JPH09268176A - Aralkylpiperidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound useful as an acetylcholinesterase inhibitor and useful for treating and preventing various senile dementia, especially senile demantia of Alzheimer type. SOLUTION: This compound is represented by formula I A is formula II [C is H or hydroxy; D is H or a lower hydroxyalkyl; R is H, a lower alkyl or a lower alkoxy; (m) is 0-4], etc.; B is H, hydroxy, etc.; (n) is 0-2} or its salt, e.g. 1-benzyl-4-(5, 6-dimethoxy-1-indanon-2yl) hydroxymethylpiperidine. The compound of formula I is obtained by reacting a compound of formula III with a compound of formula IV. The compound of formula I is has strong acetylcholinesterase inhibiting activity having high selectivity and increases an amount of acetylcholine in a brain and is useful for treating and preventing memory disturbance, etc. The compound is orally, intravenously, intramuscularly, transrectally or percutaneusly administered at a daily dose of 0.01-1000mg, preferably 1-100mg.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel acetylcholinesterase inhibitor having an excellent effect as a medicine, preferably a therapeutic / ameliorating agent for various senile dementia, more preferably an Alzheimer-type senile dementia therapeutic / preventive agent.

[0002]

BACKGROUND OF THE INVENTION With the rapid increase in the aging population, it has been eagerly desired to establish a treatment method for senile dementia such as Alzheimer-type senile dementia. However, at present, various attempts have been made to treat senile dementia with drugs, but no drug that is fundamentally effective against these diseases yet exists.

[0003]

BACKGROUND ART The development of therapeutic agents for these diseases has been studied from various directions. As a powerful direction, senile dementia of the Alzheimer type is accompanied by a decrease in the cholinergic function of the brain. Development from the direction of cholinesterase inhibitors has been proposed and is being attempted. Typical examples include cholinesterase inhibitors such as physostigmine and tetrahydroaminoacridine.

[0004]

[Problems to be solved by the present invention] However, these drugs have drawbacks such as insufficient effects and unfavorable side effects, and there is no definitive therapeutic drug under the present circumstances.

Therefore, the present inventors have conducted extensive research over various compounds for many years in order to develop a drug having a long duration of action and high safety. as a result,
The present invention has been completed by finding that the aralkyl piperidine derivative represented by the general formula (I) described below achieves the intended purpose.

Specifically, the aralkyl piperidine derivative represented by the following structural formula (I) has a potent and highly selective acetylcholinesterase inhibitory activity and is effective in increasing the amount of acetylcholine in the brain and in a memory impairment model. In addition, it has a great feature that it has a long duration of action and high safety as compared with physostigmine which has been generally used in this field, and the value of the present invention is extremely high.

The compound of the present invention was discovered based on the acetylcholinesterase inhibitory action, and therefore, it is effective in treating various diseases caused by the central choline function, that is, in vivo deficiency of acetylcholine as a neurotransmitter. Effective for treatment and prevention. Representative examples include various types of dementia typified by Alzheimer's senile dementia, and other examples include Huntington's disease, Pick's disease, and late-onset dyskinesia.

Therefore, an object of the present invention is to provide a novel aralkylpiperidine derivative which is effective as a medicine, especially for the treatment / prevention of diseases of the central nervous system, and also to provide a process for producing the same. It is to provide a medicine containing as an active ingredient.

[0009]

The aralkylpiperidine derivative (I) according to the present invention is represented by the following general formula.

[0010]

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[Wherein n is 0 or an integer of 1 to 2 and A is a group represented by the following general formula:

[0012]

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(In the formula, C means a hydrogen atom or a hydroxy group, D means a hydrogen atom or a lower hydroxyalkyl group. R is a group selected from the same or different hydrogen atoms, a lower alkyl group and a lower alkoxy group. And m is 0
Or, it means an integer of 1 to 4. ) Or a group represented by the following chemical formula,

[0014]

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(In the formula, R and m have the same meanings as described above.) B means a hydrogen atom or a hydroxy group, and A and B
May form a double bond to form a group represented by the following chemical formula. (In the formula, R and m have the same meanings as described above.)]

[0016]

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Here, the lower alkyl group in the definition of R means a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, for example, methyl group, ethyl group, n-propyl group, i -Propyl group, n-butyl group, i-butyl group, t-butyl group, pentyl group, hexyl group and the like can be mentioned. The lower alkoxy group means a group in which an oxygen atom is bonded to the lower alkyl group, and specific examples thereof include a methoxy group, an ethoxy group and a propoxy group.

Next, the lower hydroxyalkyl group in the definition of D means the above lower alkyl group substituted with a hydroxy group, and specifically, for example, hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group. Base, 1-
Hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1-hydroxy-i-propyl group, 2-
Examples thereof include hydroxy-i-propyl group, hydroxybutyl group, hydroxypentyl group and hydroxyhexyl group.

More preferably, the above aralkylpiperidine derivative (I) is as follows:
I), which is represented by the following general formula.

[0020]

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[Wherein A is a group represented by the following general formula,

[0022]

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(Wherein C means a hydrogen atom or a hydroxy group, D means a hydrogen atom or a lower hydroxyalkyl group) or a group represented by the following chemical formula,

[0024]

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B represents a hydrogen atom or a hydroxy group, and A and B may form a double bond to form a group represented by the following chemical formula. ]

[0026]

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The aralkyl piperidine derivative is more preferably the aralkyl piperidine derivative (III), which is represented by the following general formula.

