WO1994024115A1 - Novel piperazine derivative - Google Patents

Abstract

A compound represented by general formula (I) and salts thereof, wherein R1 represents lower alkyl, cycloalkyl, phenyl, phenyl-substituted lower alkyl or phenoxy-substituted lower alkyl, wherein the cycloalkyl, phenyl and the phenyl groups of the phenyl-substituted lower alkyl and phenoxy-substituted lower alkyl may be substituted by one or more lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkoxy or lower alkylenedioxy groups; R?2 and R3¿ represent each independently hydrogen, halogen, lower alkyl, hydroxy, lower alkoxy or cyano; A and B represent each independently lower alkylene; and n represents 0 or 1. This compound is useful as remedies for functional disorder of cranial nerves, such as dementia, depression, schizophrenia and anxiety, diseases accompanying immunopathy and endocrine anomaly, and digestive ulcer.

Description

 Description New piperazine derivative Technical field

 The present invention has an affinity for receptors and receptors, and is used to treat dementia, depression, schizophrenia, anxiety and other cranial nerve dysfunctions, diseases associated with immune and endocrine disorders, and digestive ulcers. It relates to a new compound that is useful as an agent.

Background art

 Many 1,2-diphenylbiperazine derivatives have been studied as analgesics (Japanese Patent Publication No. 47-634, Japanese Patent Publication No. 49-188, J. Med. Chem., _0_1240 (1975)). Etc.), a substituent in which a substituent such as an alkyl group, an alkenyl group, a cycloalkyl group, or a phenylalkyl group is introduced at the 4-position of the piperazine ring. A substituent such as a halogen atom, a hydroxy group, or a lower alkoxy group is added to the phenyl ring. The compounds introduced have been reported.

 It has also been reported that 1,2-diphenylpyrazine derivatives in which the 4-position of the piperazine ring is substituted with a phenylalkyl group or a phenoxyalkyl group have a calcium antagonism and a cerebral nerve function improvement action ( JP-A-63-141 966, JP-A-3-72229).

As described above, the focus of the research is on the introduction of substituents on the phenyl ring of 1,2-diphenylethylbiperazine derivatives and on the introduction of various substituents on the 4-position of the piperazin ring. One The introduction of an oxygen atom into the alkylene chain connecting the phenyl groups of the above has not been studied.

 Many researches have recently been conducted on the γ receptor, and compounds with strong affinity for the σ receptor are used in diseases associated with cranial nerve dysfunction such as dementia, depression, schizophrenia, anxiety, immune disorders and endocrine disorders. It is becoming clear that it is useful as a therapeutic agent for diseases such as gastrointestinal ulcer (J. Neuropsychiatry C1ii. N eurosci., 7-15 (1989); Eur. J. Biochem. , 2H, 633-642 (1991); I. Pharmacol. Exp. The r. ', 255, _1354-1359 (1990)). However, a 1,2-difullebiperazine derivative having a strong affinity for the σ receptor has not yet been reported.

Disclosure of the invention

 As described above, many studies have been conducted on the introduction of substituents on the phenyl ring of 1,2-diphenyldiperpiperazine derivatives and on the introduction of various substituents on the 4-position of the piperazine ring. However, no studies have been made on compounds in which an oxygen atom has been introduced into the alkylene chain connecting two phenyl groups, and studies on the synthesis of these compounds and on their pharmacological actions have been very interesting issues. Was.

By the way, it has been reported that some of the 1,2-diphenyldibiperazine derivatives have a morphine-like physical dependence (Japanese Patent Publication No. 61-333827). Since morphine-like compounds with physical dependence are not preferred for use as medicines, it is possible to find compounds without such physical dependence. Was an important issue.

 The present inventors focused on the alkylene chain of the diphenylalkylpiperazine derivative, synthesized a novel piperazine derivative having an oxygen atom introduced into the alkylene chain, and examined its pharmacological action.o

First, [ ³ H] (+) — N-aryl normetazosin ([ ³ H] (+) — SKF—10047) was used as a labeled ligand, and the piperazine derivative of the present invention and the receptor were identified. As a result of examining the affinity, it was found that the piperazine derivative of the present invention had a strong affinity for the σ receptor. In addition, similar to SKF-1 0 0 4 7, a labeled label compound of (+) -pentazocine ((+) — Τ Τ ら れ), which is known as a ligand for the receptor ([ ³ (] (+)) — の Τ) was also examined for the above-mentioned affinity, and as in the case of [ ³の] (+) — SKF—10047, the pyrazine derivative of the present invention showed a strong resistance to Hiresep Yuichi. Showed affinity. From this, the compound of the present invention is useful for the treatment of cranial nerve dysfunction such as dementia, depression, schizophrenia, and insecurity, diseases associated with immunoreceptor and endocrine disorders, and digestion, It was found to be useful as a therapeutic agent for organ ulcers and the like.

Next, an experiment was conducted to determine the presence or absence of a morphine-like effect, another subject. It is known that a compound having a morphine-like action has a strong affinity for receptor (Li fe Sci., 33 (Sup 1), 431 (1983)), and has an affinity for receptor. If weak, the morphine-like effect of the compound is considered weak. It can be cut off. ^{Therefore, [3 H] [D -} A 1 a 2, N -M e - L - P he 4, G ly- ol "] Enkefu A Li down ^{([3 H] D AMG O} ) a labeled Li cancer de Then, as a result of examining the affinity of the novel piperazine derivative for the receptor, it was found that the affinity was very weak, and that it showed substantially no morphine-like action.

 The present invention provides a novel pyrazine compound represented by the following general formula [I] and a salt thereof (hereinafter, referred to as the compound of the present invention).

[In the formula, R ¹ represents a lower alkyl group, a cycloalkyl group, a phenyl group, a phenyl lower alkyl group or a phenyl lower alkyl group, and a phenyl ring of a phenyl group, a phenyl lower alkyl group or a phenyl lower alkyl group. And the cycloalkyl group may be substituted with one or more lower alkyl groups, lower alkenyl groups, lower alkynyl groups, hydroxy groups, lower alkoxy groups or lower alkylenedioxy groups.

R ² and R ³ are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group or a cyano group.

A and B are the same or different and represent a lower alkylene group. You.

 n represents 0 or 1. same as below. ]

To explain the above definition in more detail, lower alkyl is a straight chain having 1 to 6 carbon atoms such as methyl, ethyl, propyl, hexyl, isopropyl, and teft.-butyl. Or a branched alkyl, and a lower alkenyl is a straight-chain or branched alkenyl having 2 to 6 carbon atoms containing a double bond such as vinyl, aryl, and hexenyl, and a lower alkynyl is Represents a straight-chain or branched alkynyl having 2 to 6 carbon atoms containing a triple bond such as ethynyl, propynyl, hexynyl and the like.Lower alkoxy is methoxy, ethoxy, propoxy, hexyloxy, Is a straight-chain or branched alkoxy having 1 to 6 carbon atoms such as isopropoxy, tert.-butoxy, etc., and cycloalkyl is cyclopropyl, cyclolob. Cycloalkyl having 3 to 8 carbon atoms such as cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; lower alkylene means methylene, ethylene, (dimethyl) It represents a straight-chain or branched alkylene having 1 to 6 carbon atoms such as methylene, (methyl) methylene and the like. The lower alkylenedioxy is methylenedioxy, ethylenedioxy, (dimethyl) methylenedioxy, (getyl). ) Represents an alkylenedioxy in which a straight-chain or branched alkylene having 1 to 6 carbon atoms exists between two oxygen atoms such as methylenedioxy, etc., and a halogen atom means fluorine or chlorine. Indicates bromine, iodine. Examples of the salts include pharmaceutically acceptable salts such as hydrochloride, sulfate, maleate and fumarate.

Preferred examples of the compounds of the present invention are those in which R ¹ is a lower alkyl group, a cycloalkyl group, a phenyl group, a phenyl lower alkyl group or a phenyloxy lower alkyl group, and Is different and includes a compound of a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a cyano group. More preferred examples include R ¹ is a cyclohexyl group or a phenylethyl group, R ² is a hydrogen atom or a halogen atom,

³ is a compound represented by a hydrogen atom, a halogen atom or a lower alkoxy group. In particular, a compound in which R ² is a hydrogen atom or a fluorine atom and R ³ is a hydrogen atom, a fluorine atom or a methoxy group is preferable. Further, the lower alkylene group of A and B is preferably a methylene group.

Examples of the compounds of the present invention which have particularly excellent effects include 1- (2-benzyloxy-1-1-phenylethyl) -4-cyclohexylbiperazine, 1- (1-benzyloxymethyltinole-2—phenylethyl 1) 4—cyclohexylolepiperazine, 4—cyclohexyl 1 1— [2— (4—fluorobenziloxoxy) 1—1-phenylenyl) piperazine, 4—cyclohexyl 1—1—2— (4— —Methoxybenzyloxy) 1- 1-phenylethyl) piperazine and 1- (2—benzyloxy 1- 1-phenylethyl) 1-4- (2—phenylethyl) piperazine, and the respective salts And stereoisomers and optically active isomers. Representative methods for synthesizing the compounds of the present invention include the following a) and b) ^)

 a)

[VI

[VII

R'N (CH ₂ CH ₂ X) ₂

 [VII]

II:

[In the formula, R ⁴ represents a protecting group for an amino group such as a lower alkanoyl group or a lower alkoxycarbonyl group, and X represents a leaving group such as a halogen atom or a lower alkane sulfonyloxy group. ]

 In the method a), first, the amino group of the compound represented by the formula [11] is protected to give a compound of the formula [111], and the compound of the formula [IV] is reacted with the compound of the formula [IV] to obtain a compound of the formula [11] The compound of formula [V] is converted to the compound of formula [V], and then the protecting group for the amino group is removed to obtain a compound of formula [VI]. The compound of formula [VII] is reacted with a compound of formula [VII] to form a piperazine ring. To obtain the compound [I] of the present invention.

