JP2920727B2 - New 1,4- (diphenylalkyl) homopiperazine 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 is used for diseases such as dementia, depression, schizophrenia, anxiety and other cerebral nerve dysfunctions, immune disorders and endocrine disorders.
The present invention relates to a novel 1,4- (diphenylalkyl) homopiperazine derivative useful as a therapeutic agent for gastrointestinal ulcer and the like.

[0002]

2. Description of the Related Art Recently, many studies on the σ receptor have been carried out, and compounds having a strong affinity for the σ receptor have been associated with cerebral nerve dysfunction such as dementia, depression, schizophrenia, anxiety, immune abnormality and endocrine abnormality. Is useful as a therapeutic agent for cancer and digestive ulcers (J. Neuropsychiatry Clin. Neurosci., 1, 7).
-15 (1989); Eur.J. Biochem., 200, 633-642 (1991);
J. Pharmacol. Exp.Ther., 255 , 1354-1359 (199
0)).

On the other hand, it has been reported that 1,4- (diphenylalkyl) piperazine derivatives have affinity for the σ receptor (WO 91/09594). However, the effect of replacing the piperazine ring with a homopiperazine ring on the affinity for the σ receptor has not been studied.

Further, it has been reported that 1,4- (diphenylalkyl) homopiperazine derivatives protect the brain from ischemia or hypoxia, improve cerebral dysfunction or prevent the progression of the dysfunction (Japanese Patent Laid-Open No. Hei 3 (1999)). -2144). However, what is specifically shown in this report is only a compound in which three trimethoxy groups are introduced into both of the two phenyl rings, and a compound in which two alkoxy groups are introduced into one phenyl ring. Nothing is disclosed. Of course, there is no report on the affinity for the σ receptor in this document.

[0005]

SUMMARY OF THE INVENTION How the substitution of the piperazine ring of a 1,4- (diphenylalkyl) piperazine derivative with a homopiperazine ring changes the affinity for a sigma receptor. No studies have yet been made on compounds into which two have been introduced, and studies on the synthesis of these compounds and on their pharmacological actions have been very interesting subjects.

[0006]

Means for Solving the Problems The present inventors have made 1,4-
By replacing the piperazine ring of the (diphenylalkyl) piperazine derivative with a homopiperazine ring and focusing on the phenyl ring, a new 1,4- (diphenylalkyl) homopiperazine derivative having two alkoxy groups introduced therein was synthesized, and its pharmacology was investigated. The effect was studied.

[ ³ H] (+)-pentazocine ([ ³ H] (+)-P
As a result of examining the affinity for the σ receptor using TZ) as a labeling ligand, it was found that the novel 1,4- (diphenylalkyl) homopiperazine derivative of the present invention has a strong affinity for the σ receptor.

[0008]

DISCLOSURE OF THE INVENTION The present invention relates to a compound represented by the following general formula [I] and salts thereof (hereinafter, referred to as the compound of the present invention).

[0009]

Embedded image [In the formula, R ¹ represents a hydrogen atom, a halogen atom or a lower alkyl group. R ² and R ³ 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. When the above definition is explained in more detail, a halogen atom means fluorine, chlorine, bromine, or iodine, and a lower alkyl means 1 to 6 of methyl, ethyl, propyl, hexyl, isopropyl, tert.-butyl and the like. Represents a straight-chain or branched alkyl having a carbon atom of
Methoxy, ethoxy, propoxy, hexyloxy, isopropoxy, tert.-butoxy, etc., represents a straight-chain or branched alkoxy having 1 to 6 carbon atoms, and lower alkylene means methylene, ethylene, trimethylene, tetramethylene , Pentamethylene, hexamethylene, (dimethyl) methylene, (diethyl) methylene and the like, and represents a linear or branched alkylene having 1 to 6 carbon atoms.

The salts include pharmaceutically acceptable salts such as hydrochloride, sulfate, oxalate, maleate, fumarate and the like.