[0028]

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[In the formula, B, C and D have the same meanings as described above, and B and C may form a double bond. ]

The aralkyl piperidine derivative is more preferably a compound selected from the following compound group, but the present invention is not limited thereto. (1) 1-benzyl-4- (5,6-dimethoxy-1-indanone-2-yl) hydroxymethylpiperidine (2) 1-benzyl-4-hydroxy-4- (5,6-dimethoxy-1-indanone -2-yl) hydroxymethylpiperidine (3) 1-benzyl-4-hydroxy-4- (5,6-dimethoxy-1-indanone-2-yl) methylpiperidine (4) 2- (1-benzylpiperidine-4 -Ylidene) methyl-5,6-
Dimethoxy-1-indanone (5) 1-benzyl-4- (5,6-dimethoxy-2-hydroxymethyl-1-indanone-2-yl) methylpiperidine (6) 1-benzyl-4- [3- (4 , 5-Dimethoxy-2-carboxyphenyl) -2-oxo] propylpiperidine

The aralkylpiperidine derivative according to the present invention may have a double bond or an asymmetric carbon atom in the molecule and may have geometrical isomers or optical isomers, but the present invention is not limited thereto. However, any single isomer may be used, or a mixture of two or more kinds (EZ mixture, racemate, diastereomer mixture, etc.) may be used.

Further, the pharmacologically acceptable salt in the present invention is not limited as long as it forms an addition salt with the aralkylpiperidine derivative according to the present invention, and specifically, for example, hydrochloride and sulfuric acid. Addition salts of inorganic acids such as salts, nitrates, hydrobromides, hydroiodides, perchlorates, phosphates, oxalates, maleates, fumarates,
Organic acid addition salts such as succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, and other sulfonic acid addition salts, amino acid addition salts, etc. Can be mentioned.

The dosage forms of the compounds of the present invention include oral preparations such as powders, fine granules, granules, tablets, coated tablets and capsules, external preparations such as ointments and patches, suppositories and injections. Formulations and the like. In the case of formulation, it can be produced by a conventional method using an ordinary formulation carrier.

That is, in order to produce an oral preparation, after adding an aralkyl piperidine derivative and an excipient and, if necessary, an antioxidant, a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent, etc. , Powders, fine granules, granules,
Tablets, coated tablets, capsules, etc.

As the excipient, for example, lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide, etc., and as the binder,
For example, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polypropylene glycol polyoxyethylene block polymer, meglumine, etc. For example, starch, agar, gelatin powder,
Crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin, pectin, carboxymethylcellulose / calcium, etc., and examples of lubricants include magnesium stearate, talc, polyethylene glycol, silica, hardened vegetable oil, etc. As for the flavoring agent, cocoa powder, peppermint brain, aroma powder, peppermint oil, dragon brain, cinnamon powder and the like are used as the flavoring agent. Of course, these tablets and granules can be sugar-coated and optionally coated as needed.

In the case of producing an injectable preparation, a pH adjusting agent, a solubilizer, an isotonicity agent, etc., and a solubilizing agent, a stabilizer, an antioxidant, etc. are added to the aralkylpiperidine derivative, if necessary. Then, it is formulated by a conventional method.

The method for producing the external preparation is not limited,
It can be manufactured by an ordinary method. In other words, base materials used in the formulation include pharmaceuticals, quasi-drugs,
Various raw materials usually used for cosmetics and the like can be used.

Specific examples of the base material used include, for example, animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyhydric acids. Raw materials such as alcohols, water-soluble polymers, clay minerals, purified water, etc. are added, and if necessary, pH adjusters, antioxidants, chelating agents, antiseptic / antifungal agents, colorants, fragrances, etc. are added. However, the base material for the external preparation according to the present invention is not limited to these. If necessary, components such as a blood flow promoter, a bactericide, an anti-inflammatory agent, a cell activator, vitamins, amino acids, a humectant, a keratolytic agent, and the like can be added. The amount of the above-mentioned base material added is such that the concentration is usually set in the production of the external preparation.

The clinical dose of the aralkylpiperidine derivative according to the present invention varies depending on the symptoms, severity, age, complications, etc. and is not limited, but it varies depending on the type of salt, administration route, etc. mg to 1000
mg, preferably 0.1 mg to 500 mg, more preferably 1 mg to 100 mg, which is orally, intravenously, intramuscularly, rectally or transdermally.

[0040]

EFFECTS OF THE INVENTION Next, in order to show the usefulness of the compound of the present invention as an acetylcholinesterase inhibitor, pharmacological experimental examples are given below as examples of the effects, but it goes without saying that the compound of the present invention or its use is not limited thereto.

(Method) Using rat brain homogenate as a source of acetylcholinesterase, the method of Ellman et al ^.
Based on this, the acetylcholinesterase inhibitory activity was measured. Rat brain homogenate was spiked with acetylthiocholine as a substrate, subject and DTNB [5,5'-Dithiobis- (2-nitro
benzoic acid)] was added and after incubation, the thiocholine produced reacted with DTNB, and the resulting yellow product was 412n
It was measured as the change in absorbance at m, and the acetylcholinesterase inhibitory activity (IC ₅₀ , μM) was determined. ^* ； Ellman, GL, Courtney, KD, Andres, V. and F
eatherstone, RM (1961) Biochem. Pharmacol., 7 , 8
8-95.

(Results) The following table shows typical examples of the compounds of the present invention.
Acetylcholinesterase inhibitory activity, IC ₅₀Value (μM)
Show as.

[0043]

[Table 1]

[IC ₅₀ (μM); Example 1: 0.79, Example 2: 3.8, Example 3: 4.3, Example 4: 2.7, Example 5:
0.045, Example 6: 0.090, Example 7: 1.3, Example 8: 5
2] From Table 1, it is clear that the compound of the present invention has excellent acetylcholinesterase inhibitory activity.

Next, examples will be given below for specifically explaining the present invention, but it goes without saying that the present invention is not limited thereto.

EXAMPLES Example 1 1-Benzyl-4- (5,6-dimethoxy-1-indano
Synthesis of (n-2-yl) hydroxymethylpiperidine

[0046]

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The title compound has two asymmetric carbon atoms in the molecule, and there are a total of four types of optical isomers, but usually 2
Obtained as a set of diastereomers (1), (2).

