JP2883970B2 - New 1,4- (diphenylalkyl) piperazine derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention has an affinity for a sigma receptor, and has cerebral nerve dysfunctions such as dementia, depression, schizophrenia, anxiety, diseases associated with immunological abnormalities and endocrine abnormalities, and digestion. Novel 1,4- useful as a therapeutic agent for organ ulcers
The present invention relates to (diphenylalkyl) piperazine derivatives.

[0002]

2. Description of the Related Art Recently, a large number of studies on the σ receptor have been carried out, and compounds having a strong affinity for the σ receptor are associated with cerebral nerve dysfunction such as dementia, depression, schizophrenia, anxiety, immune abnormality and endocrine abnormality. It is becoming clear that it is useful as a therapeutic agent for diseases such as carcinoma and gastrointestinal ulcer (Journal of Neuropsychiatry 1, 7-15 (1
989); Eur. J. Biochem., 200, 633-642 (1991); J. Ph.
armacol. Exp. Ther., 2 55, 1354-1359 (1990)).

On the other hand, it has been reported that 1,4- (diphenylalkyl) piperazine derivatives have affinity for the σ receptor (WO 91/09594). However, this report mainly relates to a compound in which the phenyl ring has no substituent, and the effect of introducing a substituent on the phenyl ring on the affinity for the σ receptor has not been studied.

[0004] Although the purpose, action, and effect are different from those of the present invention, there are the following prior arts which report compounds whose chemical structures are close to those of the present invention. 1,4-
Many compounds in which both of the two phenyl rings of the (diphenylalkyl) piperazine derivative have no substituent or compounds in which both of the two phenyl rings have a substituent have already been synthesized (Chem. Ber., 100, 3045 (1967) ); J. Pharm.
Sci. , 72, 304 (1983)). However, there are few research reports on 1,4- (diphenylalkyl) piperazine derivatives having a substituent on only one phenyl ring and not having a substituent on the other phenyl ring.

For example, as a compound in which one phenyl ring has no substituent and the other phenyl ring is substituted with an alkoxy group, a compound in which the 3-position is substituted with a methoxy group and the 2-position is substituted with a hydroxy group (Pharmazie 29) , 189 (1970)) or 2,
Compounds in which the 3- and 4-positions are substituted with a methoxy group
-83771) has only been reported. Of course, there is no report on the affinity of these compounds for the σ receptor.

[0006]

How the affinity of the 1,4- (diphenylalkyl) piperazine derivative to the sigma receptor is changed by introducing a substituent into the phenyl ring has not yet been studied. It has been an important issue to find a compound having a strong affinity for a sigma receptor by introducing a substituent.

[0007] Further, there has been little research on introducing a substituent into only one phenyl ring of a 1,4- (diphenylalkyl) piperazine derivative, and research on the synthesis of such a compound has also been an interesting subject. .

[0008]

Means for Solving the Problems The present inventors have developed a novel 1,4-type compound in which a specific substituent is introduced into only one phenyl ring.
As a result of synthesizing a (diphenylalkyl) piperazine derivative and examining the effect on a sigma receptor, it was found that a compound into which two alkoxy groups had been introduced had a strong affinity for a sigma receptor.

Furthermore, these compounds not only have an affinity for the sigma receptor, but also have an improving effect on learning disorders due to cerebrovascular disorders and an effect of increasing the amount of acetylcholine in the brain, and are particularly useful as therapeutic agents for cerebral nerve dysfunction. I found something.

[0010]

DISCLOSURE OF THE INVENTION The present invention relates to a compound represented by the following general formula [I] and a salt thereof (hereinafter, referred to as the compound of the present invention) and a therapeutic agent for cerebral nerve dysfunction containing the same as an active ingredient.

[0011]

Embedded image [Wherein, R ¹ and R ² are the same or different and represent a lower alkoxy group. A and B are the same or different and represent a lower alkylene group. same as below. To explain the above definition in more detail, lower alkoxy refers to straight or branched alkoxy having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, t-butoxy, hexyloxy and the like. The term "lower alkylene" means a linear or branched alkylene having 1 to 6 carbon atoms such as methylene, ethylene, propylene, butylene, (dimethyl) methylene, and (diethyl) methylene.

Examples of the salts include pharmaceutically acceptable salts such as hydrochloride, sulfate, maleate and fumarate.