Of the compounds of the present invention, preferred examples are those wherein R ¹ is a hydrogen atom or a halogen atom, R ² and R
^{And 3} is a compound of the same lower alkoxy group. More preferably, R ¹ is a hydrogen atom or a fluorine atom,
² and R ³ are compounds represented by adjacent methoxy groups. A is trimethylene or tetramethylene;
B is preferably ethylene or trimethylene.

Among the compounds of the present invention, an example of a compound having particularly excellent action is 1- [3- (3,4-dimethoxyphenyl) -1-propyl] -4- (4-phenyl-1
-Butyl) homopiperazine, 1- (3,4-dimethoxyphenethyl) -4- [3- (4-fluorophenyl)-
1-propyl] homopiperazine and 1- (3,4-dimethoxyphenethyl) -4- (3-phenyl-1-propyl) homopiperazine, and their respective salts.

The compound of the present invention can be obtained, for example, by introducing a phenylalkyl group into two nitrogen atoms of homopiperazine. At this time, there is no restriction on the order in which the phenylalkyl groups are introduced. Representative methods for synthesizing the compound of the present invention include the following a) and b).

A)

Embedded image [Wherein X ¹ and X ² represent a halogen atom. B)

Embedded image [Wherein X ¹ and X ² represent a halogen atom. The method of a) comprises reacting a compound represented by the formula [V] with homopiperazine (formula [VI]) to obtain a compound of the formula [VII], which is then reacted with a compound of the formula [VIII]. To obtain the compound [I] of the present invention.

On the other hand, in the method of b), first, a compound represented by the formula [VIII] is reacted with homopiperazine to give a compound of the formula [I
X], which is then reacted with a compound of the formula [V] to give the compound [I] of the present invention.

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

In order to examine the usefulness of the compound of the present invention, an experiment was conducted on the affinity of the compound of the present invention for the σ receptor. For detail in the section of Pharmacological Test described ^{later, [3 H] (+)} - result of examining the affinity with σ receptors PTZ as labeled ligands, the compounds of the present invention σ
It was found to show strong affinity for the receptor.

Furthermore, a learning disability model using scopolamine, which is known as a disease model for dementia due to cerebrovascular disease, that is, a method such as Starter (Psychopharmacolo)
gy, 107, 144-159 (1992)), the compound of the present invention had an improving effect on learning disability.

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 (New Engl. J. Med., 315 , 1241-1245 (198)
6)) Therefore, Matsuno et al. (Brain Res., 575, 3
15-319 (1992)), when the amount of acetylcholine in the rat brain was measured, the compound of the present invention showed an increasing effect on acetylcholine.

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 abnormalities, digestive ulcers, etc., and also has an effect of improving learning disorders due to cerebrovascular disorders and increasing the amount of acetylcholine in the brain Thus, it was found to be particularly useful as a therapeutic agent for cranial nerve dysfunction.

The method of administration of the compound of the present invention may be oral or parenteral. Examples of the dosage form 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. Formulated with a binder such as cellulose and polyvinylpyrrolidone, a disintegrant such as low-substituted hydroxypropylcellulose and calcium carboxymethylcellulose, a coating agent such as hydroxypropylmethylcellulose, macrogol and silicone resin, and a film agent such as a gelatin film. be able to. The dose is appropriately selected depending on the condition, dosage form, etc., but usually 1 mg to 1000 mg, preferably 1 mg to 200 mg, may be administered once or several times a day.

[0022]

【Example】

 Reference Example 1 4-phenylbutyl chloride (Reference compound 1-1)

Embedded image Thionyl chloride (6.53 ml) was added dropwise to a solution of 4-phenyl-1-butanol (9.00 g) in chloroform (40 ml) with stirring under ice cooling, and the mixture was heated under reflux for 2.5 hours. Water is added to the reaction solution, and extracted with diethyl ether. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 10.1 g of the title compound (reference compound 1-1).
(99.9%).

