JPH09165384A - New diphenylpropylpiperazine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new derivative consisting of a specific diphenylpropylpiperazine derivative, having a strong specific affinity to σ- receptors and useful for treating cerebral nerve function disorders, immunopathy, diseases accompanied by endocrine disturbance, gastrointestinal ulcers, etc. SOLUTION: This new diphenylpropylpiperazine derivative is expressed by formula I [R is H, a lower alkyl, a cycloalkyl, a (substituted) phenyl lower alkyl], e.g. 1-butyl-4-(1,3-diphenyl-2-propyl)piperazine dihydrochloride. The compound of formula I has a specifically strong affinity to σ-receptors and is useful as a treating agent for cerebral nerve function disorders such as schizophrenia, dementia, depression and anxiety, diseases accompanied by immunopathy or endocrine disturbance, gastrointestinal ulcers, etc. This compound is obtained by reacting 1,3-diphenyl-2-propylamine of formula II with an amine compound of formula III (X is a halogen, a lower alkanesulfonyloxy).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to σ receptors, particularly σ1
Remedies for cranial nerve dysfunction such as schizophrenia, dementia, depression, anxiety, diseases associated with immune disorders and endocrine disorders, and gastrointestinal ulcers, etc. that have strong specific affinity for receptors The present invention relates to a novel diphenylpropylpiperazine derivative useful as

[0002]

2. Description of the Related Art Various diphenylalkylpiperazine derivatives have been synthesized so far, and many of them are expected to be useful as pharmaceuticals. For example,
Diphenylmethylpiperazine derivatives typified by flunarizine and cinnarizine exhibit antiarrhythmic activity (Japanese Patent Publication No. 46-24024) and specifically activate an enzyme that desaturates highly unsaturated fatty acids. Improvement of fatty acid deficiency and control of platelet aggregation, vasodilation / constriction, bronchodilation / contraction, etc. (JP-A-5-2710)
69), and 1,2-diphenylethylpiperazine derivatives have an analgesic / antitussive action (Japanese Patent Publication No. 61-33827) and a control action of cerebral injury due to anoxia or ischemia (Japanese Patent Laid-Open No. 2-36171). Having, [1- (1,
It has been disclosed that a 2-diphenyl) propyl] piperazine derivative has an analgesic effect (Japanese Patent Laid-Open No. 53-124277). However, the asymmetric carbon is not present in the molecule due to the symmetric phenyl ring 1,3
-Diphenyl-2-propylpiperazine derivative has not been reported yet.

On the other hand, many researches have been conducted on the σ receptor, and compounds having a strong affinity for the σ receptor have been reported to be neuropathy such as schizophrenia, dementia, depression and anxiety.
It is becoming clear that it is useful as a therapeutic agent for diseases associated with immune disorders and endocrine disorders, gastrointestinal ulcers, etc. (J. Pharmacol. Exp. Ther., 255, 1354-1359 (199
0), Eur. J. Biochem., 200, 633-642 (1991)).

Recently, the existence of σ ₁ and σ ₂ as subclasses of σ receptor has been revealed (Trends P
harmacol. Sci., 13 , 85-86 (1992)). And N, N-dipropyl-2- [4-methoxy-3- (2-phenylethoxy) phenyl] -ethylamine, which is a compound known to have a selective affinity for the σ ₁ receptor Hydrochloride (Eur. J. Pharmacol., 251, R1-R2 (199
4)) is useful as a therapeutic agent for schizophrenia (L
ife Sci., 53, PL285-PL290 (1993)) has been reported. In addition, σ ₂ receptors were found in rat myocardium (Eur. J. Pharmacol., 209, 245-248 (1991)), and 75-80% of σ receptors present in rat liver and kidney were σ
₂ Receptor (Eur. J. Pharmacol., 268, 9-18
(1994)) and the like are also reported.

[0005]

As described above, various studies have been conducted on diphenylalkylpiperazine derivatives, but one nitrogen atom on one side of the piperazine ring has
A piperazine derivative having a 3-diphenyl-2-propyl group introduced therein has not been studied yet, and a synthetic study of this compound and a pharmacological action thereof, in particular, a study on an affinity for σ receptor are very interesting subjects. Met.