 Further, by reacting the compound of the formula [11] with the compound of the formula [! V] in the presence of a base such as sodium hydride, the compound of the formula [VI] can be directly obtained. Is also possible.

b)

[Villi

IX:

R NH ₂ [Wherein, Y represents a halogen atom. ]

The method of b) comprises reacting the compound of formula [VI] obtained by the method of a) with a halogenated alcohol such as 2-bromoethanol to give the compound of formula [VI] with the compound of formula [V111]. After that, thionyl chloride or methanesulfonyl chloride or the like is reacted therewith, the compound of the formula [V111] is led to the compound of the formula [], and then R ¹ NH ₂ is reacted to form a piperazine ring. To obtain the compound [I] of the present invention.

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

 The compound represented by the general formula [I] has optical isomers, all of which are included in the present invention. When an optically active material is used, an optically active substance can be obtained.However, when a racemic substance is used as a raw material, a racemic product can be optically separated using an optical resolving agent or the like. it can.

First, in order to examine the usefulness of the compound of the present invention, an experiment was conducted on the affinity of the compound of the present invention for the σ receptor. For more information is given in the section Pharmacological Test described ^{later, [3 Η] (+)} - SKF - 1 0 0 4 7 a as a labeled ligand, the results of examining the affinity of the compound of the present invention to jump receptor However, it was found that the compound of the present invention shows a strong affinity for the receptor. Et al ^{is, [3 Η] (+)} - Ρ where the T Zeta was as a labeled ligand consider the affinity, the compounds of the present invention ^{[3 Η] (+) -} SKF - 1 0 0 4 7 of As in the case, it showed strong affinity for the σ receptor. Next, an experiment was performed to determine whether the compound of the present invention exhibits a morphine-like effect. It is known that a compound having a morphine-like action has a strong affinity for a β receptor, and if the affinity for a receptor is weak, it can be determined that the compound has a weak morphine-like action. Thus, the affinity of the compound of the present invention for the ^ receptor was examined using [ ³ H] DAMG0 as a labeled ligand. As a result, it was found that the compound of the present invention has a weak affinity for the // receptor, and the compound of the present invention does not substantially exhibit a morphine-like effect.

 In order to apply a certain compound as a drug, it is preferable that the difference between the effect expression amount and the side effect expression amount is large. That is, in the present invention, it is preferable that the affinity for the β receptor is strong and the affinity for the β receptor is weak, and the experimental results described below show that the compound of the present invention is excellent as a pharmaceutical. It proves.

Furthermore, a learning disorder model due to ischemia, which is known as a disease model of dementia due to cerebrovascular disorders, that is, four arteries are obtained by the method of Pulsinel li (Stroke, H, 267-272 (1979)). When an experiment was carried out using a rat in a state of cerebral ischemia due to occlusion, the compound of the present invention had an improving effect on learning disability.A compound that increases the amount of acetylcholine in the brain was dementia. J. Med, 315, 1241-1245 (1986)), it was reported by Matsuno et al. (Brain Res., 575, 315-). 319 (1992)) When the amount of acetylcholine in the rat brain was measured, the compound of the present invention showed an effect of increasing acetylcholine.

 From the results of the above pharmacological tests, the compound of the present invention shows that the compound of the present invention is a disease involving dementia, depression, schizophrenia, anxiety, etc. It has a wide range of pharmaceutical uses as a therapeutic agent for organ ulcers and the like, and is particularly useful as a therapeutic agent for cranial nerve dysfunction.

 The method of administration of the compound of the present invention may be oral or parenteral. Examples of the dosage form include tablets, capsules, soft capsules, granules, and injections. The compound of the present invention can be formulated using a technique that is widely used. For example, oral preparations such as tablets, capsules, soft capsules, and granules may be used, if necessary, in lactose, starch, crystal cell mouth, bulking agents such as vegetable oils, lubricating agents such as magnesium stearate, talc, etc. Binders such as hydroxypropylcellulose and polyvinylidene, disintegrants such as low-substituted hydroxypropylcellulose mouth, calcium carboxymethylcellulose, hydroxypropylmethylcellulose, macrogol, silicone It can be formulated using a coating agent such as a resin or a film agent such as a gelatin film. The dosage is appropriately selected depending on the symptoms, dosage form, etc., but usually 1 mg to 100 mg, preferably 1 mg to 200 mg per day may be administered once or in several divided doses.o

BEST MODE FOR CARRYING OUT THE INVENTION

Reference example 1 (R) -1 1-benzyloxymethyl-2-phenylphenylethyl hydrochloride (Reference compound 11)

1) A solution of (R) _1-hydroxymethyl-1-2-phenylphenylamine (3.0 g) in tetrahydrofuran (25 ml) was added to a solution of ditert-butylethylcarbonate (4. A solution of 3 g) in tetrahydrofuran (25 ml) is added dropwise with stirring. The reaction solution is concentrated under reduced pressure to obtain 3.1 g (62%) of (R) -N-tert.-butoxycarbone 1-hydroxymethyl-2-phenylenylamine.

 mp 93-95. C

^{_{[A] D 20 + 2 7.}} 9 ° (c = l. 0, main Tano Lumpur) IR (KB r, cm one ¹⁾ 3 3 5 7, 2 9 8 4 2 9 3 9, 1 6 8 7, 1 5 2 9, 1 4 4 4, 1 3 6 7, 1 3 1 6, 1 2 7 0, 1 1 6 8

2) In a nitrogen atmosphere, a suspension of 60% hydrogenated sodium mineral oil suspension (0.35 g) in dimethylformamide (40 ml) was added to ice sodium sodium chloride. While cooling with (R) -N-tert.-butoxycarbonyl 1-hydroxymethyl-2-phenylethylamine (2.0 g) and benzylformamide (4 lg) in dimethylformamide (2 0 ml) The solution is added dropwise. The reaction solution is stirred for 1 hour under ice cooling. Water is added to the reaction mixture, and the mixture is extracted with ethyl ether. The organic layer is washed with water and saturated saline, After drying over anhydrous magnesium sulfate, the mixture is concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography, and 2.2 g (82%) of (R) -1-benzyloxymethyl-l-N-te-di-butoxycarbonyl 2- 2-phenylethylamine was obtained. obtain.

^{_{[A] D 20 + 1 7.}} 6 ° (c = 0. 6, METHANOL)

IR (Fi 1 m, cm- ¹ ) 17 13, 1 496, 1 454, 1 3 9 1, 1 3 6 6, 1 2 4 9, 1 1 7 0, 1 1 1 8 , 1

0 5 6, 1 0 2 8

 3) Dissolve (R) -1 -benzyloxymethyl-N-tert, -butoxycarbonyl-12-phenylethylamine (2.0g) in a solution of hydrogen chloride in ethyl acetate and stir for 2 hours. The reaction solution is concentrated under reduced pressure to obtain 1.4 g (86%) of the title compound (reference compound 11).

 m p 15 4 to 15 5. C

^{_{[A] D 20 - 3 3.}} 1 ° (. C = l 0, main Tano ^{Lumpur) IR (KB r, cm- 1} ) 2 8 6 2, 1 5 9 8, 1 5 0 9,

1 4 6 6, 1 4 5 3, 1 3 6 2, 1 1 7 1, 1 1 1 6

 The same operation as in Reference Example 1 is performed to obtain the following compound.

 · (S) 1-1-benzyloxymethyl-12-phenylethylamine hydrochloride (Reference compound 1-2)

 mp 155-15-156. C

^{_{[A] D 20 + 3 4.}} 7 ° (c = 1. 0, main Tano Ichiru) IR (KB r, cm- 2 8 6 3, 1 5 9 8, 1 5 0 9, 1 4 9 6, 1 4 5 3, 1 3 6 2, 1 1 7 1, 1 1 1 7, 1 0 8 6

 • (R)-1-(4 — benzodioxime. Tyl) 1 2 — phenylethylamine hydrochloride (reference compound 13)

 m p 1 4 3 to 49 ° C

_Ί 20 ―

^{[ «3 0 (c = 1.} 0, METHANOL)" D one 8.