[0048]

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5,6-dimethoxy-1-indanone 5.00 g (26.0
mmol) in 100 ml of tetrahydrofuran, and under a nitrogen atmosphere, 4.53 ml of hexamethylphosphoramide (HMPA) (26.0
(mmol) was injected. Cool it to -78 ° C and
Diisopropylamide mono (tetrahydrofuran), 1.
5M-Cyclohexane solution [CAS registration number, 123333-84-6] 1
9.1 ml (28.7 mmol) was added and stirred for 1 hour. 1 at -78 ℃
After injecting a solution of 6.35 g (31.2 mmol) of benzyl-4-formylpiperidine in tetrahydrofuran (30 ml), the solution was cooled to 1 at -78 ° C.
Stir for 5 minutes. After adding 1% -ammonium chloride aqueous solution and warming to room temperature, the precipitated crystals were collected by filtration and recrystallized three times from chloroform / n-hexane to give white crystals of the diastereomer (1) 1.23 of the title compound. got g. (yield;
Next, the filtrate was extracted with ethyl acetate, and the organic layer was further washed with saturated saline. After drying, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (methylene chloride / methanol system) to obtain 0.4 g of white crystals. This was recrystallized from chloroform / n-hexane,
Diastereomer of title compound as white crystals (2) 0.
26 g were obtained. (Yield; 2.5%)

Diastereomer (1) Rf value (TLC); 0.45 (methylene chloride: methanol = 10:
1). Melting point; 205-206 ℃. ¹ H-NMR (400MHz, CDCl ₃ ); δ (ppm) 1.50-1.60 (2H, m), 1.6
0-1.73 (2H, m), 1.79 (1H, dd, J = 4Hz, 13Hz), 1.92-2.02 (2H, m
m), 2.74-2.84 (2H, m), 2.98 (2H, bt, J = 11Hz), 3.17 (1H, dd, J
= 8Hz, 17Hz), 3.51 (2H, s), 3.67 (1H, dd, J = 3.2Hz, 8Hz), 3.90
(3H, s), 3.96 (3H, s), 4.30 (1H, bs), 6.86 (1H, s), 7.15 (1H,
s), 7.22-7.35 (5H, m). FAB-MS; m / z = 396 (M + H ⁺ ).

Diastereomer (2) Rf value (TLC); 0.36 (methylene chloride: methanol = 10:
1). Melting point; 176-177 ° C. ¹ H-NMR (400MHz, CDCl ₃ ); δ (ppm) 1.36-1.57 (3H, m), 1.5
8-1.65 (1H, m), 1.93-2.03 (4H, m), 2.82-2.87 (1H, m), 2.93-
3.01 (2H, m), 3.03 (1H, d, J = 8Hz), 3.16 (1H, dd, J = 4Hz, 17H
z), 3.53 (2H, s), 3.89 (3H, s), 3.96 (3H, s), 4.13 (1H, dd, J =
2.4Hz, 8Hz), 6.88 (1H, s), 7.14 (1H, s), 7.23-7.34 (5H, m). FAB-MS; m / z = 396 (M + H ⁺ ).

Example 2 1-Benzyl-4-hydroxy-4-
(5,6-dimethoxy-1-indanone-2-yl) hydroxymethy
Synthesis of lupiperidine

[0053]

[Chemical 21]

This title compound also has two asymmetric carbon atoms in the molecule, and there are a total of four types of optical isomers.
Obtained as a set of diastereomers (3), (4).

[0055]

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1-benzyl-4-cyano-4-trimethyloxy
Ryloxypiperidine hydrochloride (2) 1-benzyl-4-cyano-4-hydroxypiperidine (1) [CAS
Registration number, 6094-60-6] 10.3 g (47.7 mmol) was dissolved in methylene chloride (100 ml), and under nitrogen atmosphere ice cooling, 7.28 ml (57.3 mmol) of chlorotrimethylsilane and 7.32 of triethylamine.
After adding ml (52.5 mmol) dropwise, the mixture was stirred at room temperature for 30 minutes. Further, 4.24 ml (33.4 mmol) of chlorotrimethylsilane was added,
The mixture was stirred at room temperature for 1 hour and 15 minutes. A 10% -ammonium chloride aqueous solution and 2N-hydrochloric acid were added to wash the organic layer, and further washed with saturated saline. After drying, the residue obtained by concentration under reduced pressure was solidified with isopropyl ether to obtain 8.09 g of the title compound (2) as a colorless solid. (Yield; 52%)

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 0.25 (9
H, s), 2.10 (1H, bs), 2.24 (1H, bs), 2.69-3.01 (4H, m), 3.34
(1H, bs), 3.52 (1H, bs), 4.12-4.22 (2H, bs), 7.42-7.48 (3H,
m), 7.61-7.70 (2H, bs). FAB-MS; m / z = 289 (M + H ⁺ ).

1-benzyl-4-formyl-4-trimethyl
Silyloxy piperidine (3) The compound (2) 8.01 g (24.7 mmol) in methylene chloride (150ml)
In a nitrogen atmosphere, 61.6 ml (61.6 mmol) of a 1.0 M diisobutylaluminum hydride / hexane solution was added dropwise at -55 ° C over 10 minutes. After stirring at -65 ° C for 30 minutes,
1.0M-diisobutylaluminum hydride / hexane solution
7.40 ml (7.40 mmol) was added and the mixture was further stirred for 15 minutes. The organic layer was washed by adding 50% -acetic acid aqueous solution and saturated saline, and further washed with diluted saline, 10% -sodium carbonate aqueous solution, and diluted saline. After drying, it was concentrated under reduced pressure to give the title compound as a pale yellow oil.
(3) 4.67 g was obtained. This was used for the next reaction without purification. (Yield: 65%)

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 0.15 (9
H, s), 1.54-1.62 (2H, m), 1.86-1.95 (2H, m), 2.37-2.47 (2H, m)
m), 2.54-2.65 (2H, m), 3.51 (2H, s), 7.25-7.34 (5H, m), 9.50
(1H, s).

