JPH11269172A - 2-(1-piperidiylalkanoly)-1,2,3,4-tetrahydroisoquinoline derivative or its salt - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having excellent inhibitory action on If current, reducing action on frequency of heart, useful as a preventive and a therapeutic agent for ischemic heart diseases such as angina pectoris, cardiac infarction, or the like, and cardiovascular diseases such as congestive cardiac insufficiency, irregular pulse, or the like. SOLUTION: This compound is shown by the formula [R<1> and R<2> are each H, a lower alkyl, an O-lower alkyl or the like; X is O, S, SO, SO2 or the like; R<3> is H or a lower alkyl; A<1> to A<3> are each a lower alkylene; B is a (substituted) hydrocarbon ring or a hetero ring which may be condensed with a (substituted) benzene ring], such as 6,7-dimethoxy-2- 3-[4-(3,4- methylenedioxyphenoxyl)piperidino]propionyl}-1,2,3,4-tetrahydroisoquin oline hydrochloride. The compound of formula I is obtained by acylating a tetrahydroisoquinoline compound with acrylic acid chloride and successively subjecting the acylated substance and a piperidine compound to a Michael addition reaction in a solvent such as tetrahydrofuran or the like under cooling with ice or at a room temperature or under heating conditions.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a medicament, particularly a novel 2- (1-piperidylalkanoyl) -1,2,3,4-tetrahydroisoquinoline derivative or its salt having an If current inhibitory action, and a compound thereof. The present invention relates to a medicine containing, as an active ingredient, a heart rate lowering agent.

[0002]

2. Description of the Related Art As a drug having a heart rate lowering effect, and drugs that act conventionally to neurotransmitter receptors and ion channels are known, in the former adenosine receptor agonists, M ₂ muscarinic receptor agonists And β-adrenergic receptor antagonists, and the latter include calcium channel inhibitors. These heart rate-lowering drugs can be used for various clinical symptoms resulting from an imbalance between the supply and demand of oxygen in the myocardium, eg, angina, ischemic heart disease such as myocardial infarction, or arrhythmia, heart failure, etc. Has been confirmed to be useful as an agent for preventing and treating cardiovascular diseases. However, these drugs have not only a heart rate-lowering effect, but also an inhibitory effect on atrioventricular conduction and cardiac contractile function, or a blood pressure lowering effect, and sometimes they may exert an effect leading to complete cardiac arrest. In particular, it was feared that it would be used in patients with impaired cardiac function. On the other hand, it is known that cells such as the sinoatrial node, which has a physiological pacemaker activity of the heart, and the atrioventricular node, the His bundle, and the Purkinje fibers, which constitute the stimulation conduction system, spontaneously generate electrical excitation. In cells with cardiac pacemaker activity, the permeability to cations such as sodium and potassium ions has no selectivity and is activated by hyperpolarization of the membrane potential. Its presence has been confirmed and is termed the If current (Difrancesco D. et al. J. Physiol. 377: 6
1-88, 1986, Irisawa H, et al. Physiol. Rev. 73:19
7-227, 1993; Diffracesco D., Annu. Rev. Physiol., 5
5: 455-472, 1993). In the heart, this If current contributes to the formation of diastolic depolarization of cells having pacemaker activity and is thought to be a current that regulates heart rate.