Preferred examples of the groups defined above will be described in detail below.

Preferred examples of the lower alkylene groups "A" and "B" include an ethylene, propylene or butylene group, that is, a linear alkylene group having 2 to 4 carbon atoms. Preferred examples of the combination of "A" and "B" include "A" is propylene, "B" is ethylene, "A" and "B" are both propylene, "A" and "B" are both ethylene, "A" is butylene and "B" is ethylene. A particularly preferred example is "A"
Is propylene and "B" is ethylene, "A" and "B"
Are propylene combinations. A preferred example of R ¹ and R ² is a methoxy group, particularly preferably a compound in which the methoxy group is located at an adjacent substitution position, and most preferably a methoxy group is located at the 3-position and 4-position, respectively. It is.

Examples of preferred specific compounds include 1-
[2- (3,4-dimethoxyphenyl) ethyl] -4-
(3-phenylpropyl) piperazine, 1- [2-
(3,4-dimethoxyphenyl) ethyl] -4- (2-
Phenylethyl) piperazine, 1- [2- (3,4-dimethoxyphenyl) ethyl] -4- (4-phenylbutyl) piperazine, 1- [3- (3,4-dimethoxyphenyl) propyl] -4- ( 3-phenylpropyl) piperazine, or salts thereof.

Examples of particularly preferred specific compounds include:
1- [2- (3,4-dimethoxyphenyl) ethyl]-
4- (3-phenylpropyl) piperazine, 1- [3-
(3,4-dimethoxyphenyl) propyl] -4- (3
-Phenylpropyl) piperazine, or salts thereof.

Representative synthetic methods of the compound of the present invention are the following methods 1) and 2).

1)

Embedded image [In the formula, X represents a reactive group such as a halogen atom or a lower alkanesulfonyloxy group. same as below. In this method, a compound of the formula [IV] is reacted with 2-bromoethanol to give a compound of the formula [V], which is then reacted with thionyl chloride or methanesulfonyl chloride to give a compound of the formula [V]. This is a method for obtaining a compound [I] of the present invention by leading to a compound of the formula [VI] and then reacting the compound with an amine derivative of the formula [VII].

2)

Embedded image This method is different from the method 1) in that the reaction order is changed.
The reaction conditions and the like are the same as in method 1).

The compound obtained by the above method can be converted into the above-mentioned salts by a conventional method.

The compound represented by the general formula [I] may have optical isomers, all of which are included in the present invention.

In order to examine the usefulness of the compound of the present invention, first, an experiment was conducted on the affinity of the compound of the present invention for the σ receptor. The details will be shown in the section on pharmacological tests described below, but it is not possible to use [ ³ H] (+) SKF-10047 or [ ³
H] (+)-PTZ was used as a labeling ligand to examine the affinity for the σ receptor. As a result, it was found that the compound of the present invention exhibited strong affinity for the σ receptor.

Next, it has been reported that compounds that increase the amount of acetylcholine in the brain are useful as therapeutic agents for dementia and the like (The New England Journal of Medication).
cine, 315, 1241-1245 (1986)) and Matsuno et al. (Brain Research, 575, 315-319 (1992)).
When the amount of acetylcholine in the rat brain was measured, the compound of the present invention showed an acetylcholine increasing effect.

A learning disorder model due to ischemia, which is known as a disease model of dementia due to cerebrovascular disorder, that is, the method of Pulsinelli et al. (Stroke 10 , 267 (1979))
Based on the method described above, experiments were performed using rats with occluded arteries and transient cerebral ischemia, using the method of Yasumatsu et al.
90, 321 (1987)), the compound of the present invention had an improving effect on learning disability.

From the results of the above pharmacological tests, the compounds of the present invention have a strong affinity for the σ receptor, and are associated with σ receptors such as dementia, depression, schizophrenia, anxiety, etc. Has a wide range of pharmaceutical uses as a therapeutic agent for cerebral nerve dysfunction, diseases associated with immune and endocrine disorders, gastrointestinal ulcers, etc., and also has an effect of increasing the amount of acetylcholine in the brain and improving learning due to cerebrovascular disorders. Thus, it was found to be particularly useful as a therapeutic agent for cranial nerve dysfunction.