[0006]

Means for Solving the Problems The present inventors focused their attention on the diphenylalkyl moiety of a diphenylalkylpiperazine derivative, and found that the asymmetric carbon in the molecule represented by the following general formula [I ] And a salt thereof (hereinafter referred to as the compound of the present invention) were synthesized and their pharmacological actions were examined. (+)-Pentazocine (hereinafter, (+) which is a selective ligand for σ ₁ receptor
-PTZ) and 1,3-di (2-tolyl) guanidine (hereinafter referred to as DTG) which is a non-selective ligand for both σ ₁ and σ ₂ receptors, and the compound of the present invention and σ ₁ and As a result of examining the affinity with the σ ₂ receptor,
It has been found that the compounds of the present invention have respective affinities for the σ ₁ and σ ₂ receptors, and in particular have a particularly strong affinity for the σ ₁ receptor.

[0007]

Embedded image

[Wherein R is a hydrogen atom, a lower alkyl group,
It represents a cycloalkyl group or a phenyl lower alkyl group, and the phenyl ring of the phenyl lower alkyl group may be substituted with a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylenedioxy group or a nitro group. same as below. ]

The groups defined above will be described in more detail. The halogen atom means fluorine, chlorine, bromine and iodine. Lower alkyl refers to straight chain or branched alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl, butyl, hexyl, isopropyl, tert.-butyl, (dimethyl) ethyl and the like. Cycloalkyl means cyclic alkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The lower alkoxy refers to a linear or branched alkoxy having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, hexyloxy, isopropoxy, tert.-butoxy and the like. The lower alkylenedioxy is 1 to 6 between two oxygen atoms such as methylenedioxy, ethylenedioxy, (dimethyl) methylenedioxy, (diethyl) methylenedioxy.
Represents an alkylenedioxy in which a linear or branched alkylene having 4 carbon atoms is present.

The salt in the compound of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt.
Examples thereof include sulfate, phosphate, lactate, maleate, fumarate, oxalate and the like. The compound of the present invention may be in the form of a hydrate.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION Preferred examples of the compounds of the present invention include the following.

In the general formula [I], R represents a hydrogen atom, a lower alkyl group, a cycloalkyl group or a phenyl lower alkyl group, and the phenyl ring of the phenyl lower alkyl group is a halogen atom, a lower alkyl group or a lower alkoxy group. A compound which may be substituted.

In the general formula [I], R represents a lower alkyl group, especially a butyl group, a cycloalkyl group, especially a cyclohexyl group, or a phenyl lower alkyl group, especially a phenethyl group, and the phenyl ring of the phenyl lower alkyl group is a halogen atom, especially A compound which may be substituted with a chlorine atom or a lower alkoxy group, particularly a methoxy group, is particularly preferable.

Specific examples of preferred compounds of the present invention include:
1-butyl-4- (1,3-diphenyl-2-propyl) piperazine, that is, 1-butyl-4-dibenzylmethylpiperazine (the following formula [II]), and salts and hydrates thereof can be mentioned.

[0015]

[Chemical 6]

A typical synthetic method of the compound of the present invention is a method represented by the following reaction formulas a) and b).

A)

Embedded image

[In the formula, X represents a halogen atom or a reactive group such as a lower alkanesulfonyloxy group. same as below. ]

The method a) is carried out by 1,3 represented by the formula [III].
-A method for obtaining the compound of the present invention by reacting diphenyl-2-propylamine, that is, dibenzylmethylamine, with a compound represented by the formula [IV] to form a piperazine ring.

B)

Embedded image

The method b) is performed by N, N- represented by the formula [V].
Bis (2-substituted ethyl) (1,3-diphenyl-2-propyl) amine compound, that is, N, N-bis (2-substituted ethyl) dibenzylmethylamine compound, and a primary amine represented by the formula [VI] or This is a method of obtaining a compound of the present invention by reacting with ammonia to form a piperazine ring.