[0003] Therefore, an effect of lowering the heart rate by suppressing the If current defining the slope of the diastolic depolarization is expected. In fact, a new type of drug that actually inhibits If current and exerts a heart rate lowering effect has recently been reported. Such If current inhibitors can selectively reduce heart rate and also reduce myocardial oxygen consumption without inhibiting atrioventricular conduction and cardiac contractile function. Therefore, inhibitors of If current are distinguished from conventional activities such as various receptor agonists and calcium channel inhibitors in that they have no inhibitory effect on atrioventricular conduction and cardiac contractile function or no cardiac arrest effect. Therefore, an If current inhibitor is expected to be a prophylactic and therapeutic agent for ischemic heart disease (eg, angina pectoris, myocardial infarction, etc.) and circulatory system diseases (arrhythmia, heart failure, etc.) with few side effects. Further, it is also useful in controlling an excessively increased heart rate and controlling the heart rate to a constant state, for example, during an operation using anesthesia. In addition, not only cells having pacemaker activity but also intrinsic cardiomyocytes which do not usually have pacemaker activity, that is, atrial and ventricular myocytes, have this property of If current (there is no selectivity in cation permeability and excessive It has been reported that an ionic current similar to that activated by polarization and activated by β receptor stimulation exists (Ha
ngang 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 the action potentials are recorded from these cells. Diastolic depolarization, which gradually depolarizes, is observed. In these pathological conditions, an increase in If current has been confirmed, and If current contributes to the formation of diastolic depolarization, which is expected to be the cause of abnormal automatic hyperactivity (Elisabetta, C. et al.). ., Circulation. 94: 1674-1
681, 1996; Elisabetta, C. et al., Circulation. 9
5: 568-571, 1997). Therefore, an If current inhibitor is considered to be useful for suppressing abnormal automatic hyperactivity in these disease states.

[0004] It is known that Zatebradine, which is known as a compound having a heart rate lowering action, is based on the If current inhibitory action. However, it has been reported that Zatebradine causes a visual impairment together with a heart rate lowering effect (William H. F.
rishman, J. Am. Coll. Cardiol, 26: 305-312, 1995;
Stephen P. Glasser et al., The American Journal of
Cardiology, 79: 1401-1405, 1997). It is known that a current (Ih current) having a property similar to the If current exists in photoreceptors (Shaul Hestrin, J. Phys.
iol. 390: 319-333, 1987), Zatebradine.
It is anticipated that such visual impairment will occur because the Ih current and the Ih current are inhibited at the same time. I
In research on f-current inhibitors, separation from Ih current-inhibiting action is one of the issues. On the other hand, derivatives such as substituted lower alkyl-1,2,3,4-tetrahydroisoquinoline represented by the following general formula have been reported as compounds having a heart rate lowering action (JP-A-1-45381; E
P292840). However, it has a different structure from the compound of the present invention, and does not describe the If current inhibitory action.

[0005]

Embedded image [Wherein A is -CH2-, -CH2-CH2-, -CH
= CH-, B represents -CH2-, -CH2-CH2
-, -CO- or -CH2-CO-, E represents 1 to 1 carbon atoms.
Straight-chain alkylene having 3 carbon atoms and optionally substituted with alkyl having 1 to 3 carbon atoms, m represents a number 1, 2, 3, 4, 5 or 6; 0,1,
Represents 2 or 3, where n + m must represent 3, 4, 5 or 6. For other symbols, refer to the above-mentioned publication. Further, as a compound having an anti-tachycardia effect or a vasodilatory effect, a β-amino acid amide derivative represented by the following general formula has been reported (JP-A-2-138172). However, there is no description about the If current inhibitory action and the heart rate lowering action.

[0006]

Embedded image (Where Z is l 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.

[0007]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel compound having a superior If current suppressing action.

[0008]

Means for Solving the Problems The present inventors have conducted intensive studies on the above-mentioned agents for suppressing the If current, and as a result,
The present invention has been completed based on the finding that a series of compounds represented by the following general formula (I) suppresses If current and has a heart rate lowering effect in the heart. That is, the following general formula (I)
2- (1-piperidylalkanoyl) -1, represented by
The present invention relates to a 2,3,4-tetrahydroisoquinoline derivative or a salt thereof, and a drug containing the derivative or a salt thereof as an active ingredient, particularly an If current inhibitor, especially a drug that is a heart rate lowering agent.