Incidentally, it has been reported that certain piperazine derivatives have morphine-like physical dependence (Japanese Patent Publication No. 61-33827). Such an action is not preferred as a pharmaceutical. Thus, an experiment was performed to determine whether the compound of the present invention exhibited a morphine-like effect. It is known that a compound having a morphine-like action has a strong affinity for the μ receptor. If the affinity for the μ receptor is weak, it can be determined that the compound has a weak morphine-like action. The affinity of the compound of the present invention for the μ receptor was examined using [ ³ H] DAMGO as a labeled ligand. As a result, the affinity of the compound of the present invention for the μ receptor was weak, and it was found that the compound of the present invention showed substantially no morphine-like action.

To apply a compound as a pharmaceutical,
It is preferable that the difference between the effect expression amount and the side effect expression amount is large. That is, in the present invention, it is preferable that the affinity for the σ receptor is strong and the affinity for the μ receptor is weak, and the experimental results described below prove that the compound of the present invention is excellent as a pharmaceutical. is there.

The method of administration of the compound of the present invention may be oral or parenteral, and the dosage forms include tablets, capsules, soft capsules, granules and injections. It can be formulated using known techniques. For example, oral preparations such as tablets, capsules, soft capsules, and granules may be used, if necessary, in lactose, starch, crystalline cellulose, bulking agents such as vegetable oils, lubricating agents such as magnesium stearate, talc, and hydroxypropyl. It can be formulated using a binder such as cellulose and polyvinylpyrrolidone, a disintegrant such as calcium carboxymethylcellulose, a coating agent such as hydroxypropylmethylcellulose, macrogol, a silicone resin, and a film agent such as a gelatin film. The dose is appropriately selected depending on the condition, dosage form, etc., but is usually 1 mg to 1000 mg / day.
mg may be administered once or in several divided doses.

[0029]

Reference Example (Production of Intermediate)

Reference Example 1 N, N-bis (2-hydroxyethyl) -2- (3,4
-Dimethoxyphenyl) ethylamine (Reference compound 1-
1)

Embedded image 2- (3,4-dimethoxyphenyl) ethylamine (2
0 g) and 2-bromoethanol (73.4 g) in an ethanol (250 ml) solution.
g) and reflux for 24 hours. The insoluble material is removed by filtration, concentrated under reduced pressure, and then added with chloroform (300 ml). This solution is washed with a 10% aqueous sodium hydrogen carbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oil is purified by silica gel column chromatography to give 13.5 g (46%) of the title compound.

IR (Film, cm ^-1 ) 3383,294
1,1516,1464,1262,1236,114
2,1029

Using the same method as in Reference Example 1, the following compound was obtained.

N, N-bis (2-hydroxyethyl)-
3- (3,4-dimethoxyphenyl) propylamine (Reference compound 1-2) IR (Film, cm ^-1 ) 3386, 2941, 1515,
1463,1261,1156,1029,764

Reference Example 2 N, N-bis (2-chloroethyl) -2- (3,4-dimethoxyphenyl) ethylamine hydrochloride (Reference compound 2)
-1)

Embedded image N, N-bis (2-hydroxyethyl) -2- (3,4
-Dimethoxyphenyl) ethylamine (Reference compound 1-
1,10.9 g) in chloroform (50 ml) solution,
After addition of thionyl chloride (14.4 g) dropwise under ice cooling, the mixture is refluxed for 45 minutes. The reaction solution is concentrated under reduced pressure, and isopropanol is added to obtain 10.2 g (74%) of the title compound.

Mp 147-149 ° C. IR (KBr, cm ⁻¹ ) 2326, 1520, 1466,
1268,1238,1159,1140,1028

The following compounds were obtained in the same manner as in Reference Example 2.

N, N-bis (2-chloroethyl) -3-
(3,4-dimethoxyphenyl) propylamine hydrochloride (Reference compound 2-2) mp 112-123 ° C (ethyl acetate-isopropyl ether) IR (KBr, cm ^-1 ) 2394, 1519, 1471,
1263, 1234, 1157, 1138, 1025

Reference Example 3 N, N-bis (2-hydroxyethyl) -2-phenylethylamine (Reference compound 3-1)

Embedded image N, N-bis (2-hydroxyethyl) amine (90.8 g) and sodium iodide (21.6 g) are added to a solution of 2-phenylethyl bromide (20 g) in ethanol (100 ml), and the mixture is refluxed for 3 hours. After concentrating the reaction solution under reduced pressure, a saturated aqueous solution of sodium hydrogen carbonate is added, and the mixture is extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound 1
7.5 g (77%) are obtained.