IR (KBr, m " ¹ ) 28 68, 2673, 2582, 2502, 1558, 1504, 1445, 712

-(S) 1 1 1 1 (—Cross benzyloxymethyl) 1 2—Phenylethylphane borates (Reference compounds 114)

 m p 150-52 ° C

[A ^J D tens ^{9. 0 0 (c = 1. 0} , main Tano ^{Lumpur) IR (KB r, m- 1} ) 2 8 7 9, 2 6 7 4, 2 5 8 3, 2 5 0 3, 1 5 8, 1 5 0 4, 1 4 5 7, 1 1 2 0

• (R) 1-1-(— Cyanobenziloxymethyl) 1-2—Phenethyllephane hydrochloride (Reference compound 15)

 m p 5 7 6 5 ° C

 l a] 20

^{D 1. 9 0 (c = 1.} 0, main Tano Lumpur) IR (KB r, m " 1) 2 8 6 0, 2 7 3 9, 2 5 7 7, 2 2 2 7, 1 6 0, 1 5 8 3, 1 4 9 6, 1 4 5 6, 1 3 5 7, 1 1 0 4

 • (R) 111 (4-tert.-butylbenzyloxymethyl)-2-phenylethylamine hydrochloride (Reference compound 1-16) m p 5 5 16 0 ° C

 i 20

D 3 7.2. (c = l.0, methanol) IR (KB r, cm— ¹ ) 2886, 1614, 1586, 5 one

1 508, 1 496, 1 4 7 5, 1 4 5 6, 1 1 3 4

• (R) -111-benzyloxymethyl-2- (4-methylfurininyl) ethylamine hydrochloride (Reference compounds 117)

• (R) — 1-benzyloxymethyl-1-2- (4-methoxyfuninyl) ethylamine hydrochloride (Reference compound 118)

• (R) — 1-benzyloxymethyl-2- (4-fluorofuunyl) ethylamine hydrochloride (Reference compound 119)

• (R) -1-1-benzyloxymethyl-2- (4-chlorophenylinyl) ethylamine hydrochloride (Reference compound 110)

• (R) —1—benzyloxymethyl 2 -— (4-cyanofuninyl) ethylamine hydrochloride (Reference compound 111) Reference example 2

窒素気流下、 6 0 %水素化ナ ト リ ウム鉱油懸濁物 （ 1. 6 g ) のテ トラ ヒ ドロフラ ン （ 1 0 m l ) 懸濁液に、 氷冷下、 ( R ) — 2— ヒ ドロキシ一 1—フエニルェチルァ ミ ン （5. 0 g ) のテ ト ラ ヒ ドロフラ ン （ 7 0 m l ) 溶液を滴下し、 2 時間加熱還流する。 反応液を氷冷し、 塩化 4ーメ トキシベン ジル （6. 3 g) のテ ト ラ ヒ ドロフラ ン （2 0 m l ) 溶液を' 滴下し、 室温下 1 0時間撹拌する。 この溶液を水、 飽和食塩 水で洗浄し、 無水硫酸マグネシゥムで乾燥後減圧濃縮する。 得られる油状物をシリ カゲルカラムク ロマ トで精製し、 標記 化合物 （参考化合物 2— 1 ) 4. 8 g (5 1. 2 %) を得る < [a] _D ²⁵ - 2 4. 1 ° ( c = l . 0, ク ロ口ホルム） I R (F i 1 m, c m^-1) 3 3 7 9, 3 0 2 9, 2 8 5 5 ， 1 6 1 2 , 1 5 1 3, 1 2 4 8, 1 0 8 8， 1 0 3 4， 8 2 2, 7 5 8 , 7 0 2 (R) -2- (4-Methoxybenzyloxy) 1-1-phenylethylamine (Reference compound 2-1)

Under a nitrogen stream, a suspension of 60% sodium hydride mineral oil (1.6 g) in tetrahydrofuran (10 ml) was added to a suspension of (R) -2H A solution of droxy-1-phenylethylamine (5.0 g) in tetrahydrofuran (70 ml) is added dropwise, and the mixture is refluxed for 2 hours. The reaction mixture is cooled on ice, a solution of 4-methoxybenzyl chloride (6.3 g) in tetrahydrofuran (20 ml) is added dropwise, and the mixture is stirred at room temperature for 10 hours. The solution is washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily residue was purified by silica Kagerukaramuku Loma DOO, the title compound (Reference Compound 2 1) 4. obtain 8 g (5 1. 2%) <[a] D 25 - 2 4. 1 ° (c = l. 0, cross-hole form) IR (F i 1 m, cm ^-1 ) 3 3 7 9, 3 0 2 9, 2 8 5 5, 16 1 2, 1 5 1 3, 1 2 4 8, 1 0 8 8, 1 0 3 4, 8 2 2, 7 5 8, 7 0 2

 The same procedure as in Reference Example 2 is performed to obtain the following compound.

 • (R) —2— (3,4-dimethoxybenzyloxy) 111-fuunylethylamine (Reference compound 2-2)

^{[a] D 20 - 1 2.} 9 ° (. c = l 5, main Tano Lumpur) IR (F i 1 m, cm "1) 2 9 3 4, 2 9 0 2, 2 8 5 5, 1 5 9 3, 1 5 1 5, 1 4 6 4, 1 4 5 3, 1 2 6 5, 1 2 3 8, 1 1 5 7, 1 1 3 8, 1 0 8, 7, 1 0 2 8, 7 6 3, 7 0 2

 • (R) -2- (2-Fluorobenzyloxy) 1-1-phenylethylamine (Reference compound 2-3)

[a] _D ^{i 0-1} 22.1 ° (c = l.2, methanol) IR (F i 1 m, cm ^-1 ) 30 29, 28 9 7, 2 8 5 9

, 1 5 8 7, 1 4 9 2, 1 4 5 5, 1 3 5 6, 1 2 3 1, 1

1 1 4, 1 0 8 8, 8 4 2, 7 5 8, 7 0 1

 • (R) — 2— (3-Fluorobenzyloxy) 111-phenylethylamine (Reference compound 2-4)

[] _D ²⁰ — 1 8.8 ° (c = 0.5, methanol) IR (F i 1 m, cm- ¹ ) 3 3 8 1, 3 3 0 6, 3 0 6 2, 3 0 2 9, 2 8 5 8, 1 6 1 8, 1 5 9 0, 1 4 8 8, 1 4 5 1, 1 2 5 5, 1 1 0 6, 8 6 8, 7 5 9, 7 0 1

• 2-benzyloxy 1- (2-funolelophenyl) ethylamine (Reference compound 2-5)

IR (Film, cm " ¹ ) 3 3 8 1, 3 3 1 2, 3 0 6 4, 3 0 3 1, 2 8 5 9, 1 5 8 4, 1 4 8 8, 1 4 5 4, 1 3 5 9, 1 2 2 4, 1 0 9 7, 8 3 4, 7 5 9, 6 9 8

• 2-benzyloxy, / — 1— (4-methoxyphenyl) ethylamine (Reference compound 2-6)

IR (F i 1 m, cm " ¹ ) 3 3 7 8, 2 8 5 3, 16 1 0, 15 12, 1 2 4 7, 8 3 2, 7, 3 7, 6 9 8

Reference example 3

 (R) -2- (4-Fluorobenzyloxy) 1-1-phenylethylamino fumarate (Reference compound 3)

窒素気流下、 6 0 %水素化ナ ト リ ウム鉱油懸濁物 （ 0. 3 2 g) のテ トラ ヒ ドロフラ ン （3 m l ) 懸濁液に、 氷冷下、 ( R ) — 2— ヒ ドロキシー 1ーフヱニルェチルァ ミ ン （1. 0 g ) のテ ト ラ ヒ ドロフラ ン （ 1 5 m l ) 溶液を滴下し、 1 . 5時間加熱還流する。 反応液を氷冷し、 塩化べンジル （1 . 3 g) のテ ト ラ ヒ ドロフラ ン （5 m l ) 溶液を滴下し、 4 0 °Cで 2 0時間撹拌する。 有機層を水、 飽和食塩水で洗浄し 、 無水硫酸マグネシウムで乾燥後減圧濃縮する。 得られる油 状物をシリ カゲルカラムク ロマ トで精製後、 メ タノール （2 O m 1 ) とフマル酸 （ 0. 5 5 g) を加え、 減圧濃縮を経て 標記化合物 （参考化合物 3) 5 g ( 5 7 を得る

Under a nitrogen stream, a suspension of 60% sodium hydride mineral oil (0.32 g) in tetrahydrofuran (3 ml) was added to a suspension of (R) -2H A solution of droxy 1-phenylethylamine (1.0 g) in tetrahydrofuran (15 ml) is added dropwise, and the mixture is refluxed for 1.5 hours. The reaction solution is cooled with ice, a solution of benzyl chloride (1.3 g) in tetrahydrofuran (5 ml) is added dropwise, and the mixture is stirred at 40 ° C for 20 hours. The organic layer is washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oil The residue was purified by silica gel column chromatography, methanol (2 Om1) and fumaric acid (0.55 g) were added, and the mixture was concentrated under reduced pressure to give 5 g (57) of the title compound (Reference compound 3).

 m p 1 22 44 to 1 26 ° C

 20

 D4.2 (c = 0, methanol)

IR (KB r, cm " ^L ) 3 0 65, 3 0 4 0, 2 8 7 7, 2 5 1 8, 1 6 9 7, 1 5 1 1, 1 2 8 1, 1 2 2 1, 1 0 9 4, 8 2 8, 6 4 0

Reference example 4,

(R) — 2-benzyloxy 1-phenylethylamine (Reference compound 4-1)

1) To a solution of (R)-2-hydroxy 1-phenylethylamine (15.5 lg) in pyridine (60 ml), add anhydrous acetic acid (31.2 ml) dropwise under ice-cooling. . The reaction solution is stirred at room temperature for 3 hours, concentrated under reduced pressure, and added with ethyl acetate. The solution was washed with water and saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and concentrated under reduced pressure to give (R) —2-acetoxy-N-acetyl-1-phenylphenylamine (18.8 g). 7 7%).

 mp 1 11 77-1 118. C

 20

D 7 5 (c = 0 5, methanol) IR (KB r, cm—32 9 6, 1 7 3 1, 1 65 2, 5 56, 1 3 7 6, 1 2 4 9, 1 0 42, 7 0 1 2) To a solution of (R) —2—acetoxy N—acetyl-1 1—phenylethylamine (19.6 g) in tetrahydrofuran (200 ml), add An aqueous solution (200 ml) of titanium monohydrate (7.4 g) was added, and the mixture was stirred for 2 hours. 6 N hydrochloric acid (15 ml) is added to the reaction mixture, and the reaction mixture is concentrated under reduced pressure. Add sodium chloride to the concentrate and extract with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give (R) -N-acetyl-2-hydroxy-1-phenylphenylamine 13.5 g (85%). obtain.