[0009]

Embedded image (The symbols in the above formulas have the following meanings, respectively: R ¹ , R ² : identical or different, a hydrogen atom, -lower alkyl, -O-lower alkyl, or R ¹ and R ² are taken together as- O-lower alkylene-O-, X: O, S, SO, SO ₂ , CH ₂ , NR ³ , or CO, R ³ : hydrogen atom or lower alkyl, A ¹ : lower alkylene, A ² : lower alkylene, A ³ : lower alkylene, or absent, B: a substituted or unsubstituted hydrocarbon ring or a substituted or unsubstituted benzene ring.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The compound (I) of the present invention will be described below in detail. In the definition of the general formula of the present invention, unless otherwise specified, the term “lower” means a straight or branched carbon chain having 1 to 6 carbon atoms. "Lower alkyl" is preferably lower alkyl having 1 to 4 carbon atoms,
More preferred are methyl, ethyl, propyl and isopropyl. The “lower alkylene” is preferably methylene or ethylene for A ^{1 in} the general formula, and methylene, ethylene or propylene for A ² and A ³ . A ² and A ³ may not be present. For some compounds, it may be preferable that A ² and / or A ³ be absent. Note that “not exist” means
It means that the piperidine ring and X or X and B ring are directly connected. The hydrocarbon ring of the “optionally substituted hydrocarbon ring” is a saturated or unsaturated, monocyclic or condensed hydrocarbon ring, preferably “aryl” or “cycloalkyl”. “Aryl” is preferably aryl having 6 to 14 carbon atoms, and includes dihydro, trihydro and tetrahydro forms in which a hydrogen atom is added to any carbon atom of the aryl group. More preferably, it is phenyl or naphthyl. "Cycloalkyl" is preferably cycloalkyl having 3 to 8 carbon atoms, and more preferably cyclohexyl.
"Hetero ring optionally condensed with a benzene ring" of "hetero ring optionally substituted and condensed with a benzene ring" refers to a ring in which a benzene ring is condensed to a hetero ring or an uncondensed hetero ring. It is a heterocycle. "Heterocycle"
A heteroaryl or saturated heterocycle containing 1 to 4 heteroatoms consisting of an oxygen atom, a sulfur atom or a nitrogen atom, wherein heteroaryl is a 5- to 6-membered monocyclic heteroaryl (furyl, thienyl, pyridyl, etc.), Bicyclic heteroaryl in which two 5- to 6-membered heteroaryls are fused (such as naphthyridinyl) is exemplified. Saturated heterocycles have 5 members or more
It is a 7-membered ring, and piperidyl and piperazinyl are preferred.

The substituent of the "optionally substituted hydrocarbon ring" or the "optionally substituted heterocyclic ring which may be condensed with a benzene ring" is usually a group capable of substituting these rings. Any may be used. Preferably, halogen atom (F, Cl, Br, I), lower alkyl, lower alkenyl (vinyl etc.), lower alkynyl (ethynyl etc.), hydroxy, mercapto, halogeno lower alkyl (trifluoromethyl etc.), -O-lower alkyl , -S
- lower alkyl, -CO-O-lower alkyl, carboxy, sulfonyl, sulfinyl, -SO ₂ - lower alkyl, -SO- lower alkyl, -CO- lower alkyl, carbamoyl, -CO-NH- lower alkyl, -CO- N
(Lower alkyl) ₂ , nitro, cyano, amino, -NH
-Lower alkyl, -N (lower alkyl) ₂ and -O-lower alkylene-O-. These substituents may be substituted with one or more, preferably one to three. 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 substituent, a geometric isomer or a tautomer exists. The present invention includes all separated or mixed forms 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. , Lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid,
Examples thereof include acid addition salts with organic acids such as methanesulfonic acid, ethanesulfonic acid, and glutamic acid. Furthermore, the present invention also includes hydrates of compound (I), solvates such as ethanol, and polymorphic substances.

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

First manufacturing method

Embedded image (In the formula, R ¹ , R ² , A ² , A ³ , B and X have the above-mentioned meanings.) The present production method is based on the tetrahydroisoquinoline compound (II)
And an acrylic acid chloride to carry out an acylation reaction to obtain a compound (III), followed by a Michael addition reaction of the compound (III) with a piperidine compound (IV) to give the compound (I) of the present invention.
This is a method for obtaining a. The acylation reaction may be performed using a conventional method, and the Michael addition reaction may be performed in a solvent such as tetrahydrofuran, dichloroethane, alcohol, dioxane or the like under ice-cooling or at room temperature and heating conditions. Further, triethylamine, triton B, potassium hydroxide and the like may be added as additives.