IR (Film, cm ^-1 ) 3084, 30
62, 2940, 2860, 1603, 1496, 74
9,699

By operating in the same manner as in Reference Example 1, the following compound is obtained.

• 4-fluorophenethyl chloride (Reference compound 1-2)

3,4-dimethoxybenzyl chloride (Reference compound 1-3) IR (Film, cm ^-1 ) 2958, 1606, 159
2,1515,1464,1263,1160,113
7,1027

3,4-dimethoxyphenethyl chloride (Reference compound 1-4) IR (Film, cm ^-1 ) 2999, 2955, 283
4,1607,1591,1515,1261,102
8

3- (3,4-dimethoxyphenyl) propyl chloride (Reference compound 1-5) IR (Film, cm ^-1 ) 2998, 2834, 160
7,1591,1516,1258

Reference Example 2 3- (4-fluorophenyl) propyl chloride (Reference compound 2-1)

Embedded image 1) Under a nitrogen atmosphere, lithium aluminum hydride (6.
85g) in diethyl ether (300ml) suspension,
Under ice cooling, 4-fluorocinnamic acid (10.00 g) in tetrahydrofuran (100 ml) -diethyl ether (3
0 ml) The solution in the mixture was added dropwise with stirring, and the mixture was refluxed for 5 hours. The reaction was cooled with ice-sodium chloride and
Add N hydrochloric acid and extract with ethyl acetate. The organic layer is washed with an aqueous sodium hydrogen carbonate solution and then with a saturated saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 9.28 g (quantitative) of 3- (4-fluorophenyl) -1-propanol.

IR (Film, cm ^-1 ) 3345, 29
39,2867,1600,1509

2) 3- (4-fluorophenyl) -1-
Propanol (9.28 g) in chloroform (65 m
1) To the solution, thionyl chloride (6.59 ml) was added dropwise with stirring under ice cooling, and the mixture was refluxed for 3 hours. The reaction solution is concentrated under reduced pressure, water is added to the obtained oil, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated aqueous solution of sodium hydrogen carbonate and then with a saturated saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography to give the title compound (Reference compound 2-1) 7.68.
g (73.9%).

IR (Film, cm ^-1 ) 2958, 16
01,1510

By operating in the same manner as in Reference Example 2, the following compound is obtained.

.3- (p-tolyl) propyl chloride (Reference compound 2-2)

4- (3,4-dimethoxyphenyl) butyl chloride (Reference compound 2-3) IR (Film, cm ^-1 ) 3000,2937,283
4,1590,1517,1465,1261,115
6,1029,758

Reference Example 3 4- (4-fluorophenyl) butyl chloride (Reference compound 3-1)

Embedded image 1) To a solution of 3- (4-fluorophenyl) propyl chloride (Reference compound 2-1, 1.73 g) in acetonitrile (18 ml) was added potassium cyanide (1.04 g) and 18-crown-6 (0.02 g). 1.5
Heat to reflux for hours. Water is added to the reaction solution, and extracted with ethyl acetate. The organic layer is washed with a saturated aqueous solution of sodium hydrogen carbonate and then with a saturated saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 4- (4-fluorophenyl) butyronitrile.

2) 6N sodium hydroxide (11.9 ml) was added to a solution of 4- (4-fluorophenyl) butyronitrile (1.14 g) in ethanol (35 ml), and the mixture was refluxed for 5 hours. The reaction solution is concentrated under reduced pressure, water is added to the obtained oil, and the aqueous layer is washed with diethyl ether. The aqueous layer is made acidic by adding 6N hydrochloric acid, and extracted with ethyl acetate.
The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 4- (4-fluorophenyl) butyric acid.