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

In order to examine the usefulness of the compound of the present invention, the affinity of the compound of the present invention for σ ₁ and σ ₂ receptors was examined. The details will be shown in the section of the pharmacological test described later, but it is (+)-P which is a ligand selective for the σ ₁ receptor.
TZ and results of studies using DTG is a non-selective ligands to both receptors sigma ₁ and sigma _2, the present invention compounds exhibit their affinity for sigma ₁ and sigma ₂ receptors, sigma receptors It was clarified that it is useful for a wide range of diseases such as schizophrenia involving the body, dementia, depression, anxiety and other cranial nerve dysfunction, diseases associated with immune disorders and endocrine disorders, and gastrointestinal ulcers. Also, compared to the σ ₂ receptor,
Since it has been found that it has a strong affinity specifically for the σ ₁ receptor, the compound of the present invention has a small effect on the myocardium and the like, and thus the compound of the present invention is effective in treating cranial nerves such as schizophrenia, dementia, depression and anxiety. It is suggested to be particularly useful as a therapeutic agent for dysfunction.

The compound of the present invention can be administered orally or parenterally. Examples of the dosage form include tablets, capsules, granules, powders, injections and the like, and the compound of the present invention can be formulated using a commonly used technique. For example, tablets, capsules, granules, oral agents such as powders, lactose, crystalline cellulose, fillers such as starch, magnesium stearate, lubricants such as talc, binders such as hydroxypropylcellulose polyvinylpyrrolidone, Carboxymethyl cellulose Calcium, low-substituted hydroxypropylmethyl cellulose and other disintegrants,
Hydroxypropyl methylcellulose, macrogol,
A coating agent such as a silicone resin may be used if necessary.

The dose of the compound of the present invention can be appropriately selected depending on the symptoms, age, dosage form, etc., but in the case of an oral preparation, it is usually 0.1-6000 mg, preferably 1-600 mg per day
May be administered once or in several divided doses.

The production examples, formulation examples and pharmacological test results of the compounds of the present invention are shown below, but these examples are for the purpose of better understanding of the present invention and do not limit the scope of the present invention. Absent.

[0027]

【Example】

Production Example Example 1 1-Butyl-4- (1,3-diphenyl-2-propyl) piperazine dihydrochloride (Compound 1-1)

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Sodium iodide (670 mg) was added to a solution of 1,3-diphenyl-2-propylamine hydrochloride (592 mg) and N, N-bis (2-chloroethyl) butylamine hydrochloride (350 mg) in dimethylformamide (20 ml). And anhydrous potassium carbonate (1.24 g)
And the whole is stirred at 60 ° C. for 2 hours. After allowing to cool, water is added to the reaction solution and extraction is performed 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 obtained oily substance is purified by silica gel column chromatography to obtain 1-butyl-4- (1,3-diphenyl-2-propyl) piperazine, to which 4N hydrogen chloride / methanol (4 ml) is added, and the reaction liquid is reduced in pressure. After concentration, 367 mg (60.2 mg) of the title compound (Compound 1-1) was obtained.
%).

Mp 280 ° C. or higher IR (KBr, cm ⁻¹ ) 2993, 2959, 293
1,2336,1456,745,697

By using the same method as in Example 1, the following compounds are obtained.

1-cyclohexyl-4- (1,3-diphenyl-2-propyl) piperazine dihydrochloride (Compound 1-2) mp 280 ° C. or higher IR (KBr, cm ⁻¹ ) 2936, 2251, 145
7,142,1396,1277,744,694

1- (1,3-diphenyl-2-propyl) -4-phenethylpiperazine dihydrochloride (compound 1-
3) mp 280 ° C. or higher IR (KBr, cm ⁻¹ ) 2979, 2361, 145
7, 1379, 1086, 958, 742, 696

1- (3,4-dimethoxyphenethyl)
-4- (1,3-Diphenyl-2-propyl) piperazine dihydrochloride (Compound 1-4) mp 254-256 ° C (decomposition) IR (KBr, cm ^-1 ) 2986, 2360, 151
8, 1455, 1261, 1239, 1028, 74
6,698

1- (1,3-diphenyl-2-propyl) -4-methylpiperazine dihydrochloride (Compound 1-5)

1- (1,3-diphenyl-2-propyl) -4-ethylpiperazine dihydrochloride (Compound 1-6)

1- (1,3-diphenyl-2-propyl) -4-propylpiperazine dihydrochloride (compound 1-
7)