Second manufacturing method

Embedded image (Wherein, R ¹ , R ² , A ¹ , A ² , A ³ , B and X have the above-mentioned meanings, and Z ¹ means a halide or a leaving group.) This is a method of subjecting (II) to a conventional acylation reaction to obtain a compound (V), followed by amination of the piperidine compound (IV). The amination reaction is pyridine, tetrahydrofuran,
It is preferable to carry out the reaction in an inert solvent such as methylene chloride under ice-cooling or at room temperature while heating.

Third manufacturing method

Embedded image (In the formula, R ¹ , R ² , A ¹ , A ² , A ³ , B and X have the above-mentioned meanings.) In this production method, the compound (II) and the piperidine compound (VI) are subjected to an amidation reaction according to a conventional method. To obtain the compound (I) of the present invention. The amidation reaction is a conventional amidation reaction,
Specifically, the compound (II) without solvent or in the solvent
And compound (VI) in an equimolar amount to an excess of compound (VI). The reaction temperature differs depending on the type of the reaction compound and is set as appropriate.

(Production Method of Starting Compound (IV)) The piperidine compound as the starting compound can be synthesized according to the following Production Methods 1 to 4 according to a conventional method.

Manufacturing method 1

Embedded image

Manufacturing method 2

Embedded image

Manufacturing method 3

Embedded image

Manufacturing method 4

Embedded image (Wherein A ² , A ³ and Z ¹ have the above-mentioned meanings, Y is a protecting group, X ¹ is S or O, Z ² is lithium or magnesium halide, etc., and R ⁴ is alkyl-substituted amino. The reaction products obtained by the above production methods are isolated and purified as various solvates such as free compounds, salts thereof and hydrates. The salt can be produced by subjecting it to a usual salt formation treatment. Isolation and purification include extraction, concentration, distillation,
It is performed by applying ordinary chemical operations such as 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. Optical isomers can also be synthesized from appropriate optically active starting compounds. 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 efficiently performing optical resolution is appropriately selected.

[0021]

EFFECT OF THE INVENTION The compounds of the present invention have an activity of inhibiting If current, selectively reduce heart rate and show a potent and specific activity of reducing myocardial oxygen consumption. And ischemic heart disease such as myocardial infarction, and is useful as a prophylactic / therapeutic agent for cardiovascular diseases such as congestive 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 the associated arrhythmias, and arrhythmias,
In particular, it is highly useful for preventing or treating supraventricular arrhythmias. In addition, the compounds of the present invention are expected to have the effect of reducing vascular hemodynamic compression and thereby reducing the complications of atherosclerosis, especially coronary atherosclerosis. Further, the compound of the present invention is an agent which suppresses an excessively elevated heart rate and is useful also in the case where the heart rate is controlled 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 it has no inhibitory action on atrioventricular conduction or cardiac contractile function and high selectivity of heart rate lowering action on visual impairment. ing. Further, it is known that, in addition to the If current, an ion current that contributes to the formation of an action potential in the heart includes a current that passes through a Na channel, a K channel, and a Ca channel. Since there is no significant inhibitory effect on the above-mentioned ionic current other than the If current present at a dose that inhibits the If current, it is expected that there are few side effects due to current inhibition other than the If current. Therefore, the compound of the present invention is useful as a heart rate-lowering agent with 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.