3) Lithium aluminum hydride (0.42 g) in diethyl ether (10 ml) under a nitrogen atmosphere
Add 4- (4-fluorophenyl) butyric acid (0.9
A solution of 1 g) in a mixture of tetrahydrofuran (10 ml) and diethyl ether (3 ml) was added dropwise with stirring.
Heat to reflux for 5 hours. The reaction solution is cooled with ice-sodium chloride, 1N hydrochloric acid is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 4- (4-fluorophenyl) -1-butanol.

4) 4- (4-fluorophenyl) -1-
Butanol (0.50 g) in chloroform (3.5 m
1) Thionyl chloride (0.26 ml) was added dropwise to the solution with stirring under ice cooling, and the mixture was refluxed for 3 hours. The reaction solution is concentrated under reduced pressure, water is added to the obtained oil, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (reference compound 3-1).

The same procedure as in Reference Example 3 was carried out to obtain the following compound.

4- (p-tolyl) butyl chloride (Reference compound 3-2)

Example 1 1- (3,4-Dimethoxybenzyl) -4-phenethylhomopiperazine dihydrochloride (Compound 1)

Embedded image 1) Sodium iodide (7.4) was added to a solution of homopiperazine (13.53 g) in dimethylformamide (60 ml).
7g) and potassium carbonate (8.10g) are added and stirred. A solution of phenethyl bromide (6.78 ml) in dimethylformamide (40 ml) is added dropwise to the reaction solution, and the mixture is further stirred at 50 ° C. for 4 hours. Water is added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 7.81 g (77.0%) of N-phenethyl homopiperazine.

IR (Film, cm ^-1 ) 3305, 29
33,2815,1602,1583,1497

2) N-phenethyl homopiperazine (2.
00g) in dimethylformamide (30 ml) solution,
Add potassium carbonate (2.71 g) and sodium iodide (2.93 g) and stir. 3,4-Dimethoxybenzyl chloride (Reference compounds 1-3, 2.1
A solution of 9 g) in dimethylformamide (5 ml) is added dropwise and stirred at 50 ° C. for 5 hours. Water is added to the reaction solution, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and a 1N hydrochloric acid-diethyl ether mixed solution (2: 1) was added to the obtained oil for 15 minutes.
Add 0 ml and extract. The aqueous layer is made alkaline with 4N sodium hydroxide and extracted with ethyl acetate. The organic layer is washed with water and then with a saturated saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oily product was purified by silica gel column chromatography, and 1- (3,4-dimethoxybenzyl) -4-phenethylhomopiperazine (1.88 g (5
4.4%).

IR (Film, cm ^-1 ) 2934, 28
30,1591,1514,1261,1234

3) 1- (3,4-dimethoxybenzyl)
To a solution of -4-phenethyl homopiperazine (1.64 g) in ethanol (5 ml) is added a 4N hydrogen chloride / ethyl acetate solution (5.4 ml), and the mixture is stirred. The precipitated crystals are collected by filtration to give the title compound (0.88 g, 44.6%).

Mp 219.2-223.0 ° C. (decomposition)
(Ethanol) IR (KBr, cm ^-1 ) 2956, 2465, 161
0, 1593, 1523, 1272, 1249

By operating in the same manner as in Example 1, the following compound is obtained.

1- (3,4-dimethoxyphenethyl)
-4-Phenethylhomopiperazine dihydrochloride (compound 2) mp 225-227 ° C (decomposition) (ethanol) IR (KBr, cm ^-1 ) 3029, 2952, 240
6,1594,1516,1491

1- (3,4-dimethoxyphenethyl)
-4- (4-Fluorophenethyl) homopiperazine dihydrochloride (Compound 3)

1- [3- (3,4-dimethoxyphenyl) -1-propyl] -4-phenethylhomopiperazine dihydrochloride (compound 4) mp 206.1-211.1 ° C. (decomposition) (ethanol Ethyl acetate) IR (KBr, cm ^-1 ) 2956, 2438, 160
6,1591,1517

1- [3- (3,4-dimethoxyphenyl) -1-propyl] -4- (4-fluorophenethyl) homopiperazine dihydrochloride (compound 5)

