 1 1 3- (3-bromopropoxy) methoxybenzene

Reference Example 12 4- (3-bromopropoxy) methoxybenzene

Reference Example 13 5- (3-bromopropoxy) -2,3-dihydro-1H-indoline

Reference Example 14 1- (3-Bromopropoxy) -3,4-ethylenedimethoxybenzene

Reference Example 15 1- ( ³ -Bromopropoxy) -2-chlorobenzene

Reference Example 16 1 one (3-blanking opening Mopuropokishi) - ³ _ chlorobenzene

Reference Example 17 1- (3-bromopropoxy) -4-benzene

Reference Example 18 1- (3-bromopropoxy) -4-methoxycarbonylbenzene

Reference Example 19 1- (3-Bromopropoxy) -4-cyanobenzene

Reference Example 20 1- (3-bromopropoxy) -4-ethoxybenzene Reference Example 21 1- (3-bromopropoxy) -4-fluorobenzene

Reference Example 22 1- (3-bromopropoxy) -4-nitrobenzene

Reference Example 23 1- (3-bromopropoxy) -4-bromobenzene

Reference Example 24 1- (3-bromopropoxy) -4-methylbenzene

Reference Example 25

6,7-Dimethoxy-2- (3-piperidyl) -1,2,3,4-tetrahydroisoquinoline dihydrochloride A suspension of 1.50 g of dichloroethane (20 ml) and 1.0 g of a 40% aqueous chloroacetaldehyde solution were used. 2- [1- (2-chloroethyl) -3-piperidyl] -6,7-dimethoxy-1,2,3,4-tetrahydrohydrogenation 1.27 g of isoquinoline were obtained as an oil.

Reference Example 26

Perform a conventional reductive amination reaction using a solution of 3.62 g of 3,4-dimethoxyphenethylamine in 60 ml of dichloroethane and 4.51 g of N-benzyl-3-piridone hydrochloride monohydrate. Thus, 5.17 g of (1-benzyl-3-piperidyl)-[2- (3,4-dimethoxyphenyl) ethyl] amine was obtained as a pale brown oil.

Reference Example 27

(1 -Benzyl-3-piperidyl)-[2- (3,4-dimethoxyphenyl) ethyl] amine 5.17 g of tetrahydrofuran solution (100 ml) and methyl chloroformate (1.24 ml) were used in a conventional manner. By carrying out the acylation reaction, 5.91 g of methyl (1-benzyl-3-piperidyl)-[2- (3,4-dimethoxyphenyl) ethyl] carbamate was obtained as a pale yellow oil.

Reference Example 28

Methyl (1-benzyl-3-piperidyl)-[2- (3,4-dimethoxyphenyl) ethyl] dibamate A solution of 6.31 g of dichloroethane (120 ml), dimethylaminopyridine 4.67 g, anhydrous trifluoromethanesulfone By performing a cyclization reaction using 10.3 ml of acid, 2- (1-benzyl-3-piperidyl) -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1 (2H) 3.1 g was obtained as a pale brown oil.

Reference Example 29

By removing 3.09 g of 2- (1-benzyl-3-piperidyl) -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1 (2H) -one from the benzyl group, 6, 1.86 g of 7-dimethoxy-2- (3-piperidyl) -1,2,3,4-ditrahydroisoquinolin-1 (2H) -one was obtained as a pale yellow solid.

The compounds of Reference Examples 30 to 33 were obtained in the same manner as in Reference Examples 26 to 29.

