JP3421702B2 - Sigma receptor antagonist - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a sigma receptor antagonist containing a phenylalkylamine derivative as an active ingredient.

[0002]

2. Description of the Related Art Antipsychotics are used not only for the treatment of schizophrenia but also for the treatment of problematic behaviors (aggressive behavior, mental agitation, loitering, delirium, etc.) in cerebrovascular disorders and senile dementia. However, conventional antipsychotics have a strong side effect of extrapyramidal disorders, which is a big problem. In order to solve this problem, the development of antipsychotic drugs in recent years is approached from a completely different aspect from the mechanism of action of conventional drugs. One of them is a sigma receptor antagonist. The sigma receptor is considered to be a receptor involved in psychological abnormalities such as hallucinations and delusions, and a compound having a specific affinity for this receptor exhibits an anti-schizophrenic action without causing extrapyramidal disorders.

The sigma receptor antagonist is a sigma receptor biological research, schizophrenia treatment, problem behavior in cerebrovascular disorder / senile dementia, neurodegenerative disease Huntington's disease, Parkinson's disease, Zilderat It has been suggested that it is effective for movement disorders such as myotonia and late onset dyskinesia seen in Rett's disease and the like (Walker,
J. M. et al, Pharmacological
Reviews, Vol. 42, p. 355, 1990.
Year). As a compound of this type, for example, rimcazole is known, but although its affinity and specificity for sigma receptors are not sufficient,
Shows some effect in clinical trials (Snyde
r, S. H. et al, J .; Neurosychi
Atry, Vol. 1, p. 7, 1989), it has been revealed in animal tests that hallucinatory symptoms or cognitive dysfunction are improved (PCT. WO91 / 03243).
Thus, sigma receptors are considered to be involved in mental disorders, cognitive disorders and their associated motor functions, and compounds with a specific affinity for this receptor treat psychiatric disorders without causing extrapyramidal disorders. Shows the action.

Furthermore, animal experiments have shown that sigma receptor antagonists are effective for memory impairment (Early et al.,
Brain Research, Volume 546, Volume 281
P., 1991), affecting the acetylcholine nervous system (Matsuno et al., Brain.
Research, vol. 575, p. 315, 1992.
Year; Junien et al. , Eur. J. Pha
rm. , Vol. 200, p. 343, 1991), and there is a very high possibility that it can be an effective drug for diseases such as Alzheimer's disease, cerebrovascular disorder and senile dementia. It has also been suggested that it is useful as an anxiolytic or antidepressant (PCT. WO90 / 1406).
7).

On the other hand, sigma receptor antagonists have the effect of indirectly modifying the function of the NMDA receptor in the brain in animal tests, and of protecting neuronal cell death during cerebral ischemia ( Rao, TS et al, Molcu.
lar Pharmacology, Volume 37, 97
It is also useful as a therapeutic drug for cerebrovascular disorders from page 8 (1990).

As described above, sigma receptor antagonists are useful for schizophrenia, problematic behavior in cerebrovascular disorders / senile dementia, anxiety, depression, neurodegenerative cognitive and motor dysfunction, and cerebrovascular disorders. A therapeutic effect such as nerve cell death is expected.

[0007]

SUMMARY OF THE INVENTION An object of the present invention is to provide a sigma receptor antagonist having excellent affinity and specificity.

[0008]

Means for Solving the Problems The inventors of the present invention have made extensive studies in view of the above objects, and as a result, have found that the newly synthesized phenylalkylamine derivative has an excellent sigma receptor antagonistic effect, and completed the present invention. .

The present invention provides the formula [I]

[0010]

[Chemical 2]

(Wherein X ¹ represents a halogen atom, a hydroxyl group or an alkoxy group having 1 to 5 carbon atoms, X ² represents a hydrogen atom, a halogen atom or an alkoxy group having 1 to 5 carbon atoms, and R ¹ Or R ² are the same or different and each represents an alkyl group having 1 to 7 carbon atoms, and m and n are the same or different and each represents an integer of 2 to 5) or a pharmaceutically acceptable derivative thereof. It is a sigma receptor antagonist having an acceptable salt as an active ingredient.

In the present invention, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The alkoxy group is a linear or branched alkoxy group having 1 to 5 carbon atoms, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a tert-butoxy group, a pentoxy group. Base,
Examples include an isopentoxy group. Of these, a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group is preferable, and a methoxy group is more preferable. The alkyl group is a chain or branched alkyl group having 1 to 7 carbon atoms, and examples thereof include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, pentyl group, isopentyl group, hexyl group. Group, isohexyl group, heptyl group, isoheptyl group and the like. Of these, a methyl group, an ethyl group, a propyl group, an isopropyl group or a butyl group is preferable, and a propyl group is more preferable.

The pharmaceutically acceptable salt of the compound of the formula [I] is, for example, a salt with a mineral acid such as sulfuric acid, hydrochloric acid or phosphoric acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid. It is a salt with an acid, an organic acid such as trifluoroacetic acid and methanesulfonic acid, and is preferably a salt with hydrochloric acid or oxalic acid.

Preferred compounds according to the present invention have the formula [I]
In, X ¹ is an alkoxy group having 1 to 3 carbon atoms, X ² is a hydrogen atom, R ¹ and R ² are alkyl groups having 1 to 4 carbon atoms, and m and n are 2 or 3. A phenylalkylamine derivative according to claim 1 or a pharmaceutically acceptable salt thereof, and specific examples of these are as follows.

N, N-di-n-propyl-2- [4-methoxy-3- (2-phenylethoxy) phenyl] ethylamine oxalate N, N-di-n-propyl-3- [4- Methoxy-3-
(2-Phenylethoxy) phenyl] propylamine
Oxalate N, N-di-n-propyl-2- [4-methoxy-3-
(3-Phenylpropoxy) phenyl] ethylamine
Oxalate N, N-di-n-propyl-2- [4-hydroxy-3
-(2-Phenylethoxy) phenyl] ethylamine
Hydrochloride N, N-di-n-propyl-2- [4-methoxy-3-
[2- (4-fluorophenyl) ethoxy] phenyl]
Ethylamine hydrochloride N, N-di-n-propyl-2- [4-methoxy-3-
[2- (3-Chlorophenyl) ethoxy] phenyl] ethylamine oxalate N, N-di-n-propyl-2- [4-methoxy-3-
[2- (4-methoxyphenyl) ethoxy] phenyl]
Ethylamine oxalate N, N-di-n-propyl-2- [3-methoxy-4-
(2-Phenylethoxy) phenyl] ethylamine oxalate N, N-di-n-propyl-2- [3-methoxy-2-
(2-Phenylethoxy) phenyl] ethylamine oxalate N, N-di-n-propyl-3- [3-methoxy-2-
(2-Phenylethoxy) phenyl] propylamine
Oxalate N, N-di-n-propyl-2- [3-methoxy-2-
(3-Phenylpropoxy) phenyl] ethylamine
Oxalate N, N-di-n-propyl-2- [5-methoxy-2-
(2-Phenylethoxy) phenyl] ethylamine hydrochloride N, N-di-n-propyl-2- [4-methoxy-2-
(2-Phenylethoxy) phenyl] ethylamine oxalate N, N-di-n-propyl-2- [2-methoxy-4-]
(2-Phenylethoxy) phenyl] ethylamine oxalate.

The compound of the formula [I] can be produced by the method shown below (wherein R ³ is an alkyl group having 1 to 5 carbon atoms and R ⁴ is 1 carbon atom). ~ 7 is a linear or branched alkyl group, X ³
Is an arbitrary halogen atom, Y is a hydrogen atom or an alkoxy group having 1 to 5 carbon atoms, and R ¹ , R ² , X ¹ ,
X ² , m and n are as defined above. ).

[Route 1]

[0018]

[Chemical 3]

Step a: Hydroxybenzaldehyde of formula (1) or hydroxybenzoate and halide of formula (2) in the presence or absence of a phase transfer catalyst and in the presence of a base in a solvent inert to the reaction. By reacting, a compound of formula (3) is obtained. The phase transfer catalyst used in this reaction is a quaternary ammonium salt such as benzyltriethylammonium chloride, tetrabutylammonium bromide and trioctylmethylammonium chloride. The base is an inorganic base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, potassium fluoride or sodium hydride or an organic base such as triethylamine or pyridine. The solvent inert to the reaction is an organic solvent such as N, N-dimethylformaldehyde, acetonitrile, dichloromethane, chloroform, tetrahydrofuran, benzene, toluene, methanol, ethanol or a mixed solvent of these organic solvents and water. The reaction is stirred at room temperature to 150 ° C. for 3 to 48 hours, preferably at room temperature to 70 ° C. for 5 to 24 hours.

