JPH0859632A - Novel 1,4- (diphenylalkyl) homopiperazine derivative - Google Patents

Abstract

(57) [Summary] [Structure] [Chemical Formula 1] [In the formula, R ¹ represents a hydrogen atom, a halogen atom or lower alkyl, R ² and R ³ represent the same or different lower alkoxy, and A and B represent the same or different lower alkylene. ] The compound shown by these, or its salt. [Effects] The compound of the present invention has an affinity for the σ receptor and is associated with cranial nerve dysfunction such as dementia, depression, schizophrenia and anxiety, diseases associated with immune disorders and endocrine disorders, gastrointestinal ulcers, etc. It is useful as a therapeutic agent for

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention has an affinity for the σ receptor and is associated with cerebral nerve dysfunction such as dementia, depression, schizophrenia and anxiety, and diseases associated with immune disorders and endocrine disorders.
The present invention relates to a novel 1,4- (diphenylalkyl) homopiperazine derivative useful as a therapeutic agent for digestive ulcers and the like.

[0002]

2. Description of the Related Art Recently, many studies have been conducted on the σ receptor, and compounds having a strong affinity for the σ receptor have been reported to be associated with cerebral nerve dysfunction such as dementia, depression, schizophrenia and anxiety, immune abnormality and endocrine abnormality. It is becoming clear that it is useful as a therapeutic agent for diseases such as caries disease and digestive system ulcer (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 an affinity for σ receptors (WO91 / 09594). However, the effect of substituting the piperazine ring with a homopiperazine ring on the affinity for the σ receptor has not been studied.

Further, it has been reported that a 1,4- (diphenylalkyl) homopiperazine derivative protects the brain from ischemia or hypoxia, and improves cerebral dysfunction or prevents the progression of the dysfunction (Japanese Patent Laid-Open No. 3-539). -2144). However, only the compound in which three trimethoxy groups are introduced into both of the two phenyl rings is specifically shown in this report, and regarding the compound in which two alkoxy groups are introduced into one phenyl ring, No disclosure is made. Of course, this reference does not report the affinity for the σ receptor.

[0005]

The substitution of the piperazine ring of a 1,4- (diphenylalkyl) piperazine derivative with a homopiperazine ring will change the affinity for the σ receptor, especially the alkoxy group on the phenyl ring. The compound into which two of these are introduced has not been studied yet, and the research on the synthesis and the pharmacological action of this compound was a very interesting subject.

[0006]

The present inventors have found that 1,4-
By replacing the piperazine ring of the (diphenylalkyl) piperazine derivative with a homopiperazine ring, and further focusing on the phenyl ring, a novel 1,4- (diphenylalkyl) homopiperazine derivative with two alkoxy groups introduced was synthesized and its pharmacology. The effect was examined.

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

[Chemical 7] [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 each represents a lower alkoxy group. A and B are the same or different and each represents a lower alkylene group. ] More specifically explaining the above definition, the halogen atom represents fluorine, chlorine, bromine and iodine, and the lower alkyl is 1 to 6 such as methyl, ethyl, propyl, hexyl, isopropyl and tert.-butyl. Represents a linear or branched alkyl having a carbon atom of, and lower alkoxy is
A straight-chain or branched alkoxy having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, hexyloxy, isopropoxy, and tert.-butoxy is shown, and lower alkylene is methylene, ethylene, trimethylene, tetramethylene. , Pentamethylene, hexamethylene, (dimethyl) methylene, (diethyl) methylene and the like, which represent a straight chain or branched alkylene having 1 to 6 carbon atoms.

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

Among the compounds of the present invention, preferred examples of R ¹ are hydrogen atom or halogen atom, R ² and R
Examples thereof include compounds having a lower alkoxy group in which ³ are the same. More preferable example is that 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, examples of compounds having particularly excellent action include 1- [3- (3,4-dimethoxyphenyl) -1-propyl] -4- (4-phenyl-1).
-Butyl) homopiperazine, 1- (3,4-dimethoxyphenethyl) -4- [3- (4-fluorophenyl)-
Examples thereof include 1-propyl] homopiperazine and 1- (3,4-dimethoxyphenethyl) -4- (3-phenyl-1-propyl) homopiperazine, and respective salts thereof.

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, the order of introducing the phenylalkyl groups is not limited. Typical synthetic methods for the compound of the present invention include the following a) and b).

A)

Embedded image [In the formula, X ¹ and X ² represent a halogen atom. ] B)

[Chemical 9] [In the formula, X ¹ and X ² represent a halogen atom. The method of a) is carried out by first reacting the compound of formula [V] with homopiperazine (formula [VI]) to give a compound of formula [VII], which is then reacted with a compound of formula [VIII]. Then, the compound [I] of the present invention is obtained.

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

The compound obtained by the above method can be converted into the salts as 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. The details will be described in the section of the pharmacological test described later. As a result of examining the affinity with the σ receptor using [ ³ H] (+)-PTZ as a labeled ligand, the compound of the present invention has σ
It was found to have a strong affinity for the receptor.