1- (1,3-diphenyl-2-propyl) -4-hexylpiperazine dihydrochloride (compound 1-
8)

1- (1,3-diphenyl-2-propyl) -4-isopropylpiperazine dihydrochloride (Compound 1
-9)

1-tert.-butyl-4- (1,3-diphenyl-2-propyl) piperazine dihydrochloride (compound 1
-10)

1-cyclobutyl-4- (1,3-diphenyl-2-propyl) piperazine dihydrochloride (compound 1
-11)

1-cyclopentyl-4- (1,3-diphenyl-2-propyl) piperazine dihydrochloride (compound 1-12)

1-benzyl-4- (1,3-diphenyl-2-propyl) piperazine dihydrochloride (Compound 1-1
3)

1- (1,3-diphenyl-2-propyl) -4- (3,4-dimethoxybenzyl) piperazine dihydrochloride (Compound 1-14)

1- (1,3-diphenyl-2-propyl) -4- (4-methylphenethyl) piperazine dihydrochloride (Compound 1-15)

1- (1,3-diphenyl-2-propyl) -4- (4-methoxyphenethyl) piperazine dihydrochloride (compound 1-16)

1- (3,5-dimethoxyphenethyl)
-4- (1,3-diphenyl-2-propyl) piperazine dihydrochloride (Compound 1-17)

Example 2 1- (3,4-dichlorophenethyl) -4- (1,3-
Diphenyl-2-propyl) piperazine dihydrochloride (Compound 2-1)

Embedded image

N, N-bis (2-chloroethyl) (1,
3-diphenyl-2-propyl) amine hydrochloride (255
mg) and 2- (3,4-dichlorophenyl) ethylamine (130 mg) in dimethylformamide (15 m
l) To the solution, sodium iodide (205 mg) and anhydrous potassium carbonate (312 mg) were added, and the whole was adjusted to 80-9.
Stir at 0 ° C. for 2 hours. After allowing to cool, water is added to the reaction solution and extraction is performed 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 obtained oil was dissolved in ethanol (20 ml), 6N hydrochloric acid (0.5 ml) was added, and the reaction mixture was concentrated under reduced pressure to give 92 mg (26 mg) of the title compound (Compound 2-1).
%).

Mp 280 ° C. or higher IR (KBr, cm ⁻¹ ) 2983, 2365, 149
7, 1456, 1032, 956, 744, 696

By using the same method as in Example 2, the following compounds are obtained.

1- (1,3-diphenyl-2-propyl) piperazine dihydrochloride (Compound 2-2)

1- (3,4-dichlorobenzyl) -4
-(1,3-Diphenyl-2-propyl) piperazine dihydrochloride (Compound 2-3)

1- (1,3-diphenyl-2-propyl) -4- (4-fluorophenethyl) piperazine dihydrochloride (compound 2-4)

1- (4-chlorophenethyl) -4-
(1,3-Diphenyl-2-propyl) piperazine dihydrochloride (Compound 2-5)

[Formulation Example] General preparation examples of the oral preparation and injection of the compound of the present invention are shown below.

1) Tablet Formulation 1 In 100 mg The compound of the present invention 1 mg Lactose 66.4 mg Corn starch 20 mg Carboxymethyl cellulose calcium 6 mg Hydroxypropyl cellulose 4 mg Magnesium stearate 0.6 mg

A tablet having the above-mentioned formulation is coated with 2 mg of a coating agent (for example, a usual coating agent such as hydroxypropylmethylcellulose, macrogol, silicone resin) to obtain a target coated tablet (the tablet having the following formulation is also available. the same).