Reference Example 30 6-Methoxy-2- (3-piperidyl) -1,2,3,4-tetrahydroisoquinolin-1 (2H) -one Reference Example 31 6,7-methylenedioxy-2- (3-piperidyl) -1 , 2,3,4-tetrahydroisoquinoline-2H) -on

Reference Example 32 6 - ethoxy - 7-methoxy - 2 - (3-piperidyl) - 1, 2,3, ⁴ - tetrahydroisoquinoline - 1 (2H>

-Talent

Reference Example 33-Fethoxy-6-methoxy-2- (3-piperidyl) -1, 2,3,4-tetrahydroisoquinoline-1 (2H)

-ON

Reference example 34

6,7-Dimethoxy-2- (3-piperidyl) -1,2,3,4-tetrahydroisoquinolin-1 (2H) -one 1.60 g of ethanol solution (20 ml) was added to D-tartaric acid 0.83 g, 95% By carrying out the optical resolution reaction using ethanol water, (1) -6,6-dimethoxy-2- (3-piperidyl) -1,2,3,4-tetrahydroisoquinoline-1 (2H)- 650 mg of on-D-tartrate were obtained. The product showed an optical activity of 99.5% (using column DAICEL

CHIRALPAK AD (0.46 × 25 cm), solvent 2-propanol: hexane: getylamine = 50: 50: 0.1; the optical activity was measured in the same manner).

Reference Example 35

It was distilled off under reduced pressure of the mother liquor of Example 34, the residue - tartaric acid 0.32 mg, 95% aqueous ethanol ethanol - by carrying out the optical resolution reaction using Le solution (6ml), (+) - 6, 7- 460 mg of dimethoxy-2- (3-piberidyl) -1,2,3,4-tetrahydroisoquinolin-1 (2H) -one L-tartrate was obtained. The product is

It showed an optical activity of 99.5%.

Reference Example 36

2.35 g of N-butoxycarbonyl-3-hydroxypiperidone was subjected to a conventional Swern oxidation reaction using a dichloromethane solution (10 mI) of 2.29 g of N-butoxycarbonyl-3-hydroxypiperidine to give 2.35 g of N-butoxycarbonyl-3-piperidone as a pale yellow oil. Obtained as a product. 7-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride

(J. Med. Chem., 1987, 30, 2208) A conventional reductive amination reaction was carried out using 1.90 g of dichloroethane solution (30 ml) and 2.35 g of Nt-butoxycarbonyl-3-piridone. This gave 2.97 g of 7-methoxy-2- (Nt-butoxycarbonyl-3-piperidyl) -1,2,3,4-tetrahydroisoquinoline as a pale brown oil.

Reference Example 37

7-Methoxy-2- (N-1-butoxycarbonyl- ³ -piperidyl) -1,2,3,4-tetrahydroisoquinoline 2.95 g of methanol solution (30 ml) to remove the butoxycarbonyl group As a result, 1.80 g of 7-methoxy-2- (3-piperidyl) -1,2,3,4-tetrahydroisoquinoline dihydrochloride was obtained as pale yellow crystals.

Reference example 38 3-hydroxypiperidine is obtained by N-alkylation reaction using 1.52 g of acetonitrile solution (20 ml) and 4- (3-bromopropoxy) -1,2-methylenedioxybenzene 4.08 g to obtain 3-hydroxypiperidine. 4.27 _g of 1- [3- (3,4-methylenedioxyphenoxy) propyl] piperidine was obtained as a pale brown oil.

Reference example 39

4- (3,4-dimethoxy-phenylalanine) -. By performing the reduction reaction of a conventional method using butyric acid methyl ester ² ² 0 g of Jikuroroetan solution (20 ml), 4- (3,4-dimethoxy Hue sulfonyl) 1.15 g of -butyraldehyde was obtained as a foil.

Reference example 40

By performing reductive Amino reaction of a conventional method using Bok base Njiru 3- piperidines pyrrolidone hydrochloride hydrate ¹ 5.0 g of亍卜Rahidorofuran suspension and (90 ml) glycine dimethyl § Se tar 6.99 g, ( 16.33 g of 1-benzyl-3-piperidyl)-(2,2-dimethoxy) ethylamine was obtained as an oil.

Reference Example 41

(1-benzyl-3-piperidyl)-(2,2-dimethoxy) ethylamine 5.95 g of acetonitrile solution (60 ml) and 3,4-dimethoxybenzoyl chloride 4.71 g by performing a conventional acylation reaction using 10.0 g of N- (1-benzyl-3-piperidyl) -N- (2,2-dimethoxyethyl) -3,4-dimethoxybenzamide was obtained as an oil.