[0022] (test method) 1. If Current Inhibition Test <Myocardial Isolation> Male Hartley guinea pigs weighing about 200 to 350 g were stunned by hitting the head, and the heart was immediately removed while exsanguinating the carotid artery. 95%
Tyr sufficiently mixed gas of oxygen + 5% carbon dioxide gas
The heart was transferred into ode's solution, and the sinoatrial node (pacemaker) site (about 3 × 5 mm) was cut out. The excised sinoatrial node contained collagenase (Yakult) (1.5 mg /
ml) Enzyme treatment at 37 ° C. for 30 minutes in Ca ²⁺ -free Tyrode solution. After that, K ⁺ rich solution
The sample was allowed to stand in an ion ("KB recovery solution") at 4 ° C for 1 hour or more. The treated sinoatrial node was minced with an injection needle and pipetting was performed to obtain isolated cardiomyocytes. <Measurement of current> The isolated myocardium was spread in a dedicated chamber, and the patch-clamp method (whole cell mode) was applied to spindle-shaped cells undergoing spontaneous contraction. The holding potential is -40 mV, and from this potential, -10, -20, -3
By applying hyperpolarizing pulses (1 second) sequentially to 0,..., -80 mV, an If current was induced. Since the If current due to the -80 mV hyperpolarizing pulse was the largest, the efficacy evaluation was based on the I-induced by the -80 mV pulse.
The effect of the test compound on the f-current was evaluated. <Efficacy evaluation> Extracellular fluid containing test compound (Tyrode
Perfusion), an If current is induced by a hyperpolarizing pulse of -80 mV at 5 second intervals, and the 100th pulse (about 8 minutes)
Recorded. It was confirmed that the action of the drug reached saturation after 90 pulses or more. The If current inhibitory action of the test compound was measured by measuring the If currents obtained before the perfusion of the drug solution and after 90 pulses, respectively, and compared with the concentration (IC ₅₀ ) of the substance that inhibits the If current by 50%.

[0023] 2. Heart rate lowering effect test A male Hartley guinea pig weighing about 250 to 350 g was stunned by hitting the head, and then exsanguinated and killed to remove the heart. Kr fully aerated with 95% oxygen + 5% carbon dioxide
A right atrial specimen was prepared in ebs-Henseleit solution. The specimen is mounted on a stainless steel hook and 95
Krebs-H fully ventilated with 5% oxygen + 5% carbon dioxide
The suspension was suspended under a load tension of 0.5 g in a Magnus tube filled with enseleit liquid, and the heart rate of spontaneous oscillation was recorded. After suspending the sample and allowing it to stabilize for at least one hour, add the test compound cumulatively into the Magnus tube at 30 minute intervals, determine the concentration-effect curve from the value 30 minutes after substance administration, and determine the effect did. The heart rate lowering effect is the concentration of the substance that reduces spontaneous heart rate by 30% before administration of the test substance (E
C30). As a result, the compound of the present invention showed a strong heart rate lowering effect. Pharmaceutical compositions containing one or more of the compounds of the present invention or salts thereof are prepared using conventional pharmaceutically acceptable carriers. The administration of the pharmaceutical composition of the present invention may be oral administration or parenteral administration such as injection, suppository, transdermal, inhalant, or intravesical injection. The dosage is determined according to the individual case, taking into account symptoms, age of the subject, gender, etc. However, in the case of oral administration, the usual dosage is 0.1 mg per adult per day.
/ Kg to about 100mg / kg, and in one go,
Alternatively, it is administered in 2 to 4 divided doses. When given intravenously due to symptoms, the dose is usually 0.0
It is administered once to several times a day in the range of 1 mg / kg to 10 mg / kg. 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 such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, agar, pectin. , Magnesium metasilicate and magnesium aluminate. The composition may contain, in a conventional manner, additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose glycolate, a stabilizer such as lactose, glutamic acid or asparagine. A solubilizing agent such as an 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 a 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 water. , Ethanol. The composition may contain, in addition to the inert diluent, auxiliaries 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 water-insoluble solutions and suspensions include ethylene glycol, propylene glycol, polyethylene glycol, cocoa butter,
Olive oil, vegetable oils such as sesame oil, alcohols such as ethanol, gum arabic, polysorbate 80
(Product name). Such compositions may further comprise additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), and solubilizing agents (eg, glutamic acid, aspartic acid). May be included.
These are, for example, filtration through a bacteria storage filter,
It is sterilized by blending or irradiation with a bactericide. They can also be used in the preparation of a sterile solid composition which is dissolved in sterile water or a sterile solvent for injection before use.