Step b: The aldehyde or ester of (3) is reduced with a reducing agent in a solvent inert to the reaction and then halogenated with a halogenating agent to obtain a compound of formula (4). Solvents that can be used for the reduction are tetrahydrofuran, diethyl ether, benzene, toluene, methanol, ethanol, etc., and the reducing agent is an aluminum-based reducing agent such as lithium aluminum hydride or a boron-based reduction such as sodium borohydride. An agent or the like is used. This reaction is carried out at 0 to 100 ° C with stirring for 1 to 10 hours, preferably at 0 ° C to room temperature with stirring for 1 to 5 hours.

As the halogenating agent in the halogenation, thionyl chloride, phosphorus oxychloride, phosphorus oxybromide,
Phosphorus pentachloride, concentrated hydrochloric acid, hydrobromic acetic acid solution, hydroiodic acid, etc. are used, and the solvent is solvent-free, or dichloromethane, tetrahydrofuran, benzene, toluene, N, N-dimethylformamide, hexamethylphosphine. A single solvent or a mixed solvent such as folic triamide is used. This reaction is carried out at 0 to 130 ° C. with stirring for 1 to 24 hours, preferably at room temperature to 100 ° C. with stirring for 2 to 10 hours.

Step c: The halide of formula (4) can be converted to a carboxylic acid of formula (5) by cyanation and subsequent hydrolysis. In the cyanation of this step, potassium cyanide, sodium cyanide or copper cyanide is used as a cyanating agent without catalyst or in the presence of a catalyst. Here, the catalyst is a phase transfer catalyst such as crown ethers such as 18-crown-6, tetrabutylammonium bromide, trioctylmethylammonium chloride and benzyltriethylammonium chloride. As the solvent, acetonitrile, benzene,
Toluene, chloroform, dichloromethane, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, acetone, methyl ethyl ketone and the like are used alone or as a mixed solvent with water. The reaction is carried out at room temperature to 150 ° C. with stirring for 3 to 24 hours.

The hydrolysis is carried out with a base such as sodium hydroxide, potassium hydroxide or calcium hydroxide, or an acid such as hydrochloric acid, sulfuric acid or acetic acid. Solvents used here are alcohols such as ethanol, dioxane,
Ethers such as 1,2-dimethoxyethane, N, N-
It is a mixture of water with an organic solvent such as dimethylformamide. The reaction is carried out under reflux with stirring for 5 to 24 hours.

Step d: Next, the carboxylic acid of the formula (5) is used as a mixed acid anhydride or an acid halide to activate the carboxyl group, and then the amine of the formula (6) is reacted to amidate, It can be reduced to give compounds of formula (7) according to the invention.

In order to use the compound of the formula (5) as a mixed acid anhydride in the above, the compound of the formula (5) and ethyl chlorocarbonate, isobutyl chlorocarbonate, in the presence of a base (triethylamine, N-methylmorpholine, etc.), React with acetic anhydride, acetic acid chloride, etc. in a solvent. The solvent used here is tetrahydrofuran, dichloromethane, N, N
-Dimethylformamide, toluene, benzene and the like. Further, in order to convert the formula (5) into an acid halide, the formula (5)
Compounds such as thionyl chloride, thionyl bromide and the like into benzene, toluene, dichloromethane, chloroform, N, N
-React in a solvent such as dimethylformamide or without solvent.

In the reduction, lithium aluminum hydride, sodium bis (methoxyethoxy) aluminum hydride, borane-tetrahydrofuran complex or the like is used as a reducing agent, and tetrahydrofuran, 1,2 is used as a solvent.
-Dimethoxyethane, toluene and the like are used. The reaction is carried out at 0 to 150 ° C. with stirring for 1 to 24 hours, preferably at room temperature to 80 ° C. with stirring for 2 to 10 hours.

[Route 2]

[0028]

[Chemical 4]

Step e: The carboxylic acid of the formula (5) obtained in Route 1 can be reduced with a reducing agent and then the halide of the formula (8) can be obtained in the same manner as the halogenation of the step b. Here, the reducing agent is lithium aluminum hydride, sodium bis (methoxyethoxy) aluminum hydride,
Borane / tetrahydrofuran complex is used, and the solvent is tetrahydrofuran, 1,2-dimethoxyethane, ether, toluene, benzene, or the like. The reaction is 0
It is performed by stirring at ~ 70 ° C for 1 to 8 hours.

Step f: The halide of formula (8) is reacted with the amine of formula (6) in the presence of a base to give a compound of formula (7)
The compound according to the present invention can be obtained. As the base in this reaction, inorganic bases such as sodium carbonate and potassium carbonate, tertiary amines such as triethylamine, diisopropylethylamine, N-methylmorpholine and N, N-dimethylaniline, amines of the formula (6) and the like are used, As the solvent, acetonitrile, methanol, ethanol, isopropanol, toluene, benzene, tetrahydrofuran, dioxane, N, N-dimethylformamide and the like are used. The reaction is 5 to 50 ° C to 150 ° C.
The stirring is performed for 48 hours, preferably at 50 to 100 ° C. for 8 to 48 hours.

Hereinafter, the halide of the formula (8) is repeatedly subjected to the cyanation and hydrolysis of step c, the reduction and the halogenation of step e, and the obtained halide is reacted with an amine in the same manner as in step f. Sequential carbon number (formula [I]
It is possible to obtain compounds of the invention of the formula [I] in which the number of n in is extended.

[Route 3]

[0033]

[Chemical 5]

Step g: The cinnamic acid ester compound of formula (9) can be obtained by reacting the aldehyde of formula (3) (Y = H) obtained in Route 1 with phosphorus ylide. The phosphorus ylide used here is diethylphosphonoacetate ethyl anion, triphenylphosphoranilidene methyl acetate and the like. Tetrahydrofuran, 1,2-dimethoxyethane, dichloromethane, chloroform, benzene, toluene, N, N-dimethylformamide and the like are used as the reaction solvent. The reaction is carried out at −78 to 100 ° C. with stirring for 1 to 24 hours, preferably −30 to 50.
It is carried out by stirring at ℃ for 2 to 15 hours.

Step h: The cinnamic acid ester compound of formula (9) reduces the double bond and hydrolyzes the ester to give the compound of formula (1)
It is led to the carboxylic acid of 0). Here, reduction means hydrogenation, palladium / carbon, platinum or the like is used as a catalyst, and solvent is ethyl acetate, benzene, toluene,
Examples include methanol, ethanol and dichloromethane.
The reaction is carried out at 0 to 60 ° C. with stirring for 1 to 24 hours, preferably at room temperature for 1 to 10 hours with stirring.

The hydrolysis is carried out using sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, hydrochloric acid, sulfuric acid, acetic acid, etc. in an organic solvent such as methanol, ethanol, tetrahydrofuran, dioxane or in the organic solvent and water. In a mixed solvent for 1 to 36 hours at room temperature to 10
The stirring is performed at 0 ° C., preferably at room temperature for 2 to 12 hours.

Then, the carboxylic acid of the formula (10) can be converted to the compound of the formula (11) according to the present invention by the same operation as the step d, or the same operation as the steps e and f.

Hereinafter, from the carboxylic acid of the formula (10), a compound in which n in the compound of the formula [I] is an arbitrary integer can be synthesized by sequentially using the steps e, c, d and f. it can.

[Route 4]

[0040]

[Chemical 6]

Step i: The benzyl group can be removed by reducing the benzyloxy compound of formula (12) to obtain the compound of formula (13). Here, the reduction is hydrogenation using palladium / carbon or palladium hydroxide / carbon as a catalyst and a solvent such as ethanol, methanol, ethyl acetate or benzene, and Birch reduction using sodium / liquid ammonia or the like.

Then, the phenol compound of the formula (13) can be converted to the compound of the formula [I] according to the present invention by reacting with the compound of the formula (2) in the same manner as in the step a.