Reference Example 42

N- (1-benzyl-3-piperidyl) -N- (2,2-dimethoxyethyl) 3,4-dimethoxybenzamide (97.4 g) was subjected to a conventional cyclization reaction using acetic acid-concentrated sulfuric acid. 64.5 g of 2- (tribenzyl- ³ -piperidyl) -6,7-dimethoxy-1,2-dihydroisoquinolin-1 (2H) -one hydrochloride was obtained as pale yellow crystals. Reference Example 43

2- (1-benzyl-3-piperidyl) -6,7-dimethoxy-1,2-dihydroisoquinolin-1 (2H) -one 15.0 g of dimethoxy-2_ (3-piperidyl) -1,2,3,4-tetrahydroisoquinolin-1 (2H) -one was obtained as a colorless powder.

In the same manner as in Reference Example 2, the compound of Reference Example 44 was obtained.

Reference Example 44 1- (3-Bromopropoxy) _4-trifluorobenzene

Example 1

To a suspension of 3.0 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride in 3.0 g of chloroform was added dropwise 1.29 g of triethylamine at room temperature, and the mixture was stirred for 1 hour. 3.15 g of tribenzyl-3-piridone hydrochloride hydrate and 1.41 g of triethylamine were added to the mixture, and the mixture was stirred at room temperature for 10 minutes. Ice-cooled mixture 4.6 g of drunk acid and 3.12 g of sodium triacetoxyborohydride were sequentially added, and the mixture was returned to room temperature and stirred for 1.5 hours. The reaction solution was ice-cooled, the pH was adjusted to 10 with 1N sodium hydroxide, and the mixture was extracted twice with black hole form. The port-form layer was washed with saturated saline, dried over magnesium sulfate, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography (chloroform-methanol = 100: 1). (Bok benzyl - ³ - piperidyl) -6,7-dimethoxy - 1, 2, ^3, to give 4-tetrahydroisoquinoline quinoline 2.71 g as an oil. 350 mg of this compound was converted into a hydrochloride with ethyl acetate containing 4N hydrochloric acid, and recrystallized from ethanol to obtain 200 mg of dihydrochloride as white crystals. Example 2

6,7-dimethoxy-2- (3-piperidyl) - 1, 2, ^3, was added dropwise at room temperature Toriechiruamin 200mg to § cell Tonido J Le (8 ml) suspension of 4-tetrahydroisoquinoline dihydrochloride 350mg Stirred for 10 minutes. To the reaction solution, 270 mg of 1- (3-bromopropoxy) -3,4-methylenedioxybenzene and 150 mg of potassium carbonate were added, and the mixture was stirred at 80 ° C for 6 hours. After evaporating the solvent under reduced pressure, the obtained residue was dissolved in chloroform and washed with 1 N sodium hydroxide and saturated saline, and dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography on silica gel (chloroform: methanol = 50: 1) to give 6,7-dimethoxy-2-U- [3- (3,4-methylenediamine). (Oxyphenoxy) propyl] -3-pyridyl H, 2,3,4-tetrahydroisoquinoline (420 mg) was obtained as an oil. Furthermore, the hydrochloride was prepared with ethyl acetate containing 4N hydrochloric acid and recrystallized from acetonidyl to obtain 240 mg of dihydrochloride as white crystals.

Example 3-13

In the same manner as in Example 2, compounds shown in Tables 3 and 4 below were obtained using the compounds of Reference Examples 3 to 13.