Formulation 2 In 100 mg Compound of the present invention 5 mg Lactose 62.4 mg Corn starch 20 mg Carboxymethyl cellulose calcium 6 mg Hydroxypropyl cellulose 4 mg Magnesium stearate 0.6 mg Coating agent 2 mg

Formulation 3 In 100 mg The compound of the present invention 20 mg Lactose 51 mg Corn starch 15 mg Carboxymethyl cellulose calcium 5 mg Hydroxypropyl cellulose 5 mg Magnesium stearate 1 mg Talc 1 mg Coating agent 2 mg

Formulation 4 In 100 mg Compound of the present invention 40 mg Lactose 34 mg Corn starch 10 mg Carboxymethyl cellulose calcium 5 mg Hydroxypropyl cellulose 5 mg Magnesium stearate 2 mg Talc 2 mg Coating agent 2 mg

Formulation 5 In 220 mg Compound of the present invention 100 mg Lactose 67 mg Corn starch 20 mg Carboxymethyl cellulose calcium 10 mg Hydroxypropyl cellulose 10 mg Magnesium stearate 4 mg Talc 4 mg Coating agent 5 mg

2) Capsule Formulation 1 In 150 mg, the compound of the present invention 5 mg Lactose 145 mg

By changing the mixing ratio of the compound of the present invention and lactose, the component amount of the compound of the present invention was 10 mg / capsule,
30mg / capsule, 50mg / capsule, 100mg
/ Capsules were also prepared.

3) Granules Formulation 1 In 100 mg Compound of the present invention 30 mg Mannitol 46.5 mg Polyvinylpyrrolidone K-30 7 mg Eudragit RL 15 mg Triacetin 1.5 mg

Formulation 2 In 130 mg Compound of the present invention 50 mg Lactose 55 mg Potato starch 20 mg Hydroxypropylcellulose 4 mg Talc Trace amount

4) Injectable Formulation 1 In 10 ml The compound of the present invention 10 to 100 mg Sodium chloride 90 mg Sodium hydroxide Suitable amount Sterile purified water Suitable amount

[Pharmacological Test] In order to investigate the usefulness of the compound of the present invention, a report by Leitner et al. (Eur. J. Pharmacol., 259,
65-69 (1994)), using (+)-PTZ which is a selective ligand for σ ₁ receptor and DTG which is a non-selective ligand for both σ ₁ and σ ₂ receptors. , The affinity of the compound of the present invention for σ ₁ and σ ₂ receptors was examined.

(Experimental Method) 1. Preparation of membrane preparation The brain was removed from a Hartley-type guinea pig, and 8 times the brain weight of Tris-hydrochloric acid buffer solution (50 mM, pH 7.7, 0.3) was used.
(2M sucrose is included), crushed with a polytron, homogenized with a homogenizer under ice cooling, and
The supernatant was obtained by centrifugation (1,000 xg) at 10 ° C for 10 minutes.
Ultracentrifuge the supernatant for 20 minutes at 4 ℃ (24,000 × g)
Then, the resulting pellet was mixed with an equal volume of Tris-HCl buffer (5
A membrane preparation was obtained by washing with 0 mM, pH 7.7, the same below) and performing ultracentrifugation again under the above conditions.

2. Affinity for σ ₁ receptor Pre-labeled with ³ H (+)-PTZ (hereinafter [ ³ H]
The specific binding amount of (+)-PTZ) was determined by the following method. [ ³ H] (+)-PTZ (5 nM) dissolved in Tris-hydrochloric acid buffer was added to a membrane preparation (protein amount: about 100 μg) suspended in Tris-hydrochloric acid buffer (test compound: (Not added), and 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, [ ³ H] (+)-PTZ (5
(+)-PTZ (100 μm) which has no radioactivity with nM)
The mixture of M) was added (no test compound was added), and the amount of binding to the membrane preparation was determined using the same method as described 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 membrane preparation (protein amount: 100 μg) and [ ³ H] (+)-PTZ was measured in the presence of the test compound, and the concentration of the test compound was changed to obtain The specific binding amount of [ ³ H] (+)-PTZ obtained was 50%.
The concentration of the test compound to be suppressed (IC ₅₀ ) was determined.

3. Affinity for σ ₂ receptor The specific binding amount of DTG labeled with ³ H in advance (hereinafter referred to as [ ³ H] DTG) was determined by the following method. Membrane preparation suspended in Tris-HCl buffer (protein amount: 100)
[ ³ H] D dissolved in Tris-HCl buffer
TG (5 nM) and (+)-PTZ (200 nM) were added (test compound was not added), and it was made to react at 25 degreeC for 90 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, [ ³ H] DTG (5n) was added to the membrane preparation (protein amount: 100 μg).
M), non-radioactive DTG (100 μM) and (+)-PTZ (200 nM) were added (no test compound was added), and the amount of binding to the membrane preparation was determined using the same method as above, The amount of non-specific binding was used. 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 membrane preparation (protein amount: 100 μg) and [ ³ H] DTG was measured in the presence of the test compound, and the concentration was determined in advance by changing the concentration of the test compound [ ^3. The concentration (IC ₅₀ ) of the test compound at which the specific binding amount of H] DTG was suppressed by 50% was determined.