1-benzyl-4- (5,6-dimethoxy-1-yne
Danone-2-yl) hydroxymethyl-4-trimethylsilyl
6.15 g (32.0 mmol) of oxypiperidine (5) 5,6-dimethoxy-1-indanone (4) was dissolved in tetrahydrofuran (80 ml), and hexamethylphosphoramide (HMPA) 5.56 ml (32.0 mmol) was added. This was cooled to −78 ° C. under a nitrogen atmosphere, and lithium diisopropylamide mono (tetrahydrofuran), 1.5M-cyclohexane solution (20.3 ml, 30.4 mmol) was added, and the mixture was stirred for 25 minutes. -
At 78 ° C., a solution of the compound (3) 4.66 g (16.0 mmol) in tetrahydrofuran (30 ml) was added dropwise over 10 minutes, and further at −78 ° C.
It was stirred for 30 minutes. Saturated ammonium chloride solution and water
After the (1: 1) mixture was added and the temperature was raised to room temperature, the mixture was extracted with ethyl acetate, and the organic layer was further washed with saturated brine.
After drying, concentration under reduced pressure gave a pale yellow residue. This was purified by silica gel column chromatography (methylene chloride / methanol system) to give the title compound (5) as a pale yellow solid.
3.94 g was obtained. (Yield; 51%)

Melting point: 174-175 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 0.02 (9 H, s), 1.31-1.3
8 (1H, m), 1.44-1.60 (2H, m), 1.75-1.82 (1H, m), 2.28-2.40
(2H, m), 2.57-2.76 (2H, m), 3.08-3.13 (1H, m), 3.20-3.34 (2
H, m), 3.45-3.56 (2H, m), 3.90 (3H, s), 3.96 (3H, s), 4.13 (1
H, s), 6.85 (1H, s), 7.16 (1H, s), 7.21-7.34 (5H, m). FAB-MS; m / z = 484 (M + H ⁺ ).

1-benzyl-4-hydroxy-4- (5,6-dime
Toxy-1-indanone-2-yl) hydroxymethyl piperi
Gin [diastereomer (3)] tetrahydrofuran (25 ml) with 1.0M tetrabutylammonium fluoride / tetrahydrofuran solution 9.18 ml (9.18 mm
ol) was added, and a solution of 2.96 g (6.12 mmol) of the compound (5) in tetrahydrofuran (10 ml) was added dropwise under a water bath. After stirring for 15 minutes, ethyl acetate was added, and the mixture was washed twice with saturated aqueous sodium hydrogen carbonate and once with saturated brine. After drying, the mixture was concentrated under reduced pressure, ethyl acetate was added to the obtained residue, and the precipitated crystals were collected by filtration to obtain 1.73 g of the diastereomer (3) of the title compound. The filtrate was concentrated and purified by silica gel column chromatography (methylene chloride / methanol system) to obtain 0.18 g of the diastereomer (3) of the title compound. (Yield: 75% in total) These were further dissolved in a mixed solution of methanol and methylene chloride, concentrated under weak reduced pressure until crystals started to precipitate, and then cooled with ice to give diastereomers of the title compound as colorless prism crystals. I got (3).

Diastereomer (3) Melting point: 185-186 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ (ppm) 1.26-1.42 (2 H, m),
1.61-1.81 (2H, m), 2.19-2.28 (2H, m), 2.48-2.58 (2H, m), 2.
87-2.96 (2H, m), 3.14-3.22 (1H, m), 3.43 (2H, ABq, J = 14Hz),
3.76 (3H, s), 3.84 (3H, s), 3.85 (1H, m), 4.11 (1H, s), 4.71 (1
H, d, J = 6.2Hz), 7.03 (1H, s), 7.08 (1H, s), 7.19-7.33 (5H,
m). FAB-MS; m / z = 412 (M + H ⁺ ). HPLC (Inertsil ODS-2, 4.6 × 150 mm, CH ₃ CN: H ₂ O: 70% HCl
O ₄ = 300: 700: 1, 1.0ml / min, 254nm) retention time:
3.78min (100%).

1-benzyl-4-hydroxy-4- (5,6-dimme
Toxy-1-indanone-2-yl) hydroxymethyl piperi
Gin [diastereomer (4)] 974 mg (2.01 mmol) of the above compound (5) was dissolved in methanol (10 ml), and 2 N-hydrochloric acid 2.0 ml (4.0 mmol) was added dropwise in a water bath.
After stirring for 10 minutes, water and ethyl acetate were added, and the mixture was made basic with saturated aqueous sodium hydrogen carbonate, extracted, and washed with saturated brine. After drying, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (methylene chloride / methanol system), the fraction containing the target substance was concentrated, and then dissolved in a mixed solution of methanol and methylene chloride. After concentrating under weak reduced pressure until crystals started to precipitate, the mixture was ice-cooled to obtain 376 mg of the diastereomer (4) of the title compound as colorless prism crystals. (Yield; 45%)

Diastereomer (4) Melting point: 180-181 ° C. ¹ H-NMR (400 MHz, DMSO-d ₆ ); δ (ppm) 1.31-1.77 (4 H, m),
2.20-2.33 (2H, m), 2.48-2.57 (2H, m), 3.04-3.25 (3H, m), 3.
45 (2H, ABq, J = 14Hz), 3.53 (1H, dd, J = 3.7Hz, 5.6Hz), 3.79 (3
H, s), 3.87 (3H, s), 4.64 (1H, s), 4.86 (1H, d, J = 5.6Hz), 7.05
(1H, s), 7.12 (1H, s), 7.20-7.34 (5H, m). FAB-MS; m / z = 412 (M + H ⁺ ). HPLC (Inertsil ODS-2, 4.6 × 150mm, CH ₃ CN: H ₂ O: 70% HCl
O ₄ = 300: 700: 1, 1.0ml / min, 254nm) retention time:
4.85min (99.2%).

Example 3 1-Benzyl-4-hydroxy-4-
(5,6-dimethoxy-1-indanone-2-yl) methylpiperidi
Synthesis

[0067]

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[0068]

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1-benzyl-4-hydroxy-4- (5,6-dim
Toxy-1-indanone-2-ylidene) methylpiperidine (5) isocyanidemethyl-1H-benzotriazole (alias; 1H
-Benzotriazol-1-ylmethyl isocyanide) 2
Dissolve 0.0 g (126 mmol) in tetrahydrofuran (500 ml),
1-Benzyl-4-piperidone (1) 23.4m under nitrogen atmosphere ice cooling
After injecting 1 (126 mmol) and 14.8 ml (254 mmol) of (anhydrous) ethanol, 31.5 g (253 mmol) of 90% -potassium t-butoxide was added. After stirring for 30 minutes under ice cooling, the mixture was stirred overnight at room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure to obtain 32.1 g of compound (2) as a brown oily residue. This residue was used in the next reaction without purification.