Example 14

2- [1- (2-chloroethyl) -3-piperidyl] -6,7-dimethoxy-1,2,3,4-pentahydroisoquinoline shown in Reference Example 25 320 mg, 3,4-dimethoxyphenol A toluene mixture of 150 mg, 1 N sodium hydroxide, 1 ml tetrabutylammonium bromide, 30 mg was stirred at 90 ° C. for 10 hours. After evaporating the solvent under reduced pressure, the obtained residue was dissolved in chloroform, washed with saturated saline and dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (chloroform: methanol = 100: 1) to give 6,7-dimethoxy-2- {1- [2- (3,4-dimethoxy). [Phenoxy) ethyl] -3-piperidyl H, 2,3,4-ditrahydroisoquinoline (230 mg) was obtained as an oil. Further, oxalic acid salt was recrystallized from acetonitrile to obtain 235 mg of linixic acid salt as white crystals. Examples 15-16

In the same manner as in Example 14, the compounds shown in Table 3 below were obtained.

Example 17

To a suspension of 6,7-dimethoxy-2- (3-piperidyl) -1,2,3,4-tetrahydroisoquinoline dihydrochloride (700 mg) in dichloroethane (20 ml) was added dropwise 400 mg of triethylamine at room temperature for 10 minutes. Stirred. To the reaction mixture, 400 mg of 3- (4-methoxyphenyl) propionic acid, 460 mg of 1-ethyl- ^3- [ ^3- (dimethylamino) propyl] carbodiimide hydrochloride and 140 mg of 1-hydroxybenztriazole were sequentially added, and the mixture was added at room temperature for 3 hours. While stirring. The reaction solution was washed with 5% sodium bicarbonate and saturated saline, and the organic layer was dried over magnesium sulfate. The residue obtained by evaporating the solvent was dissolved in tetrahydrofuran (20 ml), and lithium aluminum hydride (220 mg) was slowly added under ice-cooling. The reaction solution was heated under reflux for 1 hour and then cooled on ice. Water was added to the reaction solution until the foaming was completed, and the precipitated unnecessary substances were removed by filtration. The residue obtained by distilling the filtrate was purified by silica gel column chromatography (form: methanol = 50: 1) to give 6,7-dimethoxy-2- {1- [3- (4-methoxyphenyl). ) Propyl] -3-piperidyl} -1,2,3,4-tetrahydroisoquinoline (530 mg) was obtained as an oil, which was further converted to a hydrochloric acid salt with ethyl acetate containing 4 N hydrochloric acid, and recrystallized from acetonitrile to give dihydrochloride. 380 mg of the salt were obtained as white crystals.

To a suspension of 6,7-dimethoxy-2- (3-piperidyl) -1,2,3,4-tetrahydroisoquinoline dihydrochloride (350 mg) in dichloroethane (15 ml) was added dropwise 200 mg of triethylamine at room temperature for 10 minutes. Stirred. 170 mg of 3- (3-methoxyphenyl) propionaldehyde, 120 mg of acetic acid and 270 mg of sodium triacetoxyborohydride were sequentially added to the reaction solution, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was adjusted to pH 10 with 1N sodium hydroxide, and extracted twice with chloroform. The chromate-form layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue obtained was purified by silica gel column chromatography (chloroform-methanol = 100: 1). 310 mg of 1,7-dimethoxy-2- {1- [3- (3-methoxyphenyl) propyl] -3-piperidyl} -1,2,3,4-tetrahydroisoquinoline were obtained as an oily substance. Further, oxalate was recrystallized from acetonitrile to obtain 185 mg of oxalate as white crystals.

Example 1 9-23

In the same manner as in Example 18, the compounds shown in Table 3 below were obtained.

Example 24

6,7-Dimethoxy-2- (3-piperidyl) -1,2,3,4-tetrahydroisoquinolin-1 (2H) -one A suspension of 3.0 g of acetate nitrile (8 ml) was added at room temperature to 1- (3 - bromopropoxy) - ^3, ⁴ - methylenedioxyphenyl O carboxymethyl benzene 2.94g And 1.52 g of potassium carbonate, and the mixture was stirred at 80 ° C for 6 hours. After the precipitated salt was filtered off, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in chloroform, washed with 1N sodium hydroxide and saturated saline, and dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (chloroform: methanol = 100: 1) to give 6,7-dimethoxy-2- {1- [3- ( ³ 3.52 g of 2,4-methylenedioxyphenoxy) propyl] -3-piperidyl} -1,2,3,4-tetrahydroisoquinolin-1 (2H) -one was obtained as an oily substance. Further, the hydrochloride was prepared with ethyl acetate containing 4N hydrochloric acid and recrystallized from ethanol to obtain 3.1 g of hydrochloride as white crystals.