 m p 101-102. C

^{_{[] D 20 - 1 0 9.}} 4 ° (c = 0. 5, METHANOL) IR (KB r, cm " 1) 3 1 9 0, 1 6 4 0, 1 5 6 0, 1 3 7 6, 1 3 1 4, 1 0 6 7, 6 9 9, 5 5 7

 3) In a nitrogen atmosphere, a suspension of 60% sodium hydride mineral oil suspension (1.1 g) in dimethylformamide (100 ml) was added with ice-sodium chloride. While cooling, a solution of (R) -N-acetyl-1-2-hydroxy-1-1-1-phenylethylamine (4.5 g) in dimethylformamide (30 ml) and benzyl bromide (4.7 g) ) In dimethylformamide (30 ml) was added dropwise, and the mixture was stirred at room temperature for 1.5 hours. Water is added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 4.4 g (65%) of (R) -N-acetyl-12-benzyloxy1-1-phenylethylamine. obtain.

mp 100 to 101. C ^{_{ί α '] D 20 - 4}} 5. 7. (C = 0.5, methanol) IR (KBr, cm- ¹ ) 3 2 7 1, 1 6 4 4, 1 5 6 0, 1 1 1 2, 1 0 8 7, 7 6 4 , 7 4 8, 7 0 1

 4) 2N hydrochloric acid (40 ml) was added to a solution of (R) -N-acetyl-12-benzyloxy-1 1-phenylethylamine (2.6 g) in ethanol (40 ml), and 2N hydrochloric acid (40 ml) was added. Reflux for 0 hours. After concentration of the reaction solution under reduced pressure, water is added to dissolve the concentrate, and the resulting aqueous solution is washed with a mixture of getyl ether and ethyl acetate (1: 1). The aqueous layer is made alkaline by the addition of potassium carbonate and extracted with ethyl acetate. The organic layer is washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.4 g (65%) of the title compound (Reference compound 4-1).

^{_{[] D 20 - 2 0. 6}} ° (c = 0. 5, main Tano Lumpur) IR (F i 1 m, cm- 1) 3 3 7 9, 3 0 2 8, 2 8 5 5, 1 6 0 3, 1 4 5 2, 1 0 9 4, 7 3 8, 6 9 9

 The same procedure as in Reference Example 4 is performed to obtain the following compound.

 • (S) —2—benzyloxy 1—phenylethylamine (Reference compound 4-2)

^{_{[A] D 20 + 1 8.}} 1 ° (c = 0. 6, main Tano ^{Lumpur) IR (F ilm, cm- 1} ) 3 3 7 9, 3 0 2 9, 2 8 5 6, 1 6 0 3, 1 4 5 3, 1 0 9 4, 7 3 7, 6 9 9

Example 1

(R) — 1 — (1 —benzyloxymethyl-1-2-phenylphenyl) — 4-cyclohexylbiperazine dihydrochloride (Compounds 11)

 1) To a solution of (R) — 1-benzyloxymethyl-12-phenylphenylamine hydrochloride (Reference compound 11, 0.2 g) in dimethylformamide (20 ml) was added N, N-bis ( 2—Chloroethyl) Add cyclohexylamine hydrochloride (0.35 g), sodium iodide (0.37 g) and sodium carbonate (0.69 g), and add 5 Stir at 0 ° C for 1 hour. Add water to the reaction mixture and extract with ethyl acetate. The organic layer is washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography, and (R)-1- (1-benzyloxymethyl-l- 2-phen-2-letyl) 14-cyclohexylbiperazine 0.25 g (77 %)

1 R (F i 1 m, cm ^-1 ) 2 9 2 7, 2 8 5 3, 2 8 1 1, 1 4 9 5, 1 4 5 3, 1 1 5 8, 1 1 2 3, 1 0 6 7, 1 0 2, 8, 9 8 2

2) (R) — 1— (1-benzyloxymethyl-2-phenylenyl) -1-cyclohexylbiperazine (0.18 g) in methanol (10 ml) solution was added to hydrogen chloride methanol. The mixture was concentrated under reduced pressure to give 0.18 g (83%) of the title compound (compound 11-1). mp 267-12 69. C (decomposition)

W-18.6 ° (c =]. 0, cross-hole holm) IR (KB r, cm ^_1 ) 2 9 3 ^6,2 9 0 8, 2 5 0 ^6,2 3 4 1, 1 4 94, 144, 115, 109, 75 The same operation as in Example 1 is performed to obtain the following compound.

 • (S)-1-1 (1-benzyloxymethyl-1-2-phenylethyl)-4-cyclohexylpiperazine dihydrochloride (compounds 1-2)

 m p 26 7 to 26 8 ° C (decomposition)

[«] _D ²⁰ + 18.2 ° (c =]. 0, cross-hole holm) IR (KB r, cm" ¹ ) 2 9 3 6, 2 9 0 7, 2 5 0 7,

2 3 2 4, 1 4 9 4, 1 4 4 5, 1 1 2 4, 1 0 9 9, 7 5 1

 • (R) -11- (1-benzyloxymethyl-1-2-phenylethyl) 1-41- (2-phenylethyl) pirazazine dihydrochloride (Compound 13)

 m p 2 6 2 6 6 ° C (decomposition)

 20

[H] D 5.1 ° (c = l. 0, methanol) IR (KB r, cm ^_1 ) 3 0 6 3, 3 0 3 2, 2 9 9 2, 2 9 1 8, 2 4 9 7, 1 4 8 0

 • (S)-1- (1-benzyloxymethyl-2-phenylethyl)-4- (2-phenylethyl) piperazine dihydrochloride (Compounds 1-4)

mp 2 5 2 5 3 ° C (decomposition) ^{_{[A] D 20 + 1 5.}} 9. (C = l.0, methanol) IR (KB r, cm— ¹ ) 3063, 3032, 2992, 29918, 2498, 1448 0

 • (R)-1-[1-(4-benzoyl benzomethyl)-2-pheninoleethyl]-4-cyclohexizolebiperazine dihydrochloride (compounds 15)

 m p 280 ° C or higher

[a] _D '°-26.1 ° (c = 1.0, Holm with mouth opening)

IR (KB r, cm ^-1 ) 2994, 2978, 2942, 2901, 2863, 2643, 2428, 1489, 1 4 4 5

 • (S) — 1 — [1 — (4 — benzoyl methoxymethyl) — 2 — fluorinylethyl] 1-4-cyclohexylbiperazin dihydrochloride (compound 16)

 m p 280 ° C or higher

^{_{[A] D 20 + 2 5.}} 5 ° (c = l. 0, click b port Holm)

IR (KB r, cm "" ¹ ) 2 9 9 4, 2 9 7 8, 2 9 4 3, 2 9 0 1, 2 8 6 2, 2 6 4 3, 2 4 2 8, 1 4 8 9, 1 4 4 4

 • (R) — 1 — [1 — (4 — cyano benzoyloxymethyl) — 2 — phenylethyl] — 4 — cyclohexinolepirazazine dihydrochloride (compounds 17)

 m p 2 6 6 to 2 6 7 ° C

[a] _D ²⁰ — 30.0 ° (c = 1.0, cross-hole holm) IR (KBr, cm— ¹ ) 30 ¹³ , 2995, 2997, 2 9 4 0, 2 8 5 8, 2 6 4 2, 2 5 1 1, 2 4 2 8, 2 2 26, 1 4 9 2

 • (R) — 1— [1- (4-tert.-butylethylsiloxymethyl) 1—2-phenyletyl] 1—4— syrup mouth hexinolepiperazine dihydrochloride (compounds 18)

 m p 26 9-2 7 1. C (decomposition)

^{_{[a] D 20 - 2 7.}} 9 0 (c = 1. 0, ^{METHANOL) IR (KB r, cm- 1} ) 3 4 2 8, 3 0 6 1, 3 0 0 3, 2 9 3 8, 2 8 6 3, 2 5 0 2, 2 2 0, 1 4 8 3, 1 4 4 9, 1 4 0 2

 • (R) — 1— (1—Benzyroxymethyl-1-2-phenylethyl) -14-Phenylpiperazine Dihydrochloride (Compounds 19)

 • (R) 1 1 1 [1—Benzyloxymethyl 1 2— (4—Methylphenyl) ethyl] — 4-SiC Mouth hexizolebiperazine dihydrochloride (Compound 11 10)

 • (R) — 1 [1—Benzyloxymethyl 2- (4-methoxyethoxy) ethyl] — 4-cyclohexylbiperazine dihydrochloride (Compound 111)

 '(R) — 1— [1-Benzyroxymethyl 2 -— (4-fluorophenyl) ethyl] 141-cyclohexynolepiperazine dihydrochloride (Compounds 11-12)

• (R)-1-[1-benzoyloxymethyl-1-2-(4-chlorophenyl) ethyl] 1-4-oct-hexinolepiperazine dihydrochloride (compounds 11-13) • (R) — 1 — [1-benzyloxymethyl-2- (4-cyanophenyl) ethyl] — 4-cyclohexylbiperazine dihydrochloride (compounds 11 to 14)

Example 2

 (R) 1 1 (1 1-benzyloxymethyl-1 2-phenylethyl) — 4 Cyclopentylbiperazine dihydrochloride (Compound 2-1)

 1) In a sealed tube, add 2-cyclohexane to a solution of (R) -1-1-benzyloxymethyl-2-fuunleethylamine hydrochloride (Reference Compound 11-5.0) in ethanol (80 ml). Add ethanol (15.6 g), sodium iodide (18,7 g) and potassium carbonate (8.6 g) and stir at 150 ° C for 15 hours You. The insoluble material is removed by filtration, concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer is washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography to give (R) -11-benzyloxymethyl-1-N, N-bis (2-hydroxyxethyl) 1-2-phenylethylamine 6.5 g (95% ).