IR (Film, cm ^-1 ) 3382,302
6,2947,1495,1455,1047,74
7,700

Using the same method as in Reference Example 3, the following compound was obtained.

N, N-bis (2-hydroxyethyl)-
3-phenylpropylamine (Reference compound 3-2) IR (Film, cm ^-1 ) 3373, 2943, 1496,
1454,1031,749,700

N, N-bis (2-hydroxyethyl)-
4-phenylbutylamine (Reference compound 3-3) IR (Film, cm ^-1 ) 3377, 2936, 1496,
1454,1041,748,700

N, N-bis (2-hydroxyethyl)-
5-phenylpentylamine (Reference compound 3-4) IR (Film, cm ^-1 ) 3378, 2934, 1495,
1453,1043,747,699

Reference Example 4 N, N-bis (2-chloroethyl) -2-phenylethylamine hydrochloride (Reference compound 4-1)

Embedded image To a solution of N, N-bis (2-hydroxyethyl) -2-phenylethylamine (Reference compound 3-1, 33.5 g) in chloroform (160 ml), 57.1 g of thionyl chloride is added dropwise while stirring with ice cooling. The reaction is stirred at room temperature for 10 minutes and refluxed for an additional hour. After the reaction solution was concentrated under reduced pressure, ethyl acetate and isopropyl ether were added, and the resulting crystals were collected by filtration to obtain 39.2 g (87%) of the title compound.

Mp 116-117 ° C. (ethyl acetate-
Isopropyl ether) IR (KBr, cm ^-1 ) 3008, 2423, 1498,
1479, 1456, 760, 746, 704

Using the same method as in Reference Example 4, the following compound was obtained.

N, N-bis (2-chloroethyl) -3-
Phenylpropylamine hydrochloride (Reference compound 4-2) mp 98-100 ° C. (ethyl acetate-isopropyl ether) IR (KBr, cm ⁻¹ ) 2965, 2360, 1484, ¹
458,1325,936,753,696

N, N-bis (2-chloroethyl) -4-
Phenylbutylamine hydrochloride (Reference compound 4-3) mp 100-112 ° C (ethyl acetate-isopropyl ether) IR (KBr, cm ^-1 ) 2945, 2459, 1487,1
444,1420,926,741,698

N, N-bis (2-chloroethyl) -5
Phenylpentylamine hydrochloride (Reference compound 4-4) mp 69-75 ° C (ethyl acetate-isopropyl ether) IR (KBr, cm ^-1 ) 2937, 2859, 2459, ¹
454,901,742,695

[0049]

【Example】

Example 1 1- [2- (3,4-dimethoxyphenyl) ethyl]-
4- (3-phenylpropyl) piperazine dihydrochloride (Compound 1-1)

Embedded image N, N-bis (2-chloroethyl) -2- (3,4-dimethoxyphenyl) ethylamine hydrochloride (Reference compound 2
-1,0.69 g) and 3-phenylpropylamine (0.41 g) in dimethylformamide (20 ml) were added potassium carbonate (0.83 g) and sodium iodide (0.90 g), and the mixture was heated at 70 ° C. for 2 hours. Stir.
Water is added to the reaction solution, and extracted with ethyl acetate. The organic layer is washed with water and then with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oil was dissolved in ethanol, 6N hydrochloric acid (2 ml) was added, and the solution was concentrated under reduced pressure to give 0.68 g (77%) of the title compound (Compound 1-1).
%).

Mp 258-260 ° C. (decomposition) IR (KBr, cm ⁻¹ ) 3977, 2355, 1518,
1265, 1140, 1028, 754, 704

Using the same method as in Example 1, the following compound was obtained.