Examples 25-29

In the same manner as in Example 2, the compounds shown in Tables 5 and 6 described below were obtained.

Example 30

To a solution of oxalyl dichloride (0.257 ml) in dichloromethane (6 ml) at -70 ° C was added a solution of 0.266 ml of dimethylsulfoxide in dichloromethane (2 ml), and the mixture was stirred at -70 ° C for 10 minutes under an argon atmosphere. . At -70 ° C, a solution of 0.419 g of 3-hydroxy-1- [3- (3,4-methylenedioxyphenoxy) propyl] piperidine obtained in Reference Example 21 in dichloromethane (3 ml) was added at -70 ° C. Was added and stirred at -70 ° C for 1 hour under an argon atmosphere. To the reaction solution was added 0.836 ml of triethylamine at -70 ° C, and the mixture was stirred under ice-cooling for 1 hour. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, which was then dissolved in chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 3-hydroxy-1- [3-- 0.43 g of (3,4-methylenedioxyphenoxy) propyl] piridone was obtained as a pale yellow oil.

6-Methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (J. Med.Chem., 1987, 30, 2208) To 0.300 g of a dichloroethane solution (10 ml) was added 0.209 ml of triethylamine, and the mixture was added at room temperature. Stirred for 10 minutes. 0.430 g of 3-hydroxy-1- [3- (3,4-methylenedioxyphenoxy) propyl] piridone, 0.172 ml of acetic acid, and 0.381 g of sodium triacetoxyborohydride were sequentially added to the reaction solution. The mixture was stirred at room temperature for 4 hours. The reaction solution was made alkaline (pH about 10) with a 1N aqueous sodium hydroxide solution, dissolved in chloroform, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (form: methanol = 49: 1) to give 6-methoxy-2- {1- [3- (3,4-methylenedioxyphenoxy). Propyl]-3-piperidylt

0.465 g of 1,2,3,4-tetrahydroisoquinoline was obtained as a pale brown oil. 6-Methoxy-2-11- [3- (3,4-methylenedioxyphenoxy) probild 3-piperidyl 1,2,3,4-pentahydroisoquinoline 0.465 g in ethyl acetate solution (8 ml) Then, under ice-cooling, 0.685 ml of 4N ethyl acetate hydrochloride solution was added, the reaction solution was concentrated under reduced pressure, and the residue was crystallized from acetonitrile-methanol to give 6-methoxy-2-{1-[-( 3,4-methylenedioxyphenoxy) propyl] -3-piperidyl} -1,2,3,4-tetrahydroiso 0.340 g of quinoline dihydrochloride was obtained as colorless crystals.

Examples 31-32

In the same manner as in Example 30, the compounds shown in Table 6 below were obtained.

Example 33

6,7-Dimethoxy-2- (3-piperidyl) -1,2,3,4-tetrahydroisoquinolin-1 (2H) -one A suspension of 630 mg of acetonitrile (8 ml) was added at room temperature to 1- (3 -Bromopropoxy) -3,4-dimethoxybenzene (720 mg) and potassium carbonate (360 mg) were added, and the mixture was stirred at 80 ° C for 6 hours. After the precipitated salt was filtered off, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in chloroform, washed with 1N sodium hydroxide and saturated saline, and dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (chloroform: methanol = 100: 1) to give 6,7-dimethoxy-2- {1- [3- (3,4 -Dimethoxyphenoxy) provild-3-piperidyl} -1,2,3,4-dihydrohydroquinoline_1 (2H) -one 1.0Og was obtained as an oil. To give the hydrochloride salt 7 ² 0 m _g as white crystals by further 4N hydrochloric acid containing acetic acid Echiru into a hydrochloride ethanol by Li recrystallization.