[0025]

The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the scope of the present invention.

Reference Example 1 (Table 1) A solution of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (7.0 g) in tetrahydrofuran (60 ml), triethylamine (3.29 g) and acrylic acid chloride (2.94 g) were prepared. 1- (6,7-dimethoxy-1,2,2,
6.1 g of 3,4-tetrahydroisoquinolin-2-yl) propenone were obtained as white crystals.

Reference Examples 1-1 to 1-3 were synthesized in the same manner as Reference Example 1 (Table 1). Reference Example 2 A solution of 1- (tert-butoxycarbonyl) -4-hydroxypiperidine (4.0 g) in tetrahydrofuran (20
ml), triphenylphosphine (6.82 g), azodicarboxylic acid diethyl ester (1.08 g) and sesamol (4.14 g) in a conventional Mitsunobu reaction.
-(Tert-butoxycarbonyl) -4- (3,4-
4.78 g of methylenedioxyphenoxy) piperidine were obtained. The obtained compound was subjected to a conventional deprotection reaction to give 2.30 g of 4- (3,4-methylenedioxyphenoxy) piperidine as colorless crystals.

Reference Examples 2-1 to 2-33 in the same manner as Reference Example 2.
Was synthesized (Tables 2-3). Reference Example 3 A conventional acylation method using a solution of 11.5 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride in 100 ml of tetrahydrofuran, 6.07 g of triethylamine and 7.76 g of chlorobutyric acid chloride. By performing the reaction, 11.3 g of 4-chloro-1- (6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl) butan-1-one was obtained as pale yellow crystals. m. p. 197-202 ° C

REFERENCE EXAMPLE 4 A conventional reductive amination reaction was carried out using 996 mg of 1- (tert-butoxycarbonyl) -4-piperidone in acetic acid (10 ml) and 720 mg of 3,4-methylenedioxyaniline. Gave 1.41 g of 1- (tert-butoxycarbonyl) -4- (3,4-methylenedioxyanilino) piperidine as a brown oil. _{^{1 H-NMR (CDCl 3)}} ; 1.22-1.35 (2
H, m), 1.46 (9H, s), 2.00-2.04
(2H, m), 2.89 (2H, t), 3.25-3.
34 (2H, m), 4.02-4.06 (2H, m),
5.85 (2H, s), 6.05 (1H, dd), 6.
24 (1H, d), 6.65 (1H, d)

Reference Example 5 1- (tert-butoxycarbonyl) -4- (3,4-dimethoxyanilino) piperidine was obtained in the same manner as described above. ¹ H-NMR (CDCl ₃ ); 1.25-1.37 (2
H, m), 1.47 (9H, s), 2.01-2.05
(2H, m), 2.92 (2H, t), 3.23 (1
H, s), 3.31-3.38 (1H, m), 3.81
(3H, s), 3.84 (3H, s), 4.02 (2
H, brs), 6.16 (1H, dd), 6.24 (1
H, d), 6.73 (1H.d)

REFERENCE EXAMPLE 6 A dimethylformamide solution (20 ml) of 1- (tert-butoxycarbonyl) -4-hydroxypiperidine (604 mg), 614 mg of 3,4-methylenedioxybenzyl chloride and 132 mg of sodium hydride were used in a conventional manner. By performing the addition reaction, 1- (tert
-Butoxycarbonyl) -4- (3,4-methylenedioxybenzyloxy) piperidine (450 mg) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ); 1.47 (9H, s),
1.53-1.61 (2H, m), 1.82 (2H, b
rs), 3.04-3.13 (2H, m), 3.50-
3.58 (1H, m), 3.75-3.80 (2H,
m), 4.45 (2H, s), 5.85 (2H, s),
6.78 (1H, s), 6.85 (1H, s)