1- [2- (3,4-dimethoxyphenyl) ethyl] -4- (2-phenylethyl) piperazine dihydrochloride (compound 1-2) mp 268-272 ° C. (decomposition) IR (KBr, cm ^-1 ) 3430, 2938, 2300,
1519, 1447, 1264, 1234, 1026

1- [2- (3,4-dimethoxyphenyl) ethyl] -4-benzylpiperazine dihydrochloride (compound 1-3) mp 250-253 ° C. (decomposition) IR (KBr, cm ⁻¹ ) 2978 , 2360, 1520,
1467, 1267, 1236, 1149, 1027

1- [2- (3,4-dimethoxyphenyl) ethyl] -4- (4-phenylbutyl) piperazine dihydrochloride (compound 1-4) mp 280 ° C. or higher (ethanol) IR (KBr, cm) ^-1 ) 2361, 1522, 1469,
1445, 1264, 1162, 1027, 696

1- [3- (3,4-dimethoxyphenyl) propyl] -4- (2-phenylethyl) piperazine dihydrochloride (compound 1-5) mp 254 ° C. (decomposition, ethanol) IR (KBr, cm ^-1 ) 2360, 1518, 1455,
1236,1139,1028,754,703

1- [3- (3,4-dimethoxyphenyl) propyl] -4- (3-phenylpropyl) piperazine dihydrochloride (compound 1-6) mp 254 ° -257 ° C. (decomposition, methanol) IR ( KBr, cm ^-1 ) 2984, 2394, 1515,
1452, 1258, 1235, 1155, 1029

1- [3- (3,4-dimethoxyphenyl) propyl] -4- (4-phenylbutyl) piperazine dihydrochloride (compound 1-7) mp 256-259 ° C. (decomposition, ethanol) IR ( KBr, cm ^-1 ) 2377, 1514, 1451,
1258, 1234, 1156, 1029, 699

Example 2 1- (3,4-Dimethoxybenzyl) -4- (2-phenylethyl) piperazine dihydrochloride (Compound 2-1)

Embedded image N, N-bis (2-chloroethyl) -2-phenylethylamine hydrochloride (Reference compound 4-1, 1.0 g), 3,
4-dimethoxybenzylamine (1.2 g), potassium carbonate (1.5 g) and sodium iodide (1.1 g)
Is suspended in dimethylformamide (35 ml) and the suspension is stirred at 30-38 ° C. for 2.5 hours. Ice water is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oil is purified by silica gel column chromatography and then dissolved in methanol. Concentrated hydrochloric acid was added to this methanol solution, and the precipitated crystals were collected by filtration to give the title compound 0.8.
g (55%).

Mp about 280 ° C. (decomposition) IR (KBr, cm ⁻¹ ) 3347, 2980, 2335,
1590, 1520, 1449, 1265, 1245
1159,1022,949,914,760,70
1,650

Using the same method as in Example 2, the following compounds were obtained.

1- (3,4-dimethoxybenzyl)-
4- (3-phenylpropyl) piperazine dihydrochloride (compound 2-2) mp 257-260 ° C (decomposition, ethanol) IR (KBr, cm ^-1 ) 2362, 1523, 1453,
1276, 1166, 1020, 750, 699

1- [2- (2,5-dimethoxyphenyl) ethyl] -4- (3-phenylpropyl) piperazine dihydrochloride (compound 2-3) mp 240 ° C. (decomposition, ethanol) IR (KBr, cm ^-1 ) 2990, 2391, 1501,
1467, 1227, 1044, 959, 699

1- (3,4-dimethoxybenzyl)-
4- (4-phenylbutyl) piperazine dihydrochloride (compound 2-4) mp 255 ° C. (decomposition, ethanol) IR (KBr, cm ⁻¹ ) 2945, 2338, 1519,
1445, 1267, 1164, 1023, 761

1- [2- (3,4-dimethoxyphenyl) ethyl] -4- (5-phenylpentyl) piperazine dihydrochloride (compound 2-5) mp 260-268 ° C. (decomposition, ethanol) IR ( KBr, cm ^-1 ) 2932, 2338, 1521,
1453,1263,1162,1144,700

[Formulation Examples] Examples of the formulation of the compound [I] of the present invention are shown below.

[0066]

[0067]

[0068]

[0069]

[0070]

【The invention's effect】

“Pharmacological test” In order to examine the usefulness of the compound of the present invention, an experiment on the affinity for the σ receptor was performed.

1-1. [ ³ H] as labeling ligand
(+) Experiment using SKF-10047 Reference of Matsuno et al. (European Journal of Pharmacolog
y 231, 451-457 (1993)).
The affinity for the receptor was determined.

