JPH11349481A - Sigma receptor-binding agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prepare a sigma receptor-binding pharmaceutincal agent highly effective in antagonism or pungency to a sigma receptor, having safety and useful as a preventive, therapeutical and ameliorative agent, etc., for schizophrenia and aporioneurosis by including a specific benzylpiperidine derivative as an active component. SOLUTION: This pharmaceutical agent is prepared by including a benzylpiperidine of formula I [the bond of formula II is a single or double bond; R<1> is an atomic group of formula III or the like; R<2> is H or a lower alkoxy; (n) is 0-4] or its pharmacologically acceptable salt [e.g. 1-benzyl-4-(3,4- dihydro-4-oxoquinazolin-3-yl)piperidine, or the like] as an active component. The dose of the compound of formula I is pref. 1-500 mg/day and the pharmaceutical agent is oral administration, by intravenous injection, by intramuscular injection, by per rectum administration or by percutaneous administration.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an agent for preventing, treating or ameliorating a disease in which a sigma receptor binding effect is effective, and more specifically, for preventing, treating or ameliorating a disease in which a sigma receptor antagonistic or stimulating effect is effective. Ameliorating agents, more specifically, for example, schizophrenia,
The present invention relates to an agent for preventing, treating and improving anxiety, and an agent for improving intellectual function.

[0002]

BACKGROUND OF THE INVENTION The sigma receptor was proposed by Martin et al. In 1976 as one of subtypes of opiate receptors to which morphine and the like bind and express hallucinations. It turned out to be an opiate receptor. In addition, most antipsychotics (schizophrenia drugs) have affinity for sigma receptors, especially haloperidol (Haloperidol), which is widely used clinically due to its excellent therapeutic effect, It turned out to have a strong affinity, leading to the sigma receptor being considered to be greatly involved in the mechanism of action of antipsychotics. On the other hand, conventional antipsychotic drugs such as haloperidol have a dopamine D2 receptor blocking action as a main mechanism of action, and the accompanying occurrence of side effects such as extrapyramidal symptoms cannot be avoided. Against such a background, a compound having a sigma receptor binding action is a therapeutic agent for a new disease,
In particular, schizophrenia treatment / amelioration agents without anxiety manifestation such as extrapyramidal symptoms, anxiolytics, more preferably negative for schizophrenia with the main symptoms of flattening of emotions, reduced motivation, and poor language. It is expected as an agent for treating and improving symptoms.

[0003]

BACKGROUND OF THE INVENTION As a compound having a sigma receptor binding action, for example, 1-cyclopropylmethyl-4- [2- (4-fluorophenyl) -2-oxoethyl] disclosed in Japanese Patent Publication No. 5-505172 is disclosed. Piperidine / hydrobromide (Code name: DuP73
1) -cycloalkylpiperidines such as 4), N, N-dipropyl-2- [4-methoxy-3- (2-phenylethoxy) phenyl] ethylamine.hydrochloride (code name) described in WO92 / 1259 : NE-100) and other (alkoxyphenyl) alkylamine derivatives, and other N-allylnormethazocine (code name:
SKF-10047), 1- (3,4-dimethoxyphenethyl) -4- (3-phenylpropyl) piperazine dihydrochloride (code name: SA450
3) etc. are known so far.

[0004]

[Problems to be solved by the present invention] However, conventional sigma receptor binding agents are still under development, and no drug has been confirmed to be effective and safe in clinical practice. Therefore, a sigma receptor binding agent with high clinical utility has not yet been developed, and a new compound that is structurally different from conventional known compounds and that has a balance between efficacy and safety has been sought. Had been.

[0005]

The inventors of the present invention have made intensive studies for many years in order to solve the above problems and to develop a sigma receptor binding agent having high efficacy and safety. . As a result, they have unexpectedly found that the benzylpiperidine derivative (I) represented by the following structural formula or a pharmacologically acceptable salt thereof achieves the intended purpose, and have completed the present invention.

Here, the sigma receptor binding agent according to the present invention is a benzylpiperidine derivative (I) represented by the following general formula or a pharmacologically acceptable salt thereof.

[0007]

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In the formula, a bond represented by the following general formula:

[0009]

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Is a single bond or a double bond, and R ¹ is an atomic group selected from the following:

[0011]

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Wherein R ² is a hydrogen atom or a lower alkoxy group, n is 0 or an integer of 1 to 4, and Ac is an acetyl group.