Further, a learning disorder model by scopolamine known as a disease model of dementia due to cerebrovascular disorder, that is, the method of Starter et al. (Psychopharmacolo)
gy, 107, 144-159 (1992)), the compound of the present invention had an improving effect on learning disability.

A compound that increases the amount of acetylcholine in the brain is reported to be useful as a therapeutic agent for dementia and the like (New Engl. J. Med., 315 , 1241-1245 (198).
6)), the literature of Matsuno et al. (Brain Res., 575, 3
15-319 (1992)), the amount of acetylcholine in rat brain was measured, and the compounds of the present invention showed an action of increasing acetylcholine.

From the results of the above-mentioned pharmacological tests, the compounds of the present invention have a strong affinity for the σ receptor, and are diseases associated with the σ receptor, such as dementia, depression, schizophrenia and anxiety. It has a wide range of medicinal uses as a therapeutic agent for cranial nerve dysfunction, diseases associated with immune disorders and endocrine disorders, and gastrointestinal ulcers. Furthermore, it has an improving action on learning disorders due to cerebrovascular disorders and an increasing action on the amount of acetylcholine in brain. Therefore, 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, and examples of dosage forms include tablets, capsules, soft capsules, granules, injections, etc. It can be formulated using known techniques. For example, oral preparations such as tablets, capsules, soft capsules and granules may be supplemented with lactose, starch, crystalline cellulose, extenders such as vegetable oil, lubricants such as magnesium stearate and talc, hydroxypropyl, etc. Formulated using binders such as cellulose, polyvinylpyrrolidone, etc., low-substituted hydroxypropylcellulose, disintegrators such as calcium carboxymethylcellulose, coating agents such as hydroxypropylmethylcellulose, macrogol, silicone resin, and film agents such as gelatin film. be able to. The dose is appropriately selected depending on the symptoms, dosage form, etc., but usually 1 mg to 1000 mg, preferably 1 mg to 200 mg may be administered once or in several divided doses per day.

[0022]

【Example】

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

[Chemical 10] 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 the mixture is extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, 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%) is obtained.

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

By the same procedure 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)

[Chemical 11] 1) Lithium aluminum hydride (6.
85 g) in diethyl ether (300 ml) suspension,
Under ice cooling, 4-fluorocinnamic acid (10.00 g) in tetrahydrofuran (100 ml) -diethyl ether (3
0 ml) of the mixed solution is added dropwise with stirring, and the mixture is heated under reflux for 5 hours. The reaction solution was cooled with ice-sodium chloride, and 1
Add N hydrochloric acid and extract with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 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-
Chloroform (65m) of propanol (9.28g)
l) Thionyl chloride (6.59 ml) was added dropwise to the solution while cooling with ice, and the mixture was heated under reflux for 3 hours. The reaction mixture is concentrated under reduced pressure, water is added to the obtained oily substance, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography to give the title compound (reference compound 2-1) 7.68.
g (73.9%) are obtained.

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

By the same procedure 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)

[Chemical 12] 1) Potassium cyanide (1.04 g) and 18-crown-6 (0.02 g) were added to a solution of 3- (4-fluorophenyl) propyl chloride (Reference compound 2-1, 1.73 g) in acetonitrile (18 ml), 1.5
Heat to reflux for hours. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 4- (4-fluorophenyl) butyronitrile.

2) To a solution of 4- (4-fluorophenyl) butyronitrile (1.14 g) in ethanol (35 ml) was added 6N sodium hydroxide (11.9 ml), and the mixture was heated under reflux for 5 hours. The reaction solution is concentrated under reduced pressure, water is added to the obtained oily matter, and the aqueous layer is washed with diethyl ether. The aqueous layer is acidified with 6N hydrochloric acid and extracted with ethyl acetate.
The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 4- (4-fluorophenyl) butyric acid.

3) Diethyl ether (10 ml) of lithium aluminum hydride (0.42 g) under a nitrogen atmosphere.
4- (4-fluorophenyl) butyric acid (0.9
1 g) of tetrahydrofuran (10 ml) -diethyl ether (3 ml) mixed solution 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 brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4- (4-fluorophenyl) -1-butanol.

4) 4- (4-fluorophenyl) -1-
Butanol (0.50g) in chloroform (3.5m
l) Thionyl chloride (0.26 ml) was added dropwise to the solution while cooling with ice, and the mixture was heated under reflux for 3 hours. The reaction mixture is concentrated under reduced pressure, water is added to the obtained oily substance, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (reference compound 3-1).

By the same procedure as in Reference Example 3, the following compound is obtained.

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

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

[Chemical 13] 1) To a solution of homopiperazine (13.53 g) in dimethylformamide (60 ml), sodium iodide (7.4
7 g) and potassium carbonate (8.10 g) are added and stirred. A dimethylformamide (40 ml) solution of phenethyl bromide (6.78 ml) was added dropwise to the reaction solution, and the mixture was further stirred at 50 ° C. for 4 hours. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 7.81 g (77.0%) of N-phenethylhomopiperazine.