(Experimental method) The preparation of the membrane preparation was carried out according to the article by Tam et al. (Proc. Natl. Acad. Sci. USA 80 , 6703-6707 (198).
According to 3)), the following method was used.

Hartley guinea pigs (body weight 300 to 40)
The brain was excised from 0 g), homogenized in Tris-HCl buffer (50 mM, pH 7.7, containing 0.32 M sucrose) 8 times the brain weight, and centrifuged to obtain a supernatant.
The supernatant was ultracentrifuged for 20 minutes, and the resulting pellet was suspended in Tris-HCl buffer (50 mM, pH 7.7; the same applies hereinafter), followed by centrifugation again to obtain a membrane sample.

[ ³ H] (+)-SKF-10047
Was determined by the following method. [ ³ H] (+)-SKF-10047 (5 n) dissolved in Tris-HCl buffer was added to a membrane preparation suspended in Tris-HCl buffer.
M) (without adding the test compound) and reacted at 25 ° C. for 30 minutes. After completion of the reaction, the reaction solution was subjected to suction filtration with a glass filter, and the radioactivity on the filter was measured with a liquid scintillation counter to determine the total binding amount. [ ³ H] (+)-SKF-10047 (5 nM)
(+)-SKF-10047 (1) having no radioactivity
00 μM) (without adding the test compound),
The amount of binding to the membrane preparation was determined using the same method as above, and was defined as the amount of non-specific binding. The difference between the total binding amount and the non-specific binding amount thus obtained was defined as the specific binding amount.

Next, the membrane preparation and [ ³ H] (+)-SKF-
The amount of binding of 10047 was measured in the presence of the test compound, and the concentration of the test compound was changed, whereby the previously determined specific binding amount of [ ³ H] (+)-SKF-10047 was suppressed by 50%. The compound concentration (IC ₅₀ ) was determined.

(Results) Table 1 shows the results of the compounds 1-1, 1-2 and 1-3 as an example of the experimental results.

[0077]

[Table 1] As shown in Table 1, the compound of the present invention is [ ³ H] (+)
It was found that the specific binding amount of -SKF-10047 was significantly inhibited at a low concentration, indicating that the compound of the present invention has a strong affinity for the σ receptor.

1-2. [ ³ H] as labeling ligand
Experiments using (+)-PTZ DeHaven-Hudkins et al. (Eur. J. Pharmacol., 227,
371-378 (1992)), [ ³ H] (+)-PTZ
Was used as a labeled ligand, and the affinity for the σ receptor was determined by the following method.

(Experimental method) The preparation of the membrane preparation was carried out according to the article by Tam et al. (Proc. Natl. Acad. Sci. USA, 80 , 6703-6707 (198).
According to 3)), the following method was used.

Hartley guinea pigs (body weight 300 to 40)
The brain was excised from 0 g), homogenized in Tris-HCl buffer (50 mM, pH 7.7, containing 0.32 M sucrose) 8 times the brain weight, and centrifuged to obtain a supernatant.
The supernatant was ultracentrifuged for 20 minutes, and the resulting pellet was suspended in Tris-HCl buffer (50 mM, pH 7.7; the same applies hereinafter), followed by centrifugation again to obtain a membrane sample.

The specific binding amount of [ ³ H] (+)-PTZ was determined in advance by the following method. The membrane preparation suspended in Tris-HCl buffer was dissolved in Tris-HCl buffer [
^[3 H] (+)-PTZ (5 nM) was added (the test compound was not added), and the mixture was reacted at 37 ° C. for 150 minutes. After completion of the reaction, the reaction solution was subjected to suction filtration with a glass filter, and the radioactivity on the filter was measured with a liquid scintillation counter to determine the total binding amount. In addition, [ ³ H] (+)
-PTZ (5 nM) and no radioactivity (+) -PT
A mixture of Z (100 μM) was added (the test compound was not added), and the amount of binding to the membrane standard was determined using the same method as described above, and was defined as the amount of non-specific binding. The difference between the total binding amount and the non-specific binding amount thus obtained was defined as the specific binding amount.

Next, the amount of binding between the membrane sample and [ ³ H] (+)-PTZ was measured in the presence of the test compound, and the [ ³ H] ( +)-P
The concentration (IC ₅₀ ) of the test compound at which the specific binding amount of TZ was suppressed by 50% was determined.