[Route 5]

[0044]

[Chemical 7]

Step j: The nitrile of the formula (14) obtained by the method of the step c is reduced to a primary amine derivative represented by the formula (15). The reduction here is carried out by hydrogenation using palladium / carbon, platinum dioxide or the like as a catalyst and ethanol, ethyl acetate, benzene or the like as a solvent, or lithium aluminum hydride or sodium bis (methoxyethoxy) aluminum hydride as a reducing agent. , Borane / tetrahydrofuran, sodium trifluoroacetyloxyborohydride, etc., and tetrahydrofuran, ether, 1,2-dimethoxyethane, toluene, benzene, etc. are used as the solvent. The reaction is carried out at 0 to 150 ° C. for 1 to 24 hours, preferably at room temperature to 80 ° C. for 2 to 10 hours with stirring.

Step k: The present invention represented by the formula (16) by subsequently reacting the primary amine derivative represented by the formula (15) with a halide represented by the formula R ⁵ -X ³ in the presence of a base. Is led to the compound related to. Here, the base is an organic base such as pyridine, triethylamine or N-methylmorpholine, or an inorganic base such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium hydroxide or sodium hydroxide, The solvent is stirred in a solvent such as dichloromethane, benzene, toluene, tetrahydrofuran, N, N-dimethylformamide, ethanol at 0 to 100 ° C. for 2 hours to 4 days, preferably at room temperature for 1 to 2 days.

[0047]

INDUSTRIAL APPLICABILITY The compound of the formula [I] according to the present invention has excellent sigma receptor antagonism, and is useful for the treatment of schizophrenia, depression, anxiety and cerebrovascular disorder / problem of old age, and neurodegenerative diseases. It is effective for cognitive and motor dysfunction such as certain Alzheimer's disease, Parkinson's disease, and Huntington's disease.

The method of administering the compound of formula [I] includes parenteral administration and oral administration. The dosage form is an injection for parenteral administration and any one dosage form selected from tablets, granules, powders, capsules, syrups and suspensions for oral administration. Is. These dosage forms can be appropriately selected according to the symptoms and age of the patient and the purpose of treatment. In the preparation of various dosage forms, conventional excipients (eg, crystalline cellulose, starch, lactose, mannitol, etc.), binders (eg,
Hydroxypropyl cellulose, polyvinylpyrrolidone, etc.), lubricants (eg magnesium stearate,
Talc, etc.), a disintegrating agent (eg, carboxymethylcellulose calcium, etc.), etc. can be used, and an ordinary production method (eg, the method defined in the 12th revised Japanese Pharmacopoeia) can be used.

The dose of the phenylalkylamine derivative is 0.01 to 100 mg (at the time of oral administration and parenteral administration) when treating an adult, and this is administered in 2 to 3 divided doses per day. This dose can be appropriately increased or decreased depending on the age, weight and condition of the patient.

The sigma receptor antagonism of the compound of formula [I] will be described below with reference to test examples. Test Example 1 [Receptor binding experiment] Male Wistar rats were used as animals. As a [ ³ H] -labeled ligand, (+) [ ³ H] 3-PPP [3- (3-hydroxyphenyl) -Nn-propylpiperidine] is used as a sigma receptor, and (−) [ ³ H is used as a D ₂ receptor. ] Sulpiride was used respectively. The binding reaction using the [ ³ H] -labeled ligand was carried out by Molecular Pharmacology,
Volume 32, p. 772 (1987), Journa
l of Pharmacy and Pharmac
It was carried out by the following methods (1) and (2) described in LOGY, Vol. 32, p. 820 (1987).

(1) (+) [ ³ H] 3-PPP binding: A membrane preparation obtained from whole rat brain, (+) [ ³ H] 3-PPP and a test drug were added to 50 mM Tris-HCl buffer (pH 8). ．
The reaction was carried out in 0) at 21 ° C. for 90 minutes.

(2) (-) [ ³ H] sulpiride bond: A membrane preparation obtained from rat striatum, (-) [ ³ H] sulpiride and a test drug were added to a 50 mM Tris-HCl buffer (pH 7.
The reaction was carried out in 7) at 37 ° C. for 10 minutes. After completion of each reaction, the mixture was suction-filtered through a glass filter (GF / B), and the radioactivity of the filter paper was measured with a liquid scintillation spectrometer. 10 μM (+) 3-PPP, 10 μM
The binding when reacted in the presence of (−) tiapride was defined as nonspecific binding of (+) [ ³ H] 3-PPP and (−) [ ³ H] sulpiride, respectively, and total binding and nonspecific binding were performed. The difference was defined as the specific binding. An inhibitory curve was obtained by reacting a constant concentration of [ ³ H] -labeled ligand and a test drug with varying concentrations under the conditions of (1) to (2) above, and a test for inhibiting each binding by 50% from this inhibitory curve. The drug concentration (IC ₅₀ ) was determined, and the results are shown in Table 1.

[0053]

[Table 1]

(Note 1) A: N, N-di-n-propyl-2- [5-chloro-2
-(2-Phenylethoxy) phenyl] ethylamine
Oxalate B; N, N-di-n-propyl-3- [5-chloro-2
-(2-Phenylethoxy) phenyl] propylamine oxalate C; N, N-di-n-propyl-4- [5-chloro-2
-(2-phenylethoxy) phenyl] butylamine
Oxalate D; N, N-di-n-propyl-2- [4-chloro-2
-(2-Phenylethoxy) phenyl] ethylamine
Hydrochloride E; N, N-di-n-propyl-2- [5-bromo-2
-(2-Phenylethoxy) phenyl] ethylamine
Oxalate F; N, N-di-n-propyl-3- [5-bromo-2
-(2-Phenylethoxy) phenyl] propylamine oxalate G; N, N-di-n-propyl-2- [5-fluoro-
2- (2-phenylethoxy) phenyl] ethylamine hydrochloride H; N, N-di-n-propyl-2- [3-fluoro-
2- (2-phenylethoxy) phenyl] ethylamine oxalate I; N, N-di-n-propyl-2- [4-methoxy-
3- (2-phenylethoxy) phenyl] ethylamine oxalate J; N, N-di-n-propyl-3- [4-methoxy-
3- (2-Phenylethoxy) phenyl] propylamine oxalate K; N, N-di-n-propyl-2- [4-methoxy-
3- (3-phenylpropoxy) phenyl] ethylamine oxalate L; N, N-di-n-propyl-2- [4-hydroxy-3- (2-phenylethoxy) phenyl] ethylamine hydrochloride M; N, N-di-n-propyl-2- [4-methoxy-
3- [2- (4-fluorophenyl) ethoxy] phenyl] ethylamine hydrochloride N; N, N-di-n-propyl-2- [4-methoxy-
3- [2- (3-chlorophenyl) ethoxy] phenyl] ethylamine oxalate O; N, N-di-n-propyl-2- [4-methoxy-
3- [2- (4-Methoxyphenyl) ethoxy] phenyl] ethylamine oxalate P; N, N-di-n-propyl-2- [3-methoxy-
4- (2-phenylethoxy) phenyl] ethylamine oxalate Q; N, N-di-n-propyl-2- [3-methoxy-
2- (2-Phenylethoxy) phenyl] ethylamine oxalate R; N, N-di-n-propyl-3- [3-methoxy-
2- (2-phenylethoxy) phenyl] propylamine oxalate S; N, N-di-n-propyl-2- [3-methoxy-
2- (3-phenylpropoxy) phenyl] ethylamine oxalate T; N, N-di-n-propyl-2- [5-methoxy-
2- (2-Phenylethoxy) phenyl] ethylamine hydrochloride U; N, N-di-n-propyl-2- [4-methoxy-
2- (2-phenylethoxy) phenyl] ethylamine oxalate V; N, N-di-n-propyl-2- [2-methoxy-
4- (2-phenylethoxy) phenyl] ethylamine oxalate.

(Note 2) The value of rimcazole is Europ
ean Journal of Pharmacolog
y, 155, 345 (1988). The value of D ₂ receptor is [ ³ H].
Values are given for spepilone binding.

Test Example 2 [Study on Antagonism of (+) SKF10047-induced Abnormal Behavior] (1) Drug Dose Compounds I, J and Q according to the present invention were each 0.0
01, 0.01, 0.1 mg / kg was orally administered. The preparation was carried out by dissolving 10 mg of each test drug in 1 ml of dimethylsulfoxide, diluting with physiological saline to 0.1 mg / kg, and further adding 0.01 and 0.001 mg of this solution.
/ Kg was diluted with physiological saline to prepare a preparation (mouse 1
Administer 0.1 ml per 0 g). Compound A according to the present invention
And rimcazole are 0.03, 0.1,
0.3, 1.0, 3.0, 10.0 mg / kg was orally administered. The preparation was suspended in a 5% gum arabic solution.
(+) SKF10047 was orally administered at 30 mg / kg. The preparation was dissolved in physiological saline.