 20 one 3.7 (c = 0, methanol)

IR (F i 1 m, cm " ¹ ) 3 4 1 0, 3 0 2 7, 3 0 0 6 , 29 26, 28 86 2, 14 95, 1 45 54, 100 64

2) To a solution of (R) -11-benzyloxymethyl-N, N-bis (2-hydroxyxethyl) -12-phenylethylamine (7.0 g) in form-cloth (20 ml), ice-NaCl While cooling with a stream, a solution of thionyl chloride (7.6 g) in chloroform (20 ml) was added dropwise, and the mixture was refluxed for 25 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting oil was purified by silica gel column chromatography to give (R) -1-benzyloxymethyl-1-N, N-bis (2-chloroethyl) -12-phenylethylamin hydrochloride 2. 0 g (24%) are obtained.

 [α] 20

 D + 8.7 ° (c = l.0, methanol)

IR (F i 1 m, cm " ¹ ) 3 0 8,6,3,06,3,0 28,3,0 4,2 9 5 4,2 8 6,0,2 3,5 9,1 6 0 3 , 1 5 8 5, 1 4 9 6

3) (R) — 1-Benzyloxymethyl-N, N-bis (2-chloroethyl) — 2-phenylphenylamine hydrochloride (0.5 g) in dimethylformamide (30 ml) solution Add pentylamine (0.13 g), gallium carbonate (1.0 g) and sodium iodide (0.56 g), and stir at 60 ° C for 3 hours. Water is added to the reaction solution, and extracted with ethyl acetate. The organic layer is washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography to give (R) -1- (1-benzyloxymethyl-2-phenylethyl) -14-cyclopentylbiperazine, and the hydrogen chloride methanol solution was added thereto. In addition, vacuum concentration Obtain 0.1 g (18%) of the title compound (Compound 2) via mp 247-248 ° C (decomposition)

 [α] 20

 D 9.4 ° (c = 1.0, cross-hole holm)

IR (KB r, cm- ¹ ) 30 08, 2959, 2873 4, 23 66, 1492, 1445, 1336

 The same operation as in Example 2 is performed to obtain the following compound.

 • (S) — 1- (1-benzyloxymethyl-2-1-phenylethyl) 1-4-cyclopentylbiperazine dihydrochloride (Compound 2-2)

 m p 2 39 to 24 1 ° C (decomposition)

 20

 D + 9.2. (c = l. 0, meta-nor)

IR (KB r, cm- ¹ ) 3 0 3 1, 2 9 6 0, 2 8 7 4, 2 3 6 4, 1 4 9 3, 1 4 5 2, 1 3 6 8

 • (R) -11- (1-benzyloxymethyl-1-2-phenylethyl) — 4-— (2-methylcyclohexyl) piperazine dihydrochloride (compound 2-3)

 m p 25 0 ~ 25 3 ° C

[H] D ²⁰ 1 1 3.0 ° (c = 0.31, methanol) IR (KBr, cm- ¹ ) 2 9 3 1, 2 4 2 4, 1 4 5 4,

1 0 6 5, 7 5 0, 7 0 1

 • (R) -11- (1-benzyloxymethyl-1-2-phenylethyl) -14- (3-methylcyclohexyl) piperazine dihydrochloride (compounds 214)

mp 2 5 8 to 26 1 ° C ^{_{[a] D 20 - 1 6.}} 4 ° (c = 0. 6 4, METHANOL - ^{Le) IR (KB r, cm- 1} ) 2 9 2 9, 2 3 6 6, 1 4 5 5, 7 4 9, 7 0 0

 • (R) — 1 — (1 — benzyloxymethyl 2 — phenylethyl) 1-4 — (4 — methylcyclohexyl) piperazin dihydrochloride (compound 2 — 5)

 m p 2 6 6 to 2 6 7 ° C

 20 6.0 ° (c = 0.67, methanol)

I R (K B r, cm-29 29, 2 25 8, 1 48 3, 1 4 5 2, 1 0 5 1, 1 0 0 2, 7 4 8, 7 0 0

 • (R) — 1— (1—Benzyroxymethyl-2-phenylphenyl) 1-4— (2,3—dimethylcyclohexyl) piperazin dihydrochloride (Compound 2—6)

 m p 24 9 to 250 ° C (decomposition)

^{[ «] D 20 - 1 6.} 9 ° (c = 0. 7 2, METHANOL Ichiru) IR (KB r, cm- 2 9 3 4, 2 3 6 6, 1 4 9 5,

1 4 4, 1 3 7 7, 1 2 9 0, 1 0 9 6, 1 0 6 6, 7 5

0, 6 9 9

 • (R) — 1— (1—Benzyroximetinole 2—Funylethinole) 1-41 (1—Echininolesic hexyl) piradine dihydrochloride (Compound 2—7)

 mp2224-225. C

 20 7 (c = 0 67, methanol)

IR (KB r, cm— ¹ ) 3 3 6 5, 3 2 9 6, 3 1 5 5, 2 9 3, 5, 2 9 1, 2 1 0 5, 1 4 5 2, 1 2 8 2 0 6 9, 7 3 0, 7 0 0

 • (R) 1-1 (1-benzyloxymethyl-1-2-phenylethyl) _ 4-Cyclopropylpyrazine dihydrochloride (Compound 2-8)

 m p 2 19 ° C (decomposition)

^{Non] D 20 - 2 4. 0 °} (. C = l 0,, main Tano ^{Lumpur) IR (KB r, cm- 1} ) 3 0 3 3, 2 9 7 3, 2 8 8 2,

2 3 5 8, 1 49 3, 1 4 5 3, 1 3 8 1, 1 2 8 0, 1 2

0 1

 • (R)-1-(1 -benzyloxymethyl- 1-2-phenylethyl)-1-4-cyclopropyl biperazine dihydrochloride (Compound 2-9)

 m p 23 to 23 33 ° C (decomposition)

 20

[ ^α ] D-20.1 ° (c = 1.0, methanol) IR (KB r, cm- ¹ ) 3 8 56, 3 0 3 0, 2 9 7 0,

2 3 6 4, 1 4 9 4, 1 4 5 5, 1 3 9 9, 1 1 1 3

• (R)-1- (1-benzyloxymethyl-2-phenylethyl) 1-4-cycloheptylbiperazine dihydrochloride (Compound 2-10)

 m p 280 ° C (decomposition)

[«] D ²⁰ 1 16.8 ° (c = l. 0, methanol) IR (KB r, cm— ¹ ) 3 0 2 9, 2 9 9 4, 2 9 3 2,

2 8 6 3, 2 6 3 9, 1 4 9 4, 1 4 4 6, 1 2 8 8, 1 1 0 1

• (R) 1- (1-benzyloxymethyl-2-phenyl) 4- (1) -Vinylcyclohexylbiperazine dihydrochloride (Compound 2-1 1)

Example 3

 (R) -1-(2-Benzyloxy 1 1-phenylethyl) —44-cyclohexylcyclohexylsilubipiperalazin dihydrochloride (Compound 3 —

ニルェチルア ミ ン (参考化合物 4一 1、 0. 6 5 g) および N， N— ビス （ 2 —ク ロ ロェチル） シク ロへキシルァ ミ ン塩酸塩 （ 0. 7 5 g ) のジメ チルホルムア ミ ド （ 4 0 m l ) 溶液にヨウ化ナ ト リ ゥム （ 0. 8 6 g ) および炭酸カ リ ウム （ 1. 1 9 g ) を加 え、 6 0 °Cで 5時間撹拌する。 反応液に水を加え、 酢酸ェチ ルで抽出する。 有機層を水、 飽和食塩水で洗浄し、 無水硫酸 マグネシゥムで乾燥後減圧濃縮する。 得られる油状物をシリ 力ゲルカラムク ロマ トで精製後、 塩酸 エタ ノ 一ル溶液を加 え、 減圧濃縮を経て標記化合物 （化合物 3 — 1 ) 0. 6 9 g ( 5 3 %) を得る。

N, N-bis (2-chloroethyl) cyclohexylamine hydrochloride (0.75 g) dimethyl formamide (0.71 g) of nilethylamine (Reference compound 41, 0.65 g) (40 ml), add sodium iodide (0.886 g) and potassium carbonate (1.19 g) to the solution, and stir at 60 ° C for 5 hours. Add water to the reaction mixture and extract with ethyl acetate. The organic layer is washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography, ethanol ethanolic hydrochloride solution is added, and the mixture is concentrated under reduced pressure to obtain 0.69 g (53%) of the title compound (compound 3-1).

 m p 2 4 5 ° C

^{_{[A] D 20 - 2 5.}} 6 ° (c = 0. 5, METHANOL) IR (KB r, c m '1) 2 9 3 9, 2 4 0 4, 1 4 5 6,

0 4, 9 4 2, 9 2 4, 7 5 0, 7 0 6 The same operation as in Example 3 is performed to obtain the following compound.