(Results) Table 1 shows examples of the compound of the present invention.
As a comparatively known compound using compound 1-1, compound 1-2, compound 1-3 and compound 1-4, Japanese Examined Patent Publication No. 49-1
(-)-(R) -1 which is one of the 1,2-diphenylethylpiperpyrazine derivatives disclosed in JP-A-88.
-Cyclohexyl-4- (1,2-diphenylethyl)
The results for piperazine (hereinafter referred to as compound A) are shown.

[0074]

[Table 1]

As shown in Table 1, the compounds of the present invention have σ
It was found to have affinities for the ₁ and σ ₂ receptors, respectively. Moreover, affinity for sigma ₁ receptor of the compounds of the present invention, as compared to that for sigma ₂ receptors 40
It was found that the compound of the present invention had a strong affinity specifically to the σ ₁ receptor, more than twice as strongly.

[0076]

From the results of the above-mentioned pharmacological tests, the compound of the present invention has an affinity for the σ receptor and exhibits cerebral nerve dysfunction such as schizophrenia, dementia, depression and anxiety, and immunological abnormalities. It has been clarified that it has a wide range of pharmaceutical uses as a therapeutic agent for diseases associated with endocrine abnormalities, digestive ulcers and the like. further,
Considering that it has a specifically strong affinity for the σ ₁ receptor as compared with the σ ₂ receptor, it is expected that the compound of the present invention has less effect on myocardium and the like. It is expected to be particularly excellent as a therapeutic agent for cranial nerve dysfunction such as schizophrenia, dementia, depression and anxiety.

Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display location A61K 31/495 ACL A61K 31/495 ACL AED AED C07D 295/06 C07D 295/06 A 295/08 295/08 A

Claims (9)

[Claims] 1. A compound represented by the following general formula [I] and salts thereof. Embedded image [In the formula, R represents a hydrogen atom, a lower alkyl group, a cycloalkyl group or a phenyl lower alkyl group, and the phenyl ring of the phenyl lower alkyl group is a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylenediene group It may be substituted with an oxy group or a nitro group. ] 2. A compound represented by the following general formula [I] and salts thereof. Embedded image [In the formula, R represents a hydrogen atom, a lower alkyl group, a cycloalkyl group or a phenyl lower alkyl group, and the phenyl ring of the phenyl lower alkyl group may be substituted with a halogen atom, a lower alkyl group or a lower alkoxy group. . ] 3. A compound represented by the following general formula [I] and salts thereof. Embedded image [In the formula, R represents a lower alkyl group, a cycloalkyl group or a phenyl lower alkyl group, and the phenyl ring of the phenyl lower alkyl group may be substituted with a halogen atom or a lower alkoxy group. ] 4. The compound according to claim 3, wherein R represents a butyl group, a cyclohexyl group, a phenethyl group, a dichlorophenethyl group or a dimethoxyphenethyl group, and salts thereof. 5. A compound represented by the following general formula [I] and salts thereof. Embedded image [In the formula, R represents a lower alkyl group. ] 6. 1-Butyl-4- (1,3-diphenyl-2-propyl) piperazine and salts thereof. 7. A therapeutic agent comprising the compound according to any one of claims 1 to 6 or a salt thereof as an active ingredient for a cranial nerve dysfunction, a disease associated with an immune abnormality or an endocrine abnormality, and a disease selected from gastrointestinal ulcers. 8. A therapeutic agent for cerebral nerve dysfunction, which comprises the compound according to any one of claims 1 to 6 or a salt thereof as an active ingredient. 9. A therapeutic agent for schizophrenia, which comprises the compound according to any one of claims 1 to 6 or a salt thereof as an active ingredient.