Example 34-54

In the same manner as in Example 2, compounds shown in Table 3 and Tables 7 and 8 described below were obtained.

Example 55

In the same manner as in Example 18, the compounds shown in Table 8 below were obtained.

Example 56

(I) -6,7-Dimethoxy-2- (3-piperidyl) -1,2,3,4-tetrahydroisoquinoline-1 (2H) -one D-tartrate 650 mg in 10 ml ), And made alkaline with 5% sodium bicarbonate water under ice-cooling. The extract was extracted four times with a black hole form, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was suspended in acetonitrile (05 ml), 1- (3-bromopropoxy) -3,4-dimethoxybenzene (610 mg) and potassium carbonate (250 mg) were added, and the reaction mixture was stirred at 90 ° C. for 3 hours. After evaporating the solvent under reduced pressure, the residue was suspended in chloroform (15 ml), desalted and washed with 1N aqueous sodium hydroxide. The mixture was extracted three times with chloroform (15 ml), the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (form: form: methanol = 100: 1) to give (I) -6,7-dimethyloxy-2- {1- [3- (3,4 -Dimethoxyphenoxy) propyl] -3-piperidyl H, 2,3,4-tetrahydroisoquinolin-1 (2H) -one 61 Omg was obtained as an oil. The hydrochloride was further recrystallized from acetonitrile / ethyl acetate to obtain 460 mg of hydrochloride as white crystals. The product showed an optical activity of 99.5%.

Examples 57-59 In the same manner as in Example 56, compounds shown in Table 9 below were obtained.

Example 60

In the same manner as in Example 2, the compounds shown in Table 3 below were obtained.

Tables 1 and ² show the physicochemical properties of the reference example, and Tables 3 to 9 show the structural formulas and physicochemical properties of the compounds of the examples.

The symbols in the table have the following meaning.

Rex .: Reference example number

Ex .: Example number

Sal: salt

DATA: Physicochemical properties

mp.

dec .: decomposition

NR: Nuclear magnetic resonance spectrum (TMS internal standard) δ:

[Unless otherwise specified, reference examples use CDC, and examples use DMSO-d6.]

Me: Methi; / OME: Methoxy

Et: Etil OEt: Ethoxy

iPr: Isopropizole diOH: Dihydroxy

Ph: phenyl diOMe: dimethoxy

In: Indanil triOMe: Trimetroxy

tNapy: 5,6,7,8- 亍 trahydronaphthyl C02Me: methoxycarbonyl

OBfu: 3-oxo-benzofuranyl

Naph: Naphthyl

dlnd: 2,3-dihydro-1H-indole

Py: Pyridyl

Th: Chenil

Fu: ruffles

1-Oxpy: 1-oxopyrrolidinyl

Π / 86 OAV

- ϋ 8 εd, 3 o 9επ, 86 oi vva

Ex. R ³ R ⁴ A v Λ B Sal DATA

1 -H -H -CH ₂ --Ph 2HCI mp .: 204-206 ° C (d6C.)

5 -H -H-(CH ₂ ) ₃ -U 4-iPr-Ph 2 (C0 ₂ H) ₂ mp .: 128-130 ° C

6 -H -H-(CH ₂ ) _3-

5-ln 2HCI mp .: 173-176 ° C (dec.)

7 -H -H-(CH ₂ ) ₃ -J 6-tNaph 2HCI mp .: 158-160 ° C (dec.)

8 -H -H-(CH ₂ ) ₃ -J 6-OBfu 2HCI mp .: 165-167 ° C

9 -H -H-(CH ₂ ) ₃ -CJ 2-Naph 2HC! Mp .: 174-176 ° C

10 -H -H-(CH ₂ ) ₃ -r U 2-O e-Ph 2 (C0 ₂ H) ₂ mp .: 1 16-118 ° C

13 -H -H-(CH ₂ ) ₃ -U 5-dlnd 2HCI mp .: 164-167 ° C (dec.)