 • (S) — 1 — (2 — benzyloxy 1 — phenylethyl) 1-4-cyclohexylbiperazine dihydrochloride (Compound 3 — 2)

 m p 2 4 5 to 2 4 6 ° C

[a] _D ²⁰ + 24.8 ° (c = 0.5, methanol) IR (KB r, cm- ¹ ) 2 9 3 5, 2 4 0 3, 1 4 5 6, 1 1 1 7, 9 4 3, 9 2 4, 7 4 8, 6 9 9

 • (R) — 1 — (2 — benzyloxy 1 1 — phenylethyl) — 4 — cyclopentylbiperazine dihydrochloride (compound 3 —

3)

 m p 239-240. C

^{_{[A] D 20 - 3 0.}} 3 ° (c = 0. 5, main Tano Lumpur) IR (KB r, cm " 1) 2 9 7 9, 2 3 6 0, 1 4 5 4, 1 3 8 3, 1 1 0 6, 1 0 2 8, 7 4 6, 6 9 9

 • (R) -1-(2-Benzyloxy 1 -phenylethyl)-4-fuirubiperazine dihydrochloride (Compound 3-4) mp 171-181. C

^{_{[A] D 20 - 2 8.}} 2. (c = l.0, metano) IR (KBr, cm " ¹ ) 2982, 2952, 2887, 2434, 2312, 1559 8, 14 9 4, 1 4 5 2, 1 1 0 5, 7 5 5, 7 0 0

• (R) — 1 — (2 — benzyloxy 1 — phenylethyl) -4- (2- phenylethyl) piperazine dihydrochloride (compound 3 — 5) mp 2 20 ° C

^{_{[A] D 20 - 2 5.}} 3 ° (. C = 0 5, main Tano Lumpur) IR (KB r, cm " 1) 2 9 8 6, 2 3 6 8, 1 4 5 5, 1 3 7 3, 1 1 1 6, 9 5 1, 7 4 6, 6 9 7

 · (R) — 1 — (2 benzoyloxy 1 — phenylethyl) 1-4 1 [2-(3, 4 — dimethylphenyl) ethyl “I piperazine dihydrochloride (compound 3-6)

 m p 22 0 to 22 1 ° C

 20

[A] _D one ^{2 2. 6 0 (c = 0} . 5, main Tano Lumpur) IR (KB r, cm " 1) 2 9 8 2, 2 3 6 7, 1 5 1 8, 1 4 5 4 , 1 2 6 2, 1 1 1 3, 1 0 2 8, 7 0 1

 • (R) -1 (2-benzyloxy-1-phenylethyl) — 4-butynolepiperazine dihydrochloride (Compounds 3-7)

 m p 2 16 ° C

 20

 C a]

 D 29.5 ° (c = 0.5, methanol)

IR (KB r, cm " ¹ ) 2 9 6 1, 2 3 6 2, 1 4 5 7, 1 3 8 6, 1 0 9 5, 9 4 6, 7 4 9, 6 9 9

 • (S) — 1 (2 — benzyloxy-1 — phenylethyl)

) 1-4 -Butylpyrazine dihydrochloride (Compound 3-8)

 m p 2 18 ° C

 20

 [a] D + 27.9 ° (c = 0.5, methanol)

IR (KB r, cm " ¹ ) 2 96 1, 2 3 6 1, 1 4 5 7, 1 3 8 6, 1 10 0, 9 4 5, 7 4 9, 6 9 9

• 1— [2—benzyloxy 1— (4—methoxyphenyl) ethyl] 1-4—six-hexylpiperazine dihydrochloride Compound 3-9)

 m p 2 45 ° C (decomposition)

 I R (KBr, cm—2 9 3 8, 2 4 0 6, 1 6 1 1, 1 5 1 7, 1 2 4 6, 1 1 7 8, 1 1 0 4, 1 0 3 7 Example 4

 (R) -1-(2-benzyloxy-1-phenyleneethyl) -4-1 [2- (3,4-methylenedioxyphenoxy) ethyl] piperazine dimaleate (compound 4-1) 1) OOH OOH

(R) — 2-benzyloxy 1 1-phenylethylamine (Reference compound 4-1, 0.34 g) and N, N-bis (2-chloroethyl) 1-2 — (3,4-methyl range Sodium iodide (0.45 g) and potassium carbonate in a solution of oxyphenoxy) ethylamine hydrochloride (0.51 g) in dimethylformamide (30 ml) (0.62 g) and stirred at 70 ° C for 20 hours. Water is added to the reaction solution, and extracted with ethyl acetate. The organic layer is washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography, ethanol and maleic acid (0.16 g) were added, and the mixture was concentrated under reduced pressure to give the title compound (compound 4-1) 0.29 g ( 2 8%). mp 150 ° C

[a] _D ²⁰ — 18.2 ° (c = 0.5, methanol) IR (KB r, cm ^-1 ) 2 3 6 9, 1 6 9 9, 1 6 2 1,

1 4 8 8, 1 3 5 5, 1 1 8 8, 8 6 9, 7 0 5

 Operating in the same manner as in Example 4, the following compound is obtained.

 • (R) — 1 — (2 — benzyloxy 1 — phenylethyl) 1-4 — (2 — phenoxicetyl) piperazine dimaleate (compound 4-2)

 • (R) — 1 — (2 — benzyloxy 1-1-phenylethyl) 1-4-[2-(3, 4-dimethoxyphenoxy) ethyl] piperazine dimaleate (compound 4-3)

 • (R) —4—cyclohexyl 1— [2— (3,4—dimethoxybenzyloxy) 1-1—phenylene] pyrazine dimaleate (compound 414)

 m p 15 1 to 15 2. C

^{_{[A] D 20 - 1 2.}} 1 ° (. C = l 0, METHANOL) IR (KB r, cm- 3 0 1 3, 2 9 3 0, 2 8 6 1,

2 3 5 5, 1 6 9 5, 1 6 2 0, 1 4 6 9, 1 3 6 6, 1 1 3 8, 8 6 8, 7 7 0, 7 0 1, 6 4 7, 5 8 6

 · (R) -1-cyclohexyl-1- 1- [2— (2-fluorobenzyloxy) 1-1-phenylenyl] piperazine dimaleate (compound 415)

 m p 176-178 ° C

[a] _D ²⁰ — 1 3.2. (C = l.0, methanol) IR (KBr, cm— ¹ ) 3020, 2939, 2861, 2 3 4 7, 1 6 7 7, 1 6 2 1, 1 4 5 9, 1 3 5 2, 1 2 3 3, 8 6 9, 7 6 1, 6 5 4, 5 8 6, 4 3 6

 • (R) — 4-cyclohexyl 1- [2- (3-fluorobenzyloxy) — 1-phenylethyl] piperazine dimaleate (Compound 4-6)

 m p 7 3 1 7 5 ° C

 20 12.2 ° (c = 0.5, metall)

IR (KB r, cm— ¹ ) 3 0 1 9, 2 9 3 7, 2 8 5 9, 2 3 6 0, 16 9 9, 16 2 1, 1 4 6 0, 1 3 5 3, 8 6 9, 7 6 2, 6 5 7, 4 3 8

 • 1- [2-benzyloxy-1- (2-fluorophenyl)

) Ethyl] — 4-cyclohexinolepiperazine dimaleate (compounds 417)

 m p 5 3 1 5 5 ° C

IR (KBr, cm— ¹ ) 3 0 3 2, 2 9 2 7, 2 8 5 5, 2 3 5 1, 1 6 9 9, 1 5 8 1, 1 4 5 0, 1 3 5 5, 1 2 8 2, 1 0 9 5, 8 6 7, 7 5 7, 6 4 8, 5 8 0

Example 5

 (R) 4-cyclohexyl-1- [2- (4-methoxybenzyloxy)-1-phenylenyl] piradine difumarate (Compound 5-1)

N , N— ビス （2—ク ロ ロェチル） シク ロへキシルァ ミ ン 塩酸塩 （ 1. l l g) のジメ チルホルムア ミ ド （ 1 0 m l ) 溶液にョゥ化ナ ト リ ウム （ 1. 2 8 g) および炭酸力 リ ウム ( 1. 1 8 g) を加え、 室温下で撹拌する。 この反応液を （ R ) — 4—メ トキシベンジルォキシ一 1 ー フ ヱニルェチルァ ミ ン （参考化合物 2— 1、 1. 0 g) のジメ チルホルムア ミ ド （ 3 0 m 1 ) 溶液に加え、 4 0 °Cで 2時間、 7 0 °Cで 2時 間、 さ らに 1 0 0 °Cで 3時間撹拌する。 反応液に水を加え、 酢酸ェチルで抽出する。 有機層を水、 飽和食塩水で洗浄し、 無水硫酸マグネシウムで乾燥後減圧濃縮する。 得られる油状 物をシリ カゲルカラムク ロマ トで精製後、 メ タノールとフマ ル酸 （0. 1 4 g) を加え、 減圧濃縮を経て標記化合物 （化 合物 5— 1 ) 1 8 m g (9. 4 %) を得る。

To a solution of N, N-bis (2-chloroethyl) cyclohexylamin hydrochloride (1.llg) in dimethylformamide (10 ml) was added sodium iodide (1.28 g). ) And potassium carbonate (1.18 g), and stir at room temperature. This reaction solution was added to a solution of (R) -4 -methoxybenzyloxy-1-phenylethylamine (Reference compound 2-1, 1.0 g) in dimethylformamide (30 ml), and the solution was added. Stir at 0 ° C for 2 hours, at 70 ° C for 2 hours, and at 100 ° C for 3 hours. Water is added to the reaction solution, and extracted with ethyl acetate. The organic layer is washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography, methanol and fumaric acid (0.14 g) were added, and the mixture was concentrated under reduced pressure to obtain 18 mg of the title compound (compound 5-1) (9.4 mg). %).

 m p 19 2 ° C

^{_{[a] D 20 - 1 4.}} 1 ° (. c = l 3, methanol) IR (KB r, cm- 2 9 3 6, 2 8 5 9, 2 5 0 0, 1 8 7 3, 1 7 1 5, 1 6 5 9, 1 5 8 3, 1 4 3 0, 1 3 0 0, 1 1 7 3, 9 7 8, 9 2 3, 7 6 1, 6 3 8, 4 5 6 Example 5 By the same procedure as in the above, the following compound is obtained.