(2) Experimental method As an animal, an ICR male mouse (Charles River Japan) of 4 to 5 weeks old was used. There were 10 animals per group. One transparent animal cage each (vertical x horizontal x
(Height: 24 × 17.5 × 12 cm) and fully acclimated to the environment. 35 minutes after administration of study drug preparation (+)
SKF10047 was administered, and after 10 minutes, the stereotyped behavioral score (described in Table 2) was evaluated every 5 minutes for 40 minutes.
The D ₂₅ value (mg / kg) was determined, and the results are shown in Table 3.

[0058]

[Table 2]

[0059]

[Table 3]

(Note 1) A: N, N-di-n-propyl-2- [5-chloro-2
-(2-Phenylethoxy) phenyl] ethylamine
Oxalate I; N, N-di-n-propyl-2- [4-methoxy-
3- (2-phenylethoxy) phenyl] ethylamine oxalate J; N, N-di-n-propyl-3- [4-methoxy-
3- (2-phenylethoxy) phenyl] propylamine oxalate Q; N, N-di-n-propyl-2- [3-methoxy-
2- (2-Phenylethoxy) phenyl] ethylamine oxalate (Note 2) Rimcazole manufactured by Aldrich was used.

[0061]

EXAMPLES The present invention will be described in detail below with reference to production examples and examples. Production Example 1 Production of 5-bromo-2- (2-phenylethoxy) benzaldehyde 66.02 g of 5-bromosalicylaldehyde was added to N, N-
It was dissolved in 260 ml of dimethylformamide, 113.35 g of anhydrous potassium carbonate and 111.71 ml of (2-bromoethyl) benzene were added, and the mixture was stirred at room temperature for 38 hours. After distilling off the solvent under reduced pressure, ethyl acetate and water were added to the residue for liquid separation,
The organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and recrystallized from isopropanol to obtain 5-bromo-2- (2-phenylethoxy) benzaldehyde (82.62 g). m. p. 79-80 ° C.

The following compounds were obtained in the same manner as above using the corresponding starting materials. 3-Fluoro-2- (2-phenylethoxy) benzaldehyde NMR (CDCl ₃ ) δ (ppm); 3.13 (2
H, t, J = 6.8 Hz), 4.50 (2H, dt, J
= 1.9, 6.8 Hz), 7.06 (1H, m), 7.
21 to 7.37 (6H, m), 7.57 (1H, m),
10.12 (1H, d, J = 0.9Hz) MS m / e; (M ⁺ ) 224.

3-Methoxy-2- (2-phenylethoxy) benzaldehyde NMR (DMSO) δ (ppm); 3.05 (2H,
t, J = 7.5 Hz), 3.87 (3H, s), 4.3
8 (2H, t, J = 7.5 Hz) 7.12 to 7.39 (8H, m), 9.99 (1H,
s) MS m / e; 256 (M ⁺ ).

5-methoxy-2- (2-phenylethoxy) benzaldehyde NMR (CDCl ₃ ) δ (ppm); 3.13 (2
H, t, J = 6.7 Hz), 3.79 (3H, s),
4.26 (2H, t, J = 6.7Hz), 6.91 (1
H, d, J = 9.2 Hz), 7.10 (1H, dd, J
= 3.3, 9.2 Hz), 7.20 to 7.38 (6H,
m), 10.39 (1H, s) MS m / e; 256 (M ⁺ ). 4-methoxy-2- (2-phenylethoxy) benzaldehyde _{NMR (CDCl 3) δ (ppm} ); 3.15 (2
H, t, J = 6.7 Hz), 3.84 (3H, s),
4.26 (2H, t, J = 6.7Hz), 6.41 (1
H, d, J = 2.2 Hz, 6.53 (1H, dd, J
= 2.2,8.7 Hz), 7.21 to 7.38 (5H,
m), 7.80 (1H, d, J = 8.7 Hz), 10.
28 (1H, s) MS m / e; 256 (M ⁺ ).

2-Methoxy-4- (2-phenylethoxy) benzaldehyde NMR (CDCl ₃ ) δ (ppm); 3.12 (2
H, t, J = 7.0 Hz), 3.88 (3H, s),
4.24 (2H, t, J = 7.0Hz), 6.43 (1
H, d, J = 2.2 Hz, 6.53 (1H, dd, J
= 2.2, 8.7 Hz) 7.22 to 7.39 (5H, m), 7.79 (1H,
d, J = 8.7 Hz), 10.28 (1 H, s) MS m / e; 256 (M ⁺ ).

4-Methoxy-3- (2-phenylethoxy) benzaldehyde NMR (CDCl ₃ ) δ (ppm); 3.18 (2
H, t, J = 7.5 Hz), 3.95 (3H, s),
4.28 (2H, t, J = 7.5Hz), 6.96 (1
H, d, J = 8.5 Hz), 7.18 to 7.35 (5
H, m), 7.40 (1H, d, J = 1.5 Hz),
7.45 (1H, dd, J = 1.5, 8.5Hz),
9.83 (1H, s) MS m / e; 256 (M ⁺ ).

3-Methoxy-4- (2-phenylethoxy) benzaldehyde NMR (CDCl ₃ ) δ (ppm); 3.20 (2
H, t, J = 7.5 Hz), 3.94 (3H, s),
4.30 (2H, t, J = 7.5Hz), 6.96 (1
H, d, J = 8.7 Hz), 7.21 to 7.38 (5
H, m), 7.40 to 7.45 (2H, m), 9.86
(1H, s) MS m / e; 256 (M ⁺ ) 4-benzyloxy-3- (2-phenylethoxy) benzaldehyde m.p. p. 71 to 72.5 ° C (recrystallized from isopropyl ether).

Production Example 2 Production of 5-chloro-2- (2-phenylethoxy) benzaldehyde 5 g of 5-chlorosalicylaldehyde was added to acetonitrile 3
Dissolved in 00 ml, potassium fluoride / alumina (neutral)
(2: 3) 41.48 g and (2-bromoethyl) benzene 17.45 ml were added, and the mixture was stirred at room temperature for 63 hours. The potassium fluoride / alumina was removed by suction filtration, and the solvent was distilled off under reduced pressure. The residue is subjected to silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 10: 1).
After purification by, recrystallize from isopropyl ether and
5.58 g of -chloro-2- (2-phenylethoxy) benzaldehyde was obtained. m. p. 73-74 ° C.

Production Example 3 Production of 5-fluoro-2- (2-phenylethoxy) benzyl alcohol 5-fluorosalicylic acid 4.99 g of methanol 30 m
2 ml of concentrated sulfuric acid was added to the 1-solution, and the mixture was heated under reflux for 18 hours.
After cooling the reaction solution with ice, the precipitated crystals were collected by filtration and washed thoroughly with cold methanol. The crystals were dried and then dissolved in 50 ml of N, N-dimethylformamide, 16.54 ml of (2-bromoethyl) benzene and 16.73 g of anhydrous potassium carbonate were added, and the mixture was stirred at room temperature for 1 day. The reaction solution is concentrated under reduced pressure,
The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. 50 ml of the residue is tetrahydrofuran
Lithium aluminum hydride 1.15 under ice cooling
g was added in small portions. Further, after stirring for 1 hour under ice cooling, a saturated aqueous solution of sodium sulfate was added dropwise until the generation of hydrogen disappeared. The precipitated solid was filtered off, the filtrate was evaporated under reduced pressure, and the residue was subjected to silica gel chromatography (developing solvent; n-hexane-acetone = 20: 1 to 10: 1) to give 5-fluoro-2- (2 7.07 g of -phenylethoxy) benzyl alcohol was obtained.

NMR (CDCl ₃ ) δ (ppm);
2.20 (1H, t, J = 6.3Hz, exchangeable w
ith D ₂ O), 3.08 (2H, t, J = 6.8Hz),
4.18 (2H, t, J = 6.8Hz), 4.53 (2
H, d, J = 6.3 Hz), 6.75 (1H, dd, J
= 5.0, 10.0 Hz), 6.83 to 7.00 (2
H, m), 7.19-7.38 (5H, m) MS m / e; 246 (M ⁺ ).