The above oily residue was converted into tetrahydrofuran (100 m
l), 2N-hydrochloric acid 100 ml was added, and the mixture was stirred at room temperature overnight. Under ice cooling, 120 ml of 2N-sodium hydroxide aqueous solution was gradually added, and then extracted with ethyl acetate. After drying, it was concentrated under reduced pressure to obtain a brown oily residue, which was purified by silica gel column chromatography (methylene chloride / methanol system) to obtain 9.06 g of a brown oily residue containing the compound (3).
This residue was used in the next reaction without further purification.

5,6-dimethoxy-1-indanone (4) 6.35 g (3
3.0 mmol) was dissolved in tetrahydrofuran (100 ml, and under nitrogen atmosphere, hexamethylphosphoramide 5.75 ml (33.0 mmo
l) was injected. This was cooled to -78 ° C, lithium diisopropylamide mono (tetrahydrofuran), 1.5M-
22.0 ml (33.0 mmol) of a cyclohexane solution was added and stirred for 40 minutes. A solution of the brown oily residue containing the compound (3) in tetrahydrofuran (30 ml) was injected at -78 ° C, and then the temperature was gradually raised to room temperature and the mixture was stirred overnight. After adding a saturated ammonium chloride aqueous solution, the mixture was extracted with ethyl acetate, and the organic layer was further washed with water and saturated saline. After drying, it was concentrated under reduced pressure to obtain a brown oily residue, which was purified by silica gel column chromatography (methylene chloride / methanol system) to obtain 5.00 g of white crystals. Recrystallize this from ethanol,
3.01 g of the title compound (5) was obtained as white crystals. [Compound
Yield from (3); 23%]

Melting point: 174-175 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.77 (2 H, bd, J = 13 Hz),
1.88-2.05 (3H, m), 2.46 (2H, dt, J = 2.4Hz, 11Hz), 2.63-2.71
(2H, m), 3.55 (2H, s), 3.78 (2H, d, J = 1.6Hz), 3.92 (3H, s), 3.
95 (3H, s), 6.74 (1H, t, J = 2Hz), 6.79 (1H, s), 7.27 (1H, s), 7.
23-7.37 (5H, m). FAB-MS; m / z = 394 (M + H ⁺ ).

1-benzyl-4-hydroxy-4- (5,6-dime
Toxy-1-indanone-2-yl) methylpiperidine hydrochloride The above compound (5) 2.96 g (7.52 mmol) was added to tetrahydrofuran.
Dissolve in (80 ml), 10% -palladium carbon catalyst (hydrated product) 0.
3 g was added, and hydrogenated at room temperature and atmospheric pressure for 1.5 hours. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure to give a yellow oily residue. This is subjected to silica gel column chromatography (methylene chloride /
(Methanol system) and purified the title compound 2.7
3 g were obtained.

Free form ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.63-1.82 (5H, m), 2.0
5 (1H, dd, J = 7.6Hz, 14Hz), 2.40-2.50 (2H, m), 2.62-2.70 (2
H, m), 2.76 (1H, dd, J = 4Hz, 17Hz), 2.96-3.03 (1H, m), 3.36 (1
H, dd, J = 7.6Hz, 17Hz), 3.55 (3H, s), 3.90 (3H, s), 3.97 (3H.
s), 6.85 (1H, s), 7.16 (1H, s), 7.22-7.36 (5H, m).

This was made into a hydrochloride using 11% -hydrogen chloride-containing ethanol and recrystallized from ethanol to obtain 2.26 g of the hydrochloride of the title compound as white crystals. (Yield; 70%)

Hydrochloride Melting point: 216-217 ° C. ¹ H-NMR (400MHz, CDCl ₃ ); δ (ppm) 1.75 (1H, bdd, J = 2.4H
z, 14Hz), 1.93 (2H, d, J = 7.2Hz), 1.98 (1H, bdd, J = 2.4Hz, 14
Hz), 2.37-2.53 (2H, m), 2.69 (1H, dd, J = 4Hz, 17Hz), 3.00 (1
H, dq, J = 3.2Hz, 7.2Hz), 3.12-3.30 (3H, m), 3.32-3.41 (2H,
m), 3.90 (3H, s), 3.98 (3H.s), 4.14 (2H, dd, J = 12Hz, 43Hz),
5.52 (1H, s), 6.87 (1H, s), 7.12 (1H, s), 7.42-7.50 (3H, m),
7.66-7.75 (2H, m). FAB-MS; m / z = 396 (M + H ⁺ ).

Example 4 2- (1-Benzylpiperidine-4-i)
Synthesis of (ridene) methyl-5,6-dimethoxy-1-indanone

[0078]

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[0079]

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1-benzyl-4- (5,6-dimethoxy-1-indanone-2-, described in Example 3 of JP-A 64-79151
30.0 g (79.5 mmol) of ylidene) methylpiperidine was suspended in tetrahydrofuran (500 ml) and t-butyl alcohol (250 ml), potassium tert-butoxide (8.9 g, 79.3 mmol) was added, and the mixture was heated under reflux for 1 hour under a nitrogen atmosphere. After allowing to cool to room temperature, it was diluted with ethyl acetate and washed successively with water and saturated brine. After drying, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (ethyl acetate / n-hexane system) to obtain 7 g of a beige solid. This was further pulverized from diisopropyl ether to give 6.27 g of the title compound as a beige powder. (Yield; 21%)

Melting point: 130-132 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 2.20-2.60 (8 H, m), 2.7
8 (1H, dd, J = 3.2Hz, J = 17Hz), 3.37 (1H, dd, J = 8Hz, 17Hz), 3.5
0-3.60 (1H, m), 3.54 (2H, s), 3.90 (3H, s), 3.97 (3H, s), 5.09
(1H, d, J = 8.8Hz), 6.86 (1H, s), 7.17 (1H, s), 7.22-7.36 (5H,
m). FAB-MS; m / z = 378 (M + H ⁺ ).