14 -H -H-(CH ₂ ) ₂ -U 3,4-diOMe-Ph 2 (C0 ₂ H) ₂ mp .: 106-108 ° C

15 -H -H-(CH ₂ ) ₂ -Li 4-OMe-Ph 2 (C0 ₂ H) ₂ mp .: 162-166 ° C

16 -H -H-(CH ₂ ) ₂ -C 3,4-diOMe-Ph 2 (C0 ₂ H) ₂ mp .: 109-111 ° C

_{_{17 -HH - (CH 2) 3}} - 4-OMe-Ph 2HCI mp .: 187-189 ° C

_{18 -H -H - (CH 2)} 3 - 3-OMe-P 2 (C0 2 H) 2 mp .: 97-99. C

_{19 -H -H - (CH 2)} 3 - 3,4-diOMe-Ph 2HCI mp .: 189-191 ° C (dec.)

_{20 -H -H - (CH 2)} 4 - 3,4-diOMe-Ph 2 (C0 2 H) 2 mp .: 100-102 ° C

_{21 -H -H -CH 2 - 2-} Py 2 (C0 2 H) 2 mp .: 100-103 ° C

_{22 -H -H -CH 2 - 3-} Th 2 (C0 2 H) 2 mp .: 126-129 ° C

_{23 -H -H -CH 23-Fu 2} (C0 2 H) 2 mp .: 121-123 ° C

35 = 0-(CH ₂ ) ₃ -Li 5-ln HCI mp .: 210-219 ° C

_{38 = 0 - (CH 2)} 3 - 2-CI-Ph HCI mp .: 216-218 ° C

39 = 0-(CH u 3-CI-Ph HCI mp .: 187-189 ° C

40 = 0-(CH ₂ ) ₃ -u 4-CI-Ph HCI mp .: 205-211 ° C

42 = 0-(CH ₂ ) ₃ -U 4-CN-Ph HCI mp .: 209-212 °.

44 = 0-(CH ₂ ) ₃ -Li 4-F-Ph HCI mp .: 187-192 ° C

47 = 0-(CH ₂ ) ₃ -o 2-Naph HCI mp .: 212-215 ° C

_{48 = 0 - (CH 2)} 3 - 0 4-N0 2 -Ph HCI mp .: 221-229 ° C

_{49 = 0 - (CH 2)} 3 - 0 4-Br-Ph HCI mp .: 216-218 ° C

_{60 = 0 - (CH 2)} 3 - 0 4-CF 3 -Ph HCI mp .: 217-231 ° C

-ε-

SL £ Z0IL6d £ l∑3d CO

860Α / Α

Table 9

Compounds other than the above are listed in Tables 10 to 12 below. The following compounds can be synthesized using the above-mentioned preparation methods and the methods described in the examples, and modifications thereof which are generally known to those skilled in the art, and do not require special experiments.

LLZZ0 / L6d £ / lDd f9eei86 O. -0

sLZZ0 / L6drilDd

Claims

1. A 2- (3-piperidyl) -1,2,3,4-tetrahydroisoquinoline derivative represented by the following general formula (I) or a salt thereof.

(The symbols in the formula have the following meanings.

Blue

R ', R ² : same or different, hydrogen atom, halogen atom, hydroxy, lower alkyl, halogeno lower alkyl, lower alkyl -〇-, nitro, cyanoamino, oxopyrrolidinyl, lower alkyl-O- CO-NH-, lower alkyl-CO-NH- or lower alkyl-S02-NH- group,

ste range-"

Or R ′ and R ² are in the form of-0 -lower alkylene- 0- group,

Enclosure

X: bond, oxygen atom or sulfur atom,

A: lower alkylene group,

Ring B: a hydrocarbon ring group which may be substituted or a heterocyclic group which may be S-substituted and may be condensed with a benzene ring)

2. The 2- (3-piperidyl, 2,3,4-trihydridoisoquinoline derivative or a salt thereof according to claim 1, wherein R ³ and R ⁴ are an integrated oxo group.