The following compounds were obtained in the same manner as above using the corresponding starting materials. 4-chloro-2- (2-phenylethoxy) benzyl alcohol NMR (CDCl ₃ ) δ (ppm); 2.03 (1
H, t, J = 7.0 Hz, exchangeable with D ₂ O),
3.11 (2H, t, J = 7.0Hz), 4.21 (2
H, t, J = 7.0 Hz), 4.53 (2H, d, J =
7.0 Hz), 6.83 (1H, d, J = 1.5H
z), 6.89 (1H, dd, J = 1.5, 9.5H
z), 7.15 (1H, d, J = 9.5 Hz), 7.2
0-7.40 (5H, m) MS m / e; 264 (M ⁺ +2), 262 (M ⁺ ).

Production Example 4 Production of 5-bromo-2- (2-phenylethoxy) phenylacetic acid A suspension of 0.249 g of lithium aluminum hydride in tetrahydrofuran was stirred under ice cooling while stirring with 5-bromo. 20 ml of a tetrahydrofuran solution containing 1.67 g of 2- (2-phenylethoxy) benzaldehyde was slowly added, and the mixture was further stirred for 2 hours. A saturated sodium sulfate solution was added to the reaction mixture while stirring, and after the generation of gas was completed, the reaction mixture was dried over magnesium sulfate, suction-filtered, and the filtrate was evaporated under reduced pressure. The residue was treated with 10 ml of tetrahydrofuran and hexamethylphosphoric triamide 2
After dissolving in ml, 0.48 ml of thionyl chloride was added, and the mixture was stirred at room temperature for 20 hours. After the solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed successively with water and saturated sodium bicarbonate water, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was dissolved in 15 ml of acetonitrile and potassium cyanide (0.1 ml) was added.
582 g and 18-crown-6-ether 0.123 g
Was added, and the mixture was stirred at room temperature for 18 hours. Ethyl acetate was added to the reaction solution, which was washed successively with water and saturated sodium bicarbonate water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. 30m ethanol on the residue
1 and 10 ml of 6N sodium hydroxide aqueous solution were added, and 5
After heating under reflux for an hour, the solvent was distilled off under reduced pressure. The residue was dissolved in water, washed with ether, acidified with concentrated hydrochloric acid and extracted with ethyl acetate, dried over anhydrous sodium sulfate and the solvent was distilled off to give 5-bromo-2- (2-phenylethoxy) phenylacetic acid 1 0.47 g was obtained.

NMR (DMSO) δ (ppm); 2.
99 (2H, t, J = 7.5Hz), 3.47 (2H,
s), 4.25 (2H, t, J = 7.5Hz), 6.9.
3 (1H, d, J = 10.0 Hz), 7.13 to 7.4
1 (7H, m), 12.20 (1H, brs, exchange
able with D ₂ O) MS m / e; 336 (M ⁺ +2), 274 (M ⁺ ).

The compounds obtained in Production Examples 1 to 2 were used in Production Example 4
The following compound was obtained by treating in the same manner as. 5-chloro-2- (2-phenylethoxy) phenylacetic acid NMR (DMSO) δ (ppm); 2.99 (2H,
t, J = 7.0 Hz), 3.48 (2H, s), 4.1
5 (2H, t, J = 7.0Hz), 6.99 (1H,
d, J = 10.0 Hz), 7.15 to 7.40 (7H,
m), 10.30 (1H, brs, exchangeable with
D ₂ O) MS m / e; 292 (M ⁺ +2), 290 (M ⁺ ).

3-fluoro-2- (2-phenylethoxy) phenylacetic acid m.p. p. 74-75 ° C (crystallization by acidifying an aqueous solution of sodium hydroxide with hydrochloric acid) 3-methoxy-2- (2-phenylethoxy) phenylacetic acid m.p. p. 88-89 ° C (crystallization by acidifying aqueous sodium hydroxide solution) 5-methoxy-2- (2-phenylethoxy) phenylacetic acid m.p. p. 56.5-57.5 ° C (crystallization by acidifying aqueous sodium hydroxide solution with hydrochloric acid) 4-methoxy-2- (2-phenylethoxy) phenylacetic acid m.p. p. 107-108 ° C (crystallization by acidifying aqueous sodium hydroxide solution) 2-methoxy-4- (2-phenylethoxy) phenylacetic acid NMR (CDCl ₃ ) δ (ppm); 3.10 (2
H, t, J = 6.8 Hz), 3.59 (2H, s),
3.79 (3H, s), 4.17 (2H, t, J = 6.
8 Hz), 6.42 to 6.47 (2H, m), 7.06
(1H, d, J = 9.5 Hz), 7.18 to 7.37
(5H, m), MS m / e; 286 (M ⁺ ) 4-methoxy-3- (2-phenylethoxy) phenylacetic acid m.p. p. 88-89 ° C (crystallization by acidifying aqueous sodium hydroxide solution) 3-methoxy-4- (2-phenylethoxy) phenylacetic acid m.p. p. 97-100 ° C (crystallization by acidifying aqueous sodium hydroxide solution) 4-benzyloxy-3- (2-phenylethoxy) phenylacetic acid m.p. p. 110 to 112 ° C (crystallization by acidifying aqueous sodium hydroxide solution).

Thereafter, benzyl alcohol (described in Production Example 3) was used as a starting material, and chlorination was performed in the same manner to obtain the following compound. 5-Fluoro-2- (2-phenylethoxy) phenylacetic acid m.p. p. 99-101 ° C. (crystallization by acidifying aqueous sodium hydroxide solution) 4-chloro-2- (2-phenylethoxy) phenylacetic acid m.p. p. 102.5-104.5 ° C (crystallization by acidifying aqueous sodium hydroxide solution).

Production Example 5 Production of 3- [5-bromo-2- (2-phenylethoxy) phenyl] propionic acid In a nitrogen stream, 9.1 ml of ethyl diethylphosphonoacetate was dissolved in 60 ml of tetrahydrofuran and tetrahydrofuran was cooled with ice. 3.875 g of potassium-t-butoxide dissolved in 30 ml was added, and the mixture was stirred for 40 minutes. A solution of 5-bromo-2- (2-phenylethoxy) benzaldehyde (7 g) in tetrahydrofuran (20 ml) was added to the reaction mixture, and the mixture was stirred for 18 hours while returning to room temperature. Saturated sodium bicarbonate water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with saturated sodium bicarbonate water and water. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The product was used in the next reaction without purification. Dissolve the above product in 30 ml of ethyl acetate, add 0.55 g of platinum dioxide,
The mixture was stirred under a hydrogen stream at room temperature for 36 hours. The platinum dioxide was filtered through Celite, and the filtrate was evaporated under reduced pressure. To the residue were added 6N aqueous sodium hydroxide solution (40 ml), methanol (50 ml) and dioxane (50 ml), and the mixture was stirred for 3 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in water, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate to give oily 3- [5-bromo-2- (2-phenylethoxy) phenyl] propionic acid 2 0.88 g was obtained.

NMR (DMSO) δ (ppm); 2.
35 (2H, t, J = 7.5Hz), 2.70 (2H,
t, J = 7.5 Hz), 3.03 (2H, t, J = 6.
3Hz), 4.18 (2H, t, J = 6.3Hz),
6.88 to 7.38 (8H, m), 12.09 (1H,
brs, exchangeable with D ₂ O) MS m / e; 350 (M ⁺ +2), 348 (M ⁺ ).

Instead of 5-bromo-2- (2-phenylethoxy) benzaldehyde, 3-methoxy-2-
(2-phenylethoxy) benzaldehyde or 4-
Using methoxy-3- (2-phenylethoxy) benzaldehyde, the following compounds were obtained in the same manner as above. 3- [3-methoxy-2- (2-phenylethoxy) phenyl] propionic acid NMR (DMSO) δ (ppm); 2.35 (2H,
t, J = 7.5 Hz), 2.67 (2H, t, J = 7.
5Hz), 3.00 (2H, t, J = 6.3Hz),
3.75 (3H, s) 4.13 (2H, t, J = 6.3Hz), 6.71
6.98 (3H, m), 7.17 to 7.25 (5H,
m), 12.04 (1H, brs, exchangeable with
_{D 2 O) MS m / e} ; 300 (M +) 3- [4- methoxy-3- (2-phenylethoxy) phenyl] propionic acid m. p. 77.5 to 78.5 ° C
(Recrystallized from n-hexane-toluene).