Example 5 1-Benzyl-4- (5,6-dimethoxy)
-2-Hydroxymethyl-1-indanone-2-yl) methyl pipet
Synthesis of lysine

[0083]

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[0084]

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1-benzyl-4- (5,6-dimethoxy-1-indanone-2-, described in Example 4 of JP-A-64-79151
15.0 g (39.5 mmol) of (yl) methylpiperidine was dissolved in tetrahydrofuran (200 ml), and 6.88 ml (39.5 mmol) of hexamethylphosphoramide was added. This was cooled to −78 ° C., a lithium diisopropylamide mono (tetrahydrofuran), 1.5 M-cyclohexane solution was injected, and the mixture was stirred for 30 minutes. On the other hand, 75% -paraformaldehyde 12g 170
Formaldehyde was generated by thermal decomposition at ° C, and bubbling was carried out in the above reaction solution at -78 ° C for 15 minutes. After stirring at -78 ° C for 30 minutes, the temperature was gradually raised to room temperature and the mixture was stirred overnight. 300 ml of a saturated aqueous solution of ammonium chloride was added to this, and the insoluble matter was removed by decanting. It was extracted with ethyl acetate from this and washed with saturated saline. After drying, it was concentrated under reduced pressure to obtain a light brown oily residue, which was purified by silica gel column chromatography (NH-silica gel, n-hexane / ethyl acetate system) to obtain 11.5 g of the free form of the title compound. (Yield; 71%)

Free form ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.18-1.39 (3 H, m), 1.4
3 (1H, bd, J = 12Hz), 1.47-1.55 (1H, m), 1.62-1.74 (2H, m), 1.
78 (1H, bt, J = 12Hz), 1.86 (1H, bt, J = 10Hz), 2.50-2.70 (1H,
m), 2.75 (2H, dd, J = 12Hz, 15Hz), 2.97 (2H, dd, J = 17Hz, 24H
z), 3.42 (2H, s), 3.54 (1H, d, J = 10Hz), 3.78 (1H, d, J = 10Hz),
3.89 (3H, s), 3.97 (3H, s), 6.86 (1H, s), 7.12 (1H, s), 7.11-
7.30 (5H, m).

This was converted to a hydrochloride using 11% -hydrogen chloride-containing ethanol and recrystallized from 10% -hydrous ethanol / isopropyl ether to obtain 8.40 g of the hydrochloride of the title compound. (Yield; 48%)

Hydrochloride Melting point: 175-178 ° C. ¹ H-NMR (400MHz, D ₂ O); δ (ppm) 1.08-1.23 (1H, m), 1.23-
1.54 (5H, m), 1.64 (1H, bd, J = 13Hz), 2.45-2.60 (1H, m), 2.62
-2.75 (1H, m), 2.94 (2H, dd, J = 18Hz, 28Hz), 3.05-3.16 (1H,
m), 3.16-3.26 (1H, m), 3.48 (2H, dd, J = 11Hz, 53Hz), 3.62 (3
H, s), 3.72 (3H, s), 4.00 (2H, bs), 6.92 (1H, s), 6.94 (1H, s),
7.18-7.30 (5H, m). FAB-MS; m / z = 410 (M + H ⁺ ).

Example 6 1-Benzyl-4- [3- (4,5-dimeth)
Xy-2-carboxyphenyl) -2-oxo] propylpiperi
Gin synthesis

[0090]

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[0091]

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1-benzyl-4- (5,6-dimethoxyindene
N-2-yl) methylpiperidine (2) 1-benzyl-4- (5,6-dimethoxy-1-indanone-2-yl)
Methylpiperidine (1) 100 g (0.26 mol) was added to methanol (1000
ml), and under ice cooling, sodium borohydride 19.9 g
(0.53 mol) was added slowly. The mixture was stirred under ice cooling for 1 hour and further at room temperature for 3 hours. Under ice cooling, acetic acid was gradually added to adjust the pH to 6, and the mixture was concentrated under reduced pressure. Water and saturated aqueous sodium carbonate solution were added to this residue, and the mixture was extracted with methylene chloride. After drying, it was concentrated under reduced pressure to obtain 102 g of a pale yellow oily residue. Methylene chloride (700 ml) was added to this oily residue and stirred 8.
Ethyl acetate containing 5% -hydrochloric acid (200 ml) was gradually added. After stirring at room temperature for 30 minutes, it was concentrated under reduced pressure and foamy pale yellow oily residue remained.
Got 107g. This oily residue was dissolved in methylene chloride,
Water and saturated aqueous sodium carbonate solution were added for extraction. The methylene chloride layer was washed with saturated brine, dried and concentrated under reduced pressure to give 96 g of white pink crystals. This was recrystallized from ethyl acetate to obtain 88.6 g of the title compound (2) as white pink crystals.
(Yield; 92%)

Melting point: 110-111 ° C. ¹ H-NMR (400MHz, CDCl ₃ ); δ (ppm) 1.28 (2H, dq, J = 3.6Hz,
12Hz), 1.46-1.58 (1H, m), 1.67 (2H, bd, J = 13Hz), 1.93 (2H, d)
t, J = 2.4Hz, 12Hz), 2.37 (2H, d, J = 7.2Hz), 2.86 (2H, bd, J = 12
Hz), 3.22 (2H, s), 3.48 (2H, s), 3.867 (3H, s), 3.874 (3H, s),
6.39 (1H, bs), 6.84 (1H, s), 6.98 (1H, s), 7.20-7.32 (5H, m). FAB-MS; m / z = 364 (M + H ⁺ ).