1- [4- (3,4-dimethoxyphenyl) -1-butyl] -4-phenethylhomopiperazine
Dihydrochloride (compound 6)

1- (3,4-dimethoxybenzyl)-
4- (3-phenyl-1-propyl) homopiperazine
Dihydrochloride (Compound 7) Amorphous powder IR (KBr, cm ^-1 ) 3424, 2959, 258
1,1593,1521,1454,1266,116
5,1146,1025

1- (3,4-dimethoxybenzyl)-
4- [3- (4-fluorophenyl) -1-propyl]
Homopiperazine dihydrochloride (compound 8)

1- (3,4-dimethoxyphenethyl)
-4- (3-Phenyl-1-propyl) homopiperazine dihydrochloride (compound 9) mp 208.5-212.6 ° C. (ethanol) IR (KBr, cm ⁻¹ ) 2935, 2833, 240
6,1593,1499,1266,1080

1- (3,4-dimethoxyphenethyl)
-4- [3- (p-tolyl) -1-propyl] homopiperazine dihydrochloride (compound 10)

1- (3,4-dimethoxyphenethyl)
-4- [3- (4-Fluorophenyl) -1-propyl] homopiperazine oxalate (Compound 11) Amorphous powder IR (KBr, cm ^-1 ) 3014, 2954, 262
3,1727,1609,1512

1- [3- (3,4-dimethoxyphenyl) -1-propyl] -4- (3-phenyl-1-propyl) homopiperazine dihydrochloride (compound 12) mp 205.3-209. 0 ° C. (ethanol) IR (KBr, cm ⁻¹ ) 2947, 2418, 159
0,1517,1256,1234

1- [3- (3,4-dimethoxyphenyl) -1-propyl] -4- [3- (p-tolyl) -1
-Propyl] homopiperazine dihydrochloride (Compound 13)

1- [3- (3,4-dimethoxyphenyl) -1-propyl] -4- [3- (4-fluorophenyl) -1-propyl] homopiperazine dihydrochloride (compound 14) mp 222 ２224 ° C. (decomposition) (ethanol) IR (KBr, cm ⁻¹ ) 2946, 2418, 159
1,1517

1- [4- (3,4-dimethoxyphenyl) -1-butyl] -4- (3-phenyl-1-propyl) homopiperazine dihydrochloride (compound 15) mp 195.8-205. 2 ° C. (acetone) IR (KBr, cm ⁻¹ ) 2937, 2438, 160
3,1587,1515,1453,1257,123
3,1144,1024

1- [4- (3,4-dimethoxyphenyl) -1-butyl] -4- [3- (4-fluorophenyl) -1-propyl] homopiperazine dihydrochloride (compound 16)

1- (3,4-dimethoxybenzyl)-
4- (4-phenyl-1-butyl) homopiperazine dihydrochloride (compound 17)

1- (3,4-dimethoxybenzyl)-
4- [4- (4-fluorophenyl) -1-butyl] homopiperazine dihydrochloride (compound 18)

1- (3,4-dimethoxyphenethyl)
-4- (4-phenyl-1-butyl) homopiperazine
Dihydrochloride (compound 19) mp 200-225 ° C (decomposition) (ethanol) IR (KBr, cm ^-1 ) 2981, 2952, 239
0, 1604, 1591, 1521, 1265, 123
7

1- (3,4-dimethoxyphenethyl)
-4- [4- (p-tolyl) -1-butyl] homopiperazine dihydrochloride (compound 20)

1- (3,4-dimethoxyphenethyl)
-4- [4- (4-fluorophenyl) -1-butyl]
Homopiperazine dihydrochloride (Compound 21)

1- [3- (3,4-dimethoxyphenyl) -1-propyl] -4- (4-phenyl-1-butyl) homopiperazine dihydrochloride (compound 22) mp 183 ° -195 ° C. ) (Ethanol) IR (KBr, cm ^-1 ) 2995, 2940, 285
2,2366,1606,1590,1517,127
0,1257,1234