(Results) Table 2 shows the results of Compound 1-1, Compound 1-2, Compound 1-4 and Compound 1-6 as an example of the experimental results. The results are shown as the average of 4 to 11 cases.

[0084]

[Table 2] As shown in Table 2, [ ³ H] (+)-SKF-10
Similarly to the case where 047 was examined as a labeled ligand, the compound of the present invention markedly inhibited the specific binding amount of [ ³ H] (+)-PTZ at a low concentration, and had a strong affinity for the σ receptor. Admitted.

2. Experiment on the effect of increasing the amount of acetylcholine in the brain A compound that increases the amount of acetylcholine in the brain has been reported to be useful as a therapeutic agent for dementia and the like (The New England Journal of Medicine, 315 , 1241-12
45 (1986)), an experiment was conducted on the effect of the compound of the present invention on the amount of acetylcholine in rat brain.

(Experimental method) The amount of acetylcholine in rat brain was determined by the method of Matsuno et al. (Brain Research, 575, 315-319).
(1992)), using a brain microdialysis method as follows.

Wistar male rats (weight: 280-300)
g) A probe was inserted into the rat brain, and a Ringer solution containing 3 μM ezerin sulfate was perfused, and acetylcholine recovered from the probe was quantified by high performance liquid chromatography. The amount of acetylcholine in the rat brain was measured over time, and when stabilized, the test compound suspended in a 1% methylcellulose solution was orally administered to determine the amount of acetylcholine in the brain. The amount of acetylcholine in the brain of the rats to which the test compound was not administered (average of 6 cases) was used as a control, and the result was defined as a value when the control was taken as 100 (30 minutes after administration of the test compound).
Table 3 shows the average values of 3 to 7 cases per minute).

(Results)

[Table 3] As shown in Table 3, it was confirmed that the compound of the present invention has an excellent effect of increasing the amount of acetylcholine in the brain.

3. Experiment on affinity for μ receptor Nabeshima et al. (Eur. J. Pharmacol., 114, 197-2
07 (1985)), the affinity for the μ receptor was determined by the following method. As a [ ³ H] -labeled ligand for μ receptor, [ ³ H] DAMGO, which has been reported to have high μ receptor selectivity, was used (Br.
J. Pharmac., 77, 461-469 (1982)).

(Experimental method) The preparation of the membrane preparation was carried out by Kosterlitz
The method was performed according to the following method according to the above-mentioned paper (Br. J. Pharmac., 68, 333-342 (1980)).

The brain was excised from a Wistar male rat (body weight: about 300 g), homogenized in Tris-HCl buffer (50 mM, pH 7.7, the same applies hereinafter) 20 times the weight of the brain, and then treated for more than 15 minutes. The pellet was obtained with care. This pellet was suspended in a Tris-HCl buffer, incubated at 37 ° C. for 30 minutes, and ultracentrifuged for 15 minutes to obtain a pellet, which was used as a membrane sample.

The specific binding amount of [ ³ H] DAMGO was determined in advance by the following method. [ ³ H] DAMGO (1 nM) dissolved in Tris-HCl buffer was added to the membrane preparation suspended in Tris-HCl buffer (without adding a test compound), and reacted at 25 ° C. for 30 minutes. . After completion of the reaction, the reaction solution was subjected to suction filtration with a glass filter, and the radioactivity on the filter was measured with a liquid scintillation counter to determine the total binding amount. In addition, [ ³ H] DAMGO was used as the membrane sample.
A mixture of (1 nM) and 5 μM naloxone was added (the test compound was not added), and the amount of binding to the membrane sample was determined using the same method as described above, and was defined as the amount of non-specific binding. The difference between the total binding amount and the non-specific binding amount thus obtained was defined as the specific binding amount.

Next, the amount of [ ³ H] DAMGO bound to the membrane sample was measured in the presence of the test compound, and the specific binding of [ ³ H] DAMGO determined above was determined by changing the concentration of the test compound. The concentration of the test compound at which the amount is inhibited by 50% (IC
₅₀ ) asked.

(Results) As an example of the experimental results, the IC _{50 of} Compound 1-1, Compound 1-2 and Compound 1-3 is 10,000 nM or more, and the compound of the present invention is [ ³ H]
It was found that the amount of DAMGO-specific binding was hardly inhibited. This indicates that the compounds of the present invention have a very low affinity for the μ receptor and show little morphine-like action.