The pharmacologically acceptable salt is not limited as long as it forms an addition salt with the benzylpiperidine derivative (I), and specific examples thereof include hydrochloride, sulfate,
Addition salts of mineral acids such as nitrates and phosphates, addition salts of organic acids such as acetates, oxalates, succinates, maleates and fumarates, methanesulfonate, benzenesulfonate and toluene Examples thereof include addition salts of sulfonic acids such as sulfonic acid salts, and addition salts of other amino acids.

The benzylpiperidine derivative (I) according to the present invention may have an optical isomer or a geometric isomer, but the present invention is not limited thereto, and any one of the optical isomers may be used. There may be. Similarly, the geometric isomer is not limited either, and may be any one or a mixture. Further, there is a case where a crystal polymorph exists, but it is not limited similarly, and any crystal form may be single or a mixture, and may be a hydrate other than an anhydride.

Next, the dosage form of the compound of the present invention includes, for example, oral preparations such as powders, fine granules, granules, tablets, coated tablets and capsules, external preparations such as ointments and patches, suppositories and injections. Preparations and the like. At the time of formulation, it can be produced by a conventional method using a usual pharmaceutical carrier.

That is, in order to produce an oral preparation, the compound of the present invention and an excipient and, if necessary, an antioxidant, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent and the like are added. Powders, fine granules, granules, tablets, coated tablets, capsules and the like are prepared by a conventional method.

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

In preparing an injectable preparation, a pH adjuster, a solubilizer, an isotonic agent and the like, and if necessary, a solubilizer, a stabilizer, an antioxidant and the like are added to the compound of the present invention. hand,
It is formulated by the usual 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 base materials used include animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, and 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, coloring agents, fragrances, etc. are added. However, the base material of 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 base material to be added is an amount that usually results in a concentration set in the production of an external preparation.

The benzylpiperidine derivative in the present invention
The dose of (I) varies depending on symptoms, severity, age, complications and the like and is not limited, and also varies depending on the administration route and the like, but is usually 0.01 mg to 2000 mg per day, preferably 0.1 mg to 1000 mg. And more preferably 1 mg to 500 m
g, which is administered orally, intravenously, intramuscularly, rectally or transdermally.

[0022]

Next, in order to show the usefulness of the compound of the present invention as a sigma receptor binding agent, examples of sigma receptor binding experiments are listed below as effect examples, but the use of the compound of the present invention is not limited thereto. Needless to say. This experiment was performed on We
ber et al. (Proc. Natl. Acad. Sci. 83 , 8784 8788,
1986.).

1) Preparation of Receptor Specimens Male Sprague Dawley rats (6-8 weeks old, body weight 150-290)
g) was used for the experiment. The rats were sacrificed by decapitation and the whole brain was removed. The cerebral cortex was separated, homogenized in a 10-fold amount of 0.32 M sucrose using a Teflon glass homogenizer, and centrifuged at 1,000 × g for 10 minutes. 20,000x supernatant
Centrifuged at g for 20 minutes. Obtained pellet (P2 fraction)
Was washed, suspended in 20 to 100 times the measurement buffer, and used as a receptor specimen.

2) Measurement of receptor binding The cryopreserved receptor specimen was thawed and resuspended. Each measurement was carried out at room temperature for 90 minutes at a final volume of 0.5 ml with a part of the receptor specimen, a fixed concentration of the compound and tritium-labeled 1,3-di-O-tolylguanidine in a measurement buffer. Using Brandel Model M 30R cell harvester,
Incubation was stopped by rapid filtration through Whatman GF / B glass filters. The filter was washed twice with 5 ml of ice-cold 50 mM Tris-HCl buffer (pH 7.4). Radioactivity retained on the filter is converted to scintillant (ACS II)
The measurement was performed with a liquid scintillation counter using 5 ml. Specific binding was achieved with unlabeled compound (haloperidol 10m
It was calculated by subtracting the non-specific binding measured in the presence of the unlabeled compound from the total binding measured in the absence of M). Thereafter, the inhibition rate due to the addition of the compound was determined.

The calculation formula is shown below. Binding inhibition rate (%) = [specific binding (dpm)-specific binding at compound addition (dpm)] x 100 / [specific binding (dpm)] specific binding = binding at solvent addition-non-specific binding compound Specific binding at addition = binding at compound addition-non-specific binding

The measurement results (drug concentration; 10 ^-8 M) of each compound are shown below. (In the table, the compound No. indicates the production example number.)

[0027] A: Compound of Example 38 of JP-A-2-169569 [1-benzyl-4- (5,6-dimethoxyindanone-2-yl) piperidine]

From the above results, the excellent sigma receptor binding action of the compound of the present invention is apparent. Then, in order to specifically explain the compound of the present invention, Production Examples are listed below, but it goes without saying that the present invention is not limited to these.