 · (R) —4-cyclohexyl-1- [2- (4-fluorobenzyloxy) -1-phenylphenylethyl] pyrazine nifumarate (compound 5-2)

 mp 186-16-187. C

^{_{[a] D 20 - 1 2.}} 2. (c = 0.3, methanol) IR (KBr, cm— ¹ ) 2 9 4 3, 2 8 6 2, 2 4 3 6, 1 893, 1 7 1 3, 1 660, 1 574, 1 514, 1 4 3 1, 1 3 0 9, 1 1 8 0, 9 2 6, 7 7 1, 6 4 2, 4 5 5

Example 6

 4 — Cyclohexyl 1 1 — [1 — (2 — phenylethoxymethyl) 1 2 — phenylethyl] piperazine dihydrochloride (compound 6-1)

 1) To a solution of 1- (2-phenylethoxymethyl) 1-2-phenylethanol (0.7 g) in dichloromethan (4 ml) was added triethylamine (0.57 ml) and meta-chloride. A solution of dimethyl sulfonyl (0.322 ml) in dichloromethane (4 ml) was added dropwise under ice-cooling, and the mixture was stirred for 20 minutes. After the reaction solution is concentrated under reduced pressure, water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oil is purified by silica gel column chromatography to obtain 0.75 g (82%) of 1- (2-phenylethoxymethyl) 1-2-phenylethylmethane sulfonate.

1 R (F i 1 m, cm " ¹ ) 3 0 8 6, 3 0 6 2, 3 0 2 8, 2 9 3 7, 2 8 6 7, 1 7 3 4, 1 6 0 4, 1 4 9 6

2) 1-(2-Phenylethoxymethyl) 1 2 -Phenyl To ethanol methyl sulfonate (0.6 g) was added diethanolamine (0.57 g), and the mixture was stirred at 150 ° C for 2 hours. The reaction solution is acidified by adding 1N hydrochloric acid, and washed with getyl ether. The aqueous layer is made weakly alkaline with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography, and N, N-bis (2-hydroxyxethyl) 1-1- (2-phenylethoxymethyl) 1-2-phenylethylamine 0.12 g (19% ).

IR (F i 1 m, cm " ¹ ) 3 4 1 6, 3 0 6 1, 3 0 2 6, 2 9 2 2, 2 8 6 3, 1 4 9 5, 1 4 5 4, 1 4 0 6 , 1 1 1 2

3) To a solution of N, N—bis (2-hydroxyhexyl) 1-1- (2-phenylethoxymethyl) -12-phenylethylamine (0.11) in the form of closed mouth (2 ml) was added thionyl chloride (2 ml). (0.7 ml) was added dropwise, and the mixture was refluxed for 40 minutes. The N, N-bis (2-chloroethyl) 1-1- (2-phenylethoxymethyl) 1-2, phenylethylamine hydrochloride obtained by concentrating the reaction solution under reduced pressure is treated with dimethylformamide (3 ml). ). To this solution was added cyclohexylamine (0.04 g), sodium iodide (0.14 g) and potassium carbonate (0.27 g), and the mixture was added to 50%. . Stir at C for 2 hours. Water is added to the reaction solution, and extracted with ethyl acetate. The organic layer is washed with water and saturated saline and dried over anhydrous magnesium sulfate. After drying, concentrate under reduced pressure. The obtained oil was purified by silica gel column chromatography, hydrogen chloride Z methanol solution was added, and the mixture was concentrated under reduced pressure to obtain 55 mg (36%) of the title compound (Compound 6-1).

 m p 280 ° C or higher

 IR (KB r, cm—3 0 2,8,3 0 0 8,2 9 8 3,2 9 3 3,2 8 5 9,2 6 4,6,2 5 1 5,2 3 7 8, 1 4 9 Three

 The same operation as in Example 6 is performed to obtain the following compound.

 • 4—cyclohexyl 1— [1— [2— (4-methoxyphenyl) ethoxymethyl] —2-phenylenyl] piperazine dihydrochloride (Compound 6—2)

[Formulation example]

 An example of the formulation of the compound of the present invention is shown below.

 (Tablets)

Compound of the present invention lmg Lactose 120 mg Crystalline cellulose 38 mg Degree of substitution Hydroxypropyl cellulose 5 mg Hydroxypropyl pyrsenol ore L 5 mg Magnesium stearate 1 mg Total 170 mg Compound of the present invention 5 mg Lactose 7 5 mg Senorelose 6 8 mg Low-intensity meter Hydroxypropyl cellulose Cell 10 mg Hydroxypropyl cellulose 1 L 10 mg Magnesium stearate 2 mg

 2 7 0 mg

(钦 capsule)

 Compound of the present invention 50 mg

 Vegetable oil 150 mg

 Gelatin film 1 400 mg

 3 4 0 mg

(Injection)

 Compound of the present invention 100 mg

 0.9 g of sodium chloride

 Sodium hydroxide

 Sterile purified water

 0 0 ml

`` Pharmacological test ''

 In order to investigate the usefulness of the compound of the present invention, experiments were conducted on the affinity between the receptor and the receptor.

1. Affinity with receptor 1— 1. As a labeling ligand [ ³ H] (+) — SKF— 10

When using 0 4 7

 Matsuno et al. (Eu 【. J. Pharmacol., 231, 451-457 (

According to ^{1993)), [3 Η]} (+) - was determined SKF- 1 0 0 4 7 was used as a labeled ligand, affinity against the σ receptor by the following method.

 (experimental method)

 The membrane preparation was prepared by the following method according to the paper by Tam et al. (Proc. Natl. Acad. Sci. USA, Jl ^ 703-670? (1983)).

 Brains were removed from Hartley guinea pigs (body weight: 300 to 408), and Tris-HCl buffer (50 mM, pH 7.7, 0.32) was used eight times the brain weight. (Containing M sucrose) and centrifuged to obtain a supernatant. The pellet obtained by ultracentrifuging the supernatant for 20 minutes is suspended in a tris-hydrochloric acid buffer (5 OmM, pH 7.7, the same applies hereinafter), and centrifuged again to obtain a membrane. Defended 1 Lolo.

The specific binding amount of [ ^ΰ Η] (+) — SKF— ^{10047 was} determined in advance by the following method. Doo Risu membrane specimen suspended in HCl buffer, bets squirrel - was dissolved in hydrochloric acid buffer solution ^{[3 Η] (+) -} SKF - 1 0 0 4 7 (5 η Μ) was added (test compound The reaction was carried out at 25 ° C. for 30 minutes. After completion of the reaction, the reaction solution was subjected to suction filtration with a glass filter, and the radioactivity on the filter was measured with a liquid scintillation counter to determine the total binding amount. In addition, [ ³ H] (+) — SKF— 100 4 7 ( A mixture of (5 nM) and (+)-SKF-10047 (100 M) without radioactivity was added (without adding the test compound), and the membrane was labeled using the same method as above. The amount of binding to the product was determined, and the result was defined as the amount of non-specific binding. The difference between the total binding amount and the non-specific binding amount thus obtained was defined as the specific binding amount.

Next, the amount of binding between the membrane sample and [ ³ H] (+) — SKF—10747 was measured in the presence of the test compound, and was determined earlier by changing the concentration of the test compound. [ ^ΰ Η] (+)-The concentration of the test compound at which the specific binding amount of SKF-1 0 0 4 7 is suppressed by ⁵⁰ %

(IC5 ₍₎ ) was determined.

 (Result)

 Table 1 shows the results of Compound 1-1, Compound 2-1, Compound 3-1, and Compound 3-5 as examples of the experimental results.

As shown in Table 1, the compound of the present invention was found to significantly inhibit the specific binding amount of [ ³ H] (+)-SKF-107 at a low concentration. It was found to have strong affinity for the sigma receptor.

1 — 2. When [ ^ϋ Η] (+) — Ρ Τ ^{用 い} is used as a marker ligand According to DeHaven-Hudkins et al. (Eur. J. Pharmacol., 227, 371-378 (1992)), [ ³ H] (+) — PTZ was used as a labeled ligand. The following methods were used to determine the affinity for the receptor.

 (experimental method)

 The membrane preparation was prepared according to the following method according to a paper by Tam et al. (Proc. Natl., Acad. Sci. USA, 80, 6703-6707 (1983)).

 The brain is removed from a Hartley guinea pig (body weight: 300-400 g), and a tris-hydrochloric acid buffer (5 OmM, pH 7.7, 0. After homogenization in 32 M sucrose), the mixture was centrifuged to obtain a supernatant. The pellet obtained by ultracentrifuging the supernatant for 20 minutes is suspended in Tris-monohydrochloride buffer (50 mM, pH 7.7, the same applies hereinafter), and centrifuged again to obtain a membrane. A sample was obtained.