Production Example 6 N, N-di-n-propyl-2- [3-methoxy-2-
(2-Phenylethoxy) phenyl] ethylamine hydrochloride production 3-methoxy-2- (2-phenylethoxy) phenylacetic acid (1.53 g) in toluene (7.5 ml) was added with thionyl chloride (0.8 ml) at 90 ° C. Stir for hours. The reaction mixture was concentrated under reduced pressure, 10 ml of toluene was added again, 1.70 g of di-n-propylamine was added dropwise with stirring under ice-cooling, and the mixture was further stirred at room temperature overnight. The reaction mixture was washed successively with water, diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. To a suspension of 0.42 g of lithium aluminum hydride in 10 ml of tetrahydrofuran, a solution of the above residue in 3 ml of tetrahydrofuran was added dropwise with stirring at room temperature. After heating under reflux for 3 hours with stirring, a saturated aqueous solution of sodium sulfate was added dropwise under ice cooling until the generation of hydrogen ceased. The precipitated solid was filtered off, the filtrate was evaporated under reduced pressure, and the residue was subjected to silica gel chromatography (developing solvent; n-hexane-ethyl acetate = 3: 1). The target fraction was evaporated under reduced pressure to remove the solvent, the residue was dissolved in ethanol, 4N hydrogen chloride / ethyl acetate solution was added, the solvent was evaporated under reduced pressure and recrystallized from ethyl acetate-isopropyl ether to give N, N-
Di-n-propyl-2- [3-methoxy-2- (2-phenylethoxy) phenyl] ethylamine hydrochloride 1.
15 g was obtained. m. p. 105-107 ° C.

The following compounds were obtained in the same manner as above using the corresponding starting materials (in the case of the oxalate salt, oxalic acid was used instead of the 4N hydrogen chloride / ethyl acetate solution). N, N-di-n-propyl-2- [4-methoxy-3-
Preparation of (2-phenylethoxy) phenyl] ethylamine oxalate m. p. 80-81 ° C (recrystallized from ether) N, N-di-n-propyl-2- [3-methoxy-2-
Preparation of (2-phenylethoxy) phenyl] ethylamine oxalate m. p. 135-137 ° C (recrystallized from ethanol) N, N-di-n-propyl-2- [5-methoxy-2-
(2-phenylethoxy) phenyl] ethylamine hydrochloride m.p. p. 92-93 ° C (recrystallized from ethyl acetate) N, N-di-n-propyl-2- [3-methoxy-4-
(2-Phenylethoxy) phenyl] ethylamine oxalate m.p. p. 108-110 ° C (recrystallized from isopropanol) N, N-di-n-propyl-2- [2-methoxy-4-
(2-Phenylethoxy) phenyl] ethylamine oxalate m.p. p. 132-133 ° C (recrystallized from ethyl acetate) N, N-di-n-propyl-2- [4-methoxy-2-
(2-Phenylethoxy) phenyl] ethylamine oxalate m.p. p. 137-138 ° C (recrystallized from isopropanol) N, N-di-n-propyl-3- [4-methoxy-3-
(2-Phenylethoxy) phenyl] propylamine
Hydrochloride m. p. 83-84 ° C (recrystallized from ethyl acetate) N, N-di-n-propyl-3- [4-methoxy-3-
(2-Phenylethoxy) phenyl] propylamine
Oxalate m. p. 104-105 ° C (recrystallized from ethyl acetate) N, N-di-n-propyl-3- [3-methoxy-2-
(2-Phenylethoxy) phenyl] propylamine
Oxalate m. p. 114-115 ° C. (recrystallized from ethyl acetate) N, N-di-n-propyl-2- [3-benzyloxy-4-methoxyphenyl] ethylamine oxalate m.p. p. 126-127 ° C. (recrystallized from ethanol) N, N-di-n-propyl-2- [2-benzyloxy-3-methoxyphenyl] ethylamine oxalate m.p. p. 124-126 ° C (recrystallized from ethanol) N, N-di-n-propyl-2- [4-benzyloxy-3- (2-phenylethoxy) phenyl] ethylamine hydrochloride hydrochloride m.p. p. 96-98 ° C (recrystallized from ethyl acetate).

Production Example 7 N, N-di-n-propyl-2- [5-bromo-2-
Preparation of (2-phenylethoxy) phenyl] ethylamine oxalate 10 ml of tetrahydrofuran was added to 0.184 g of lithium aluminum hydride, and 5-bromo-2- (2
15 ml of a tetrahydrofuran solution containing 1.47 g of -phenylethoxy) phenylacetic acid was added and stirred for 2 hours. Saturated aqueous sodium sulfate was added to the reaction mixture while stirring, and after the generation of gas was completed, the reaction mixture was dried over magnesium sulfate, suction filtered, and the filtrate was evaporated under reduced pressure. The residue was dissolved in 10 ml of tetrahydrofuran and 2 ml of hexamethylphosphoric triamide, and 0.48 m of thionyl chloride was dissolved.
1 was added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate, washed successively with water and saturated aqueous sodium hydrogen carbonate and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. Di-
11.3 ml of n-propylamine was added, and the mixture was heated under reflux for 26 hours. The solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate, washed successively with 1N aqueous sodium hydroxide solution and water, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; n-hexane-ethyl acetate = 5: 1), then 0.045 g of oxalic acid was added to the obtained oily substance, and recrystallized from isopropanol to obtain N, N-diethyl ether. -Propyl-2- [5-
200 mg of bromo-2- (2-phenylethoxy) phenyl] ethylamine oxalate was obtained. m. p. 160-161 ° C.

The following compounds were obtained in the same manner as above using the corresponding starting materials. N, N-di-propyl-2- (2-benzyloxy-5
-Chlorophenyl) ethylamine oxalate m.p. p. 161.5-163 ° C (recrystallized from ethanol).

Production Example 8 N, N-di-n-propyl-3- [5-bromo-2-
(2-Phenylethoxy) phenyl] propylamine
Production of oxalate salt 1.216 g of 3- [5-bromo-2- (2-phenylethoxy) phenyl] propionic acid was dissolved in 20 ml of benzene, 1.2 ml of thionyl chloride was added, and the mixture was heated under reflux for 20 minutes. After evaporating the solvent under reduced pressure, the residue was dissolved in 10 ml of benzene, 3 ml of di-n-propylamine was added, and the mixture was stirred for 2 hours. After the solvent was distilled off under reduced pressure, the residue was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The above residue was dissolved in 20 ml of tetrahydrofuran, 9.2 ml of 1M tetrahydrofuran solution of borane / tetrahydrofuran complex salt was added, and the mixture was heated under reflux for 3 hours. After cooling, 10 ml of methanol was added, the solvent was distilled off under reduced pressure, 40 ml of concentrated hydrochloric acid was added to the residue, and the mixture was heated under reflux for 1 hour. The reaction mixture was neutralized with 6N aqueous sodium hydroxide solution, extracted with ethyl acetate, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; n-hexane-ethyl acetate = 10: 1), and then oxalic acid 118m
g, recrystallized from ethyl acetate, and N, N-di-n-
Propyl-3- [5-bromo-2- (2-phenylethoxy) phenyl] propylamine oxalate 516m
g was obtained. m. p. 104-105 ° C.

Using the corresponding starting material in place of 3- [5-bromo-2- (2-phenylethoxy) phenyl] propionic acid, the following compounds were obtained in the same manner as above (in the case of the hydrochloride salt: , 4N hydrogen chloride / ethyl acetate solution or concentrated hydrochloric acid was used instead of oxalic acid).

N, N-di-n-propyl-2- [5-fluoro-2- (2-phenylethoxy) phenyl] ethylamine hydrochloride hydrochloride m.p. p. 85-86 ° C (recrystallized from toluene) N, N-di-n-propyl-2- [4-chloro-2-
(2-phenylethoxy) phenyl] ethylamine hydrochloride m.p. p. 93 to 94 ° C. (recrystallized from ethyl acetate) N, N-di-n-propyl-2- [3-fluoro-2-
(2-Phenylethoxy) phenyl] ethylamine oxalate m.p. p. 137-138 ° C (recrystallized from ethanol).