4- (5,6-dimethoxyinden-2-yl) me
Tyl -1-ethoxycarbonylpiperidine (3) The compound (2) (87.0 g, 0.24 mol) was dissolved in benzene (800 ml), and ethyl chloroformate (36.6 ml, 0.38 mol) was added. 1
After heating under reflux for an hour, the mixture was allowed to cool to room temperature, ethyl acetate was added, and the mixture was washed successively with 0.2N-hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine. After drying, it was concentrated under reduced pressure to obtain a brown oily residue, and this oily residue was purified by silica gel column chromatography (n-hexane / ethyl acetate system) to obtain 82.7 g of the title compound (3) as a colorless transparent oily residue. . (Yield; 100%)

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.08-1.
22 (2H, m), 1.25 (3H, t, J = 7.2Hz), 1.63-1.75 (3H, m), 2.39 (2
H, d, J = 6.4Hz), 2.73 (2H, bt, J = 13Hz), 3.24 (2H, s), 3.88 (3
H, s), 3.89 (3H, s), 4.05-4.20 (2H, m), 4.12 (2H, q, J = 7.2H
z), 6.41 (1H, s), 6.85 (1H, s), 7.00 (1H, s). FAB-MS; m / z = 345 (M ⁺ ).

4- [3- (3,4-dimethoxy-6-formylfe
Nyl) -2-oxo] propyl-1-ethoxycarbonylpiperi
Gin (4) The compound (3) 25.0 g (72.4 mmol) was added to tetrahydrofuran.
(350 ml), water (250 ml) and sodium metaperiodate 46.4 g (217 mmol) were added. Under ice cooling, 0.39 M-osmium tetroxide / tetrahydrofuran solution 5.57 ml (2.2 mmol)
[Prepared by dissolving 1 g of osmium tetroxide in tetrahydrofuran (10 ml)] was added dropwise over 10 minutes. After stirring at room temperature for 30 hours, 1 g of sodium bisulfite was added to 1
The mixture was stirred for 0 minutes, the insoluble matter was filtered off using Celite, and the mixture was washed with ethyl acetate. The filtrate was washed successively with saturated aqueous sodium thiosulfate solution and saturated brine, dried and concentrated under reduced pressure to give a brown oily residue. This residue is subjected to silica gel column chromatography (n-hexane / ethyl acetate system).
Purification was carried out to obtain 8.82 g of light brown crystals. This was recrystallized from ethyl acetate / n-hexane to obtain 6.30 g of the title compound (4) as pale yellowish white crystals. (Yield: 23%)

Melting point: 135-136 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.08-1.20 (2 H, m), 1.2
5 (3H, t, J = 7.2Hz), 1.70 (2H, bd, J = 13Hz), 2.00-2.13 (1H,
m), 2.55 (2H, d, J = 6.4Hz), 2.77 (2H, bt, J = 13Hz), 3.96 (6H,
s), 4.05 (2H, bs), 4.08-4.16 (2H, m), 4.12 (2H, q, J = 7.2Hz),
6.67 (1H, s), 7.30 (1H, s), 9.90 (1H, s) FAB-MS; m / z = 378 (M + H ⁺ ).

4- [3- (3,4-dimethoxy-6-carboxyl
Phenyl) -2-oxo] propyl-1-ethoxycarbonylpipe
Lysine (5) 6.14 g (16.3 mmol) of the compound (4) in acetonitrile (150 m
l), and a solution of 0.78 g (6.5 mmol) monobasic sodium phosphate in water (20 ml) and 30% -hydrogen peroxide 2.03 ml (17.9 mmol)
Was added. Next, under ice cooling, 2.06 g (22.
A solution of 8 mmol) in water (20 ml) was added dropwise over 30 minutes, and the mixture was stirred for 30 minutes as it was, and then stirred at room temperature overnight. Under ice cooling, 1.5 g of sodium bisulfite was added, and after stirring for 5 minutes, water was added and the mixture was extracted with methylene chloride. The combined methylene chloride layers were washed with saturated brine, dried and concentrated under reduced pressure to give yellowish white crystals, which were recrystallized from methanol to obtain 5.21 g of the title compound (5) as pale yellowish white crystals. .
(Yield; 81%)

Melting point: 163-164 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.08-1.22 (2 H, m), 1.2
4 (3H, t, J = 7.2Hz), 1.72 (2H, bd, J = 13Hz), 2.02-2.13 (1H,
m), 2.49 (2H, d, J = 6.4Hz), 2.79 (2H, bt, J = 13Hz), 3.93 (3H,
s), 3.94 (3H, s), 4.05 (2H, bs), 4.07-4.15 (2H, m), 4.11 (2H, s)
q, J = 7.2Hz), 6.64 (1H, s), 7.64 (1H, s). FAB-MS; m / z = 394 (M + H ⁺ ).

1-benzyl-4- (6,7-dimethoxyisoc
(Marin-3-yl) methylpiperidine (6) 4.40 g (11.2 mmol) of the compound (5) was suspended in ethanol (100 ml), and 5N-potassium hydroxide aqueous solution [85.5% -potassium hydroxide 32.8 g was added to 100 ml of water. Melted solution] was added, and the mixture was heated to reflux overnight under a nitrogen atmosphere. After cooling to room temperature, under ice cooling,
The mixture was neutralized with 5N-hydrochloric acid and 1N-hydrochloric acid, and concentrated under reduced pressure to give a salt-containing residue. This was suspended in methanol (250 ml), filtered to remove salts, and the filtrate was concentrated under reduced pressure to obtain a residue containing a small amount of salts. This residue was further added with methanol (100 ml)
After suspending in, the mixture was filtered to remove salts, and the filtrate was concentrated under reduced pressure to obtain 4.39 g of a residue containing a small amount of salt. This residue was added to ethanol (1
It was suspended in 00 ml), and 2.32 g (16.8 mmol) of potassium carbonate was added. A solution of 1.20 ml (10.1 mmol) of benzyl bromide in ethanol (2 ml) was added dropwise under ice cooling. After stirring for 10 minutes as it was, the mixture was returned to room temperature and further stirred for 5 hours. Add water and under ice cooling,
After neutralization with 1N-hydrochloric acid, the mixture was concentrated under reduced pressure, the obtained residue was suspended in water and saturated saline, and extracted with methylene chloride. The combined methylene chloride layers were dried and concentrated under reduced pressure to give a brown residue. This residue is methanol (50 ml) and benzene (50 ml)
The resulting solution was dissolved in water and 2.05M-trimethylsilyldiazomethane (5.59 ml, 11.2 mmol) was added dropwise under ice cooling. The mixture was stirred as it was for 5 minutes, further stirred at room temperature for 20 minutes, and concentrated under reduced pressure to give a brown oily residue. This oily residue was treated with tetrahydrofuran (5
0 ml), and under ice cooling, 60% -sodium hydride 0.31 g
(7.8 mmol) was added, and the mixture was stirred as it was for 5 minutes, then brought to room temperature and further stirred for 30 minutes. Neutralize with 1N hydrochloric acid under ice cooling,
Saturated saline was added, and the mixture was extracted with methylene chloride. The combined methylene chloride layer was washed with saturated brine, dried, and concentrated under reduced pressure to give a reddish brown oily residue. This oily residue was subjected to silica gel column chromatography (NH-silica gel, n-hexane / ethyl acetate system). Purification gave 1.20 g of the title compound (6) as a pale yellow oily residue. (Yield; 28%)