[0029]

[Production Example] Production Example 1 1-benzyl-4- (3,4-dihydro-4-
Synthesis of oxoquinazolin-3-yl) piperidine (1) 1-benzyl-4-formylaminopiperidine

[0030]

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5.00 g of 4-amino-1-benzylpiperidine (2
6.3 mmol) was dissolved in 25 ml of 99% formic acid and heated under reflux for 12 hours. After adjusting the pH to 10 with sodium hydrogen carbonate and 8N aqueous sodium hydroxide under ice-cooling, the mixture was extracted with 100 ml of ethyl acetate, and the organic layer was washed with 100 ml of saturated saline. After drying (MgSO ₄ ), the residue obtained by concentration under reduced pressure was purified by (NH) silica gel column chromatography (n-hexane / ethyl acetate system) to obtain 4.63 g of the title compound. (Yield; 8
1%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.48 (2H, ddd, J = 4Hz, J
= 11Hz, J = 12Hz), 1.86-1.94 (2H, m), 2.11 (2H, dt, J = 2Hz, J = 1
2Hz), 2.77-2.86 (2H, m), 3.48 (2H, s), 3.82-3.94 (1H, m), 5.
78-5.86 (1H, m), 7.22-7.34 (5H, m), 8.09 (1H, s).

(2) 1-benzyl-4- (3,4-dihydro-4-oxo
Soquinazolin-3-yl) piperidine

[0033]

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1-benzyl-4-formylaminopiperidine
1.26 g (9.19 mmol) of anthranilic acid in 1.00 g (4.58 mmol)
Was added and stirred at 150 ° C. for 4 hours. The mixture was diluted with 100 ml of ethyl acetate, and washed with 100 ml of a saturated aqueous solution of sodium carbonate and 100 ml of a saturated saline solution. After drying (MgSO ₄ ), the residue obtained by concentration under reduced pressure was recrystallized from ethanol to obtain 0.74 g of the title compound. (Yield; 51%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.93-2.06 (4H, m), 2.24
(2H, dt, J = 4Hz, J = 12Hz), 3.08 (2H, br-d, J = 12Hz), 3.58 (2H,
s), 4.84 to 4.94 (1H, m), 7.26 to 7.38 (5H, m), 7.50 (1H, ddd, J = 1
Hz, J = 7Hz, J = 8Hz), 7.68-7.78 (2H, m), 8.17 (1H, s), 8.31 (1
(H, ddd, J = 1Hz, J = 2Hz, J = 8Hz).

Production Example 2 1-benzyl-4- (4-oxo-1,2,
3,4-tetrahydroquinolin-3-yl) piperidine hydrochloride
Synthesis of

[0036]

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0.50 g (1.57 g) of 1-benzyl-4- (3,4-dihydro-4-oxoquinazolin-3-yl) piperidine obtained in the preceding Preparation Example
mmol) was dissolved in 8 ml of methanol, and adjusted to pH 3 to 4 by adding methanol containing 11% hydrogen chloride. To this, 0.11 g (1.75 mmol) of sodium hydrogen carbonate was added, and the mixture was stirred for 20 minutes and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (50 ml), saturated aqueous sodium carbonate solution (50 ml) and saturated saline.
Washed with 50 ml. After drying (MgSO ₄ ), the residue obtained by concentration under reduced pressure was recrystallized from ethyl acetate / n-hexane to obtain 0.44 g of a free form of the title compound. (Yield; 87%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.70-1.80 (4H, m), 2.1
0-2.20 (2H, m), 2.94-3.02 (2H, m), 3.52 (2H, m), 4.28 (1H, br
-s), 4.57 (2H, d, J = 3Hz), 4.57-4.66 (1H, m), 6.68 (1H, dd, J =
1Hz, J = 8Hz), 6.90 (1H, dt, J = 1Hz, J = 8Hz), 7.24-7.35 (6H,
m), 7.95 (1H, dd, J = 2Hz, J = 8Hz).

The free product (0.15 g) was converted into a hydrochloride by a conventional method, and recrystallized from ethanol to obtain 0.12 g of the title compound. Melting point: 233-236 ° C. ESI-MS: m / z = 322 (M + H +).