Production Example 9 N, N-di-n-propyl-3- [5-chloro-2-
(2-Phenylethoxy) phenyl] propylamine
Production of oxalate salt (1) Production of 3- [5-chloro-2- (2-phenylethoxy) phenyl] propanol In a stream of argon, diethylphosphonoethyl acetate 8.36 was added.
3.49 g of potassium t-butoxide was added to 100 ml of a tetrahydrofuran solution of g under ice cooling, and the mixture was stirred at the same temperature for 1 hour. Then, the reaction solution was cooled under ice-cooling with 5-chloro-2-
(2-phenylethoxy) benzaldehyde 5.40 g
A solution of tetrahydrofuran in 30 ml was added dropwise, and the temperature was adjusted to 1 at the same temperature.
After stirring for an hour, the mixture was stirred at room temperature for 19 hours. After adding 30 ml of saturated sodium bicarbonate water, extraction with ethyl acetate, drying over anhydrous magnesium sulfate, evaporation of the solvent under reduced pressure, and crude 5-chloro-2- (2-phenylethoxy) cinnamate 1
1.56 g was obtained. This compound was used in the next reaction without further purification. Crude ethyl 5-chloro-2- (2-phenylethoxy) cinnamate 11.39 g ethyl acetate 8
570 mg of platinum dioxide was suspended in a 0 ml solution, and the suspension was stirred in a hydrogen stream at room temperature for 4.5 hours. After filtration through Celite, the residue was distilled off under reduced pressure to obtain 10.76 g of crude ethyl 3- [5-chloro-2- (2-phenylethoxy) phenyl] propionate. This compound was used in the next reaction without further purification.

10.76 g of crude ethyl 3- [5-chloro-2- (2-phenylethoxy) phenyl] propionate.
Lithium aluminum hydride (1.84 g) was added to a tetrahydrofuran (100 ml) solution under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. Aqueous 25% ammonia was added until hydrogen was not generated, filtered through Celite and anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate-n-hexane = 1: 1). 9), 3- [5-chloro-2- (2
-Phenylethoxy) phenyl] propanol 3.31
g was obtained.

NMR (CDCl ₃ ) δ (ppm);
1.59 to 1.82 (2H, m) 1.67 (1H, brs, exchangeable with D ₂ O),
2.60 (2H, t, J = 7.5Hz), 3.09 (2
H, t, J = 6.5 Hz), 3.55 (2H, t, J =
6.0 Hz), 4.17 (2H, t, J = 6.5H)
z), 6.74 (1H, d, J = 10.0 Hz), 7.
02 to 7.15 (2H, m), 7.20 to 7.40 (5
H, m) MS m / e; 292 (M ⁺ +2), 290 (M ⁺ ).

(2) N, N-di-n-propyl-3-
Preparation of [5-chloro-2- (2-phenylethoxy) phenyl] propylamine oxalate 3.24 g of 3- [5-chloro-2- (2-phenylethoxy) phenyl] propanol and hexamethylphosphoric trichloride 25m tetrahydrofuran of 5ml amide
1.22 ml of thionyl chloride was added to the 1 solution under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water (100 ml), extracted with ethyl acetate, then twice with water and 4 times with saturated sodium bicarbonate water.
It was washed twice and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, crude 4-chloro-2- (3-chloropropyl)
3.21 g of -1- (2-phenylethoxy) benzene was obtained. This compound was used in the next reaction without further purification.

Crude 4-chloro-2- (3-chloropropyl) -1- (2-phenylethoxy) benzene 604m
5 ml of dipropylamine was added to g and the mixture was stirred at 120 ° C. for 39 hours. After diluting with methylene chloride, it was washed successively with saturated sodium bicarbonate water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate-n-hexane = 1: 5) to give N, N-di-n-propyl-.
0.50 g of 3- [5-chloro-2- (2-phenylethoxy) phenyl] propylamine was obtained.

A solution of 0.50 g of N, N-di-n-propyl-3- [5-chloro-2- (2-phenylethoxy) phenyl] propylamine in 10 ml of ethanol was added with a solution of 120 mg of oxalic acid in 5 ml of ethanol. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from ethyl acetate to give N, N-di-n-propyl-3- [5-chloro-2.
380 mg of-(2-phenylethoxy) phenyl] propylamine oxalate was obtained. m. p. 100-102 ° C.

Production Example 10 N, N-di-n-propyl-4- [5-chloro-2-
Production of (2-phenylethoxy) phenyl] butylamine oxalate (1) Production of 4- [5-chloro-2- (2-phenylethoxy) phenyl] butanol Crude 4-chloro-2- (3-chloropropyl) ) -1- (2
To a solution of 1.62 g of -phenylethoxy) benzene in 20 ml of acetonitrile, 681 mg of potassium cyanide and 138 mg of 18-crown-6 were added, and the mixture was heated under reflux for 11 hours. After cooling, the solvent was evaporated under reduced pressure, ethyl acetate and water were added to the obtained residue, and the ethyl acetate layer was separated.
The extract was washed 3 times with water and saturated sodium bicarbonate water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.55 g of crude 4- [5-chloro-2- (2-phenylethoxy) phenyl] butyronitrile. It was This compound was used in the next reaction without further purification.

To a solution of 1.53 g of crude 4- [5-chloro-2- (2-phenylethoxy) phenyl] butyronitrile in 15 ml of ethanol was added 15 ml of 20% (w / v) potassium hydroxide aqueous solution, and the mixture was heated under reflux for 17 hours. . After ethanol was distilled off under reduced pressure, concentrated hydrochloric acid was added dropwise until the reaction solution became acidic, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give crude 4- [5-chloro-2
-(2-Phenylethoxy) phenyl] butyric acid 1.41 g
Got This compound was used in the next reaction without further purification.

To a solution of 1.38 g of crude 4- [5-chloro-2- (2-phenylethoxy) phenyl] butyric acid in 20 ml of tetrahydrofuran was added 246 mg of lithium aluminum hydride under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. Aqueous 25% ammonia was added until hydrogen was not generated, filtered through Celite and anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate-n-hexane = 1: 8) to give 0.86 g of 4- [5-chloro-2- (2-phenylethoxy) phenyl] butanol. Got

NMR (CDCl ₃ ) δ (ppm);
1.40 (1H, s, exchangeable with D ₂ O),
1.47 to 1.68 (4H, m), 2.54 (2H,
m), 3.10 (2H, t, J = 6.5Hz), 3.5
9 (2H, m), 4.15 (2H, t, J = 6.5H
z), 6.71 (1H, d, J = 10.0 Hz), 7.
01 to 7.15 (2H, m), 7.18 to 7.40 (5
H, m) MS m / e; 306 (M ⁺ +2), 304 (M ⁺ ).

(2) N, N-di-n-propyl-4-
Preparation of [5-chloro-2- (2-phenylethoxy) phenyl] butylamine oxalate 0.86 g of 4- [5-chloro-2- (2-phenylethoxy) phenyl] butanol and hexamethylphosphoric triamide 4 ml of tetrahydrofuran 20 ml
To the solution was added thionyl chloride (0.31 ml) under ice cooling, and the mixture was stirred at room temperature for 2 hours. Pour the reaction solution into water (100 ml),
After extraction with ethyl acetate, the extract was washed with water twice and saturated sodium bicarbonate water four times, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, crude 4-chloro-2- (4-chlorobutyl) -1-
0.91 g of (2-phenylethoxy) benzene was obtained.
This compound was used in the next reaction without further purification.

Crude 4-chloro-2- (4-chlorobutyl)
10 ml of di-n-propylamine was added to 0.91 g of -1- (2-phenylethoxy) benzene, and the mixture was stirred at 120 ° C for 3 times.
Stir for 8 hours. After diluting with methylene chloride, it was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate-n-hexane = 1: 6) to give N, N-di-n-.
1.07 g of propyl-4- [5-chloro-2- (2-phenylethoxy) phenyl] butylamine was obtained. N,
N-di-n-propyl-4- [5-chloro-2- (2-
Phenylethoxy) phenyl] butylamine 1.07 g
Solution of 123 mg of oxalic acid in 5 ml of ethanol was added to a solution of 10 ml of ethanol, and the solvent was distilled off under reduced pressure.
Propyl-4- [5-chloro-2- (2-phenylethoxy) phenyl] butylamine oxalate 421 mg
Got m. p. 80-82 ° C.