Reference Example 7 A solution of 2.29 g of 1- (tert-butoxycarbonyl) -4-piperidinecarboxylic acid in tetrahydrofuran (3
0 ml) and 975 mg of N, O-dimethylhydroxyamine dihydrochloride by a conventional amidation reaction to give N-methoxy-N′-methyl-1- (tert-
1.70 g of butoxycarbonyl) -4-piperidinecarboxamide was obtained as a colorless oil. _{^{1 H-NMR (CDCl 3)}} ; 1.46 (9H, s),
1.65-1.73 (4H, m), 2.78-2.81
(3H, m), 3.19 (3H, s), 3.71 (3
H, s), 4.13 (2H, brs)

Reference Example 8 N-methoxy-N'-methyl-1- (tert-butoxycarbonyl) -4-piperidinecarboxamide 545
mg of tetrahydrofuran solution (15 ml), 1-bromo-3,4-methylenedioxybenzene 884 mg,
n-butyllithium (1.63 M hexane solution) 2.4
By performing an acylation reaction in the usual manner using 5 ml,
1- (tert-butoxycarbonyl) -4- (3,4
-Methylenedioxybenzoyl) piperidine 629 mg
Was obtained as a pale yellow oil. ¹ H-NMR (CDCl ₃ ); 1.47 (9H, s),
1.67-1.79 (4H, m), 2.87 (2H,
t), 3.27-3.34 (1H, m), 4.14 (2
H, brs), 6.05 (2H, s), 6.86 (1
H, d), 7.42 (1H, d), 7.55 (1H, d
d)

Example 1 1.0 g of 1- (6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl) propenone and 4
A toluene solution (6 ml) of 1.0 g of-(3,4-methylenedioxyphenoxy) piperidine was heated to reflux for 4 hours. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1), and 4N hydrochloric acid / ethyl acetate (10 ml) was added to an ethanol solution (10 ml) of the obtained oily substance. 2
ml) and the solvent was distilled off under reduced pressure. The obtained residue is crystallized from ethanol to give 6,7-dimethoxy-2- {3- [4- (3,4-methylenedioxyphenoxy) piperidino] propionyl} -1,2,3,4-.
1.36 g of tetrahydroisoquinoline hydrochloride was obtained as white crystals.

Example 2 4-chloro-1- (6,7-dimethoxy-1,2,3,
4-tetrahydroisoquinolin-2-yl) butane-1
To a solution of 0.15 g of -one and 0.12 g of 3- (3,4-methylenedioxyphenoxymethyl) piperidine in acetonitrile (5 ml) was added 0.088 g of potassium carbonate and 0.007 g of sodium iodide, and the mixture was heated at 80 ° C for 2 days. Stirred. The reaction solution was cooled to room temperature, made basic with 1N sodium hydroxide, and extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform: methanol = 100: 2), and 45 mg of oxalic acid was added to a methanol solution (2 ml) of the obtained oily substance. In addition, the mixture was concentrated under reduced pressure. The resulting residue was crystallized from a mixed solvent of acetonitrile and ethyl acetate to give 6,7-
Light yellow crystals of 0.048 g of dimethoxy-2- {4- [3- (3,4-methylenedioxyphenoxymethyl) piperidino] butan-1-one} -1,2,3,4-tetrahydroisoquinoline oxalate I got

Example 3 2- {3- [4- (4-nitrophenoxy) piperidino] propionyl} -6,7-methylenedioxy-1,
To a solution of 1.89 g of 2,3,4-tetrahydroisoquinoline (40 ml) in ethanol was added 1N hydrochloric acid (10 ml) and 0.19 g of palladium on carbon.
Stirred for 10 hours. After the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure. A 1N aqueous sodium hydroxide solution was added to the obtained residue to make it basic, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then concentrated under reduced pressure. 1.71 g of 2- {3- [4- (4-aminophenoxy) piperidino] propionyl} -6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline was obtained. I got The obtained 2- {3- [4- (4
-Aminophenoxy) piperidino] propionyl}-
A solution of 0.44 g of 6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline in ethanol (5 m
To 1), 4N hydrochloric acid / ethyl acetate (1 ml) was added, and the mixture was concentrated under reduced pressure. The obtained residue is crystallized from ethanol to give 2- {3- [4- (4-aminophenoxy) piperidino] propionyl} -6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline hydrochloride. 1.36 g of a salt was obtained as pale red crystals.