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

2) N-phenethylhomopiperazine (2.
00 g) in dimethylformamide (30 ml),
Add potassium carbonate (2.71 g) and sodium iodide (2.93 g) and stir. 3,4-dimethoxybenzyl chloride (reference compounds 1-3, 2.1) was added to the reaction solution.
A solution of 9 g) in dimethylformamide (5 ml) is added dropwise, and the mixture is stirred at 50 ° C. for 5 hours. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting oily substance was mixed with a 1N hydrochloric acid-diethyl ether mixed solution (2: 1) 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 saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily substance obtained was purified by silica gel column chromatography, and 1.88 g of 1- (3,4-dimethoxybenzyl) -4-phenethylhomopiperazine (5
4.4%).

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

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

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

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

1- (3,4-dimethoxyphenethyl)
-4-phenethyl homopiperazine dihydrochloride (Compound 2) mp 225 to 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 to 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 ~ 224 ° 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 (decomposition) ) (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
Four

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) 3- (3,4-dimethoxyphenyl) propyl chloride (reference compound 1-5, 2.50 g) and homopiperazine (5.83 g) in dimethylformamide (20 m
1) To the solution, potassium carbonate (3.49 g) and sodium iodide (3.22 g) were added, and the mixture was added under a nitrogen atmosphere at 50%.
Stir overnight at ° C. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is concentrated under reduced pressure, 150 ml of a 1N hydrochloric acid-diethyl ether mixed solution (2: 1) is added to the oily matter, 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 brine, 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 a solution of 3- (4-fluorophenyl) propyl chloride (Reference compound 2-1, 1.16 g) in dimethylformamide (10 ml) was added with potassium carbonate (1.83 g).
And sodium iodide (1.68 g) are added, and the mixture is stirred at 50 ° C. for 5.5 hours under a nitrogen atmosphere. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily substance obtained is purified by silica gel column chromatography.

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

[Formulation Example] An example of the formulation of the compound of the present invention is shown below.

[0083]

(Tablet) 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

The 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 the affinity for the σ receptor was conducted.

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

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

Hartley guinea pig (weight 300-40
(0 g), the brain was removed, homogenized in Tris-hydrochloric acid buffer solution (50 mM, pH 7.7, containing 0.32 M sucrose) in an amount 8 times the brain weight, and then centrifuged to obtain a supernatant.
The pellet obtained by subjecting the supernatant to ultracentrifugation for 20 minutes was suspended in a Tris-hydrochloric acid buffer solution (50 mM, pH 7.7, the same applies hereinafter) and centrifuged again to obtain a membrane preparation.

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

Next, the binding amount of the [ ³ H] (+)-PTZ with the membrane preparation was measured in the presence of the test compound, and the concentration of the test compound was varied to obtain the previously determined [ 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 an example of the experimental results.

[0095]

[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 -PTZ was significantly inhibited at a low concentration, and the compound of the present invention was found to have a strong affinity for the σ receptor.

From the results of the above-mentioned pharmacological tests, the compound of the present invention has a strong affinity for the σ receptor, and cranial nerve functions such as dementia, depression, schizophrenia and anxiety, which are diseases related to the σ receptor. It has a wide range of medicinal use as a therapeutic agent for disorders, diseases associated with immune disorders and endocrine disorders, and gastrointestinal ulcers. When considered together, it became clear that it is particularly useful as a therapeutic agent for cranial nerve dysfunction.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display area A61K 31/55 ACL

Claims (11)

[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 each represents a lower alkoxy group. A and B are the same or different and each represents a lower alkylene group. ] 2. A compound represented by the following general formula [I] and salts thereof. Embedded image [In the formula, 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 each represents a lower alkylene group. ] 3. A compound represented by the following general formula [I] and salts thereof. [Chemical 3] [In the formula, R ¹ represents a hydrogen atom or a halogen atom. R
² and R ³ represent the same lower alkoxy group in adjacent positions. A and B are the same or different and each represents a lower alkylene group. ] 4. A compound represented by the following general formula [II] and salts thereof. [Chemical 4] [In the formula, R ⁴ represents a hydrogen atom or a fluorine atom. A and B are the same or different and each represents a lower alkylene group. ] 5. A compound represented by the following general formula [III] and salts thereof. [Chemical 5] [In the formula, A and B are the same or different and each represents a lower alkylene group. ] 6. A compound represented by the following general formula [IV] and salts thereof. [Chemical 6] [In the formula, A and B are the same or different and each represents a lower alkylene group. ] 7. The compound according to claim 4, wherein A is trimethylene or tetramethylene, and B is ethylene or trimethylene, and salts thereof. 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. 1- (3,4-Dimethoxyphenethyl) -4- (3-phenyl-1-propyl) homopiperazine and salts thereof. 11. A therapeutic agent for cranial nerve dysfunction, which comprises the compound according to claim 1 or a salt thereof as an active ingredient.