Production Example 11 N, N-di-n-propyl-2- [5-chloro-2-
Preparation of (2-phenylethoxy) phenyl] ethylamine oxalate N, N-di-n-propyl-2- (2-benzyloxy-5-chlorophenyl) ethylamine oxalate 2.
After suspending 00 g in ethyl acetate and thoroughly stirring with 10% potassium hydroxide solution, the organic layer was separated, washed with water and saturated brine successively, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. . The residue obtained above is ethanol 2
Dissolve in 0 ml, add 0.48 ml of concentrated hydrochloric acid and 200 mg of 5% palladium / carbon, and add hydrogen with stirring to 1
I went for 0 hours. The catalyst was filtered off, and the solvent was distilled off under reduced pressure.
This residue was dissolved in 20 ml of N, N-dimethylformamide, 3.00 g of 2-bromoethylbenzene and 2 g of potassium carbonate were added, and the mixture was stirred at room temperature for 1 day. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel chromatography (developing solvent; dichloromethane: acetone =).
20: 1 to 5: 1). The target fraction was concentrated, dissolved in ethanol, and added with 100 mg of oxalic acid.
The solvent was distilled off under reduced pressure to obtain a solid. This solid was recrystallized from ethanol to give N, N-di-n-propyl-2- [5
0.24 g of -chloro-2- (2-phenylethoxy) phenyl] ethylamine oxalate was obtained. m. p. 166-167 ° C.

Substantially the same as above, but using the corresponding starting materials, the following compounds were obtained (in the case of the hydrochloride salt, 4N hydrogen chloride / ethyl acetate solution or concentrated hydrochloric acid was used instead of oxalic acid: .).

N, N-di-n-propyl-2- [4-methoxy-3- [2- (4-fluorophenyl) ethoxy] phenyl] ethylamine hydrochloride m.p. p. 114-116 ° C (recrystallized from ethyl acetate) N, N-di-n-propyl-2- [4-methoxy-3-
[2- (3-chlorophenyl) ethoxy] phenyl] ethylamine.hydrochloride m.p. p. 79-80 ° C (recrystallized from isopropyl ether) N, N-di-n-propyl-2- [4-methoxy-3-
[2- (4-methoxyphenyl) ethoxy] phenyl]
Ethylamine oxalate m.p. p. 110-111 ° C (recrystallized from ethyl acetate) N, N-di-n-propyl-2- [3-methoxy-2-
(3-Phenylpropoxy) phenyl] ethylamine
Oxalate m. p. 113-114 ° C (recrystallized from ethyl acetate) N, N-di-n-propyl-2- [4-methoxy-3-
(3-Phenylpropoxy) phenyl] ethylamine
Oxalate m. p. 82-83 ° C (recrystallized from isopropanol).

Production Example 12 N, N-di-n-propyl-2- [4-methoxy-3-
(2-Phenylethoxy) phenyl] ethylamine / hydrochloride production (1) 2- [4-methoxy-3- (2-phenylethoxy) phenyl] ethylamine / hydrochloride production 2.04 ml of trifluoroacetic acid was added dropwise to a suspension solution of 3.60 g of crude 4-methoxy-3- (2-phenylethoxy) phenylacetonitrile and 1.00 g of sodium borohydride in 15 ml of terahydrofuran with stirring. The mixture was heated under reflux for another 1 hour. After cooling the reaction solution to room temperature, 1.00 ml of water and 4.00 ml of concentrated hydrochloric acid were successively added dropwise, and the mixture was heated under reflux for 1 hour again.
The reaction solution was cooled to room temperature, made alkaline with 10N aqueous sodium hydroxide solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated hydrochloric acid (1.65 ml) was added to the filtrate, and the solvent was evaporated under reduced pressure. The remaining crystals were recrystallized from isopropanol to give 2- [4-methoxy-3- (2-phenylethoxy) phenyl] ethylamine.hydrochloride.
61 g were obtained. m. p. 114-115 ° C.

(2) N, N-di-n-propyl-2-
Preparation of [4-methoxy-3- (2-phenylethoxy) phenyl] ethylamine hydrochloride 2- [4-methoxy-3- (2-phenylethoxy) phenyl] ethylamine hydrochloride 2.52 g, anhydrous potassium carbonate 2 0.85 g and 1.73 g of n-propyl bromide in 10 ml of N, N-dimethylformamide at about 40 ° C.
Stir for 0 hours. The reaction solution was poured into water and extracted with ethyl acetate,
The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and a 4N hydrogen chloride / ethyl acetate solution was added. After distilling off the solvent under reduced pressure, it was recrystallized from ethyl acetate,
N, N-di-n-propyl-2- [4-methoxy-3-
2.41 g of (2-phenylethoxy) phenyl] ethylamine hydrochloride was obtained. m. p. 99-100 ° C.

Production Example 13 N, N-di-n-propyl-2- [4-hydroxy-3
-(2-Phenylethoxy) phenyl] ethylamine
Production of Hydrochloride N, N-di-n-propyl-2- [4-benzyloxy-3- (2-phenylethoxy) phenyl] ethylamine-hydrochloride 6.50 g of ethyl acetate 65 ml and 1N sodium hydroxide aqueous solution 21 ml After stirring for 20 minutes, the organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was dissolved in 60 ml of methanol, 200 mg of 5% palladium hydroxide / carbon was added, and hydrogenation was carried out for 3 hours with stirring. The catalyst was filtered off, and the solvent was distilled off under reduced pressure. The residue was dissolved in 60 ml of ethyl acetate, 5.20 ml of 4N hydrogen chloride / ethyl acetate solution was added, and the crystals precipitated by distilling off the solvent under reduced pressure were recrystallized from ethyl acetate to give N, N-di-n-propyl-2. 4.77 g of-[4-hydroxy-3- (2-phenylethoxy) phenyl] ethylamine hydrochloride was obtained. m. p. 124-125 ° C.

Example 1 N, N-di-n-propyl-2- [4-methoxy-3-
(2-Phenylethoxy) phenyl] ethylamine / hydrochloride 10 g, lactose 550 g, corn starch 30
0 g, carboxymethyl cellulose calcium 100 g
And 30 g of polyvinylpyrrolidone were mixed well, granulated with ethanol by a conventional method, dried and then sized. To this, 10 g of magnesium stearate was added and mixed, and then a tablet of 100 mg was prepared by a conventional method.

Example 2 N, N-di-n-propyl-2- [3-methoxy-2-
10 g of (2-phenylethoxy) phenyl] ethylamine hydrochloride, 590 g of mannitol and 380 g of corn starch were mixed well, and 200 g of a 10% aqueous solution of hydroxypropyl cellulose was added to the mixture to granulate,
After drying, it was passed through a No. 32 sieve to give a powder containing 1%.

Example 3 N, N-di-n-propyl-3- [4-methoxy-3-
(2-Phenylethoxy) phenyl] propylamine
After dissolving 0.5 mg of hydrochloride, 25 mg of buffer and 11 mg of sodium chloride in 2 ml of distilled water for injection, the mixture was filtered, the filtrate was dispensed into 2 ml ampoules, sealed, and then sterilized to obtain an injection.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI A61P 43/00 A61P 43/00 C07C 217/56 C07C 217/56 (72) Inventor Yutaka Kawashima 3-24 Takada, Toshima-ku, Tokyo No. 1 Taisho Pharmaceutical Co., Ltd. (72) Inventor Katsuo Hatayama 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (56) References International Publication 91/03243 (WO, A1) (58) Field (Int.Cl. ⁷ , DB name) A61K 31/135 A61P 25/02 A61P 25/18 A61P 25/24 A61P 25/28 A61P 43/00 C07C 217/56

Claims (3)

(57) [Claims] 1. The formula: (In the formula, X ¹ represents a halogen atom, a hydroxyl group or an alkoxy group having 1 to 5 carbon atoms, X ² represents a hydrogen atom, a halogen atom or an alkoxy group having 1 to 5 carbon atoms,
R ¹ or R ² are the same or different and represent an alkyl group having 1 to 7 carbon atoms, and m and n are the same or different and are 2
Indicates an integer of ˜5. ) A sigma receptor antagonist comprising a phenylalkylamine derivative represented by the formula (4) or a pharmaceutically acceptable salt thereof as an active ingredient. 2. X ¹ is an alkoxy group having 1 to 3 carbon atoms, X ² is a hydrogen atom, R ¹ and R ² are alkyl groups having 1 to 4 carbon atoms, and m and n are A sigma receptor antagonist comprising the phenylalkylamine derivative according to claim 1, which is 2 or 3, or a pharmaceutically acceptable salt thereof as an active ingredient. 3. A hydrochloride or oxalate salt.
A sigma receptor antagonist comprising the described phenylalkylamine derivative as an active ingredient.