The specific binding of [ ³ H] (+)-PTZ was determined in advance by the following method. The Application Benefits Sioux HCl buffer membrane specimen suspended in, dissolved in preparative Risu HCl buffer ^[3 H] (+) - added PTZ (5 n M) (test compound is not added), 3 The reaction was carried out at 7 C for 150 minutes. After completion of the reaction, the reaction solution was subjected to suction filtration with a glass filter, and the radioactivity on the filter was measured with a liquid scintillation counter to determine the total binding amount. Also, a mixture of [ ³ H] (+) — PTZ (5 nM) and (+) 'non-radioactive PTZ (100 M) was added to the membrane preparation (without adding the test compound). ) Using the same method as above, determine the amount of binding to the membrane sample And the amount of non-specific binding. The difference between the total binding amount thus obtained and the non-specific binding amount was defined as the specific binding amount.

Next, the membrane preparation and ^[3 H] (+) the binding of one PTZ was measured in the presence of the test of compounds, Ri by the varying the concentration of the test compound was determined previously ^[a H] (+) — The concentration (Ic5 ₍₎ ) of the test compound at which the specific binding amount of PTZ was suppressed by 50% was determined.

 (Result)

 Table 2 shows the results of compound 3-1, compound 3-5, compound 5-1, and compound 5-2 as an example of the experimental results.

 Table 2

As shown in Table 2, as in the case where [ ³ H] (+) — SKF—10047 was examined as a labeled ligand, the compound of the present invention was changed to [ ³ H] (+). — It demonstrated that PTZ significantly inhibited the specific binding of PTZ at low concentration and had strong affinity for the receptor.

 2. Affinity with μ receptor

 Nabeshima et al. (Eur. J. Pharmacol., 114, 197-207)

), The affinity for Reception was determined by the following method. Incidentally, 〃 as a ^[3 Eta] labeled Riga down de receptors, high / / receptor of choice has been reported ( Br J. Pharmac, l ^ 461 - .. Using ^{469 (1982)) C 3 H} ] DAMG 0.

 (experimental method)

 The membrane preparation was prepared by the following method according to the paper by Kosterli et al. (Br. J. Pharmac., 68, 333-342 (1980)).

Brain is removed from a Wistar male rat (body weight: about 300 g), and is dissolved in Tris-HCl buffer (50 mM, pH 7.7, the same applies hereinafter) 20 times the brain weight. After homogenizing with, ultracentrifugation was performed for 15 minutes to obtain pellets. This pellet was suspended in a Tris-HCl buffer, incubated at 37 ° C for 30 minutes, and ultracentrifuged for 15 minutes to obtain a pellet, which was used as a membrane sample.

The specific binding amount of [ ³ H] DAMG0 was determined in advance by the following method. Doo Risu membrane specimen suspended in HCl buffer, Application Benefits scan - dissolved in hydrochloric acid buffer solution ^[3 H] D AM GO to (1 n M) was added (test compound without added), 2 5 The reaction was carried out at 30 ° C for 30 minutes. After completion of the reaction, the reaction solution was subjected to suction filtration with a glass filter, and the radioactivity on the filter was measured with a liquid scintillation counter to determine the total binding amount. Further, the addition of ^[3 H] DAMGO and (1 n M) 5 〃 M Narokiso mixture on to membrane preparation (test compound without added), binding of the membrane preparation using the same method as described above The amount was determined and defined as the amount of non-specific binding. The difference between the total binding amount thus obtained and the non-specific binding amount was defined as the specific binding amount. Next, the amount of binding between the membrane sample and [ ³ H] DAMGO was measured in the presence of the test compound, and the concentration of the test compound was changed to obtain The concentration ( _{Ic5 fl} ) of the test compound at which the specific binding amount of [ ³ H] DAMGO previously determined was suppressed by 50% was determined.

 (Result)

 Table 3 shows the results of Compound 11-1, Compound 2-1, Compound 3-1, and Compound 3-5 as examples of the experimental results.

 Table 3

As shown in Table 3, it was confirmed that the compound of the present invention hardly inhibited the specific binding amount of [ ³ H] DAMG0. From this, it was found that the compounds of the present invention have very weak affinity for ^ receptors and show almost no morphine-like action.

 From the results of the above pharmacological tests, the compound of the present invention has a strong affinity for the bireceptor, shows almost no morphine-like action, and is a disease involving the receptor such as dementia, depression, and schizophrenia. It has a wide range of medical uses as a therapeutic agent for cranial nerve dysfunction such as anxiety disorders, diseases associated with immune abnormalities and endocrine abnormalities, and gastrointestinal ulcers. It proved to be useful.

Industrial applicability

The present invention has an affinity for the receptor, dementia, It is intended to provide a novel compound useful as a therapeutic agent for cranial nerve dysfunction such as depression, schizophrenia and anxiety disorder, a disease associated with immune abnormality and endocrine abnormality, and gastrointestinal ulcer.

Claims

The scope of the claims  Compounds represented by the following general formula [I] and salts thereof

[In the formula, R ¹ represents a lower alkyl group, a cycloalkyl group, a phenyl group, a phenyl lower alkyl group or a phenyl lower alkyl group; The lower alkyl group may be substituted with one or more lower alkyl groups, lower alkenyl groups, lower alkynyl groups, hydroxy groups, lower alkoxy groups, or lower alkylenedioxy groups. R ² and R ¹¹ are the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group or a cyano group.  A and B are the same or different and represent a lower alkylene group.  n represents 0 or 1. ] (2) Compounds represented by the following general formula [I] and salts thereof

[In the formula, R ¹ represents a lower alkyl group, a cycloalkyl group, a phenyl group, a phenyl lower alkyl group or a phenyloxy lower alkyl group, and a phenyl ring and a cycloalkyl group of a phenyl group, a phenyl lower alkyl group or a phenyloxy lower alkyl group. The lower alkyl group may be substituted with one or more lower alkyl groups, lower alkenyl groups, lower alkynyl groups, lower alkoxy groups or lower alkylenedioxy groups. R ² and R. Represents the same or different and represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a cyano group.  A and B are the same or different and represent a lower alkylene group.  n represents 0 or 1. ]  (3) Compound represented by the following general formula [I] and salts thereof

[In the formula, R ¹ is a butyl group, a cyclopropyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a phenyl group, a phenylethyl group or a phenyloxyl group. And the phenyl ring and cyclohexyl group of the phenylethyl group or the phenyloxyethyl group may be substituted with one or two methyl groups, vinyl groups, ethynyl groups, methoxy groups or methylenedioxy groups. . R ² represents a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a methoxy group or a cyano group.  R represents a hydrogen atom, a fluorine atom, a tert.-butyl group, a methoxy group or a cyano group.  A represents a methylene group or an ethylene group, and B represents a methylene group.  n represents 0 or 1. ] (4) R ¹ represents a cyclohexyl group, a phenylethyl group or a phenoxyethyl group, wherein the phenyl ring and the cyclohexyl group of the phenylethyl group or the phenoxyethyl group are one or more lower alkyl groups or lower alkenyl groups. 2. The compound according to claim 1, which may be substituted by a group, a lower alkynyl group, a hydroxy group, a lower alkoxy group or a lower alkylene dioxy group, and salts thereof. (5) R ¹ represents a cyclohexyl group or a phenylethyl group, wherein the phenyl ring and the cyclohexyl group of the phenylethyl group are one or more lower alkyl groups, lower alkenyl groups, lower alkynyl groups, Droxy group, lower alkoxy group 2. The compound according to claim 1, which may be substituted by a lower alkylenedioxy group, or a salt thereof. . (6) R ¹ represents a cyclohexyl group or a phenylethyl group, R ² represents a hydrogen atom or a halogen atom, R ³ represents a hydrogen atom, a halogen atom or a lower alkoxy group, and A and B are both 2. The compound according to claim 1, which is a methylene group, and salts thereof. (7) R ¹ represents a cyclohexyl group or a phenylethyl group, R ² represents a hydrogen atom or a fluorine atom, R ³ represents a hydrogen atom, a fluorine atom or a methoxy group, and A and B are both 2. The compound according to claim 1, which is a methylene group, and salts thereof. (8) The compound according to claim ^{1, wherein} R ¹ is a cyclohexyl group, R ² and R ³ are hydrogen atoms, and A and B are methylene groups, and salts thereof. (9) The compound according to claim ^{1, wherein} R ¹ is a cyclohexyl group, R ² is a hydrogen atom, R ³ is a fluorine atom, and A and B are methylene groups. (10) The compound according to claim ^{1, wherein} R ¹ is a cyclohexyl group, R ² is a hydrogen atom, R ³ is a methoxy group, and A and B are methylene groups, and salts thereof. (11) R ¹ is a phenylethyl group, R ² and R. 2. The compound according to claim 1, wherein is a hydrogen atom, and A and B are methylene groups, and salts thereof. (12) 1- (2-benzyloxy 1-phenylethyl) — 4 — Cyclohexylbiperazine and its salts.  (13) 1- (1-benzyloxymethyl-2—phenylethyl) 1-4—cyclohexylbiperazine and salts thereof.  (14) 4-Cyclohexyl 1 1 [2-(4-Fluobenzoyloxy) 1 1-Phenylethyl] piperazine and its salts.  (15) 4-cyclohexyl-1- (2-((4-methoxybenzyloxy) -1-1-1-phenylethyl) pirazazine and its salts.  (16) 1 — (2 —benzyloxy 1 1-phenylethyl) — 4 — (2 —phenylethyl) piperazine and its salts.  (11) A therapeutic agent for cerebral nerve dysfunction, comprising the compound according to claim 1 to claim 16 or a salt thereof as an active ingredient.