Example 4 2- {3- [4- (4-aminophenoxy) piperidino] propionyl} -6,7-methylenedioxy-1,
Acetic anhydride was added to a tetrahydrofuran solution (5.0 ml) of 0.43 g of 2,3,4-tetrahydroisoquinoline.
1 g was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, 1N aqueous sodium hydroxide solution was added to the residue to make it basic, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
After the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure. A 4 N hydrochloric acid / ethyl acetate (1 m
l) was added and the mixture was concentrated under reduced pressure. The obtained residue is crystallized from ethanol to give 2- {3- [4- (4-acetylaminophenoxy) piperidino] propionyl}-.
0.092 g of 6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline hydrochloride was obtained as colorless crystals.

Example 5 2- (chloroacetyl) -6,7-dimethoxy-1,
To a suspension of 270 mg of 2,3,4-tetrahydroisoquinoline in acetonitrile (6 ml) was added 3-[(3,4-methylenedioxyphenoxy) methyl] piperidine 259 m.
g and potassium carbonate (152 mg) were added, and the mixture was stirred at 80 ° C. for 2 hours. After evaporating the solvent under reduced pressure, the obtained residue was dissolved in chloroform, washed with an aqueous sodium hydroxide solution and saturated saline, and dried over sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (chloroform: methanol = 24: 1),
-Dimethoxy-2-({3-[(3,4-methylenedioxyphenoxy) methyl] piperidino} acetyl)-
504 mg of 1,2,3,4-tetrahydroisoquinoline
Was obtained as a colorless oil. Further, oxalic acid was added to form an oxalate, which was crystallized from a mixed solution of ethyl acetate-acetonitrile to obtain oxalate 380 mg as colorless crystals.

Examples 6 to 47 were synthesized in the same manner as in Examples 1 to 5 (Tables 4 and 7). Tables 1 to 3 show the chemical structural formulas and physicochemical properties of Reference Examples, and Tables 4 to 7 show the chemical structural formulas and physicochemical properties of Examples. The symbols in the table have the following meaning. mp: melting point, NMR: nuclear magnetic resonance spectrum (TMS was used as an internal standard), Me: methyl, OMe: methoxy,
OEt: ethoxy, diOMe: dimethoxy, CO2M
e: methoxycarbonyl

[0040]

[Table 1]

[0041]

[Table 2]

[0042]

[Table 3]

[0043]

[Table 4]

[0044]

[Table 5]

[0045]

[Table 6]

[0046]

[Table 7] Further, the compounds whose chemical structural formulas are listed in Table 8 can be easily prepared in substantially the same manner as described in the above Examples and Preparation Methods, or by applying some modifications obvious to those skilled in the art. can do.

[0047]

[Table 8]

Continued on front page (72) Inventor Noriyuki Masuda 21 Miyukigaoka, Tsukuba, Ibaraki Pref. Yamanouchi Pharmaceutical Co., Ltd.

Claims (3)

[Claims] 1. 2- (1-) represented by the following general formula (I)
Piperidylalkanoyl) -1,2,3,4-tetrahydroisoquinoline derivatives or salts thereof. Embedded image (The symbols in the above formulas have the following meanings, respectively: R ¹ , R ² : identical or different, a hydrogen atom, -lower alkyl, -O-lower alkyl, or R ¹ and R ² are taken together as- O-lower alkylene-O-, X: O, S, SO, SO ₂ , CH ₂ , NR ³ , or CO, R ³ : hydrogen atom or lower alkyl, A ¹ : lower alkylene, A ² : lower alkylene, A ³ : lower alkylene, or absent, B: a substituted or unsubstituted hydrocarbon ring or a substituted or unsubstituted benzene ring. 2. The compound according to claim 1, wherein X is O. 3. A medicament comprising the 2- (1-piperidylalkanoyl) -1,2,3,4-tetrahydroisoquinoline derivative according to claim 1 or a salt thereof as an active ingredient.