1- [3- (3,4-dimethoxyphenyl) -1-propyl] -4- [4- (p-tolyl) -1
-Butyl] homopiperazine dihydrochloride (Compound 23)

1- [3- (3,4-dimethoxyphenyl) -1-propyl] -4- [4- (4-fluorophenyl) -1-butyl] homopiperazine dihydrochloride (Compound 24)

1- [4- (3,4-dimethoxyphenyl) -1-butyl] -4- (4-phenyl-1-butyl) homopiperazine dihydrochloride (compound 25) mp 215.5-219. 1 ° C. (decomposition) (ethanol) IR (KBr, cm ⁻¹ ) 2940, 2860, 244
4,1605,1590,1520,1264,123
4

1- [4- (3,4-dimethoxyphenyl) -1-butyl] -4- [4- (4-fluorophenyl) -1-butyl] homopiperazine dihydrochloride (compound 26)

1- (3,4-dimethoxybenzyl)-
4- (5-phenyl-1-pentyl) homopiperazine
Dimaleate (Compound 27)

1- (3,4-dimethoxyphenethyl)
-4- (5-Phenyl-1-pentyl) homopiperazine dimaleate (compound 28) mp 144.0-145.7 ° C (ethanol) IR (KBr, cm ^-1 ) 2944, 2359, 169
8, 1575, 1519, 1456, 1356, 869

1- [3- (3,4-dimethoxyphenyl) -1-propyl] -4- (5-phenyl-1-pentyl) homopiperazine dimaleate (compound 29) mp 138.7-139 0.5 ° C (ethanol) IR (KBr, cm ^-1 ) 2940, 2360, 169
9, 1574, 1516, 1455, 1356, 869

1- [4- (3,4-dimethoxyphenyl) -1-butyl] -4- (5-phenyl-1-pentyl) homopiperazine dimaleate (compound 30)

Example 2 1- [3- (3,4-dimethoxyphenyl) -1-propyl] -4- [3- (4-fluorophenyl) -1-
Propyl] homopiperazine dihydrochloride (Compound 14)

Embedded image 1) Dimethylformamide (20m) of 3- (3,4-dimethoxyphenyl) propyl chloride (Reference compound 1-5, 2.50 g) and homopiperazine (5.83 g)
l) Potassium carbonate (3.49 g) and sodium iodide (3.22 g) were added to the solution, and 50
Stir at C overnight. Water is added to the reaction solution, and extracted with ethyl acetate. The organic layer is concentrated under reduced pressure, 150 ml of a 1N hydrochloric acid-diethyl ether mixture (2: 1) is added to the oily substance, and the mixture is extracted with 1N hydrochloric acid. The aqueous layer is made alkaline with 4N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1- [3- (3,4-dimethoxyphenyl) -1-.
2.51 g (77.4%) of [propyl] homopiperazine are obtained.

IR (Film, cm ^-1 ) 3338, 29
34, 2831, 1607, 1590, 1515

2) 1- [3- (3,4-Dimethoxyphenyl) -1-propyl] homopiperazine (1.00 g)
And potassium carbonate (1.83 g) in a solution of 3- (4-fluorophenyl) propyl chloride (Reference compound 2-1, 1.16 g) in dimethylformamide (10 ml).
And sodium iodide (1.68 g), and the mixture is stirred at 50 ° C. for 5.5 hours under a nitrogen atmosphere. Water is added to the reaction solution, and extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography.

3) The purified oil was dissolved in ethyl acetate, and a 4N hydrogen chloride / ethyl acetate solution (1 ml) was added.
Stir. The precipitated crystals were collected by filtration to give the title compound 0.56.
g (32.0%). The physical properties of the obtained compound were the same as those of the compound 14 obtained in Example 1.