3. The 2- (3-piperidyl) -1,2,3,4-tetrahydroisoquinoline derivative or a salt thereof according to claim 1, wherein R ³ and R ⁴ are each a hydrogen atom.

4. Ring B is a halogen atom, hydroxy, lower alkyl, halogeno lower alkyl, lower alkyl-0-, nitro, cyanamino, oxopyrrolidinyl, lower alkyl -〇-C〇-NH-, lower alkyl- CO- NH -, lower alkyl - S_〇 ² -NH- and - 0 from 1-3 is substituted with a substituent which may be the phenyl is selected from lower alkylene -〇- group, naphthyl, indanyl, 1, 4. The 2,3,4-tetrahydronaphthyl, furyl, chenyl, pyridyl, 2,3-dihydro-3-oxobenzofuranyl or 2,3-dihydro-1H-indolyl group. 2- (3-piperidyl) -1, 2,3,4-tetrahydroisoquinoline derivative or a salt thereof.

5. The 2- (3-piperidyl) -1, 2,3,4-tetrahydroisoquinoline derivative or a salt thereof according to claim 4, wherein A is an ethylene or propylene group and X is an oxygen atom. .

6. Even if R ′ and R ² are lower alkyl-O— groups, and ring B is substituted with one or two substituents selected from lower alkyl-0—, methylenedioxy and ethylenedioxy groups The 2- (3-piperidyl) -1,2,3,4-tetrahydroisoquinoline derivative or a salt thereof according to claim 5, which is a good phenyl group.

7. is a methoxy or ethoxy group, and ring B is a phenyl group which may be replaced by one or two substituents selected from methoxy, ethoxy, methylenedioxy and ethylenedioxy groups. 6 wherein the 2- (3-piperidyl) - 1么^3, 4-tetrahydroisoquinoline derivative or a salt thereof.

8. 6,7-Dimethoxy-2- {1- [3- (3,4-methylenedioxyphenoxy) propyl] -3-piperidylt

1,2,3,4-tetrahydroisoquinoline or a salt thereof.

9.6,7-dimethoxy-2-{1-[3- (3,4-methylenedioxyphenoxy) propylto 3-piperidylt

1,2,3,4-tetrahydroisoquinolin-1 (2H) -one or a salt thereof.

10. 6-Ethoxy - 7-methoxy-2- {1- [3- ^(3, 4-methylenedioxy O carboxymethyl phenoxyethanol) propyl:) - 3- Piberiji le} -1, 2,3,4 -亍Trahydroisoquinoline-K2H) -one or a salt thereof,

1 1 .6,7-Dimethoxy-2- 2- {1- [3- (3,4-dimethoxyphenoxy) propyl] -3-piperidylt 1,2,3,4-tetrahydroisoquinoline-1 (2H) -On or its salt.

12. 6,7-Dimethoxy-2- {1- [3- (4-methoxyphenoxy) propyl] -3-piperidyl H, 2,3,4-tetrahydrol mouth isoquinoline-1 (2H) -one Or a salt thereof.

13. 6,7-dimethoxy-2- {1- [3- (4-methoxycarbonylphenoxy) propyl] -3-piperidyl 1 么 3,4-dihydroisoquinolin-1 (2H) -one or a salt thereof .

14. 6,7-dimethoxy-2- {1- [3- (4-ethoxyphenoxy) propyl] -3-piperidyl H, 2,3,4-tetrahydroisoquinoline-1 (2H) -one or a mixture thereof salt.

15. 2- {1- [3- (3,4-dimethoxyphenoxy) propyl] -3-piperidyl} -6-ethoxy-7-methoxy-1,2,3,4-transhydroisoquinoline-1 (2H) -one or a salt thereof.

1 6. A pharmaceutical composition comprising the 2- (3-piperidyl) -1,2,3,4-tetrahydroisoquinoline derivative according to claim 1 or a salt thereof and a pharmaceutically acceptable carrier.

17. The pharmaceutical composition according to claim 16, which is an If current inhibitor.

18. The pharmaceutical composition according to claim 17, which is a heart rate lowering agent.