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.33 (2
H, dq, J = 3.6Hz, 12Hz), 1.68 (2H, bd, J = 12Hz), 1.77-1.90 (1
H, m), 1.96 (2H, dt, J = 2.4Hz, 12Hz), 2.42 (2H, d, J = 7.2Hz),
2.87 (2H, bd, J = 12Hz), 3.48 (2H, s), 3.96 (3H, s), 3.98 (3H,
s), 6.17 (1H, s), 6.73 (1H, s), 7.21-7.32 (5H, m), 7.62 (1H,
s). FAB-MS; m / z = 394 (M + H ⁺ ).

1-benzyl-4- [3- (4,5-dimethoxy-2-
Carboxyphenyl) -2-oxo] propylpiperidine 1.07 g (2.72 mmol) of the compound (6) was dissolved in ethanol (15 ml), 15 ml of 1N-sodium hydroxide aqueous solution was added, and the mixture was heated under reflux for 20 minutes under a nitrogen atmosphere. After neutralization with 1N-hydrochloric acid under ice cooling, the mixture was concentrated under reduced pressure to remove ethanol, saturated saline was added to this, extracted with methylene chloride, dried, and concentrated under reduced pressure to give a pale yellow oily residue 1.05 g Got This oily residue was dissolved in chloroform, and n-hexane was gradually added to precipitate a white powder to obtain 0.85 g of the title compound as a white powder. (Yield; 76%)

Melting point; 120 ° C. or higher. ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.70 (2 H, bq, J = 12 Hz),
1.81 (2H, bd, J = 12Hz), 1.92-2.04 (1H, m), 2.45 (2H, d, J = 6.4
Hz), 2.60 (2H, bt, J = 12Hz), 3.35 (2H, bd, J = 12Hz), 3.86 (3H,
bs), 3.90 (3H, s), 3.90-4.00 (2H, m), 4.06 (2H, bs), 6.61 (1
H, s), 7.32-7.48 (5H, m), 7.61 (1H, s). FAB-MS; m / z = 412 (M + H ⁺ ).

Claims (7)

[Claims] 1. An aralkylpiperidine derivative (I) represented by the following general formula or a pharmaceutically acceptable salt thereof. Embedded image [Wherein n is 0 or an integer of 1 to 2 and A is a group represented by the following general formula: (In the formula, C represents a hydrogen atom or a hydroxy group, D represents a hydrogen atom or a lower hydroxyalkyl group. R represents a group selected from the same or different hydrogen atoms, a lower alkyl group and a lower alkoxy group, m Means 0 or an integer of 1 to 4) or a group represented by the following chemical formula: (In the formula, R and m have the same meanings as described above.) B means a hydrogen atom or a hydroxy group, and further A and B
May form a double bond to form a group represented by the following chemical formula. Embedded image (In the formula, R and m have the same meanings as described above.)] 2. An aralkylpiperidine derivative (II) represented by the following general formula or a pharmaceutically acceptable salt thereof. Embedded image [Wherein A is a group represented by the following general formula: (In the formula, C means a hydrogen atom or a hydroxy group, D means a hydrogen atom or a lower hydroxyalkyl group.) Or a group represented by the following chemical formula: B means a hydrogen atom or a hydroxy group, and further A and B
May form a double bond to form a group represented by the following chemical formula. Embedded image ] 3. The method according to claim 1, which is represented by the following general formula.
The aralkylpiperidine derivative (III) or a pharmaceutically acceptable salt thereof described. Embedded image [In the formula, B, C and D have the same meanings as described above, and B and C may form a double bond. ] 4. The aralkylpiperidine derivative (I) according to claim 1 selected from the following compounds, or a pharmaceutically acceptable salt thereof. (1) 1-benzyl-4- (5,6-dimethoxy-1-indanone-2-yl) hydroxymethylpiperidine (2) 1-benzyl-4-hydroxy-4- (5,6-dimethoxy-1-indanone -2-yl) hydroxymethylpiperidine (3) 1-benzyl-4-hydroxy-4- (5,6-dimethoxy-1-indanone-2-yl) methylpiperidine (4) 2- (1-benzylpiperidine-4 -Ylidene) methyl-5,6-
Dimethoxy-1-indanone (5) 1-benzyl-4- (5,6-dimethoxy-2-hydroxymethyl-1-indanone-2-yl) methylpiperidine (6) 1-benzyl-4- [3- (4 , 5-Dimethoxy-2-carboxyphenyl) -2-oxo] propylpiperidine 5. An acetylcholinesterase inhibitor comprising the aralkylpiperidine derivative (I) or the pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient. 6. A therapeutic / preventive agent for senile dementia, which comprises the aralkylpiperidine derivative (I) or the pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient. 7. The therapeutic / prophylactic agent according to claim 6, wherein the various senile dementias are Alzheimer-type senile dementia.