[Formulation Examples] One example of the formulation of the compound of the present invention is shown below.

[0083]

(Tablets) Compound of the present invention 1 mg Lactose 120 mg Crystalline cellulose 38 mg Low substituted hydroxypropyl cellulose 5 mg Hydroxypropyl cellulose 5 mg Magnesium stearate 1 mg Total 170 mg

Compound of the present invention 5 mg Lactose 175 mg Crystalline cellulose 68 mg Low-substituted hydroxypropyl cellulose 10 mg Hydroxypropyl cellulose 10 mg Magnesium stearate 2 mg Total 270 mg

[0086]

[0087]

[0088]

【The invention's effect】

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

References by DeHaven-Hudkins et al. (Eur. J. Phar
macol., 227, 371-378 (1992)) and [ ³ H]
Using (+)-PTZ as a labeled ligand, the affinity for the σ receptor was determined by the following method.

(Experimental method) Preparation of a 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 1 shows the results of Compound 9, Compound 11, Compound 12, Compound 14, Compound 15, and Compound 22 as examples of the experimental results.

[0095]

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

From the results of the above pharmacological tests, the compound of the present invention has a strong affinity for the sigma receptor, and has cerebral nerve functions such as dementia, depression, schizophrenia and anxiety, which are diseases involving the sigma receptor. It has a wide range of pharmaceutical uses as a therapeutic agent for disorders, immune disorders and diseases associated with endocrine disorders, and gastrointestinal ulcers.It also has the effect of improving learning disorders due to cerebrovascular disorders and increasing the amount of acetylcholine in the brain. In view of the above, it has been revealed that it is particularly useful as a therapeutic agent for cranial nerve dysfunction.

──────────────────────────────────────────────────続 き Continuation of the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/55 601 A61K 31/55 601 (56) References JP-A-3-2144 (JP, A) JP-A-5-503517 (JP, A) International Publication 90/13539 (WO, A1) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 243/08 A61K 31/55 CA (STN) REGISTRY (STN)

Claims (11)

(57) [Claims] 1. A compound represented by the following general formula [I] and salts thereof. Embedded image [In the formula, R ¹ represents a hydrogen atom, a halogen atom or a lower alkyl group. R ² and R ³ 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 compound represented by the following general formula [I] and salts thereof. Embedded image [Wherein, R ¹ represents a hydrogen atom or a halogen atom. R
² and R ³ represent the same lower alkoxy group. A and B are the same or different and represent a lower alkylene group. ] 3. A compound represented by the following general formula [I] and salts thereof. Embedded image [Wherein, R ¹ represents a hydrogen atom or a halogen atom. R
² and R ³ represent the same lower alkoxy group at adjacent positions. A and B are the same or different and represent a lower alkylene group. ] 4. A compound represented by the following general formula [II] and salts thereof. Embedded image [In the formula, R ⁴ represents a hydrogen atom or a fluorine atom. A and B are the same or different and represent a lower alkylene group. ] 5. A compound represented by the following general formula [III] and salts thereof. Embedded image Wherein A and B are the same or different and represent a lower alkylene group. ] 6. A compound represented by the following general formula [IV] and salts thereof. Embedded image Wherein A and B are the same or different and represent a lower alkylene group. ] 7. The compound according to claim 4, wherein A is trimethylene or tetramethylene, and B is ethylene or trimethylene. 8. 1- [3- (3,4-Dimethoxyphenyl) -1-propyl] -4- (4-phenyl-1-butyl) homopiperazine and salts thereof. 9. 1- (3,4-dimethoxyphenethyl)
-4- [3- (4-Fluorophenyl) -1-propyl] homopiperazine and salts thereof. 10. A 1- (3,4-dimethoxyphenethyl) -4- (3-phenyl-1-propyl) homopiperazine and salts thereof. 11. A therapeutic agent for cranial nerve dysfunction, comprising the compound according to claim 1 or a salt thereof as an active ingredient.