Production Example 3 1-benzyl-4- (1-acetyl-4-)
Oxo-1,2,3,4-tetrahydroquinazolin-3-yl) pipe
Synthesis of lysine / hydrochloride

[0040]

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The 1-benzyl-4- (4-oxo-) obtained in the preceding Preparation Example
(1,2,3,4-tetrahydroquinolin-3-yl) piperidine 0.1
5 g (0.47 mmol) was dissolved in pyridine 3 ml, acetic anhydride 1.5 ml
Was added. After stirring at room temperature for 4 hours, the residue obtained by concentration under reduced pressure was diluted with 20 ml of ethyl acetate. The organic layer was further washed with 20 ml of a saturated aqueous solution of sodium carbonate and 20 ml of a saturated saline solution. After drying (MgSO ₄ ), the residue obtained by concentration under reduced pressure was subjected to (NH) silica gel column chromatography.
Purification by (n-hexane / ethyl acetate system) gave 0.12 g of a free form of the title compound. (Yield; 71%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.64-1.94 (4H, m), 2.1
3 (2H, t, J = 12Hz), 2.25 (3H, br-s), 2.98 (2H, bd, J = 12Hz), 3.
52 (2H, s), 4.48-4.58 (1H, m), 5.17 (2H, br-s), 7.18-7.37 (7
H, m), 7.52 (1H, dt, J = 2Hz, J = 8Hz), 8.07 (1H, dd, J = 2Hz, J = 8H
z).

This was converted into a hydrochloride by a conventional method, and recrystallized from ethanol / isopropyl ether to give the title compound 0.1
2 g were obtained. Melting point: 218-223 ° C. ESI-MS: m / z = 364 (M + H +).

Production Example 4 1-benzyl-4- (6,7-dimethoxy
1-oxo-1,2,3,4-tetrahydroisoquinolin-3-yl)
Synthesis of piperidine hydrochloride

[0044]

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1-benzyl-4- (5,6-dimethoxyindanone-2- produced according to Example 38 of JP-A-2-169569
Yl) piperidine 1.00 g (2.74 mmol) in benzene 4.89 ml (5
4.7 mmol) and 1.46 ml (27.3 mmol) of concentrated sulfuric acid and 0.27 g (4.15 mmol) of sodium azide were added. 24 at 65 ° C
After stirring for an hour, the mixture was adjusted to pH 10 with a 2N aqueous sodium hydroxide solution under ice cooling, and extracted with 50 ml of ethyl acetate × 2. The organic layer was washed with 50 ml of a saturated saline solution, dried (MgSO ₄ ), concentrated under reduced pressure, and the obtained residue was purified by (NH) silica gel column chromatography (n-hexane / ethyl acetate system). 0.25 g of a free form of the title compound was obtained. (Yield; 24%) This was further recrystallized from ethyl acetate to obtain 0.18 g of a higher purity free form of the title compound. ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.32-1.54 (3H, m), 1.7
3 (2H, dd, J = 12Hz, J = 23Hz), 1.93 (2H, br-t, J = 12Hz), 2.79-
2.99 (4H, m), 3.43-3.50 (1H, m), 3.49 (2H, s), 3.93 (6H, s),
5.96 (1H, br-s), 6.65 (1H, s), 7.23-7.35 (5H, m), 7.55 (1H,
s).

This was converted into a hydrochloride by a conventional method, and recrystallized from ethanol / diethyl ether to obtain 0.16 g of the title compound. Melting point: 235-240 ° C. ESI-MS: m / z = 381 (M + H +).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/00 643 A61K 31/00 643D 31/47 605 31/47 605 31/505 605 31/505 605 // C07D 211/32 C07D 211/32 401/04 401/04

Claims (7)

[Claims] 1. A sigma receptor binding agent comprising, as an active ingredient, a benzylpiperidine derivative (I) represented by the following general formula or a pharmacologically acceptable salt thereof. Embedded image [Wherein the bond is represented by the following general formula: Represents a single bond or a double bond, and R ¹ represents any one of the following atomic groups: (In the formula, R ² represents a hydrogen atom or a lower alkoxy group, n represents 0 or an integer of 1 to 4, and Ac represents an acetyl group.) ] 2. The sigma receptor binding agent according to claim 1, wherein the benzylpiperidine derivative is a sigma receptor antagonist or a sigma receptor stimulant. 3. An agent for preventing, treating or ameliorating a disease in which sigma receptor antagonism is effective, comprising the sigma receptor binding agent according to claim 1 as an active ingredient. 4. A preventive, therapeutic or ameliorating agent for a disease effective for stimulating a sigma receptor comprising the sigma receptor binding agent according to claim 1 as an active ingredient. 5. A schizophrenia prevention / treatment / amelioration agent comprising the sigma receptor binding agent according to claim 1 as an active ingredient. 6. An agent for preventing, treating or improving anxiety comprising the sigma receptor binding agent according to claim 1 as an active ingredient. 7. An intellectual function improving agent comprising the sigma receptor binding agent according to claim 1 as an active ingredient.