From the results of the above pharmacological tests, the compounds of the present invention have a strong affinity for the σ receptor, show almost no morphine-like action, and are associated with σ receptors, such as dementia, depression, It has a wide range of pharmaceutical uses as a therapeutic agent for schizophrenia, anxiety and other cerebral nerve dysfunctions, diseases associated with immune and endocrine abnormalities, and gastrointestinal ulcers. Considering the improvement effect on learning disorders based on vascular disorders, it is clear that they are particularly excellent as therapeutic agents for cranial nerve dysfunction.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/495 AED A61K 31/495 AED (72) Inventor Yoshiko Hirano 4-2-17-1502, Tomicho, Nara-shi (56) References JP-A-3-7229 (JP, A) JP-A-55-83771 (JP, A) JP-A-60-222472 (JP, A) JP-A-5-503517 (JP, A) International publication 94 / 24115 (WO, A1) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 295/00-295/22 A61K 31/00-31/80 CA (STN) REGISTRY (STN)

Claims (22)

(57) [Claims] 1. A compound represented by the following general formula [I] and salts thereof. Embedded image [Wherein, R ¹ and R ² are the same or different and represent a lower alkoxy group. A and B are the same or different and represent a lower alkylene group. ] 2. A is-(CH ₂ ) _2- , (CH ₂ ) _3-
Or - (CH _{2) 4} - compounds and salts thereof according to claim 1, wherein a. 3. B is-(CH ₂ ) _2- or-(C
_2. The compound according to claim 1, which is H2) _3- , and salts thereof. 4. A is — (CH ₂ ) ₃ — and B is — (CH
₂ ) The compound according to claim 1, which is _2- or a salt thereof. 5. The compound according to claim 1, wherein A and B are — (CH ₂ ) ₃ — and salts thereof. 6. The compound according to claim 1, wherein A and B are — (CH ₂ ) ₂ — and salts thereof. 7. A is — (CH ₂ ) ₄ — and B is — (CH
₂ ) The compound according to claim 1, which is _2- or a salt thereof. 8. The compound according to claim 1, wherein R ¹ and R ² are a methoxy group, and salts thereof. 9. The compound according to claim 1, wherein R ¹ is located at the 3-position and R ² is located at the 4-position, and both are methoxy groups and salts thereof. 10. A compound represented by the following formula [II] and salts thereof. Embedded image 11. A compound represented by the following formula [III] and salts thereof. Embedded image 12. A therapeutic agent for cerebral nerve dysfunction comprising a compound represented by the following general formula [I] or a salt thereof as an active ingredient. Embedded image [Wherein, R ¹ and R ² are the same or different and represent a lower alkoxy group. A and B are the same or different and represent a lower alkylene group. ] 13. A is-(CH ₂ ) _2- , (CH ₂ ) ₃
- or - (CH _{2) 4} - cranial nerve dysfunction therapeutic agent according to claim 12, wherein a. 14. B is-(CH ₂ ) _2- or-(CH
₂ ) The therapeutic agent for cranial nerve dysfunction according to claim 12, which is _3- . 15. A is — (CH ₂ ) ₃ — and B is — (C
H _{2) 2} - cranial nerve dysfunction therapeutic agent according to claim 12, wherein a. 16. The therapeutic agent for cranial nerve dysfunction according to claim 12, wherein A and B are-(CH ₂ ) _3- . 17. The therapeutic agent for cranial nerve dysfunction according to claim 12, wherein A and B are-(CH ₂ ) _2- . 18. A is-(CH ₂ ) _4- and B is-(C
H _{2) 2} - cranial nerve dysfunction therapeutic agent according to claim 12, wherein a. 19. The therapeutic agent for cranial nerve dysfunction according to claim 12, wherein R ¹ and R ² are methoxy groups. 20. The therapeutic agent for cranial nerve dysfunction according to claim 12, wherein R ¹ is located at the 3-position and R ² is located at the 4-position, and both are methoxy groups. 21. A therapeutic agent for cerebral nerve dysfunction, comprising a compound represented by the following formula [II] or a salt thereof as an active ingredient. Embedded image 22. A therapeutic agent for cerebral nerve dysfunction comprising a compound represented by the following formula [III] or a salt thereof as an active ingredient: Embedded image